CLL Diary

The Onco Wars

2012-01-31T16:18:00.000-07:00

Imagine two oncologists starting a practice, then imagine the same two oncologists having a falling out two years later. Welcome to the Onco Wars, raging now at the office where I have been receiving care for my chronic lymphocytic leukemia.

I'll call them Dr. Belle and Dr. Tower. You can think of them as Godzilla vs. Megalon, with all the attendant fire-breathing and foot-stomping that entails.

On January 23, Dr. Belle, my doctor, wrote a letter to her patients:

"It is with sadness and a heavy heart that I announce that, due to unforeseen circumstances, I will no longer be able to attend to you as your physician. This letter is to advise you that I will not provide professional medical services to you after January 30, 2012. Your current condition requires follow up and I encourage you to find a new physician promptly to continue this care . . . I suggest you contact your insurance plan representative for assistance in locating a new hematologist/oncologist to assume your care . . ."

And on January 27, Dr. Tower wrote to Dr. Belle's patients:

"Dr. Belle has recently informed us, and sent a letter to you, stating that she will be leaving the practice effective 1/30/12. Let me assure you that our office still remains committed to serving your needs and assisting in your care. I understand that Dr. Belle's departure may be upsetting to you, but I assure you that I am more than willing and able to assume your care, and would in fact be honored to do so . . ."

There is no doubt an interesting back-story here, which I don't imagine I will ever know. For me and for Dr. Belle's other patients, the big news is that we don't have a doctor anymore. Dr. Tower wants us to stay, but I hear through the grapevine that a number are choosing to go.

For me, all this comes at the worst possible time. With a lymphocyte count of about 260,000, hemoglobin of 9.4, and platelets finally having dropped to a Stage 4-level 85, the need for treatment is staring me squarely in the face, if not also socking me squarely in the jaw.

I have spun the wheel of fortune and picked a name from the measly list my health plan offers. I'll be seeing the new name soon, and hopefully I'll like this person enough to make them my new onc. Meanwhile, I won't rule out seeing Dr. Tower. But since insurance won't cover treatment at that practice, it may be time to cut the cord and go. Especially since it has been pretty much cut for me.

Ouch.

White bagging, or the seventh circle of health insurance Hell

2012-01-21T14:52:00.000-07:00

Let's say you're a patient with a low income who qualifies for help from a drug company. That drug company is willing to deliver the drug, free of charge, to an infusion center near you.

Great, right?

And let's say your insurance is contracted with Scottsdale Chemo Hut. (Sure, it would be nice to get the infusion done at your oncologist's office, but your insurance won't cover treatment there, even though it will cover office visits. That is the sixth circle of Hell, which has more circles than Saturn has rings when it comes to health insurance issues.)

So let's say you are getting everything set up with Chemo Hut, and in the process you speak to the pharmacy manager. And you are told this: Chemo Hut does not accept drugs directly from drug companies. The drug can arrive in an armored vehicle, in a suitcase chained to the wrist of the president of the company, and they'll still refuse to accept it.

And why is this? Because Chemo Hut cannot bill for it. If they use their own supplier, they can make money. Increasingly, more hospitals and infusion centers are refusing to administer free drugs that their patients qualify for. This is because they are upset about a trend known as "white bagging."

Under white bagging, insurance plans use their own specialty pharmacies to supply drugs at a cheaper rate than those purchased through the hospital supply chain. By some estimates, this now accounts for some 25% of infusions. Complimentary drugs for the less financially fortunate are collateral damage in this tug of war between insurers, who want to contain costs, and hospitals, which want to maximize profits.

Hospitals also complain about the inconvenience of having to store these drugs separately and write things like "for David Arenson only" on the outside of the box.

FYI, there is also something called "brown bagging," in which the drug is delivered to the patient, who totes it in along with their lunch. Maybe I can see that one being a problem. Chemo Hut may not want to be responsible for infusing you with ofatumumab you bought off a guy in a truck down the block.

Still, for patients who need chemotherapy and who cannot otherwise afford it, Chemo Hut and other hospitals and centers are making no exceptions, and this makes life difficult, not to mention a little more absurd than it already is.

In my case, Chemo Hut will infuse the drug if it is ordered through their supplier; our insurance company does not work with specialty pharmacies, and it has approved the drug under my medical benefit, which means I have to pay 20% coinsurance. Or, we estimate, upwards of $20,000 by the time all is said and done.

Well, lucky me, Chemo Hut also has a financial assistance program. A patient may qualify for a reduction in the bill of up to 100%. I say "may" and I use the term guardedly, because a patient may also not qualify, and be stuck with angry collection agencies and dings on their credit if they are unable to pay. The coinsurance the patient owes must now be written off as a loss. And while the insurance company will pay 80% at a negotiated rate, there is probably not a huge amount of profit there. So how much money is Chemo Hut actually making when all is said and done?

Chemo Hut could have administered free drug and still earned money on the costs of infusion, which is not chump change. But that would have been too easy. I know from running a business that sometimes you sell something and make a lot of money, and sometimes you sell something and make a little, but that you need both kinds of sales to stay profitable. (Not to mention the moral issues involved, but we're talking the health care system here, so that may not apply.)

There is one alternative, perhaps. One might ask the insurance company to approve infusion of the drug in the oncologist's office after all. The oncologist doesn't have a problem with white bagging because the oncologist actually cares about the patient. The oncologist, BTW, would like to be "in network" with the insurance and is willing to negotiate a fair price.

All of this would save the insurance company from having to pay huge sums of money for an expensive drug that can be gotten for free. Compared to the costs of the drug, paying the cost of administration is a substantial savings.

The savings would be, as they say on Vulcan, logical. This is Earth, though, specifically the United States. The insurance company (and Chemo Hut) would rather create a ridiculous financial morass that benefits no one, including the patient.

Quack, quack

2012-01-15T13:54:00.000-07:00

Just a little update. Marilyn (She Who Battles Insurance) and I are working on getting our ducks in a row. I have an appointment in early February with a doctor who is managing some clinical trials of Btk inhibitors. And in the meantime we are working on getting O+HDMP set up as a fallback.

"O" stands for "ofatumumab," aka Arzerra. Apparently it is a strange and unusual beast. We're working with one of the largest hospitals (where the infusion would take place) in one of the largest metropolitan areas (Phoenix) in the country, and ain't nobody never asked for none of that fancy 'tumumab stuff before. The inventory control manager of the hospital pharmacy is trying to figure out what it is and how to get hold of it.

Of course, all of this would be much easier if I could just have the infusion at my oncologist's office. But she's out of network, even though insurance will pay for me to see her. They just won't pay her to treat me. And this is why my brain is turning to mush, which is an unexpected side effect not of CLL, but of having American health insurance.

Surprisingly, it appears that insurance will approve ofatumumab -- under my medical benefit, not my pharmacy benefit. Medical benefit means it has to be "injected at the hospital," and I will owe 20% coinsurance. Pharmacy benefit means it's a drug with a $35 co-pay. Near as we can tell, I am going to be on the hook for something like $17,000 in coinsurance if I can't get some help from somewhere. Which means I can't afford it, unless I'd like to consider going bankrupt.

I am reminded of the late Dr. Terry Hamblin's many posts in which he discussed the merits of one drug or another, compared often negligible differences in progression-free survival, and concluded that the beaucoup expensive drug was not worth the cost. O+HDMP could turn into R+HDMP, I suppose, or chlorambucil plus prednisone, which costs almost nothing.

Meanwhile, maybe a trial will work out. . . . The big question is how a Btk inhibitor might affect marrow function. My hemoglobin is down to 9.6, and slowly trending south. Welcome to Stage 3.

What I do know is that some kind of treatment has to come soon, and February looks like the month. I'll report back when I'm finally sitting in the chair somewhere, having something happen.

Farewell, Terry Hamblin

2012-01-09T21:54:00.000-07:00

The CLL community has lost one of its best and truest friends, Dr. Terry Hamblin, to his own battle with a different cancer.

Hamblin, one of the world's leading chronic lymphocytic leukemia doctors and researchers, retired from most of his duties in the U.K. about six years ago. He could have gone sailing, or found a lucrative post with a pharmaceutical company, or disappeared into a quiet, well-earned country life. Instead, he rolled up his sleeves and went to work where he was needed most, using new internet tools to help CLL patients worldwide.

I began my blog in November 2005 and Terry's came on line just a couple of weeks later. Through his blog and his inexhaustible contributions to the ACOR CLL List, not to mention personal e-mail, Terry answered thousands of questions about the disease and its treatment. He freely gave of his lifetime of experience, even to the point of exhaustion. Over at ACOR they established something called The Professors' Posts to archive his answers so the same question did not have to be asked of him again and again (the plural in professors includes another invaluable ACOR contributor, Dr. Susan LeClair).

I called him Terry, but I always felt a little awkward about it. It's sort of like calling God "dude." He signed everything "Terry Hamblin," in the matter-of-fact way that was his trademark. When he got rushed, he tended to transpose the letters in "the," and there was always a place in my mind where I saw him as "Teh Professor." And I mean that respectfully and lovingly. In a world where our written words -- in e-mails, blog posts, discussion forums -- have become our main form of communication with one another, there are little tics, little traits that you notice.

Another thing I noticed was that Terry was always honest and direct. He told you what he thought, and he told you if he didn't know something, and he never made an effort to sugar-coat anything. In other words, he treated us patient rabble like people, like equals, like adults.

"We [doctors] really don't have the means to keep you alive for longer than about 12 years," he once wrote to me. It wasn't what I wanted to hear, but it was the truth as he saw it. That's one thing you could count on hearing from Terry Hamblin.

Terry was a bit old school. He believed in the scientific method. He had seen too many things come and go to jump on the latest bandwagon. He wasn't the cheerleader type. He liked hard evidence, and so he provided a grounded, conservative perspective as new treatments and tests unfolded. This didn't always make him the most popular voice out there, but you could always rely on him for sure and steady reasoning.

I never detected an atom of pomposity in the man, and this is no small feat in a world in which "M.D." is sometimes taken to mean "Medical Deity." Terry didn't need to have his ego stroked, and while he was justly proud of his many accomplishments, he remained, as far as I could tell, a humble, uncomplicated soul. It was as if he didn't see the invisible line that we patients see between doctors and ourselves. To him, we were all just people, and when he began his struggle with his own cancer, we CLLers came to see the full scope of his strength, his vulnerability, and his humanity. Terry was now on the journey that we had been on, experiencing the travails of cancer that go beyond medicine.

Over the years, I tried not to bother Terry too much, knowing how many inquiries he received, but I did correspond with him from time to time. He once went out of his way to discuss my case with some of the best minds in U.K. hematology, a favor I did not expect nor ask for, but for which I was grateful. He read my blog sometimes and occasionally commented here, which made me feel like maybe I wasn't a complete idiot.

Readers of his blog know that Terry Hamblin was a devout Christian. But he not only talked the talk, he walked the walk.

Last November, Terry wrote something that sums up his character in far better words than any I can offer:

I had a weepy day yesterday as I contemplated the things I had left undone. At the end of Schindler's List, Liam Neeson has a scene where he looks at his luxury car and his gold ring and thinks of how many more Jews these could have bought. "I could have done more," he exclaims.

That is how I felt. I told this to Dr John when he visited and he reassured me. None of us can ever do enough. We mustn't reproach ourselves.

Today I am much more cheerful. I went out for the first time in 2 weeks and bought some flowers for my wife. The Scripture tells us not to be weary in well-doing.

Terry never truly tired of well-doing, and he left a world of good works in his wake. There is no better testament to a life well-lived. He will be sorely missed in this little corner of Arizona, and by his friends everywhere across the globe.

New year, new challenges

2012-01-07T15:22:00.000-07:00

It's 2012, and my CLL journey continues along a new stretch of Shit Creek. I am, at the moment, paddle-free.

But let me take a moment to wish you all a Happy New Year. May we continue on in enough good health to continue on, and may we have time left over after dealing with medical matters to enjoy our lives, our loved ones, and the beauty and bounty that the Earth provides.

It's important to keep that perspective, even in difficult times. As you know, I lost my older brother to a stroke six months ago, so mortality seems that much more fragile to me than it did before.

Then, this morning, I scrolled through the list of blogs I keep on the right side of this page and found that another CLL compatriot, Jackie Sue, has passed on.

Everywhere in CLL World I see struggle; often with enough success to keep on fighting another day, sometimes with less success than was hoped. And all this is occurring against a rather jaw-dropping array of new progress in CLL, namely the kinase inhibitors such as CAL-101 and PCI-32765 and the CAR trials of juiced up killer T-cells, such as CART-19 at the University of Pennsylvania. (This PDF from CLL Global gives a good, brief rundown on both.)

I cannot help but conclude, as I think of friends I have lost, as I think of those who are struggling as I am, how close we are to salvation, and yet so far.

I blog less these days. One big reason is that I am busy with our ever-growing and ever-demanding online business, not to mention personal matters, usually my health and that of my dear Marilyn.

But when there is a little time left over, I find myself hesitating to write. In part, I have run out of useful things to jabber about. My training as a newspaper editor etched into my head that a story has to be worth being told to merit space in print.

Another reason is, for lack of a better term, battle fatigue. You can paint lipstick on the CLL experience, but it's still a pig, and after eight years I have seen enough pain, suffering, and life-altering disruption to conclude that having CLL completely and totally sucks. There's nothing good to be said about it, and therefore I find myself not wanting to talk about it.

That said, it was my promise when I started this blog to describe my journey honestly and completely, so that my experience will be a useful learning tool for those who come along. And so, the latest:

The good news is that the abscess referred to in my last post has healed, the drain has come out of my neck, and the infection is gone. The node in question has not enlarged very much; indeed that side of my neck shows less nodeyness than the other. Perhaps if we CLLers stick drains in our nodes the disease will simply drip away. (Yes, I'm kidding.)

The bad news is that my disease has entered a new, more aggressive phase. For the first time, my red counts have dropped due to marrow impaction. My hemoglobin has been in the 10 to 11 range for the past couple of months. Platelets have also fallen, to just above 100. I am on the doorstep of Stage 4, measuring by those numbers.

What's worse, the nodes have returned with a vengeance, that one area of my neck aside. My guess is that this is simply the product of ineffective control of the disease for many months, as opposed to some new mutation. Until I have a FISH test, I won't know for sure.

Let's back up for a minute. I'll try to cover some history, briefly, that would have made for several blog posts had I had the time.

After a year of treatment, I went off Revlimid (lenalidomide) last March, in part because I wanted to give my body a break. As you may recall, I had two transient ischemic attacks while on the drug. Clotting problems run in my family and claimed the lives of both my brother and my mother.

Another reason was the expectation that I might qualify for a CAL-101 clinical trial. I will call this the Godot trial, because I kept waiting and waiting and waiting for a slot to open, and was told "any day now" for what became months and months. What was supposed to have occurred in April was delayed until August. Even then, it all seemed rather promising. I had restarted Revlimid in July because the need to treat could wait no longer. Calistoga, the maker of CAL-101, was even willing to waive the requirement that I should not have had treatment 28 days before enrolling. When I was about to pack my bags, I got the bad news: due to a clerical error, the slot in question did not exist. And they could not just add a new one, since the maker of the other drug in the trial, ofatumumab (aka Arzerra), would not provide any more free drug.

I was told that drug companies hire other companies to organize and manage trials for them, and that one of these companies had made the mistake. The principal investigator was quite aplogetic and said this had never happened in all the years he had been conducting trials. Goodbye, paddle.

Meanwhile, back at Revlimid Ranch, things weren't going so well. When I restarted the drug, I did so with a great deal of care paid to the clotting issue. At the time I began Revlimid 2.0, my brother lay in the hospital, unable to move his left side and barely able to move his right.

I had a complete clotting panel done, which confirmed my propensity to clot. Indeed, it came out worse than a similar panel that was run on my brother.

I had been on warfarin for a little while prior to quitting Revlimid in March, but my clotting time always remained pretty much normal, which means fast. And so when I began Revlimid again, we added more warfarin, to which, it turns out, I don't easily respond. Later, my doctor added aspirin to the warfarin. Meanwhile, the Revlimid dose was kept minimal, at 5 mg twice a week and occasionally every other day. As it turns out, I wasn't getting enough of the drug.

In November came the first signs of trouble. My red counts showed a drop, and my lymphocyte count showed a jump. Shortly thereafter, I began to notice an orange cast to my urine. I've posted about that several times, and in the past it had always been a sign of hemolysis due to autoimmune hemolytic anemia (AIHA). I assumed that was the case this time as well.

Revlimid, an immunomodulator, had seemed to put an end to my AIHA. Tests were ordered, and in the meantime I went on Revlimid 5 mg daily in an effort to head the hemolysis off at the pass. It made sense at the time: Maybe I needed more Revlimid to control the situation.

But the testing showed no signs of AIHA, and also that red counts were continuing to drop. And the orange urine remained, which brought me to the next logical conclusion: internal bleeding due to blood thinners.

So I stopped the thinners and the orange disappeared almost immediately. And no blood thinners meant no Revlimid, which was coincidentally giving me new fits in terms of tumor flare. (Goodbye, other paddle.) After merely five days of 5 mg, the minimal dose Celgene makes and well below that considered optimal in trials, I looked freakishly flarish (see second-to-last photo in my last post).

I had always had a tumor flare reaction with Revlimid, which is actually a sign that the drug is working, but never anything like this.

It felt like a Vise-Grip was closing around my neck from the back, leaving just a bit of my Adam's Apple free, and making it hard to open my mouth very far. It was at this point that the abscess formed, although it took another week, during which steroids brought down all the flare but the abscess, before I ended up in the ER and the diagnosis was made.

During the December Drain Festival, I could not treat the CLL because of the wounded node. Now that it has been removed, and the node is healing -- the ENT doc says to give it at least two weeks -- treatment is back on the table.

I am looking into a couple of clinical trials, as well as into a treatment to keep me going in the interim. One thing I have learned about trials, of course, is that Things Take Time. Another thing I have learned is that the study drug may be free, but all other expenses, from administering the drugs to CT-scans to the cost of the drug that the study drug is being tested with, are usually out-of-pocket. Unless covered by insurance (insert guffaw here).

The treatment I may do soon is R+HDMP, or perhaps Arzerra plus HDMP, which is a whole 'nother can of worms.

I've been stymied at every turn by my increasingly stingy health insurance plan, which covers fewer and fewer doctors -- including treatment in the office of my own oncologist -- and fewer and fewer drugs. Clinical trial expenses, forget it. And while Arzerra may have FDA approval for CLL, to borrow a phrase from a popular viral video, honey badger don't care.

It's gotten so bad that I've found myself flirting with the idea of dropping coverage for six months so that I can get on the new federal Pre-Existing Condition Insurance Plan. I know, this is probably a bad idea, especially since my little hospital getaway (two fun-filled nights and three fun-filled days) came to more than $10,000, of which I will end up paying no more than a third thanks to my insurance, bad as it is

(I am so looking forward to 2014, when I'll be able to buy decent insurance under the new health care law. I have my issues with President Obama, but from where I sit, he deserves a big, wet kiss for Obamacare, imperfect as it is.)

The cherry on the sundae is that there is a fair degree of tumult at my oncologist's office that is also not helping matters.

So let's just say that external forces are not making my little canoe trip an easy one. Shit Creek is hard enough to navigate with a paddle.

But onward I go, mateys, trying not to capsize.

To quote Newt Gingrich (yes, I am quoting Newt Gingrich):

Perseverance is the hard work you do after you get tired of doing the hard work you already did.

A real pain in the neck

2011-12-04T14:58:00.001-07:00

And I mean that literally. Yes, that's me, laying in the ER, just after a drain was put into my neck.

It all began with a lymph node under my left jaw that swelled up, and kept swelling and swelling, and swelling and swelling, until I could barely open my mouth. I've heard of CLL patients getting massive nodes before, but this was no ordinary CLL event.

It turns out that a bit of bacteria, something in the strep family, got caught up in the node and caused an abscess. The CT scan at the ER pegged the node at 5.0 x 4.1 x 3.3 cm. But the way it was stretched over my neck, it felt much larger than that, and measured by touch more like five inches than 5 cm. It was crushing my neck muscles and salivary glands. Had it gone on for much longer it would have dislocated my jaw.

According to the ENT doc, such abscesses are not uncommon among the general population. (Who knew?) At first there was some concern that the abscess could have originated from a necrotic place within the lymph node, but cultures of the chocolate-brown pus showed a garden-variety strep. (The culture report states. "Mixed flora (multiple species present). Predominately Beta Hemolytic Streptococci, Group F.") Fortunately, blood cultures showed no bacteria in the blood, which would have meant sepsis, a much more serious condition and one that would have kept me in the hospital beyond the three days that I was there.

Mmm. Chocolatey brown pus in syringe at left.

I was admitted so that I could receive IV antibiotics, clindamycin, which I am now taking orally at home. The drain is still in my neck and will be there for at least another week.

I haven't been a patient in a hospital since 1964, so the whole routine took some getting used to. Who knew you could order meals at whim off a room service menu these days? Or that the nurse would strap air bags to your legs that puff up and down to prevent deep vein thrombosis? I caught up on my television viewing, even if I didn't get a whole lot of sleep.

I do believe there is a CLL-related cause to all this. Prior to the abscess, I was on Revlimid at 5 mg, for four days in a row. The tumor flare reaction was so incredibly way-over-the-top that my guess is the bacteria made its way into the node as part of that process. The tumor flare was so bad that I had to stop the Revlimid and go on steroids to bring it down. It was the failure of the one node to go down very much -- and then its ballooning overnight once I went off steroids -- that alerted me to the fact that something unusual was happening.

Now 5 mg of Revlimid over four days is a baby dose, as these things go, and I have been on and off the drug for a year and a half without the monstrous flare I encountered this time. So why the sudden overreaction in terms of tumor flare?

I can't say. What I can say is that a recent paper shows that tumor flare predicts response to Revlimid in CLL. That's a good thing in my case. But tumor flare like this???

There are a number of things going on that I'll go into later, but suffice to say that I may not be able to tolerate Revlimid to the degree needed to keep using it. I've been off of it since the flare, and until the abscess is gone and the lymph node heals, I can't do anything in terms of treatment that might put stress on the node.

In the meantime I lurk around the house like Frankenstein with one knob. Fortunately I work at home, where I can't scare small children.

This is how the tumor flare in my neck looked after four days of Revlimid, and the photo barely does justice to it; below is my neck in its more normal state some ten days later.

Hang on

2011-09-01T16:27:00.003-07:00

Here comes September 3 again, the anniversary of my diagnosis with chronic lymphocytic leukemia. It approaches each year like the garbage truck that groans down the street every Monday morning, screeching, growling, and filling the neighborhood with diesel fumes.

In other words, it’s unpleasant. But it’s made palatable by the fact that I am still here to reflect upon it.

This is my eighth anniversary, and I have the song “Hang on, Sloopy” running through my head. It’s easy to figure out why. If I have any advice to offer as a grizzled veteran of CLL, it’s “Hang on.”

* * *

On some fundamental level I have never accepted that CLL will kill me. It’s a silly disease, all these B cell clones making copies (cue the Richmeister from Saturday Night Live) and clogging up the works. The clones can be killed rather easily, it’s just that it’s nearly impossible to kill every last one. And you can have very good quality of life while living with CLL. Cancer is never good, but on the Bell Curve from Hell, CLL is at the better end.

Call me crazy –- and some of you no doubt will -– but my refusal to accept that CLL is my end is just the sort of wild-eyed faith that cancer patients who beat cancer sometimes have.

So I have spent eight years muddling through, often rejecting the advice of doctors, which is usually conflicting, about what to do.

The choices, until lately, haven’t been very good. One doctor told me to do PCR and “get on with my life.” He was reduced to mumbling when asked what I should do after PCR wore off in two or three years. Another doctor did the obligatory push for fludarabine; after he became assured that I was an adult and not prone to panic, he admitted that well, no, it really isn’t as effective over the long term as it needs to be. I've looked seriously into transplants, which have been advocated by some very reasonable people, and have come away thinking they're too risky on too many levels. (I'd still do one if I had to -- I'd do anything if I had to, except vincristine again -- but I have a very high bar when it comes to defining "have to.") What I'm saying is, scratch the surface of any responsible medical professional and they'll admit that most treatments currently in use have unfortunate limitations.

It can be easy to get swept up in the world of incremental progress that researchers make. But the bottom line is that improvements do not mean that the progress is satisfactory.

So I have waited until I have been forced to act, I have avoided the most potentially damaging options whenever possible, and I have waited some more.

Is this a wise approach? I don't know. It's what works for me. In the absence of a way to win the war, I find it better to sit and wait for the enemy, conducting a guerrilla campaign around the edges, than to go all in and claim a Pyrrhic victory.

* * *

This has come at a cost. No matter how you choose to fight CLL (or choose not to fight it) there are risks. It’s very much a war of attrition, as Terry Hamblin once put it.

This blog is filled with posts about the challenges I have faced. For those of us not “blessed” with indolent CLL, the disease can only get worse over time. Treatment helps, but it also exacerbates the situation by increasing disease resistance. This goes for softer treatments as well as harder ones. Failing to treat when you ought to -– sometimes we need to be proactive -– leads to similar consequences, since the disease will grow and potentially evolve into a worse form just for the hell of it.

In hindsight we can see how things might have been different had we done X, Y, or Z. But in the heat of battle, it is, as they used to say in the military, S.N.A.F.U. You just do your best and hope nothing explodes.

And if you don't choose too badly, if you respond decently to treatment, if your body proves more resilient than not, if a little luck comes your way, you can muddle through.

* * *

After eight years, I see tangible evidence that waiting pays off.

We’re all familiar with the great news from the University of Pennsylvania. Finally, a T cell therapy has been developed that can apparently wipe out the disease, even in cases considered to be hopeless. It’s like having a successful transplant without all the risk. This means the cure, or de facto cure, could be at our doorstep.

I have seen other drugs become available, either officially, or off-label, or in trial. There’s Revlimid, which for some people is a control. CAL-101 and other kinase inhibitors, which are doing well in studies. (I wonder how Revlimid and CAL-101 would work together?) Ofatumumab has been added to the list of options; it’s no panacea, but it helps.

I have also seen some flavors of the month fall by the wayside, notably alemtuzumab. And I have seen opinions change: The 11q deletion, once thought to be the kiss of death, isn’t always so. The point is that the longer we have to learn, the more we know.

So my thought this anniversary is to hang on. The longer you can drag things out, the greater chance that scientific progress will come up with something to save your sorry ass. It doesn’t matter how inelegantly you arrive across the finish line, just so long as you get there.

Eight years later, I’m still at Stage 2. My hemoglobin and platelets have weathered the storm. I’m no more prone to infections than I was when diagnosed. My quality of life is pretty much the same, challenged occasionally by side effects from the Revlimid I'm taking. The disease is definitely bigger and harder to treat, more node-based and less leukemic, but Revlimid is holding the line. (I got lucky with that one; luck is part of the equation, remember.)

I’m basically none the worse for wear. And crazy, of course, as a sack full of otters.

Benediction

2011-07-26T11:47:00.001-07:00

When my brother Rick was in Vietnam, a grenade went off nearby. It knocked him out. There was shrapnel in his skull.

He could see himself floating above his body. He saw loved ones around him and felt a profound sense of peace. It was, he said, the most wonderful thing he’d ever felt. (This was the mid-1960s, before reports of near-death experiences were publicized in books and the media.) It was, Rick said, the last thing he expected to happen.

And then he was awake. A paramedic had saved his life.

“Why did you do that?” my brother asked, after which he slugged the medic as hard as he could.

* * *

Rick died Friday of the stroke that felled him two months before. He was not a religious man, but the near death experience stayed with him and made him unafraid of death. Years later, after a motorcycle accident, he had the same experience, saw the same things, until he was snapped back to life.

Being unafraid of death does not always make it easy to say goodbye, of course. Fortunately, there was enough time after the stroke for the process to work its way through, and for moments to be shared. Heavy, meaningful things were said, but mostly it was just the joy of companionship. We looked at old photos and talked about old times, which became more difficult as he lost his ability to speak clearly. And he wanted to know what Marilyn and I were up to, no matter how unimportant our activities seemed to us.

We were not present for the final days of his decline. His wife, Mary, said he had begun to see his twin. Rick's twin brother was stillborn and now, somehow, Rick saw him there in the living room. What he looked like, what he communicated to Rick, I do not know. How much of the transition to death is illusion, how much is reality, I also do not know, except to say that it is a mystery that befuddles the living.

* * *

Rick confided in his wife the most, of course. At one point he told her that he had wanted to be there for me when I died, and he was sorry that, instead, I had to be there for him.

I came to realize that, somewhere in the back of my mind, having CLL had created the expectation that I would die before everyone else in my family. Not just before those who are younger, which would be expected anyway, but also before Rick, who was 11 years my senior, and even before my father and stepmother, who are now in their 70s.

Not only was this my expectation; it was obviously Rick’s as well, and perhaps is shared by other people I am close to. It’s not something they talk about, just something they assume.

This assumption conflicts with another expectation that I have, which is that I will manage to muddle through thanks to new drugs like Revlimid, and perhaps have a reasonably normal lifespan after all.

Time, which I am aware is ever-short, even for the healthy, will tell.

And if Rick’s near death experiences are right, he’ll be there for me when I die, after all -- just not on this side of the curtain.

Off and on

2011-06-26T14:57:00.000-07:00

As a newbie, CLL was the center of my universe. As time has gone on, it has become more like the chronic condition that it is -– albeit a chronic condition with a potentially deadly bite. My focus, by both choice and necessity, has gone elsewhere. I have a business to run, a family to attend to.

Other questions, big and small, tend to take over my day. What is a tambour door? Should I put the old treadmill on Craigslist or Freecycle? Why do the doves always build their nest in the windiest corner of the front porch, from which their nest will be blown away?

Of late, my time and energy has gone toward a more serious and sad situation. My older half-brother, who lives about three hours away, has had a severe, debilitating ischemic stroke. He’s been in the hospital for several weeks. At first it wasn’t clear that he would survive. But he has emerged with his faculties intact, as well as some movement on his right side. At best, he faces the prospect of a long and difficult recovery.

He’s 66, eleven years older than I am, and his current condition has shaken the frame of reference I formed as a child. He was always taller, stronger (he was in the Marines), and more world-wise. Now, in dealing with family issues and the health care system -– all the details, from the mundane to the deeply emotional, things that CLL has prepared me for -– our roles are reversed.

This is not his first stroke, and our mother died at 57 of a pulmonary embolism and had a history of phlebitis. I don’t respond to the blood thinner warfarin (Coumadin) at 2 mg and 4 mg doses. Apparently clotting issues run in the family.

Which brings us back to Revlimid (lenalidomide), a potential side effect of which is the creation of blood clots. Readers will recall that I have had two TIAs, or transient ischemic attacks (mini-strokes) while on the drug.

* * *

I am acutely aware that I have been allowed the time to deal with all things great and small courtesy of Revlimid. For a year, it stepped in to halt the progress of a fast-moving disease when nothing else would reliably work.

Starting March 15 of this year, I went off Revlimid for three months. One reason was to give my body a rest, in part because clotting issues had arisen. Another was to see how long my remission held without it. And a third was related to my application for a clinical trial involving CAL-101, the node-busting drug that has created a great deal of hope among CLLers with bulky disease, which pretty much describes me.

I may yet get into the trial, if the trial arm is ever organized. It has been “two more weeks” for months now, and even the principal investigator has stopped trying to predict when the drug companies involved will sign off on everything. When the arm is finally organized, I’ll need to be off Revlimid for 28 days before the initial round of testing and evaluation to determine my eligibility.

Meanwhile, I learned during these three months that I probably shouldn’t be off Revlimid for more than about six weeks. The first month was quite encouraging: The nodes continued to get smaller and smaller and I lost weight. The second month involved a brief plateau. During the third the nodes began to come back, steadily and surely.

A month into my “vacation,” which was also a vacation from blood thinners, I had a PT/INR test done. My clotting time came out at baseline, 1.0, which is exactly where it had been when I had been on warfarin. My oncologist has now ordered an extensive clotting panel -– Nurse Dracula took 14 vials of blood -– to determine if there is anything unusual going on. This will help us determine what the best blood-thinning strategy is.

In the meantime, I have started a minimal dose of Revlimid, 5 mg every other day, accompanied by aspirin. After a few doses I’m noticing a fair degree of tumor flare, not as bad as it was when I first began the drug, but definitely pronounced. This will probably last for two to three weeks.

* * *

During all this time my blood tests showed some interesting things.

As expected, my absolute lymphocyte count rose, from 8.6 just before I stopped to 19 two months later, then dropping back to 10.5 just before I resumed. This fallback was probably due to the CLL cells returning to the nodes.

My platelets, which had been increasing before I stopped, quickly fell back to around 130, which is what “normal” has been for me for several years.

My red count remained strong. Hemoglobin was 14.5 just before I quit, 15.1 just before I resumed. This tells me that after three months off the drug, there was no sign of the dreaded autoimmune hemolytic anemia (AIHA), which had plagued me before Revlimid.

So let me repeat here once again what I’ve said in this blog before: I am one anecdotal case but I am pretty solid evidence that Revlimid can have a huge impact on AIHA, even bad cases of it. If you are dealing with this scourge and have begun to run low on traditional options, consider Revlimid!

Finally, there is some bad news in the mix. My B2M had been as high as the 11s while I was on Revlimid. I attributed this to a great deal of ongoing cell-kill as my drug-reinforced immune system did battle with the evil clones. My vacation appears to have substantiated this as the B2M has fallen to a consistent 7.

The bad news is that my baseline B2M is that high. It’s way over the top. In a normal person it should be less than 2.3. In a CLLer it should really be less than 4. So what this tells me is that my disease is still big and aggressive.

And what this means is that Revlimid -– which hopefully will continue to work as it did before -– is going to be a constant and necessary presence in my life, stroke risk and all.

Unless, of course, things work out with CAL-101.

* * *

It's an odd existence. CLL reminds me of handling a rattlesnake. There are people who deal with venemous snakes every day, usually harvesting the venom to use as an antidote to snake bite. These people live with constant danger, and with luck they'll never be bitten. But there's a thin line between living a normal daily existence and something going terribly wrong. My childhood doctor collected snakes as a hobby, and one day his office was closed and he wasn't there anymore.

When I was in first grade we lived in Poston, Arizona, near the Colorado River. It was teeming with wildlife -- mallards, skunks, bobcats, scorpions, and many rattlesnakes. When a rattlesnake got into the house, it was my older brother's job to kill it with a shovel. He would whack off the head and the body would writhe around. I would stand behind him, holding my mother's hand, watching with fascination.

"Don't play with snakes," my mother would constantly remind me.

Alas, sometimes we have no choice.

I’ll update you in a couple of months. Please accept my apologies for any emails that have gone unanswered. I have had to leave many important things by the wayside to make time to deal with the essential.

Revlimid, the Klopman Diamond

2011-04-03T15:31:00.001-07:00

There’s an old joke about the Klopman Diamond. It goes something like this:

A businessman boarded a plane to find, sitting next to him, an elegant woman wearing the largest, most stunning diamond ring he had ever seen. He asked her about it.

"This is the Klopman Diamond," she said. "It is beautiful, but it's like the Hope Diamond; there is a terrible curse that goes with it."

"What's the curse?" the man asked.

"Mr. Klopman."

I’ve now had a year’s worth of experience with Revlimid, aka lenalidomide, and I have come to think of it as the Klopman Diamond of CLL treatments.

In my case, Revlimid is stunningly beautiful when it comes to controlling autoimmune hemolytic anemia, reducing absolute lymphocyte count, and increasing hemoglobin and platelets. It even does a respectable job of reducing lymph nodes. This is pretty much what any CLL patient could want, especially one who has had several other treatments.

But it comes with a curse: unpredictable side effects that in my case have a little too much to do with clot formation. Not for me the simple neutropenia that bedevils many patients, or just the tumor flare and fatigue I reported early on. I get the full Klopman –- i.e. the prospect that some kind of clot will do some kind of damage that I really won’t like.

Presumably the lady with the diamond stays with Mr. Klopman because he provides so well. And so it is with me and Revlimid. It’s a rocky marriage. Happy overall, but punctuated with incidents that create a certain degree of apprehension.

* * *

After a year of being on Revlimid most of the time, it’s time for a trial separation. I went off the drug on March 15 and plan to stay off until I need to go on again. It’s time to give my body a rest.

That was my oncologist’s take at a recent meeting, and I agree. There’s no proof that staying on constant Revlimid maintenance (at 5 mg daily) will be better than starting the drug again when I begin to relapse. Patients are handled both ways by leading CLL centers, and this seems to have a lot to do with the guesswork of doctors and the drug tolerance of patients.

In my case, given my proclivity for clot-related problems, there is potentially some value in the “rest” theory. As you may recall, the blood thinner warfarin (Coumadin) was added to my regimen following a TIA, or transient ischemic attack. This started at 2 mg daily. It was increased to 4 mg three days a week, 2 mg four days a week as my PT/INR tests continued to show that I was clotting quickly, like someone who was not on the drug. Even at the higher dose there’s been no improvement in clotting time. Apparently I have a somewhat supernatural ability to clot, which is not useful when taking Revlimid.

I went off Revlimid at a high point. My latest CBC confirms improvement in hemoglobin and platelets that I first reported in my post of February 20. My lymph nodes have reduced nicely; I have lost five pounds since going off the drug and the nodes have gotten smaller. I’m sure that’s not all lymph node weight I’m losing. But I do think it again proves my theory that when on the drug I am in a constant state of tumor flare; off the drug, the nodes reduce to baseline.

I’m not sure they’re at baseline yet. What I can say is that they are definitely improved over a year ago. Without a CT scan I can’t put a number on it. But the nodes I can feel in my neck and under my arms are significantly smaller and a large mass under my right arm has broken up. My abdomen is noticeably slimmer. If I were forced to guess, I'd say the reduction has been up to 50% in some areas, and I'm a very nodey guy.

* * *

After I was diagnosed in 2003, I participated in online discussions about whether chronic lymphocytic leukemia could someday be controlled as a chronic disease, much as diabetes is. It seemed like a pleasant fantasy at the time. What, we wondered, if there was a pill we could take to keep the disease in check?

Today, this might be closer than we could have imagined. Might Revlimid be it? Might CAL-101?

And to what extent will we have to take our chances with Mr. Klopman?

Only time and trial will tell.

Hemoglobin deja-vu

2011-02-20T16:10:00.000-07:00

Periodic CBCs are routine for us CLLers, and they sometimes come with surprises, usually not good ones. For the last year my CBCs have been decent, stable, and dull, but my latest required a double-take.

My hemoglobin was 15.6, up from 13.0 six weeks before. It had been in the 13s since shortly after I began taking Revlimid (lenalidomide) on March 6, 2010. (Yep, the one-year anniversary approaches. I’m thinking of celebrating with a chocolate cupcake topped with white Revlimid pills as sprinkles.)

It turns out that the last time my hemoglobin was that high was in May 2006. In fact, on the day I was diagnosed with chronic lymphocytic leukemia -– September 3, 2003 -– it was 15.6. The highest it has ever tested out at is 15.8. So something good is happening in hemo-land.

This is especially encouraging since autoimmune hemolytic anemia (AIHA) has been an almost constant drain on my hemoglobin since early 2007. I take this latest result as a further sign that Revlimid has put a stake through its heartless little heart.

Of course, absent AIHA, CLLers also face the challenge of their bone marrow clogging up with CLL cells, with a resulting gradual decline in red cell production. The NCI guidelines define hemoglobin below 10.0 as the welcome mat into Stage 3 CLL and one of the triggers for treatment. Where my hemoglobin would be absent both the Revlimid and my history of AIHA, I haven't a clue. But seeing it at the same place as it was at diagnosis does provide a not-so-cheap thrill. Maybe I'll have two of those cupcakes.

My test also showed higher platelets. Over the course of my CLL history, they have gradually declined. For the last couple of years they have generally been at about 130. The latest test puts them at 160. Platelets can jump for any number of reasons. For example, they can be sequestered in the spleen and treatment can reduce the spleen, forcing them into the bloodstream. In this case, I doubt my spleen has suddenly become smaller.

So the big question is: Is Revlimid having a positive effect in my bone marrow? A 2008 MD Anderson study of Revlimid in 44 relapsed and refractory patients reported that 26% experienced “resolution of bone marrow involvement.” How that was tested for and defined was not described in the paper, but it is encouraging nonetheless. I am also aware of patients who are on the drug for a long time and begin to experience, at a certain point, the “kicking in” of improving numbers.

I’ll have to see if the trend continues on future tests. After all, one test is interesting, two are a trend. But I have no reason the believe the test is wrong. I’ve been napping a lot less recently, even when I’ve had less than eight hours of sleep at night, which would be one result of higher hemoglobin. And not all the numbers are higher, so it’s not like the blood counting machine was ascribing a higher count to everything. (My absolute lymphocyte count remains pretty stable at 6.24.) This test was done at the same lab that I've been using for the past year.

Finally, on the Coumadin (warfarin) update front, my dose has been bumped up slightly. It’s now 4 mg on Monday, Wednesday, and Friday, 2 mg on other days. This came after my PT/INR tests continued to show that I clot faster or the same as normal even though I’m on the blood thinner. My Revlimid dose is now 5 mg five days a week, 10 mg on Wednesday and Sunday. It probably won't go any higher for the foreseeable future.

And now, the bad news

2011-01-09T12:53:00.003-07:00

“Laws are like sausages,” Otto von Bismarck once said. “It is better not to see them being made.”

The same could be said of treatments for chronic lymphocytic leukemia, especially with experimental drugs like Revlimid, aka lenalidomide.

Not long ago, I wrote about some of the positive aspects of my Revlimid experience in a piece entitled "First, the good news." Now it’s time for the promised bad news, which happened in October while I was trying to increase my daily dosage from 10 mg to 15 mg and then 20 mg.

Actually, the first sign of trouble was back in June, when I was taking 10 mg. One night, all of a sudden, I had trouble forming sentences. I could talk or write, but as I did I realized that I wasn’t saying the words I meant to say. Language is usually reflexive, but I found myself having to concentrate very hard to find the right words to form even simple sentences. I was not always successful. This lasted for about 10 minutes and stopped almost as suddenly as it had started.

I think many of us experience some loss of mental agility with age, an effect of which can be occasionally searching for words (as well as standing in front of the pantry blankly and saying “Now, why did I come over here?”). Revlimid can further (temporarily) reduce this agility by adding a layer of dullness or lack of mental swiftness. In the past I have described the drug as the enemy of multitasking.

My ten-minute word hiccup seemed similar to things I had experienced as part of aging, but also different enough and intense enough to cause me concern. I took myself off the drug immediately and looked at the list of side effects that the drug's maker, Celgene, provides. I also read up on side effects reported in CLL and Revlimid studies. Nothing obvious seemed to explain the situation, so I chalked it up to “chemo brain,” a medical catch-all that is not unlike that famous Victorian malady, “the vapors.” I resumed the Revlimid after a few days, and all was well. By the time I next saw my oncologist, I had almost forgotten about it, mentioned it in passing, and went on my merry sausage-making way.

MORE SAUSAGE

Until it happened again, on the night of October 5, four days after I began taking 20 mg. Again with the language problem, again for about 10 minutes. Marilyn said it sounded like I was trying to say two things at once. I recalled getting words almost right; for example, I wanted to say “tea” but ended up saying “Ted,” which is my father’s name. Hey, both start with a “T” and have three letters!

This time I didn’t shine it on. While on 15 mg for two weeks, I had begun to hear a periodic heart beating sound in my right ear. This got worse at 20 mg. Before the language problem hit, I had already decided to stop the Revlimid that night and have a CBC the next day. In the past, whenever I had heard a heart beating sound, it had signaled hemolysis, or an attack of autoimmune hemolytic anemia (AIHA), in which the body destroys its own red blood cells. This sound was different, though, and I wasn’t getting any other telltale signs of AIHA, such as orange urine or feeling winded while walking up stairs. Still, I didn’t want to take any chances, and a CBC seemed a logical place to start.

The CBC came out fine. All I knew for sure is that the severity and frequency of the beating sound had increased with the dosage of Revlimid and that the sound went away when I was off the drug. And, of course, I had that disturbing language thing again. I made an appointment to see my oncologist, Dr. Belle, ASAP.

Dr. Belle told me that Revlimid increases the viscosity of the blood and that the sound was probably my heart working harder to pump blood into my brain. This explained why the sound got worse with the higher dosages.

And this also explained the language trouble: Dr. Belle said I had almost assuredly had a TIA.

A what, I asked?

“Transient ischemic attack,” she said. Also known as a mini-stroke.

“I’m quite concerned about that,” she said.

I was, too. Later, after making use of Google to find out everything I could about TIAs, I was in something of an information-induced panic, after which I calmed down to a level that might be described as “heightened concern.”

I learned that TIAs, like full-fledged strokes, are caused by a blood clot in the brain. The difference between a TIA and a stroke is that a true TIA lasts less than 15 minutes and causes no permanent damage.

TIAs can affect vastly different areas of the brain, including language (leading to expressive aphasia in my case, where I can understand what is being said but have trouble expressing myself). TIAs are considered to be warnings; about one third of people who have them go on to experience a full-fledged stroke within a year.

Should the ischemic attack drag on for more than an hour, you enter the realm of official strokedom and potentially severe harm. I had narrowly missed a situation in which I might have ended up bawking bike kiss for the guest of by wife.

YOUR FRIEND AND MINE, COUMADIN

Before these incidents, I had never had a stroke or a TIA. The literature on Revlimid and CLL indicated that blood clots in the lungs and legs could be an issue, but I could find no evidence of TIA in CLL, although it was reported at least once in patients taking Revlimid for myelodysplastic syndrome.

Apparently, a TIA is a rare event, although clots are not. One patient information document for a Revlimd-CLL clinical trial classifies clotting -– defined as “formation of a blood clot that breaks loose and is carried by the blood stream and plugs another vessel” -– as one of a secondary group of possible side effects of Revlimid, occurring in 3% to 20% of patients.

The trial, using Revlimid as a single agent, is being conducted at New York’s Roswell Park Cancer Institute, arguably the country’s leading center for CLL-Revlimid research. They have been dealing with CLLers for years and have the clinical experience to know what’s what.

And guess what?

All patients in the trial -– yes, ALL–- are required to take 2 mg of the blood thinner Coumadin each day.

This, my friends, is not commonly known, and it’s not even commonly practiced in most other CLL-Revlimid trials, from what I can gather. Nor is your local oncologist likely to know about it. So consider it a public service when I say that it is a wise precaution for all CLLers, even those with no history of clotting problems, to take Coumadin (generic warfarin) with their Revlimid!

As the patients in the study are told in writing: “It is important that you take the Coumadin every day that you take the study drug lenalidomide.” (Here's an interesting little abstract.)

Obviously, those who are at high risk for clotting stand a better chance of running into trouble. But how do you know if you’re high risk?

I had no history of clots. My blood pressure is excellent, I don’t have diabetes, arterial disease, or high cholesterol. High risk? Me?

Then I had a grand “D’oh!” moment, worthy of Homer Simpson at his worst.

Back in 1977, my mother, who was only three years older then than I am now, died of a pulmonary embolism. She had a long history of thrombophlebitis, or veins being blocked by clots. My older half brother, her other son, had two strokes about ten years ago -– when he was the age I am now -– after using Vioxx. He had assumed that Vioxx, later recalled by the FDA, was the cause. But did heredity play a part, especially since he had another stroke just a few months ago? Even Homer Simpson could probably get the right answer to that one.

PROCEEDING CAUTIOUSLY

I’ve been back on 5 mg of Revlimid, as well as some Coumadin, for awhile now. A carotid ultrasound ruled out any problems with plaque in the neck, so the odds of another TIA (or worse) really seem dependent on the dose of Revlimid I take, as well as the dose of Coumadin.

After two weeks of 2 mg of Coumadin daily, I had a PT/INR test, which measures clotting time. Mine came out normal. In other words, I was clotting like a person who wasn’t on Coumadin. That’s just not a good sign. So now my doctor is fiddling with increased dosages, which is typical with Coumadin, trying to get my blood suitably thin.

Until that’s done, I’m sticking with 5 mg of Revlimid. I may never go higher, and I may end up using the 5 mg intermittently -– say three weeks on, one week off, or 5 mg every other day.

The 5 mg seems to be working fine, judging by how I reacted when I resumed the drug after a three-week treatment holiday. I got a good amount of tumor flare, which lasted about two weeks before reducing, and my B2M is high, indicating that a whole lot of cell kill is going on. My CBCs continue to be normal and I have so far been spared the low neutrophils and low platelets that are fairly common to CLLers on Revlimid.

Needless to say, I’m going to watch for symptoms very carefully. Should I experience a third TIA, despite the blood thinner, my Revlimid career will probably come to an end.

Why take a chance at all, you might ask? Well, I don’t really have a choice. That's a short sentence but a big concept. Sometimes we take risks because we have no better alternative. Revlimid is the only thing out there that appears to be able to give me long-term stable disease without the curse of AIHA.

Other therapies also come with potential for great harm, just in different form, in case you hadn’t noticed. I'd rather take my chances with carefully managing Revlimid at lower doses -- which may get me to the next drug that can control my disease but might be easier on the system (CAL-101?) -- than jump on the transplant bandwagon. Given the difficulty I would face in getting a good donor match, as well as the inherent risks that can lead to fatality, I am in no rush to go that route.

With CLL treatment, we are always playing with fire. At least I now know what I need to watch for and plan for. The only thing worse than having to manage potentially serious side effects is to suffer them without warning.

I’ve been warned.

Revlimid dosing

2010-12-17T17:09:00.008-07:00

One thing I'm learning about Revlimid and CLL is that it's a bit like the Wild West. There aren't a lot of rules, you can strike it rich or get gunned down, and you'd better be a little tough to survive what life throws at you. A shot of whisky now and then doesn't hurt, either.

Deciding on a dose (of Revlimid, that is) and how frequently to take it is a particularly open-ended subject. In one clinical trial, the goal is to get patients up to 25 mg per day, if they can tolerate it. Another study suggests that 2.5 mg to 5 mg may be the maximum tolerated dose for heavily pretreated patients. Based on reported data, Celgene Corporation, the maker of the drug, advises that more than 10 mg is potentially unsafe for CLLers. And now there's an abstract out about pulsed dosing in relapsed patients that suggests 20 mg is more effective than lower doses.

The study was done at the NIH and an abstract was presented at the recent American Society of Hematology meeting. Patients were given Revlimid three weeks on and three weeks off. Thirty-one patients had at least two cycles of therapy, which is a short period for Revlimid. Some had as many as eight, but the abstract does not address the median number, which is significant in that Revlimid can require long exposure for the best effects.

At any rate, there were no CRs; 16% had PRs, 58% stable disease, and 26% progressive disease. Of the five patients who achieved a PR, four had deletion 17p and bulky disease. Four of that five started Revlimid at 20 mg; one started at 10 mg. Pulsed dosing did not lead to fewer toxicities. Once treatment was stopped, median time to next therapy was six months, although it ranged from two to 18 and was significantly better in the PR group. The full abstract is well worth reading and can be found at the bottom of this post as well as, hopefully, through the link.

There is no "written in stone" rule about Revlimid dosing, but something of a consensus may be emerging. Based on the NIH study and other data, not all of it published, we do seem to be learning that the highest tolerable dose (up to 25 mg) may be most effective. But getting there can be a rocky road, pardner, which I will blog about within the next few weeks. Celgene is not wrong to suggest that the higher you go, the more trouble you may get into.

And staying there, or staying at any dose level, is not guaranteed. Side effects -- low neutrophils, low platelets, serious rash, blood clots, etc., etc. -- can derail the Revlimid train. As the NIH study points out, Grade 3 or 4 neutropenia was seen in 56% of cycles, "often worsening in continuing cycles." One thing we do know for sure about Revlimid is that individual response can be unpredictable, both in terms of effectiveness and side effects.

Revlimid is effective in many patients who have become refractory to other drugs, but can you become refractory to Revlimid? Apparently, yes, from what I've heard, although I don't think there have been any studies on the subject. This has happened to some patients, mostly those who have been heavily pretreated. Why this happens to some and not others, and whether it has something to do with dosages and treatment schedules, is unclear.

For those of us who achieve a remission or stable disease with the drug, how do we maintain it? Again, there's nothing set in stone. In one leading center they keep you on the highest dose you can tolerate for a year, then take you off. You're monitored and only resume Revlimid again when you begin to relapse. There aren't reports of patients becoming refractory there, so perhaps this method has a hand in maintaining the drug's usefulness.

One fascinating question is whether the Revlimid can actually train the immune system to attack CLL cells on its own, without the Revlimid. This possibility has been suggested by some serious people, but it will probably be a long time before we see any hard data.

Basically, there's still a whole lot of guessing going on when it comes to how much to take and how often. The advantage of taking more, namely better response, can be offset by worsening side effects. And, of course, one patient can do well on 5 mg when another really needs 15 or 20 to show progress.

Revlimid, like exploring unknown territory, requires that your eyes and ears be open. Back in the old days, not all maps were drawn, and not all were accurate. If you're on Revlimid, you're a trailblazer, like it or not.

Phase II Trial of Pulse Dosed Lenalidomide In Previously Treated Chronic Lymphocytic Leukemia

Georg Aue, M.D.1, Susan Soto, RN2*, Janet Valdez, PA1*, Diane C Arthur, M.D.3, Xin Tian4* and Adrian Wiestner, M.D., Ph.D.5

1Hematology Branch, National Heart, Lung, Blood Institute,, National Institutes of Health, Bethesda, MD
2National Institutes of Health, Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD
3Laboratory of Pathology, NIH/NCI, Bethesda, MD
4Biostatistics, National Heart Lung and Blood Institute, Bethesda, MD
5Hematology Branch, National, Heart, Lung, and Blood Institute, Bethesda, MD

Introduction: Lenalidomide (L) has activity in relapsed chronic lymphocytic leukemia (CLL). The mechanism of action is not well understood but may involve stimulation of anti-leukemic immune responses. Myelosuppression especially neutropenia is a concerning side effect. We reasoned that pulsed dosing of lenalidomide could reduce myelosuppression while maintaining the immune stimulatory effect. To test this concept we initiated a single center, phase II trial (ClinicalTrials.gov Identifier: NCT00465127) of lenalidomide given in cycles of 3 weeks on, 3 weeks off drug (42 day cycles).

Methods: Patients (pts) with relapsed CLL or small lymphocytic lymphoma with ANC>500/ul and platelets >20,000/ul were eligible. The primary endpoint defined as response after 4 cycles has been recorded for all participants. Pts with partial response were allowed to receive up to 4 additional cycles. The starting dose for the first 10 pts was 20 mg daily; the starting dose for pt 11 onwards was lowered to 10 mg daily because of toxicities observed in other L trials for CLL. TLS prophylaxis with Allopurinol was mandated during cycle 1-3. Deep venous thrombosis (DVT) prophylaxis was not mandated unless risk factors were present. Ibuprofen and corticosteroids were allowed to treat symptoms of a cytokine release syndrome (CRS, defined by LN swelling, fever, fatigue, pain, chills, dehydration). Responses were assessed by IWCLL criteria and included CT scanning.Patient characteristics (n=33) were: median age 64 years (36-78); median number of prior therapies 3 (range 1-7); 52% Rai stage III-IV; 70% bulky disease; 30% fludarabine refractory; 56% (of 27 pts) ZAP70 pos; 64% (of 25 pts) unmutated immune globulin VH mutation status; 43% del 17p; 15% del 11q.

Results: A total of 131 cycles of L were given. 31 pts received at least 2 cycles of therapy (range 2-8) and were evaluable for response: 5 (16%) partial response (PR), 18 (58%) stable disease, and 8 (26%) progressive disease. 4 of 5 responding pts had del 17p and bulky disease. In responders (n=5, PR) vs non responders (n=26, SD+PD) the PFS was 16 vs 6 months (p>0.01), and the time to next therapy was 17 vs 6 months (p>0.01), respectively. Once treatment was stopped, duration of response was short lived (median 6 months, range 2-18). 4 out of 5 responders were observed in the 20 mg dose starting group versus only 1 responder in the 10 mg group (p=0.03). There was no difference in the CRS score between the 2 groups (2.5 vs 1.5, p=0.17). Hematologic responses were observed in 11 out of 24 CLL pts (45%). At the completion of 4 cycles CD4 and CD8 counts increased by 20%, while NK cell counts remained unchanged. Dose modifications/withdrawl: 41% of cycles required dose adjustments prior to or during cycles 1-4. 9 pts (27%) did not complete 4 cycles of L because of: autoimmune cytopenias (2 pts), side effects (4 pts; CRS 1 pt, neutropenia 3 pts), withdrawal from study (2 pts), and disease progression (1 pt). Toxicity: Gr 3/4 neutropenia was observed in 56% of 131 cycles, often worsening with cumulative cycles. Gr 3/4 thombocytopenia and anemia were seen in 30% and 15% of cycles, respectively. Gr 1/2 and 3/4 infections occurred in 23% and 11% of cycles, respectively, 8 of those in the setting of neutropenia. Gr 3 CMV colitis, PCP pneumonia and Candedemia each were observed once. 1 patient died from streptococcal sepsis in cycle 4. Gr 1/2 and 3/4 CRS were observed in 43% and 10% of cycles, respectively. A CRS was encountered in 78% of first cycles typically within the first week, and in 48%, 38% and 30% of cycles 2-4, respectively. 6 DVTs (Gr 3) were diagnosed in 5 pts. Other common side effects were fatigue (62%), rash (39%) and muscle cramps (27%), all Gr 1/2. No case of tumor lysis syndrome was seen.

Conclusion: L cycled 3 weeks on, 3 weeks off led to stable disease in the majority of pts and induced PRs in 16% of relapsed CLL patients with high risk disease. Pulse dosing of L did not lead to reduced toxicities. Myelosuppression and infections remain a major concern. 4 out of 5 responders were observed in the 20 mg cohort arguing for higher L starting doses. Notably, side effects, particularly the CRS, were similar in the two cohorts. Once L was discontinued, the duration of response was short, suggesting a need for continued therapy in pts who are able to tolerate the drug.

Disclosures: Off Label Use: Lenalidomide is not FDA approved in Chronic Lymphocytic leukemia.

The OL Protocol: Early results from MD Anderson

2010-12-11T16:51:00.003-07:00

For the record, some results have come in from MD Anderson on the Ofatumumab and Lenalidomide trial that I was following from afar. My doctor and I decided to drop the "O" after September's infusion because it didn't seem to be particularly effective. The Lenalidomide, however, is doing me a fair amount of good. (A reminder: the "L" is Revlimid, the "O" is Arzerra.)

The protocol, discussed in an abstract presented at the just-concluded American Society of Hematology conference, is providing good results for 10 of 16 relapsed, refractory patients. There have been two CRs and eight PRs. Four patients with stable disease are continuing in the study. One patient's disease progressed, and one patient dropped out.

By comparison, I would probably qualify as having stable disease since I don't fit all the definitions of PR at this point. This is mainly due to disease bulk, which is still extensive, although moving in the right direction. It needs to show a greater than 50% reduction, and I'm probably at about 33%. (Click here for a PDF of the guidelines by which types of remissions are defined).

Here's the abstract in its entirety (paragraph breaks added by yours truly since most doctors can't write):

Combination of Ofatumumab and Lenalidomide In Patients with Relapsed Chronic Lymphocytic Leukemia: Initial Results of a Phase II Trial

Xavier Badoux, MD, Susan O'Brien, MD, William G. Wierda, MD, PhD, Stefan Faderl, MD, Zeev Estrov, MD, Kimberly Yerrow, BSN, Hagop M. Kantarjian, MD, Michael J Keating, MD and Alessandra Ferrajoli, MD

Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, TX

Frontline chemoimmunotherapies induce high response rates in patients with CLL. Once disease recurs, however, effective treatment options are limited and new therapeutic modalities and combinations are needed. Ofatumumab is a fully humanized anti-CD20 monoclonal antibody which produces an overall response rate (ORR) of 47%-58% in patients with fludarabine-refractory CLL (Wierda W. et al, 2010). Lenalidomide, an immunomodulatory agent, induces an ORR of 32-47% in patients with relapsed/refractory CLL, (Chanan-Khan A.A. et al. 2006; Ferrajoli A. et al. 2008).

The rationale for combining ofatumumab and lenalidomide is based on their single agent efficacy, distinct and potentially complimentary mechanisms of action and non-overlapping toxicity profiles. Furthermore, the combination of lenalidomide and rituximab has shown significant activity in patients with relapsed disease (Ferrajoli et al. 2009). We, therefore, designed a phase II study to evaluate efficacy and tolerability of ofatumumab and lenalidomide given in combination in patients with relapsed CLL.

Patients with active disease were eligible if they had received prior treatment with purine analog-based therapy, had an ECOG/WHO performance status of 0-2, adequate renal (creatinine clearance > 30ml/min) and hepatic function (total bilirubin < to 2 mg/dl and ALT < 2 X ULN). Patients with any neutrophil count were eligible, whereas patients with platelet counts < 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis were excluded from participation.

In this trial ofatumumab is administered intravenously weekly for four consecutive weeks (300mg week 1, 1,000 mg week 2 and all subsequent doses), then monthly for months 2-6 and once every two months for months 7-24. Lenalidomide is given orally at the dose of 10 mg daily, starting on day 9 and continued daily. Allopurinol at the dose of 300mg daily is given during the first two weeks of treatment as tumor lysis prophylaxis. Treatment duration is 24 months, and responses are assessed after 3, 6, 12, 18 and 24 months of therapy.

Thus far 26 of the 40 planned patients have been accrued to this study and we present an analysis of response and toxicity for the first 16 patients that have been on study for at least 3 months. The median age of the patients is 62 yrs (45-82). Eight patients (50%) had Rai stage III-IV disease. The median Beta-2M level was 4.4 mg/dL (2-6.1). The median number of prior treatments was 2 (1-8). Four patients (25%) were refractory to fludarabine and all pts had received prior rituximab. Nine patients (56%) had unmutated IGHV genes, 5 patients (31%) had chromosome 17p deletion and 3 patients (19%) had 11q deletion as detected by FISH analysis.

Responses were evaluated according to the 2008 IWCLL criteria: 10 of the 16 evaluable patients achieved a response [2 CR (13%), 8 PR (50%)] for an ORR of 63%. Four patients with stable disease are continuing on treatment. One patient discontinued therapy and did not return for response assessment and another patient progressed. All patients are alive.

The most common grade 3-4 treatment related adverse events observed were: neutropenia (8 pts, 50%) and anemia (2 pts, 13%). One patient (6%) developed grade 2 superficial vein thrombosis. Lenalidomide-associated tumor flare reaction was limited to grade 1 in 2 patients (13%) while a grade 3 infusion reaction was observed in 1 patient (6%) during the first ofatumumab administration. Three grade 3 infectious episodes occurred: 2 cases of pneumonia and 1 case of parotiditis. None of the patients received routine antibiotic prophylaxis. The median daily dose of lenalidomide tolerated was 5 mg/day (2.5-10 mg).

In conclusion, our initial analysis indicates that the combination of ofatumumab and lenalidomide is therapeutically active in patients with relapsed CLL. This treatment is well tolerated. Neutropenia is the most common toxicity observed. Enrollment is ongoing, and updated results will be provided.

Disclosures: Off Label Use: Ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia. O'Brien: GlaxoSmithKline: Consultancy. Wierda: GlaxoSmithKline: Honoraria, Research Funding; Celgene Corporation: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Estrov: Celgene Corporation: Consultancy. Keating: Celgene Corporation: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria. Ferrajoli: Celgene Corporation: Research Funding; GlaxoSmithKline: Research Funding.

First, the good news

2010-11-21T16:25:00.001-07:00

When last we left off on my Revlimid journey, I was planning to increase my dosage from 10 mg daily to 25.

The hope was that the higher dose would bring even more beneficial results, especially in terms of lymph node reduction. The plan was to increase the dose in two-week increments, as is done -– if the patient can tolerate it -– in a clinical trial at the leading center for Revlimid research, Roswell Park Cancer Institute in Buffalo, NY.

All went well in the beginning. I did 15 mg for two weeks and then moved to 20. That lasted for four days, after which I was able to answer the question, “Why isn’t every CLL patient on 25 mg?”

That’s also the “bad news” part of the story, which I will explain in detail soon. But first, there are some other things that deserve to be in the spotlight.

The big picture is that the more I use Revlimid, the more I am convinced of its usefulness. I’m in my ninth month of it, and despite the challenges involved in getting used to the drug and managing symptoms that arise, I have benefited greatly from it. My autoimmune hemolytic anemia is gone, my blood counts are normal, and the lymph nodes are in retreat.

Tumor flare masks lymph node reduction

One thing I’ve had a hard time figuring out all along is whether the lymph nodes are reducing and by how much. You’ll recall that I had terrible tumor flare in the beginning. After doing the Revlimid Shuffle -– two steps forward and one step back -– my doctor and I were able to calibrate the dosage so that the flare was no longer an issue. If it was there, it wasn't obvious.

Some time ago, when I was off Revlimid for five days, I noticed that my nodes got smaller. After I stopped 20 mg, I was off Revlimid for 16 days. The nodes again reduced, and kept on reducing over the entire period, which confirmed my earlier experience. This tells me that low-level tumor flare is continuous when I am on the drug, and that when I am off it the nodes recede toward their real baseline. (This is all good; tumor flare is generally considered to be evidence that the drug is working.)

To determine the actual progress I’ve made these past nine months, I would need to be off Revlimid for several weeks, after which I would need to undergo a CT scan to compare to the one I had when I started.

Since that’s not going to happen anytime soon, I am left with the second-best option, namely self-groping and educated guessing. By that measure -– and being conservative in my judgment -– I’d say the nodes are one-quarter to one-third smaller.

As someone whose disease has become node-based over time, and who probably has more disease bulk that 99% of CLL Revlimidians out there, I cannot tell you how important it is to see such progress.

And seeing is believing. You know you have CLL when you keep a folder of photos on your computer called "My Neck." Looking back at old photos, I can see that my neck is now as slim, on a consistent basis, as it was in 2004. The abdominal nodes are no doubt worse than they were in 2004, but I look less pregnant than I did nine months ago and have lost about 10 pounds since then.

B2M test is a useful measure of whether Revlimid is working

Over the course of my 7-year CLL career, my B2M, or beta-2-microglobulin, has gradually risen. B2M is a protein shed by CLL cells into blood serum; the more CLL cells there are reproducing and dying, the more your disease is proliferating, the more B2M they put out. So, as a rule, the higher your B2M, the more active your disease.

If your B2M is below 2.0, you’re considered to have “the good cancer” behaving itself. When your B2M gets past 4.0, MD Anderson says you have “the good cancer” behaving badly, which means you have less manageable, progressing disease.

Looking back on my case history, I think B2M has been an accurate measure. It was 2.2 at diagnosis in 2003, 3.0 by April 2005, 4.9 in January 2007. It has been lower, usually just after chemo has concluded and the disease is in some kind of remission. But in times of no treatment it has risen over the years, finally finding a plateau in the 4s since 2007. In June 2009, my last B2M before starting Revlimid, it was 4.5.

But there is a big caveat when it comes to B2M, During treatment, when tens of millions of CLL cells are being torn to pieces, that B2M protein can also increase in the blood. So in some cases, a high B2M is not cause for alarm. It’s a good sign.

Which brings us to August 30, when I had my first post-Revlimid B2M test. The result was a jaw-dropping 8.8. Things had been going so well. Did this test mean that the disease was progressing anyway?

After my two weeks of 15 mg and four days of 20, the B2M was 11.1. This is so high as to be almost laughable, if not also a little scary. But was it possible that the higher doses were causing more anti-disease activity, which was being reflected in the test?

Two weeks later, after I was on and off the drug and ultimately back on 10 mg, the test came out at 8.8 again.

All of which tells me that my B2M rose with treatment, increased with the higher dosages, then decreased when the dose did. At least in my case, the high B2M seems to be evidence that Revlimid is working, and is therefore jaw-dropping for a good reason.

Au revoir, Arzerra

My treatment began as the “OL Protocol,” modeled after one currently in trial at MD Anderson. The “O” is for ofatumumab, aka Arzerra. The “L” is for lenalidomide, aka Revlimid. Arzerra is an anti-CD20 monoclonal antibody, much like Rituxan, perhaps better in some ways. MD Anderson had reported that patients treated with rituximab and Revlimid did somewhat better than patients treated with Revlimid alone.

But there has been debate about this all along. Revlimid appears to downregulate CD20 on the surface of B cells, which logically means that anti-CD20 monoclonals should have a harder time working when Revlimid is present. Alternate sequencing strategies –- say, have the Arzerra first, then do the Revlimid -– have been suggested as potentially being more effective. It’s important to remember that Revlimid is still new in CLL, its mechanism of action is not completely understood, and that we are in the trial-and-error phase.

Whatever the reason, except for one brief burst of node-reduction in May, the Arzerra never seemed to do much for me. Perhaps it’s because my CLL cells had little CD20 on them to begin with, which could be the result of using Rituxan over many years. Or maybe the stars weren’t aligned properly. Following my last Arzerra infusion in early September, my oncologist and I concluded that the Revlimid was doing the work and that the Arzerra was just expensive window dressing. So we’ve stopped it, and I’m on the “L” protocol now, which we are devising as we go along.

It appears that, so long as I can tolerate Revlimid and it continues to provide benefits that outweigh the risks -– more on that next time! –- I will be taking it for the foreseeable future.

Revlimid and autoimmune hemolytic anemia

2010-10-30T15:31:00.001-07:00

When you come down with something like chronic lymphocytic leukemia, you develop empathy for everyone else who has it. And when your CLL triggers autoimmune hemolytic anemia, or AIHA, you become especially empathetic, for you have just joined an elite group.

Depending on whose figures you believe, some 5% to 11% of CLLers will come down with this red-blood-cell-destroying, potentially-life-threatening nonsense. It happened to me early in 2007. (For more details on what it is and how it's treated, read this post. The NIH has a rundown here.)

I've had a bad time of it, a more severe case than most, becoming refractory to the standard treatments: steroids, rituximab, cyclophosphamide. As of 2009 it was getting so bad that I was relapsing -- in the form of severe bouts of hemolysis of red blood cells -- every few months, no matter what treatment I did. Save for a splenectomy, which is no guarantee of long-term success, I was running out of options.

Along came Revlimid. I have discussed AIHA and Revlimid (lenalidomide) in some recent posts, but the information was buried.

I don't want to bury the lede here: I am now Coombs negative and have not had a bout of hemolysis since I began Revlimid in March. In my more giddy moments I wonder if I am cured of AIHA.

Revlimid, an immunomodulator drug, has evidently reset my immune system so that it is no longer making antibodies to my red blood cells, a process that leads to hemolysis, which is when macrophages attack those cells. My red blood cell count, along with hemoglobin and hematocrit, has been normal since shortly after I began Revlimid. The Coombs (aka Direct Antiglobulin Test) I had on Oct. 6 confirms that I am negative for those antibodies.

To the best of my knowledge, the effect of Revlimid on CLL-induced AIHA has not been studied nor reported. I believe it is potentially one of the hidden headlines in today's CLL news. Aside from my anecdotal experience, a leading researcher has also found instances where it has been beneficial. In response to an e-mail I sent, Dr. Asher Chanan-Khan wrote:

"I have some experience in context with AIHA. At least 2 patients treated with len while transfusion dependent due to AIHA, resolved their need for transfusion and at least 1 is alive without AIHA 3+ years. Although the numbers are small, it does suggest that AIHA can be controlled with control of disease with len."

What I am saying here to fellow members of the elite club nobody wants to join is this: Consider Revlimid. I was on 5 mg when progress started being made, so it probably won't require a huge dose to control the AIHA. Revlimid may be useful at the very start of your battle as the side effects are usually less problematic than those associated with the traditional first line of defense, steroids.

There is, of course, no guarantee that Revlimid will work for everyone. There is one report of Revlimid actually inducing warm body AIHA in a woman with diffuse large B cell lymphoma. But that's not CLL.

I also have been on monthly doses of Arzerra during some of this period (ending two months ago). It is possible that the anti-CD20 monoclonal antibody also contributed to my progress, although it appeared to have little effect on the disease and we have now suspended its use. The fact that I was refractory to a similar drug, Rituxan, may explain why Arzerra (ofatumumab) appeared to be providing me with little benefit.

It would be helpful if some researcher somewhere would undertake a study on Revlimid and CLL-induced AIHA; if the results are what I think they will be, Revlimid could become an important tool in the battle to control CLL, reset the immune system, and perhaps put an end to the scourge of AIHA for large numbers of patients.

UPDATE

Today is January 18, 2011. It has now been almost five months since I quit the Arzerra. Still no sign of AIHA or hemolysis, red counts remain in the normal range, nothing out of whack.

If pigs could fly, we'd all choose the perfect treatment

2010-10-10T17:07:00.001-07:00

There was an interesting exchange in the comments section of Dr. Terry Hamblin’s recent blog post The ultimate FCR advice.

The post concerns a pivotal study of 817 patients by the German CLL Study Group. The investigators conclude that there is a survival advantage for most patients who use FCR as frontline therapy and that FCR can change the natural course of chronic lymphocytic leukemia.

The respected study shows that FCR is more effective than FC, meaning that the addition of rituximab is essential to getting the best results.

The exception to the “FCR is golden” rule is those patients with dysfunctional TP53 pathways, including those with the 17p deletion. FCR needs a functional cell-kill pathway to work, and giving FCR to these high-risk patients is so counterproductive that, Dr. Hamblin indicates, it crosses the line into criminal incompetence.

Of particular interest to my 11q-deleted self is that the our group responded well to FCR. Says Dr. Hamblin: “It is important to recognize that the del 11q patients now fall into this intermediate group. CLL8 has removed indecision as to whether they should be intermediate or high risk. If they are getting FCR they are at intermediate risk.”

All of these are big bullet points in the world of CLL.

After reading Dr. Hamblin’s analysis of the study, one reader was still not convinced that FCR is a good way to go and left this comment:

“Unlike Dr. Hamblin, I don't think FCR should be used as a first-line therapy. Why? Because when the patient relapses (and he will relapse), he will be in a precarious situation indeed. Fludarabine-refractory disease means that the patient has a poor prognosis.

“My opinion is that there are many treatments now available that are more benign than FCR. These include HDMP+Rituximab, Revlimid+R, flavopiridol, EGCG and others. Clinical trials using such agents as CAL-101, ABT-263, Perixifor+R and others could be considered as well.

“When you use FCR, you shoot the whole wad. Why not try something less toxic to start?”

(I don’t want to get sidetracked here, but except for Rituxan, steroids, and perhaps Revlimid, most of the treatments mentioned above are not feasible for most patients, few of whom have access to clinical trials. EGCG is not a reasonable alternative as it doesn’t appear to do much except in the most indolent of cases.)

Here’s Dr. Hamblin’s reply:

“None of the treatments you mention has ever been compared to FCR so you are asking people to buy a pig in a poke.

“It is true that we don't yet know where to go after FCR, but that is the time for all your experimental treatments.

“I'd rather buy my pig in a poke after I'd been eating roast turkey for 10 years.”

The first thing that ran through my mind is this: It wasn’t that long ago that FCR was the pig in the poke.

* * *

I was diagnosed in 2003, seven years and one month ago. At the time, all I knew is that I was CD38 negative, a good prognostic sign. None of today’s other important prognostic tests -– IgVH mutational status, ZAP-70, FISH -– were available to me. Our CLL researchers were still examining those pigs.

MD Anderson was just starting to report good news about FCR, albeit based on retrospective studies that came in for some criticism. People were intrigued by the results but a little wary of MDA’s pig farming techniques. The German Study confirms that MDA was basically right, even if some of the I’s weren’t dotted and some of the T’s weren’t crossed.

The idea of risk-adapted therapy in CLL was just gaining a foothold. It may be hard for today’s new patients to believe, but most doctors used to make treatment decisions in the dark. They assumed all CLL cases were basically the same, and pretty much treated everyone with the same thing (chlorambucil, and later fludarabine).

Clinical symptoms were used to decide when treatment should begin, which is the one thing that has not changed, nor should it. A recent editorial in haematologica includes this comment:

“In spite of this clinically relevant risk hierarchy, the decision to treat is currently not based on the risk profile but on symptomatic disease. This is important and further supported by the observation that in some subgroups of patients, such as those with 17p deletion (and mutated IGHV), the disease may have an indolent course.”

In other words, we know a lot more thanks to prognostic tests, but the most reliable bottom line resides with symptoms such as swollen nodes, dropping hemoglobin, dropping platelets, frequent infections, and lymphocyte doubling time. Assumptions -- such as “all 11q patients are high risk” or “all 17p patients are screwed” –- may not always be correct. With CLL, the learning curve goes on well into the horizon. The more we know, the more we realize we don’t know.

* * *

So, back in the Dark Ages, I was faced with a decision: FCR or single-agent Rituxan?

My disease looked more like an indolent thing that had finally started getting out of control than it did a goose-stepping disaster. After I was diagnosed, I recalled my last CBC –- from 1996 -– and began to suspect that I had CLL back then. The results showed my lymphocyte count to be a little high, which was chalked up by my doctor at the time to me having an infection, even though I didn’t feel sick.

In 2004, when I got my first FISH result, it gave some credence to the relatively-indolent theory. My result was “normal,” meaning whatever chromosomal damage I had was not on the test. I was not 17p-deleted, nor 11-q deleted.

But because of clinical synptoms –- swollen spleen and nodes and a high lymphocyte count –- the doctors I was seeing seemed to agree that I needed some sort of treatment. Two years later, CLL expert Dr. John Byrd told me I probably could have waited awhile longer, and in retrospect I think he was right. (This is why I suggest all new patients see a CLL expert doctor or two before deciding when and how to treat.) But at the time I was living in the universe of knowledge that I was living in.

Do I chose the pig in the poke? Or the other pig in the poke?

FCR struck me as overkill given what I knew about my disease. It was also fraught with questions about side effects and after effects. These weren’t so evident in the early days, and we have learned a lot since: FCR can severely weaken the already weakened immune system, giving rise to a host of problems. Viral reactivation can lead to Richter’s Transformation. Potentially fatal pulmonary problems can develop. Myelosuppression can be severe. Autoimmune hemolytic anemia (AIHA) can result. And so on. FCR has a bit of a Russian Roulette aspect, assuming your gun has about 30 chambers.

The other pig was single-agent Rituxan, also new and virtually untested as a treatment concept. The remission wouldn’t be as good or as long, but the side effects and risks were much more benign. Since it was a soft-glove treatment, it seemed reasonable to start it sooner rather than later, when the disease would be even more out of control.

So that’s the way I went. I responded pretty well for a couple of years, during which I also learned that my disease was worse than I had thought: I tested positive for 11q, I was IgVH unmutated, I was ZAP-70 positive.

* * *

Dr. Byrd also told me that CLL is a long journey, and that the nature of that journey is profoundly influenced by your first treatment.

If I could go back to 2003, armed with the results of the prognostic tests that I have had since, as well as the results of the German Study and other clinical trials conducted since, would I have chosen FCR?

Probably. Given the full scope of my prognostic markers, the argument in favor certainly would have been stronger. And the weakness that single-agent Rituxan has demonstrated in most patients over the long haul would have made that option less attractive.

Knowing that FCR would be my first treatment, and having had the sense to see Dr. Byrd at the outset, I might have been able to wait another year, perhaps even two, before undertaking it. Judging by the way I first responded to single-agent Rituxan, I probably would have gotten a CR, and the remission probably would have lasted a good three to five years but no longer. We know that unmutated folk like myself relapse faster. That card was dealt when the CLL was born.

Would my FCR experience have been uneventful, giving me years of “worry-free” living? Or would I have not dodged all the bullets that come with firing that big gun?

I have enjoyed relatively good quality of life along the path that I did choose, with the exception of coming down with AIHA in 2007. Might FCR have spared me that? Or might it have caused it to happen, as it recently did to a fellow patient I know?

Might the 11q have been avoided? Or might 17p have resulted from FCR’s selection of CLL clones with dysfunctional TP53 pathways?

Assuming all had gone well, I’d likely be in relapse now, on my second treatment, perhaps even a third. Ironically, I might be on Revlimid to keep the disease in check, which is exactly where I am.

Either path would have led me to the same place, namely the likelihood of needing a stem cell transplant to survive in the long term.

Either path is likely to have prolonged my life. The German Study cannot answer long-term survival questions: How many FCR patients will be alive after, say, 10 years, compared to others? A study in the 1990s showed that single-agent fludarabine led to longer remissions than chlorambucil, but as time went on, it became clear that fludarabine did not provide longer overall survival. Rituxan will probably make a difference in the statistics. But will it have to be part of a chemoimmunotherapy regimen (FCR) to make that difference, or will using it as a single agent also have an impact?

I said before that I'd probably choose FCR if I could go back in time. It would be the logical thing to do given my prognostics and the options available in 2003. (Would I have tried Revlimid first had it been a choice? Hmmm.) But there is no guarantee that, had I chosen FCR, I would be in any better shape than I am today.

My guess is that for patients with “mild” cases of CLL, FCR will prove more of a game changer than it will for us “intermediate risk” folk. It makes sense that the more you beat down something that doesn’t grow very fast, the longer it will take to come back.

Will a study conclude in, say 2018, that FCR increases survival of 11q-deleted, unmutated patients by three years, or three months, or not at all? (For that matter, will 11q deletion be an antiquated measure, having given way to some new, more specific way to understand what is driving an individual’s CLL?)

My point is that, as my experience demonstrates, CLL choices are ever-shifting. Nothing is frozen in time. And treatment results can vary greatly by individual because, on some level, CLL cases are as unique as fingerprints.

We are at the beginning of the era of risk-assessment, not the end of it. For all our knowledge -– and the light shed by the German Study should not be discounted -- we are still playing a guessing game. Given everything we don’t know, everything is still, to one degree or another, a pig in a poke.

So judge your pigs as best you can and hope that the one you choose doesn’t turn out to be a turkey.

Onward and upward with Revlimid

2010-09-28T18:13:00.000-07:00

At the end of my last post, I posed the question of what to do about my Revlimid dose, which is providing stable disease at 10 mg per day.

Do I accept that as the end point and maybe even step it back a bit if stable disease can be maintained at a lower dose? (After all, we really don't know what Revlimid is doing to my body, and what its long-term effects will be.)

Or do I increase the dose in the hope that the more drug I take, the more effective it will be? (After all, we are dealing with CLL here, and knocking it back is worth the risk, which may turn out to be small given Revlimid's history in CLL so far.)

Run this question by one of the leading experts on CLL and Revlimid and the answer is: Bump it up.

And so, for almost two weeks now, I've been on 15 mg of the stuff.

I have a friend who is in a clinical trial at New York's Roswell Park Cancer Institute, where Dr. Asher Chanan-Khan is the principal investigator, and where the clinical nurses also know more than a thing or two about Revlimid and CLL. Chanan-Khan and his staff have been doing Revlimid (aka lenalidomide) trials for several years and probably know more about its effects on CLLers than anyone else. This fellow patient kindly agreed to run my case by the powers that be.

The patient is in a trial for untreated patients, in which participants are stepped up to 25 mg at two week intervals, starting with 5 mg. Optimally, patients will then stay on 25 mg for six months, which is the level at which the best results have been seen. After that, patients will go into a lower dose Revlimid maintenance program. One patient has been in treatment for 52 months.

Some patients can't tolerate the drug, of course, and have to drop out. Others get good results at lower doses than 25 mg, so they are never bumped up all the way. There's a certain finessing that goes along with determining Revlimid dosages.

Ironically, the higher the dose, the easier the drug seems to be on most patients. Nurses report more problems in the beginning, with smaller doses, as the body gets used to the drug. My friend, who is now at 25 mg, reports that his experience bears this out.

Much to my surprise given my rocky Revlimid history of tumor flare and rash, my experience is bearing it out also. The only ripple is that I have experienced more tumor flare -- the usual, non-dramatic kind, nothing like I had in the beginning. This is understandable given the increase in dosage. Tumor flare is a good sign, according to Dr. Chanan-Khan, who says it means the drug is working.

Chanan-Khan also thinks the Revlimid is doing most of the work in the protocol I'm on, which also involves periodic infusions of the anti-CD20 monoclonal antibody Arzerra (ofatumumab).

I discussed all this with my oncologist, and she agreed that bumping up the dose at two week intervals was worth a try so long as I can tolerate the drug. We'll continue with the Arzerra for the time being. So the original OL protocol has now been modified to reflect higher doses of Revlimid. One of the advantages of following a clinical trial from afar is that you can modify it if necessary since you aren't locked into a search for empirical data. Your primary concern is clinical results.

My friend also has 11q-deleted CLL and has noticed progress with his lymph nodes as time has gone on and dosages have increased. At 5 mg and 10 mg some of his nodes became soft and squishy and at 25 mg he notices node masses separating.

Since nodes are my biggest challenge, I'm hoping for tangible progress as time goes on. I had some beginning in May, when a big node mass under my right armpit separated, but things appear to have found a plateau since then.

It's important to remember that Revlimid is an immunomodulator, not a traditional chemo drug, so progress will be slower and less complete -- but I hope significant enough in the course of time to keep the disease down without taking on the risks associated with fludarabine, cyclophosphamide, and the like.

Tomorrow, 20 mg.

The Vitruvian Rat

The OL protocol after six months

2010-09-05T13:50:00.001-07:00

It was six months ago to this day that I first downed a Revlimid capsule. Cheers! Salud! L'chayim!

I was embarking on the pill half of my latest CLL treatment protocol: Arzerra (aka ofatumumab), the anti-CD20 monoclonal antibody; and Revlimid (aka lenalidomide), an immunomodulator. I call it the OL protocol.

As readers of this blog know, I had my challenges with the Revlimid: tumor flare, rash, fatigue. It's not a fun drug. My body got used to it, but I'm not sure I have.

I'm just about to end a week-long, doctor-approved Revlimid treatment holiday. The OL protocol has me slogging through 10 mg of the stuff every day. In myeloma protocols, and in at least one CLL clinical trial that I know of, patients get three weeks on and one week off. During this week off I have slowly seen the drug-induced fatigue and dullness leave my body. I have more energy again and I'm mentally sharper. Revlimid subtly but surely detracts from certain aspects of quality of life. So the results had better be worth it.

Are they?

The results so far have been mixed, a combination of disappointment and relief, and might technically be considered to be "Stable disease Plus."

The disappointment has been in the lymph nodes, where most of my 11q-deleted disease resides. Back in May I thought I was finally having some luck in that department. But rather than presaging progress to come, it turns out May's results were an anomaly. Further treatment has not yielded any more progress. The nodes are pretty much where they were when I began.

Which is to say they appear to be (with the naked eye and roving hands, as opposed to an abdominal CT scan) stable. While I was hoping for more, I have learned after seven years of fighting this thing to be content with treading water. It beats drowning.

Nodes, like facts, are stubborn things, at least in my case. The only thing that will really blast them -- and I'm not at all confident that it would get rid of them completely -- is heavy-duty chemo. Steroids provide a nice reduction, but it is fleeting. The addition of cyclophosphamide provides a longer reduction, but not that long. FCR would probably do better, as would R-CHOP or the like. But the results would last how long? It's best not to take that sort of step unless I really have no other choice, and unless I'm prepared to roll the dice on a transplant afterward. But it is also best not to let the nodes get any worse, which means that keeping them stable, while not optimal, is important.

An area where the protocol has worked has been in the peripheral blood. My absolute lymphocyte count has been "normal" for months now, dropping from 11.8 on Feb. 23, the day before the protocol began with my first Arzerra infusion, to 3.2 as of last week. In clinical terms this means absolutely nothing. The blood is not where the disease is congregating.

I have also been spared the neutropenia and thrombocytopenia that can accompany the protocol. My platelets, which have slowly dropped over the years, landing in the 120s a couple of years ago, have remained stable.

The really good news -- and the "relief" I mentioned above -- is that there has been no sign of autoimmune hemolytic anemia (AIHA) since I began the OL protocol. On the quality-of-life scale, dealing with sudden bouts of severe hemolysis of red cells has been the bane of my existence since the first incident occurred in early 2007. Over the course of time I became refractory to more and more AIHA treatments, including steroids and Rituxan. It was even getting to the point that the RCD protocol (Rituxan, cyclophosphamide, and dexamethasone) was only holding me for three months.

Here I am, six months later, with normalized red counts, hemoglobin testing in the 13s and 14s, and no signs of orange pee or pounding in my ear. I can't leap tall buildings in a single bound, but I can at least climb the stairs with ease.

I am thinking that the Revlimid, doing its immunomodulating thing, is probably responsible, or primarily so. I had already become refractory to Rituxan, and Arzerra is a cousin of that drug. Dr. Chanan-Khan, the CLL Revlimid research guru, told me that he knows of two actively hemolysing patients whose situations were turned around when they were given Revlimid.

The take-home message to all of you fellow AIHA-ers is: Consider Revlimid.

This is the big "Plus" in "Stable disease Plus" and -- along with maintaining evident stability of the nodes -- is a big reason why I will continue to take the drug and work with the protocol. My doctor and I are discussing ways to tweak it or change it, given that it appears I will have no more progress with the nodes the way things are. The question is: What is the minimum dosage I need to maintain stable disease and keep the AIHA in its box? And another question: To what degree is the Arzerra contributing to this stability? And of course: Will upping the dose of Revlimid give better results on the nodes?

There are always more questions than answers in CLL.

At last, progress on the nodes

2010-06-01T01:39:00.002-07:00

“Good news, everyone!”

Fans of Futurama and its doddering professor and sometime inventor Hubert J. Farnsworth will recognize that expression and know the voice that goes with it. If I may take a little more liberty in the style of the good professor:

“The Lenalidomide-Ofatumumab Leukemi-o-meter De-noder appears to be working!”

Not all of Farnsworth’s inventions pan out, of course -– and not all patients get good results with the Revlimid (lenalidomide) and Arzerra (ofatumumab) protocol that I’m on. In its own way, the protocol is as chancy and experimental as Farnsworth’s inspirations often turn out to be in Matt Groening's sci-fi cartoon TV show.

More than one fellow CLLer has reported to me that our expert doctors, big names you’ve heard of, are intrigued by Revlimid but have no idea how it does what it does. (Farnsworthian indeed!)

For patients, of course, the bottom line is results. After struggling with Revlimid dosages, tumor flare, fatigue, and a rash during a three-month period and seeing very little progress, I have to admit that I was becoming a bit pessimistic. Even the Arzerra, an anti-CD20 monoclonal antibody -- supposedly better than Rituxan, to which I have responded in the past -- appeared to be a bust.

Like a mantra, I found myself repeating a fact to myself from one study: The median time to best response is 5.9 months. Or as a researcher with experience in Revlimid trials told a friend of mine: “If it doesn’t work within six or seven months, it’s not going to work on you.”

* * *

The last thing I expected was that progress would be sudden. But it has been, like turning on a light switch. I alluded to it in my last post, which was mainly concerned with a Revlimid-induced rash that I had developed.

In the week prior to my May 20 monthly Arzerra infusion, I had finally managed to get my Revlimid dose up to 10 mg daily, which is what the protocol calls for. This obviously raised the levels of the drug in my body (ergo the rash). I began to suspect some subtle progress on the nodes in my neck. On Thursday the 20th, I had 1000 mg of Arzerra. Over the next four or five days, the switch went on. I began losing weight, and my neck and abdomen showed visible progress.

But the best example of change was the nodal mass under my right arm. What had been a hard baseball-like thing (well, half a baseball) -– a number of nodes that had grown together -– simply fell apart. I can feel individual nodes there now, but they’re no longer connected.

I’m making an educated guess that this could be going on in the abdomen, which has slimmed down considerably. I’m still full of nodes, but the masses may be breaking apart as each node reduces in size. My neck is looking positively scrawny as a mass on the right side has undergone a similar fate.

Why the Arzerra chose that weekend to kick in, I don’t know. To give my body a break from the rash, I was off Revlimid from May 20 until the night of May 24. But levels of the drug, which had been building while I was managing 10 mg daily, had to have been high on May 20, the day of the Arzerra infusion. Revlimid is an immunomodulator and perhaps it had sufficiently started to change the microenvironment in which my CLL cells live and my immune system functions, creating a more advantageous environment for the Arzerra. That's only a guess. (If the experts don't know how it works, I don't think I'm going to figure it out.) Whether that modulation has do to with dosage levels or length of time used, I can’t know for sure, although it stands to reason that both are a factor and that dosage is important.

That’s why I am anxious to get to and stay at the optimal dose of 10 mg daily. We all respond differently to drugs and their dosages. A tiny dose of vincristine, which probably would have gone unnoticed in another patient, once gave me peripheral neuropathy for months. Claritin, the allergy medicine, doesn’t work for me at all at the recommended dose. If I exceed that dose and take two Claritin, it does work. So in the case of one drug I am more sensitive than average, in the case of the other I am less so.

Revlimid in CLL is still a work in progress. But studies tend to indicate, and my own anecdotal experience suggests, that the higher the dose of Revlimid on average, the better the response. I surmise that CLLers on Revlimid should be on as high a dose as they can tolerate, 10 mg being the limit recommended by the drug’s manufacturer, Celgene.

* * *

Meanwhile, back at the rash . . . To control the rash, I began taking 4 mg of dexamethasone every morning starting May 25. The plan was to do 10 mg of Revlimid every other day and use the steroid to control the rash, easing myself up to adding 5 mg and later 10 mg on the “off” day.

At first, the steroid would work for much of the day, the rash only starting to return to my belly at night. After about four days, it began to work better. I’m now taking 5 mg of Revlimid on the “off” day and the dex seems to be able to control the rash over a 24-hour cycle. Another couple of goes at 10-5 and I’ll try 10-10; if the rash remains under control, then I’ll stop the steroid, perhaps reducing it to every other day at first.

* * *

Since I am on a steroid now, that does bring up questions about what role it may or may not be playing in my node reduction.

First, it must be remembered that the cascade of progress began several days before the first little green steroid pill touched my lips.

Second, I have had a fair amount of experience with steroids during efforts to control my autoimmune hemolytic anemia (AIHA). Four mg of dex is a pretty minimal dose (equivalent to about 21 mg of methylprednisolone.) It’s nothing to sneeze at, but 4 mg, in the past, has done little in and of itself to reduce my nodes.

Now, since I’ve started taking it, the progress on my nodes has continued (albeit at a slower pace than the post-Arzerra burst). It’s possible that it is a coincidence, but it’s also possible that the dex is a contributing factor, working in synergy with the Arzerra (anti-CD20 monoclonal/steroid combinations are well-known in CLL treatment.) Once I’m off of it -– hopefully, sometime in the next week to ten days my body will be adapted to 10 mg of Revlimid daily without causing a rash -– I’ll be able to judge whether it has had any effect. Obviously, if the nodes come back a little, that might indicate that it has.

But the bottom line is that the underlying progress is a result of the OL (ofatumumab-lenalidomide) protocol. Why or how it suddenly decided to visibly work after three months is a Farnsworthian mystery. My advice to those starting Revlimd and Arzerra is to hold on, get ready for the long haul, and be aware that you may not see immediate results like you do with most treatments. That makes it a little counterintuitive and a little hard to take at times, but you might just be surprised one day. I certainly am.

Rash decisions, and other Revlimid news

2010-05-24T22:23:00.003-07:00

My latest CBC is suitable for framing: Lymphocyte count “normal.” Red count “normal.” Platelets “normal.”

But all is not picture perfect, as swollen lymph nodes remind me every time I pass a mirror. There have been some developments on that front, which I’ll get to in a moment.

But first, speaking of red, I have run into a rash roadblock. Taking Revlimid (lenalidomide) is not unlike playing a video game with your health. Once one problem is solved, another is presented. The goal is to successfully navigate your way through each challenge and get to where you want to go, which in this case is a meaningful remission.

I had finally managed to get myself up to taking 10 mg every day again without inciting major tumor flare or becoming a complete zombie. And then, last week, about four or five days in, a rash started to develop. Each day it grew worse until it was apparent that Something Had to Be Done.

The rash didn’t itch and it wasn’t painful. Imagine a series of small, pastel-red spots, which started on the feet and ankles and then began to appear everywhere. Fortunately, I was scheduled for a doctor visit and Arzerra (ofatumumab) infusion last Thursday. By Wednesday night, my face was starting to turn red.

As Dr. Belle said when she saw me, “I feel sick just looking at you.” So she suggested that we stop Revlimid for three or four days, long enough to let the rash clear. Keeping the body in a state of so much inflammation is not good, she said. The last thing we want to do is trigger some sort of zany, inappropriate response from the CLL clones.

So here I am on the last day of no Revlimid, the rash gone except for the stubborn feet and ankles. The plan is to resume Revlimid at 10 mg every other day and manage any new rash with dexamethasone and antihistamines. (The Benadryl I had on Wednesday and Thursday made only a mild dent in the rash, thus the steroid. I also had a 125 mg hydrocortisone shot on Thursday, which was part of my Arzerra premeds.)

If I can tolerate 10 mg every other day, we’ll add 5 mg on the “off” day and work back up to 10 mg every day. Since I was rashless when I was doing 5-10-5-10 before, I suspect that I won’t have much of a problem again until I get to 10 every day. We shall see, hopefully not red.

* * *

Meanwhile, I began to notice some subtle progress on the lymph nodes when I was back up to 10 mg daily. Dr. Belle says my spleen is reduced and that some of my neck nodes are spongier. I have lost about eight pounds in the past two months or so, and the weight loss seems to be accelerating. Is it water weight? Spleen and lymph node weight? It’s not from exercise, which Revlimid fatigue tends to prevent, and I’m not on a diet.

And being off Revlimid while having Arzerra has also been interesting. For the first time I am noticing some neck slimming following an Arzerra infusion. Could this mean that the Arzerra is working better without the Revlimid added to it? Could the Revlimid have been contributing to some subtle tumor flare that was masking the effectiveness of the Arzerra all along? Or could the higher doses of Revlimid that I had been taking have set the stage for the Arzerra to work more effectively than in the past? After all, the Revlimid doesn’t disappear from your system immediately when you stop taking the pill. I suppose this will sort itself out as the game goes on. Let’s just say that for the first time I am cautiously optimistic that this protocol may be doing something about my disease bulk.

* * *

The last thing I’ve noticed during my mini-vacation from Revlimid is how much more clear-headed I am starting to become. It’s easier to get things done, and not just because my

energy level is higher. I am losing that Revlimid-induced quality that can best be described as “dullness.” It’s not so much fatigue as it is feeling listless and not on top of things, like there’s a layer of invisible cotton between me and the world. I have to admit that this feeling is hard to take over the long haul. It’s easier to cope with tumor flare or a rash. Hopefully, when I’m back to 10 mg daily and rash-free, it will gradually disappear. Otherwise it’s going to be a long nine months, which is how long I have left to go on this protocol. Of course, if I do get to that meaningful remission at the end of the game, it will have been worth it.

Life in the slow lane

2010-05-11T13:16:00.002-07:00

It’s been about nine weeks since I started lenalidomide, aka Revlimid. With nearly ten months to go in the protocol, it’s still hard to point to any significant progress.

As you may recall, the initial dose of 10 mg daily led to severe tumor flare and was cut back to 5 mg within the first week. This lower dose was accompanied by a reduction of drug-induced fatigue, as well as a reversal of the tumor flare.

After about a month, my oncologist decided it was time to work our way back up to ten again. For a few weeks I did 10 mg every third day –- 5 mg, 5 mg, 10 mg, 5 mg, 5 mg, 10 mg -– and so on. That proved tolerable, so I am now on 10 mg every other day.

This has been accompanied by the return of noticeable fatigue on the day following the 10 mg dose. Yesterday I was about as zonked as I get. It’s not a sick or fluish feeling, more like a spaced-out, moving-through-Jello, can’t-deal-with-anything-complicated kind of thing. I got a full night’s sleep –- that’s one thing you can count on with Revlimid –- but also required two naps during the day. Prior to Revlimid, I always used to wake up refreshed from a nap. Now I usually wake up almost as tired as I did before I started.

My reaction of late to 10 mg has not always been so severe; perhaps the drug is beginning to build up in my body. So it will be interesting to see how my tolerance to it develops. The plan is, of course, to go back to 10 mg daily as soon as I can stand it.

Besides the Revlimid I am getting monthly infusions of ofatumumab, aka Arzerra. I haven’t had any infusion reactions, nor any dramatic results.

My CBCs do show progress. Absolute lymphocyte count has dropped from around 12k to a just-above-normal 5k. Platelets are holding steady at low normal, neutrophils remain strong, and the hemoglobin, hematocrit, and overall red count have improved and now sit at low normal as well. I’m pretty sure my autoimmune hemolytic anemia will stay in its box as long as I’m on this protocol.

But the real battle is in the lymph nodes, where most of my disease resides, and where it's hard to know what's happening, other than "not much so far." During my 5 mg month the nodes seemed to be getting just a tad better -– a little softer and spongier in the neck, for example. I've lost a few pounds, so my abdomen looks a little less distended, but it's a leap of faith to say that I lost abdominal lymph node weight.

I think it's accurate to say that the nodes show no truly measurable improvement since I started all this nine weeks ago. How much is drug resistance, how much is the propensity of Revlimid to cause even mild tumor flare, it’s hard to say. The other factor is that it could be too early for noticeable improvement; many patients report that it takes several months to see progress, and one study showed that it took patients a median time of about six months to show best results. The sooner I can get back to 10 mg daily, the sooner things may start looking better.

So a lot of this is a waiting game, accompanied by intermittent bouts of fatigue. For those of us used to seeing rather immediate results from traditional chemo, it’s also a lesson in patience.

The only thing I can safely conclude so far is that the protocol has brought me stable disease. The nodes are not really improving but they’re not getting worse. The AIHA is under control. My red counts have improved, though this potential added energy is offset by Revlimid fatigue. Only time will tell whether I get from stable disease to partial remission.

Take two aspirin and call Obama in the morning

2010-04-04T15:27:00.015-07:00

My recent post celebrating the passage of health insurance reform led to an interesting debate in the comments section. There are sincere people on both sides who put forth arguments of merit. At the risk of causing more headaches for myself and others, I want to address some of the points made.

First, this new law is about as conservative as a liberal reform can be. There is no public option. The bill was supported by Big Pharma, with which the White House cut a deal early on. While these factors may be mightily annoying to some people on the left, they also mean that the worst fears of those on the right are unlikely to be realized. Decisions about what care you can have will still be made by corporate bureaucrats –- as opposed to government bureaucrats –- although the reforms do provide some better consumer protections, such as changes to the appeals process. Drug companies will still be able to charge American customers an arm and a leg and a spleen, which means they will still have money and incentive to develop new therapies for CLL and other diseases. There will be no government-mandated NICE program, like they have in the U.K.

The concerned physician wrote in his comment that "Healthcare providers will either grow wealthier, or they will leave the system, further diminishing availability of care." I am guessing that with a new group of 32 million captive customers, health insurance companies won't suffer. They have enough money to hire attorneys to exploit loopholes or gray areas in the law, which has already begun, as the recent flap over whether they can weasel out of covering children with preexisting conditions demonstrates. There are lots of ways for health insurers to game the new system, just as they have gamed the old.

On another point I made, the doctor wrote: "I hope that you really don't believe that many people died for lack of coverage. As a physician I categorically assure you that that has not been the case."

Alas, there is plenty of evidence that more than a few people have suffered fatal consequences from lack of insurance. Last fall, researchers reported in the American Journal of Public Health that an estimated 45,000 deaths per year in the United States are associated with the lack of health insurance. A 2007 study from The American Cancer Society found that uninsured cancer patients are 1.6 times more likely to die within five years of their diagnosis than those with private insurance.

The bottom line, as I see it, is that the current system is unfair (take refusal to cover preexisting conditions as an example) and unworkable for too many people (the estimated 45 million Americans who have no insurance, those even with insurance who face bankruptcy if they become seriously ill, those with chronic diseases -- hint, hint -- who face dollar caps on coverage, those whose insurance can be lost at any minute due to the capricious whims of an insurance company).

This reform package is flawed and will no doubt need some corrections as time goes on. There may well have been better ways to go about it. But in correcting some of the worst abuses, it is a step in the right direction. We may have gone from bad to middling, but as we CLLers know from our treatment experience, a partial response is better than none at all.

Post Secret CLLer?

2010-03-28T17:04:00.005-07:00

I found this image on Post Secret, the blog run by Frank Warren, a guy in Maryland who encourages people to send in anonymous post cards. These cards usually express things that the senders would otherwise keep to themselves.

No, I didn't send it in, and I can't be sure it's from a patient with chronic lymphocytic leukemia. But it does speak for all of us, I imagine, although I don't feel guilty for not suffering more.

The fog lifts

2010-03-27T17:06:00.001-07:00

The fatigue that accompanied the start if my lenalidomide (Revlimid) therapy has pretty much disappeared after about three weeks. I didn't realize how bad it was until I started to come out of it and suddenly found myself with a lot more energy than I expected to have. I had started to forget what "normal" felt like.

After therapy began on March 4, I began sleeping nine to ten hours a night and napping for perhaps an hour during the day. Even during my waking moments I was running (or I should say moseying) at about half speed. As this routine dragged on it became rather depressing. I have been fortunate in that I have not had the CLL-related fatigue that some patients report. Living with a drug-induced taste of it for a few weeks opened my eyes to how difficult it can be.

Is the cessation of fatigue dose-dependent? I started at 10 mg daily, which was reduced to 5 mg about a week in. The fatigue still continued for awhile, though. I will no doubt attempt to step up to 10 mg again at some point in the near future. I'll just have to see if the fatigue returns.

Other than that, there is little to report so far. Blood work shows that my red counts continue to improve. There's no sign of low platelets or low neutrophils, either or both of which can accompany Revlimid therapy. It is possible that there is a slight, incremental improvement in my lymph nodes, but these can wax and wane under normal circumstances so I hesitate to read too much into it. One study put the median time to best response at 5.9 months and I haven't even been on lenalidomide for a month yet. Patience is both an art and a discipline.

Finally

2010-03-23T14:36:00.002-07:00

Today, with President Obama's signature, health care reform became the law of the land. It’s not perfect but it’s a significant improvement over the mess we have now. The United States has taken a big step toward joining the industrialized world when it comes to insuring that the basic needs of its citizens are met.

It is a shame that thousands of Americans had to die on the way to this day because they couldn't afford insurance or because their insurance provider found a reason to drop them when they got sick or refused to cover preexisting conditions.

Despite their crocodile tears, Republicans did nothing when they controlled Congress and the White House to address those issues, not even basic matters of fairness that most reasonable people would agree upon. Now they have gone off the deep end, embracing all manner of wingnuttery.

A new Harris Poll of Republicans shows that 67% believe that President Obama is a socialist, 57% believe he is a Muslim, 45% agree with the Birthers that Obama was "not born in the United States and so is not eligible to be president," 38% say the president is "doing many of the things that Hitler did," and 24% believe that Obama "may be the Antichrist."

And these people think they know better when it comes to health care?

Republican pols, of course, are running around like headless chickens pandering to the rightest of the right wing, squawking "repeal" and saying that Americans are against health care reform. Today's USA Today/Gallup Poll shows Americans supporting the measure by 49% to 40%. As Taegan Goddard of Political Wire pointed out on Monday, analyzing a CNN poll: “Parsing the numbers shows that many of those against the plan actually oppose it because 'it is not liberal enough.' In fact, 52% of Americans either support the current legislation or think it should be more liberal, while only 43% oppose the plan saying it is 'too liberal.' "

At some point in the future, people will look back and wonder what all the fuss was about. And more people will be alive to wonder, thanks to this legislation.

Lenalidomide lets loose

2010-03-14T17:28:00.008-07:00

In a word, brutal. That's how I would describe my first ten days of lenalidomide, aka Revlimid.

I took my first 10 mg dose on Thursday, March 4. For the next two days the main symptom was fatigue, which is common among those starting the drug. It was nothing insurmountable, but it did require an extra hour or two of sleep at night and a nap during the day. (I took the pill at bedtime, which is recommended.) Waking hours were accompanied by a certain amount of cat-like lethargy, but I was still able to work at my home business. I would not want to be starting Revlimid while holding a high-pressure job or managing a busy household. This drug is the enemy of multitasking.

By Saturday I was starting to feel noticeable effects of tumor flare, which is where the brutality comes in. It seemed as if my lymph nodes (and probably spleen) were growing by the hour. My abdomen became so distended that I looked at least eight months pregnant. A baseball was developing under my right arm. By sometime Sunday my neck was wider than my head. I could barely button my largest pair of pants. I was eating less because I was feeling full faster -- my spleen was probably pressing on my stomach and the abdominal bloat was pushing up from the other direction. I would say that in a matter of just a few days my lymph node bulk increased by at least 50%, and that's just a rough guess. It could have been upwards of 100% in some areas.

Each nightly pill added fuel to the fire. It seemed as if the nodes were intent on growing whether there was space for them to do so or not. While I knew that tumor flare is a normal side effect of lenalidomide, it was still scary. It provided me with a snapshot of how much worse my chronic lymphocytic leukemia could get if things got that much more out of control.

By Sunday evening I was experiencing a new symptom: trouble getting a deep breath. Up until then I was willing to tough it out, despite the discomfort. Bloated, distended, ready to give birth to an alien baby, that I could handle. Shallow breathing, not so much.

The shortness of breath was not constant, nor was I feeling like I was going to pass out. I was getting enough oxygen. But it was disconcerting, to say the least, and it was becoming more frequent the longer I stayed on the drug. Perhaps a mass of nodes was pressing on my diaphragm, or perhaps nodes were interfering somewhere else with the breathing process, or perhaps both. I couldn't help but wonder how much worse it might get.

I should interject here that, according to studies, tumor flare can crop up anywhere from 0 to 56 days after starting Revlimid. Median time to resolution is 14 days. I was just four days in.

By Monday night I had the intuitive sense that taking more Revlimid had the potential to push me into the realm of unintended consequences. I considered using steroids to dampen the inflammation since ibuprofen had proven worthless -- both ibuprofen and steroids are accepted methods of managing tumor flare -- but steroids also interfere with the ability of Revlimid to prod an immune response to the CLL. So it seemed somewhat counterproductive to start down that road, and I had no idea how long it might take for steroids to begin to work effectively.

Ultimately, I decided not to take the drug. I checked with my doctor on Tuesday, and on her advice I didn't take it that night, either. The shallow breathing actually worsened on Tuesday, to the point that I curtailed most physical activity. I didn't feel an improvement of symptoms until Wednesday, especially later in the day, a few hours after I had my weekly 1000 mg dose of oftatumumab.

I met with my doctor that day -- try holding an intelligent conversation a half hour after you have gotten 50 mg of intravenous benadryl -- and we decided to temporarily scale my Revlimid dosage back to 5 mg. Since then, the tumor flare has continued to abate.

There is some debate about whether tumor flare presages a better response to the drug. A report issued by Celgene, the drug's maker, summarizing the findings of various studies, put it this way:

"There have been conflicting reports regarding the association of response to therapy with the occurrence of tumor flare (TFR) symptoms. Padmanabban et al. reported (2006) that TFR may be associated with clinical response and Coleman et al. reported (2008) that [in] four CLL patients, symptoms of TFR signaled a response. Sher et al. also stated that the occurrence and severity of TFR appeared to correlate with clinical response (2009). However, Ferrajoli et al. reported that, in their 2008 study, TFR did not predict for a higher response rate, but did develop more frequently in patients with lymph nodes >5 cm compared to other patients (53% vs. 15%)."

So, ultimately, there is no way of knowing for sure whether my lymph node explosion was a good thing. There's also no way of knowing whether cutting it short was a good or bad decision CLL-wise, although it certainly was the right call breathing-wise. If you can't breathe, CLL is a moot point.

Uneventful ofatumumab

2010-02-27T15:28:00.004-07:00

The start of treatment was delayed two weeks because of a cold. Colds, as some of you know, can be a particular challenge to CLLers since we have degraded immune systems with few functional B lymphocytes, lowered immunoglobulins, and too many CLL clones gumming up the finely-tuned works.

Sure enough, my lymph nodes grew as the clones reproduced in a frenzy, trying vainly to fulfill their intended function. Somehow I managed to get over the worst of the cold in a couple of days, after which it dragged on at a low level, but not quite low enough to safely begin treatment.

Once I had recovered, things got underway last Wednesday with the opening dose of ofatumumab, aka Arzerra. GlaxoSmithKline starts you out with a baby dose of the stuff, 300 mg over six hours, just to make sure you don't have any serious reactions. The infusion rate begins at 12 mg an hour and is gradually increased every half hour to 200 mg. Premeds consisted of two Tylenol, 50 mg of IV Benadryl, and 100 mg of IV hydrocortisone, aka Solu-Cortef.

Absolutely nothing happened, other than the Benadryl putting me into a rather comatose state. Being a fully-humanized monoclonal antibody, ofatumumab may cause less of an allergic reaction than its cousin, the mouse juice rituximab. I have often had mild infusion reactions to the latter -- flushed face, tightening of the throat, and the like -- usually during the first infusion of a cycle. With the ofatumumab they may as well have been giving me water. That doesn't mean no one ever gets a reaction; it can and does happen, it just didn't happen to me.

The one thing I did notice is some mild redness on my neck (below the ears) where the lymph nodes are inflamed. Back when Rituxan was working pretty well on me, I used to get the same thing. This seems to me to be more a consequence of the drug working than an infusion reaction, especially since I have only noticed it toward the end of an infusion or after it is done. Other than that, I can't report any noticeable effects of the Arzerra, but at 300 mg, I wouldn't expect to see much progress.

Next week I'll be given the customary 1000 mg dose, along with more of the dreaded Benadryl. The day after I start the lenalidomide (Revlimid), 10 mg daily. In other words, Houston, we will have lift off.

My little OL protocol: ofatumumab and lenalidomide

2010-02-09T11:05:00.025-07:00

Yes, that little ol' lab rat, me, is about to undertake a cutting-edge protocol to fight chronic lymphocytic leukemia: ofatumumab and lenalidomide.

I call it the OL protocol, and there’s a trial at MD Anderson in Houston that’s just starting to accrue patients for a two-year study of this new drug combination.

Thanks to a forward-thinking oncologist who is willing to fight like hell for her patients, and thanks to two drug companies that are willing to help those who can’t afford to pay the enormous costs of the treatment, I am going to be following that protocol from the comfort of home, or at least from a comfortable chair two hours away. I start next week.

Because I will be one of the first CLLers to try what could become an important therapy for our community, I will blog about my experience on a somewhat regular basis.

To briefly review, ofatumumab is the fully-humanized anti-CD20 monoclonal antibody that was approved for CLL in October by the FDA. It goes by the trade name Arzerra but old CLL hands (Man, I guess I am one of those!) may better know it as HuMax-CD20. It was developed by Genmab and licensed to GlaxoSmithKline.

Lenalidomide, which I wrote about in my last post, goes by the name Revlimid, and was developed by Celgene. It has been approved by the FDA for Myelodysplastic Syndrome and Multiple Myeloma and has had some interesting results in CLL.

December’s American Society of Hematology meeting included a report from MD Anderson on a trial of rituximab and lenalidomide in 37 relapsed and refractory patients, all of whom had used Rituxan in the past. The new OL trial appears to be based, in terms of timing and dosages, on their experience with RL.

Dr. Alessandra Ferrajoli and the team o' Texans reported an overall response rate of 68%, of which 51% received a Partial Remission and 16% a Nodular Partial Remission. Sixteen percent had stable disease and 16% failed the protocol.

Other studies have shown an overall response rate of 32%-47% among relapsed CLLers given single-agent lenalidomide, so MDA considered the combination with the monoclonal antibody to be “superior to single agent lenalidomide, despite all our patients having received prior rituximab.

“Additionally," the authors wrote, "there was no increase in toxicity and lenalidomide-associated tumor flare reaction was less frequent and less severe with this combination compared to single agent lenalidomide.”

For the record, a 2008 MDA study of single-agent lenalidomide in relapsed patients showed an Overall Response of 32%, which includes a Complete Response of 7%. An additional 25% achieved stable disease. A 2006 study by Dr. Asher Chanan-Khan’s group at the Roswell Park Cancer Institute in New York reported an Overall Response rate of 47%, with 9% achieving a CR. Another 18% had stable disease.

My prospects

Clearly, my response can fall anywhere on that rather large map, landing from CR to CRap. And just as clearly, this protocol is not going to be a cure for CLL nor an avenue to a molecular remission. But it may serve as a welcome and effective control, and I have reason to be optimistic as I begin.

I have always responded well to whatever new drugs I have been given and there is no change in my FISH profile that would indicate a loss of that ability. Of course, having had several treatments over the years, some disease resistance has developed in response. Indeed, the CLL cells have created a rather secure suburban community in my abdominal lymph nodes. The ability of lenalidomide to disrupt that micro-environment, including the nurse-like cells that help CLL remain comfortable, is a definite plus.

I am also younger and in better shape, both in terms of my health and disease state, than many of the participants in these trials. I can weather the side effects -- notably fatigue, tumor flare, and possibly low neutrophils and low platelets -- that may come my way.

Ofatumumab will assuredly be more effective on me than rituximab, to which I no longer respond well after many, many uses. Indeed, ofatumumab has given a new lease on life to any number of people who have tried it before me, some of whom I have known personally, and many of whom had stopped responding to Rituxan.

Readers may recall in my last post that I said I did not wish to use ofatumumab as a single agent, that it was too important a weapon to use gratuitously. That remains the case, and I don’t see the OL protocol as a wasteful extravagance.

I have a lot of abdominal lymph node bulk, enough that a year’s worth of steroids, Rituxan, and even cyclophosphamide were unable to make much of a dent in it. Ofatumumab is a new drug for me; with some luck, my nodes might respond the way they did to Rituxan when I first used it six years ago. In other words, they may undergo a noticeable reduction that can then be hammered home by the lenalidomide.

Can I completely clear the abdominal nodes? It would be quite a feat, but all things are possible in life and combination immunotherapy. Even if I can’t, can I reduce the bulk by a meaningful amount -- say 50% -- and throw my disease level back to where it was in 2005 or 2006? I think even hardened realists would say that is possible. The 2008 MDA study of single-agent lenalidomide reported a greater than 50% improvement in lymphadenopathy in 41% of patients. I'm probably starting from a worse position than most patients in that trial, but remember that we are also adding the ofatumumab.

Such a reduction in disease –- along with hopefully enhanced immunity, including a cessation of autoimmune hemolytic anemia, with its endless threat of hemolysis –- makes this an especially intriguing protocol.

Nothing else out there holds the prospect of doing all these things for me, especially with minimal toxicity, and these are all things that need to get done. For what it’s worth, some of the experts find this drug combination to be full of potential. I am told, for example, that MDA's Dr. Michael Keating is “very keen” on it.

Perspective: Playing for time vs. transplant

It’s the right thing at the right time, as far as I’m concerned, which brings up an interesting point. When I was diagnosed in 2003, neither of these agents existed for CLL. Despite the feeling among us patients that progress can never come fast enough, here is a case where two new drugs may make a significant impact on my disease. So there is indeed some wisdom in playing for time if you have the stomach for it.

Playing for time is something that you have to finesse as you go, since the disease is not static. Much depends upon your biological markers -- IgVH mutational status, chromosomal deletions per FISH, ZAP-70, and CD38. But the bottom line, which I think is sometimes given short shrift in patient discussions, is your actual disease progression, clinical history, and ability to respond to treatment.

To my mind, it's the practical stuff that counts. Which brings us to the stem cell or cord blood transplant, sometimes seen as the CLL end game. For many of us, and maybe even yet for me, that will be the case. But I think it is a little premature to be swept along on some kind of bandwagon, thinking that transplant is inevitable and maybe even desirable. Perhaps, if meaningful control of CLL can be obtained by means of OL and other agents in the pipeline, some of us will have a realistic alternative.

Frankly, transplant results are virtually impossible to predict. Talk about arbitrary and capricious: You can die. You can be cured, or at least disease free for a long, long time. You can also relapse and have to wake up to fight the whole messy, draining battle all over again. You can struggle along for years with debilitating graft vs. host conditions, from skin reactions to gastrointestinal problems to seizures. Many patients are grateful to be alive despite the side effects; others have regrets.

One wrote to me off the blog: "Do not underestimate the effects of chronic GVHD. When you read about them, they might not sound too bad; however, the collective experience of multiple GVHD effects can make life after a transplant quite miserable. And chronic, in this sense, must be seen as a permanent condition."

I will never forget Dr. Terry Hamblin's comment that he knew of two patients who were so beset by post-transplant graft v. host problems that they killed themselves.

There is a yin and yang to this, of course, and I am not discounting the success stories, those who write that they are "recovering nicely" after two years, and those who are a few years in with only minor problems, nothing to get too excited about, and with no regrets about having taken the big step.

I keep a list of blogs on the right side of this page. Scroll down and click on those of the transplant patients: Brian Koffman, Jackie Sue, Ron Gottula, Dan O’Mara, and Harvey's Journal. Take a look at Tom McCune’s website; Tom was once the CLL cure “poster child,” now in relapse. Check the posts at CLL Forum and ACOR from patients like Chonette and JursyGurl, both of whom are having success with minimal trouble so far (you go, girls!). Read Raywood's Great Stem Cell Transplant Caper, and then read all the nice comments about him on CLL Forum's "In Loving Memory" page; Ray was a character, an irrepressible optimist and guitar picker who put CLL to Country music. But all the sunshine in the world doesn't guarantee success. Neither, for that matter, does a Vulcan-like level of meticulous preparation.

Gather all this –- and more -– into your head and you may conclude, as I have, that the transplant is unpredictable at best, freakishly difficult much of the time, and, obviously, fatal at worst. You may as well go into the hospital singing "Luck Be a Lady."

"They call you lady luck
But there is room for doubt
At times you have a very un-ladylike way
Of running out . . ."

I think the outcome is well out of your hands despite however many statistics you arrange in your favor (the optimistic configuration of published data can indicate an element of wishful thinking that creeps into even the most rational of minds.) When the chips are down, you're putting all your chips on the table. A transplant, to my mind, is something you do when you HAVE to do it and no sooner.

It is not a battle that I am afraid of, but it is not one I am jumping to fight if there is a wiser way to conduct the war.

I am hoping that OL will be an effective weapon, something of a game-changer, at least for a reasonably long time. I’m 53, healthy other than the CLL -– my blood pressure tests out these days at around 120 over 70 and my primary care doctor wants to frame my lipid profile. My quality of life is good (when I’m not hemolysing).

Beyond the medical facts, CLL has taught me that I am mortal, and so it has ironically given me the gift of being able to live life fully today, to let go of old regrets and unhealthy patterns, and I am happier than I have ever been.

So why not still play for time?

There is a fine line in CLL between being too proactive and too reactive. Much of my CLL journey has been spent trying to find and stay close to that line. At times I have been more successful than others. I think -- I hope -- that I have found it with the OL protocol.

It's the line of scrimmage between me and the disease. It’s first-and-ten and I will move the ball down the field as best as I am able, however many yards at a time. I’ll report on it as I go.

Treatment update: My new friend len

2010-01-24T12:28:00.012-07:00

I suppose an update is in order. No news is good news when you have CLL, and I’ve had no news for awhile. Now I’m gearing up for treatment again, this time with lenalidomide, better known as Revlimid, also known as "len" for short.

All of last year’s treatments basically bought me stable disease. A CT scan comparison from January to September showed only marginal improvement in abdominal lymph nodes, which is where most of my 11q-deleted disease lives these days. Over time my CLL has become less leukemic, more nodal, and my blood lymphocyte count is practically normal.

I remain at Stage 2, for what it’s worth. When I’m not hemolysing due to autoimmune hemolytic anemia (AIHA), my red blood count, hemoglobin and hematocrit remain well in the normal range for a man. I’ve not seen the slow decline in those counts that follow with progressing disease. Over six years my platelets have gradually dipped, settling now in the 120s. That’s just below what’s considered normal, absolutely high enough for full clotting function, something to note but not to worry over.

My latest FISH test -- I get one every year, and the results have a huge say in how I approach treatment -– still shows the 11q deletion only, on 31 out of 200 chromosomes. This is a monoallele deletion, which means the relevant bit is broken off of the long arm of one of the set of two chromosomes #11. A biallele deletion would mean that both of the chromosomes 11 have lost the ATM gene. So hey, I’ve still got one arm to hang paper with, it seems. (A cautionary note is worth inserting here: As we all should know by now, the FISH test doesn’t probe for all possible chromosomal abnormalities that may eventually prove important in CLL. No news is good news in my case, but it may not be all the news, if you know what I mean.)

So by some measures -– including how I feel on any given day -– I am just sort of trucking along with this thing in neutral. But it ain’t quite so. There are those abdominal nodes remember, none over 5 cm, but a whole, whole lot of them. My B2M is 4.8, a little over the line MD Anderson sets (4.0) to divide between those with better disease and those with worse. For me, the action is taking place in the abdomen.

Plus I’ve got the AIHA, with its hemolysis shoe always waiting to drop, a sign that CLL has gummed up immune function and still continues to do so. I also have squamous cell skin cancer issues. I've had two SCCs removed surgically since 2005, several actinic keratoses frozen off, and I am on far-too-intimate terms with a tube of Efudex. SCCs can be deadly serious in CLLers, whose T cell surveillance function is weakened, because it is T cell surveillance that helps keep those squamous cells in check. CLLer T cells take a hit because of the lowered immunity that accompanies disease progression, and they can further tank due to immunosuppressive therapy, notably fludarabine and Campath.

I haven’t had fludarabine or Campath, which brings us to the menu of choices I now face:

Looking at all the data tells me that my disease is stable-ish but also growing, more or less behaving but capable of getting that much worse if I don’t attend to it. For years I attended to it with single-agent Rituxan, but AIHA changed that game and while Rituxan was clearing the blood the disease found other avenues for growth.

So attending to it for about the past two years has consisted of costlier therapy, RCD, or rituximab, cyclophosphamide and dexamethasone. A recent DEXA scan shows my bones are no worse than they were two years ago, marginally osteopenic here and there. But steroids are not a long-term solution. Cyclophosphamide has done me good so far, nailing hemolysis when it occurs, but it is a potentially mutagenic agent and one to which, if I’m like most other people, I will only develop disease resistance to over time.

So RCD as “maintenance” is not realistic, and “maintenance” to me now means something a lot tougher and potentially more problematic than single-agent Ritxan. I have come to the end of Easy Street and there’s a big sign there that says “Road Closed.”

* * *

So, what to do? Besides lenalidomide, or Revlimid, the FDA has approved ofatumumab, aka Arzerra, aka HuMax-CD20, aka the Monoclonal Antibody Formerly Known as Prince, for use in CLL. This is the bigger, badder, fully humanized anti-CD20 antibody, none of that wussy mouse shit. For someone who has used Rituxan to the max, its presence represents a potential new lease on life, or at least on effectiveness.

And because of that, it is an important drug in my arsenal. I am not treating it the same way I treated Rituxan. Sure, I might get a year or two of stability out of it by using it as a single agent, but then what? I think it is wiser to save Arzerra for combination therapy, the good old FCA, when that becomes front-and-center my only choice.

Which it almost is at this point: FCA, followed by a transplant at relapse, the CLL end game. But enter lenalidomide, an immunomodulator drug that intrigues and mystifies the experts. Some interesting data came out of December’s ASH conference, including a report from MD Anderson, which ran a trial of Revlimid and Rituxan in relapsed patients.

How len seems to help some CLLers is explained succinctly in this online interview with Dr. Asher Chanan-Khan, “Mr. Revlimid” himself, who goes over all the highlights from ASH, including a discussion of len at the end.

When it works -– and it doesn’t work on everyone -– lenalidomide seems to have a way of rebalancing the immune system, weakening the CLL cells themselves and compromising the nurse-like cells that protect them. Len can improve T cell and NK cell function, actually get the immune system to go toe to toe with the CLL. It works on high-risk cytogenetics such as my 11q. And while you have to watch for low neutrophils and low platelets while on the drug -– not to mention tumor flare, rashes, fatigue, nausea, and so on –- it does not appear to have the potentially mutagenic, viral-reactivating, Richtersy transformative potential of immunosuppressive chemo.

And keep in mind, for someone with AIHA, the idea of restoring an equilibrium in the immune system is powerful catnip. I have it on the best authority that two transfusion-dependent, hemolysing AIHA patients were treated with Revlimid; in both cases the hemolysis resolved and one patient is still with us three years later, free of the AIHA curse.

That, plus some added squamous control, plus the prospect of making a dent against that abdominal bulk, makes Dave a potentially very happy man. Which, defined in CLL terms, means someone who is able to control his disease, possibly even weaken it, for a long period of time without really compromising future therapy choices.

So, it’s worth a try. My insurance has rejected it, of course. It costs $60 a day per pill times 365 days and the insurance won’t even give it to patents with multiple myeloma, for which it has FDA approval. But my hem/onc, who now runs her own kick-ass office with a bent on getting patients the care they need come hell or high water, is optimistic that I can qualify for assistance from the maker, Celgene. We’re waiting on that, and on a few other details –- is it better to do with or without Rituxan, for example? –- but I hope to start soon.

* * *

Here's hoping all of you are doing well in your struggles with CLL. Even more, here's hoping you're out there living your lives to the fullest. Nobody gets off this planet alive, whether it is CLL that takes you or something else. Don't die with your regrets intact. Get real and deal and rock and roll. You only go around once, and this is it. Punch cancer in the nose and kiss life on the face.

My six years of CLL, and six things I’ve learned

2009-09-03T11:13:00.003-07:00

September 3 is here, the sixth anniversary of my big doo-doo surprise. It was on this date in 2003 that I awoke from a dream in which the room was spinning. It turns out that the room really was spinning, which meant a visit to the ER, which was followed after a couple of hours by my diagnosis of chronic lymphocytic leukemia. I was told it was a “good cancer” and sent home.

The room, as it were, has not stopped spinning since.

I was going to title this post “Six years of this crap,” but I think it’s best to look back with a more even temperament at some of the big screaming bullet points that I have run across. These are things that may be the most help to those of you who are waking up into your own CLL bad dreams.

Since 2003 I have come some distance in my understanding of the disease and what it means to cope with it. Time is a teacher, and I’m sure it has a lot more to throw my way — at least I hope it does, if you catch my drift. At six years in, I’m in my CLL middle age, both in terms of disease progression and knowledge. When it comes to the latter, I'm no longer wet behind the ears, yet wise enough to know that the learning curve goes on forever.

Here are some things I’ve learned, sometimes the hard way. They may represent a change or an evolution in thinking over some older posts in the blog. They are the truth as I see it today:

1. CLL is not the same disease for everyone. The “CLL is an indolent disease/good cancer” monster has to be staked through the heart every time it gets out of its coffin to suck your blood. It is the old, cobwebby way of thinking about CLL. Wipe those cobwebs from your eyes, unless you enjoy being mesmerized while your life drains away.

Some of us have relatively mild CLL, some of us don’t. Some of us respond really, really well to easy, breezy treatments, and others of us barely respond to nuclear chemo. This is because, for all practical purposes, we don’t have the same disease. A dog is a dog is a dog, but not all dogs are alike: Paris Hilton would look a lot more chewed up if she were carrying around a pit bull instead of a chihuahua.

Figuring out what kind of CLL you have does not involve reading tea leaves, poring over entrails, or consulting the shell of the prescient tortoise. It’s a matter of looking at the results of the tests available — IgVH mutational status, ZAP-70, FISH, CD38 — and at your clinical history (how fast your nodes are growing, how quickly your lymphocyte count is doubling, how far your hemoglobin and platelets are dropping). When I was diagnosed, the only readily-available test was CD38, so a lot has happened in six years. If you want to know what you’re dealing with, get your tests done.

2. See a a CLL expert (or two) at the very outset. Ol’ Doc Lippencot, highly regarded as she is around these parts for curin’ breast cancer and lice and possum infestations and such, didn’t know much about CLL. This is often the case with the local doctor, whose stock in trade is usually not going to be a disease that affects almost nobody.

And while patient networks and educational websites are excellent for moral support, learning about case histories, and keeping up with the latest research news, they are of limited medical expertise. This is because they are filled with seekers and guessers such as yourself, not to mention the occasional insufferable blowhard. Some of these people are downright brilliant, some of them are extraordinarily helpful. But in the final analysis they are, like yours truly, amateurs — what the dictionary defines as “lacking the skill of a professional.”

Which brings us to the professionals. Experts live and breathe CLL and have seen hundreds of people just like you, with all the variants of your disease. They have a clue. This does not make them infallible. Having consulted a few, I can say that they don’t always agree. Just as painters see the world differently, so do those who practice the art of medicine. So see a couple of the big names — or even a few, the worse your case is — just to get a consensus, or maybe that much more confused.

Our CLL experts are a great bunch — many of them are approachable by e-mail — but they’re not miracle workers and they’re not gods. Sometimes they run out of things they can do to save your life. Dr. Terry Hamblin told me in an e-mail once that, the way things stand today, doctors can only keep me alive for so long. I forgot how long “so” was — it appears to be at least six years — but the point was well taken, which leads me to:

3. The battle has a beginning and an end, and you need to be ready to fight. For those of us who don’t have indolent “goody-two-shoes” cancer, the day will come when we beat it or are beaten by it. The opening round came when that first mutant CLL clone got out of your own personal Pandora’s Box. The final round will come when it comes, and for many of us younger patients it will probably end with a transplant, win or lose (or there can even be a draw, of sorts).

Obviously, you need to be as prepared as possible. That is why patient education is important, getting the lay of the land is important, staying up with truly useful news is important, staggering your treatments intelligently is important, doing all the strategy and tactics stuff is important.

And that is also why learning to cope emotionally is important, and why this battle hinges at its heart on more than science and medicine. Healing is a big, mysterious thing. Books have been written. Bullshit has been blathered. But there is a lot about the mind-body connection that we don’t understand. Well-respected, level-headed doctors see “medical miracles” during their years of practice. I believe your chances of healing are better if you put your heart and soul into it, and the evidence seems to back me up.

Emotional preparedness can also help you cope with the inevitable surprises and slip-ups, the disruptions and disappointments (and occasional triumphs) that come with fighting cancer. It is a rough journey, a test of your faith and your stamina, something that demands that you get your inward act together.

You can walk out into the ring with all the technical skills, having read hundreds of papers and abstracts, having consulted every expert doctor within a ten thousand mile radius — but if you don’t learn to float like a butterfly and sting like a bee, if you can’t get in your groove, make knowledge and soul work together, you are fighting with one hand tied behind your back.

4. Be a pain in the ass. No, I don’t mean be a cry-baby or a whiner or a ninny (take that blood draw like an adult!). I mean learn to stand up for yourself in medical settings, learn to question things if you are uncomfortable, learn to say “No” and “Are you sure?” Do not be railroaded by doctors, office staff, or well-meaning family or friends. Be as diplomatic as the situation allows, but keep in mind the words of Teddy Roosevelt: “Speak softly and carry a big stick.”

This is where those emotional/intuitive clues come in handy. If someone says, “This is right,” but it doesn’t feel right, honor that thought. Float like a butterfly, and whack! with that stick. And the bigger the thing, the bigger the pain you must be. Do not stand on ceremony or save face; it will be at your own peril. The face you save could be you own.

5. You cannot predict the future with certainty. So far, CLL has humbled the great minds of medicine, so get your humble on. Nobody can predict the future. Nobody can know an outcome for certain. Sure, a lot of cases follow the conventional wisdom; things often, unfortunately, go by the book.

But there are exceptions. Let me tell you a story:

A patient has a sudden relapse, finds herself refractory to every therapy, has to live on transfusions. Like a Greek chorus, there is whispering offstage: “She should go into hospice.”

And now, two years later, like some mighty Greek goddess who has triumphed in an epic battle, she has survived a sudden transplant and is doing pretty well, thank you.

Bad things often happen in CLL, but good things can, too. This is not an article of faith, it is a matter of medical fact. There really IS hope, tempered as it is by this thought:

6. In the end, it often comes down to luck. Dr. Allan Hamilton is a respected neurosurgeon, and the author of a book called The Scalpel and The Soul, and his number one piece of advice after decades of practice is this: “Never underestimate luck — good or bad.”

The more I see of CLL, the more I believe this to be true.

Why do some people live and some die? My ever-practical younger brother puts it this way: “When your number’s up, your number’s up.”

It’s called Fate. This is why the best-prepared sometimes fail, why the least-prepared sometimes live. That’s no reason not to care, no reason not to make the odds as much in your favor as you think you can make them.

But nobody gets off this planet alive. Dr. Hamilton has a blog, and he talks rather poignantly (tearjerker alert) about a couple who drive up a mountain to share a glass of wine in the twilight of life.

So enjoy wine and a sunset, whatever day it is for you. Life is not all about the battles we wage to stay here. It is about how we live it while we are blessed to be here.

That can be easy to forget when you’re in the trenches battling cancer. But with time and wisdom, we can learn to savor what life is about despite the challenge it has thrown at us. And life can become all the more sweet in the face of the dangers ahead.

Nobody said beating CLL was going to be easy, but nobody who knows what they’re talking about says it can’t be done.

So here’s to six more years (come to think of it, I think the number “12" was in Dr. H’s e-mail somewhere).

With this post, I am stepping back from the blog for awhile. I have some fighting trim to get into. There are other things in life I must attend to. Over the years I have said a lot, but sometimes there is wisdom in being quiet and listening. I promise to post every few months, and I will let you know if I encounter any big health emergencies or breakthroughs. In the meantime, no news is good news. Take care, and stay as healthy as you can.

The chemo monster mash: FCR vs. FCA

2009-08-16T16:46:00.016-07:00

An interesting therapy comparison has come out in recent days, worth a mention to those who want to update their scorecards.

In this corner, weighing in at a zillion tons, breathing enough fire to melt Mt. Fuji, is our current champion, the Godzilla of CLL clemotherapy -- FCR (Fludarabine, Cyclophosphomide, and Rituximab, Genentech's long-standing anti-CD20 monoclonal antibody).

And in this corner, causing the earth to shake with the whip of its newly-minted tail, is the Mechagodzilla of CLL chemotherapy -- FCA (Fludarabine, Cyclophosphamide, and Arzerra — aka ofatumumbab, Genmab’s competing anti-CD20 monoclonal that is now very close to approval by the FDA).

We all know that the loser is going to be Tokyo. And the winner is . . .

Both, or neither, depending on how you look at it!

Genmab just announced the Phase II results of a trial of 61 chemo-naive patients who were treated with FCA. Those who received the largest dose of ofatumumab (which also used to be known as HuMax-CD20) got a 50% complete response rate as measured by the 1996 National Cancer Institute CLL guidelines. (According to Genmab, the CR rate was 32% in patients who received 500 mg of ofatumumab and 50% in those who received 1000 mg. The overall response rate was 77% in the 500 mg group and a slightly lower -- go figure! -- 73% in the 1000 mg treatment group.) Obviously, the study is ongoing, so we don’t have any idea how long those “complete responses” will last.

Compare Genmab's results to those reported by the respected German CLL8 study group in 2008 in a trial of 817 patients randomized to receive either FCR or FC. The FCR group received a 52% CR rate using the 1996 NCI criteria. Assuming some basic equivalency between the studies, that’s a two percent difference, statistically insignificant.

Progression-free survival in the German study was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm. But the difference for overall survival was not significant (91% v 88% at 2 years).

(MD Anderson has been providing its own ongoing retrospective, non-randomized information that paints a rosier picture of FCR; it is worth noting Dr. Terry Hamblin's comments here.)

Which brings us again to the perennial question: What's the "best" choice for your first therapy, and how does that impact what you do after relapse, when it's time for that second act that we often tend not to think about?

In my case, having pretty much used up Rituxan, it’s going to involve some Arzerra in the hope that it works better as a second-act agent, which it does appear to do. It is now being considered for FDA approval for those who are considered double-refractory to fludarabine and alemtuzumab (Campath), neither of which I have had yet -- but neither of which, the more I use chemotherapy of any kind, is going to work as well as it would have had it been my first choice out of the box.

So welcome to the boxed-in world we CLL patients live in. What do you chose for your first act? How does that impact what you choose for your second? (And, transplant planners, how do those choices impact that third and probably final -- and I mean "final" in the hopeful "cure" sense -- act?)

Which brings us to another bit of recently-reported information, floating around the air like Mothra:

“First-line fludarabine not superior to chlorambucil in older CLL patients”

In a study of patients over age 65, the German CLL Study Group randomized 95 patients between fludarabine and chlorambucil.

Progression-free survival was similar in the fludarabine group (19 months) and the chlorambucil group (18 months); however, clinical significance was not reached. Overall survival was also similar between the two groups (46 months vs. 64 months), but again, clinical significance was not reached.

The bottom line is that fludarabine provided a more robust response (as well as more bone marrow toxicity) but in the end that deeper remission didn’t mean the patients were living any longer, at least as of this writing. Keep in mind the OS non-difference between FCR and FC as reported by the German CLL8 group.

Of course, the trick is to track these things over a much longer time period, to see how overall survival of Regimen A vs. Regimen B goes on year after year after year.

Unless, of course, your CLL isn't giving you a decade or two to watch all the data dribble in.

Then you have to pick your monster and place your bet.

Hello Kitty, anyone?

The Hello Kitty Darth Vader, a sure sign that the end of civilization is near.

The dog days of August

2009-08-09T14:36:00.005-07:00

Anyone who has Googled "chronic lymphocytic leukemia" has run across references to the disease in dogs and, more rarely, cats. If you give Fido some chlorambucil, he goes on merrily chasing his tail, usually for a normal life span.

Recently I received a phone call from someone who read my letter to the local paper in which I explained that I have CLL and that I support health care reform. The caller left a message on my answering machine. She said she supports reform also, and then began to talk about her dog, which was recently diagnosed with CLL. If it would not be a bother, she asked, would I mind calling her back and telling her a little bit about the disease and what might be done to treat her dog?

When Marilyn and I heard the message, our reaction was the same: laughter, of the disbelieving kind. I don't mind talking about CLL to fellow patients, or to my neighbors, or to a complete stranger who has some interest in the disease. But I'm not a veterinarian.

My gut level response, to my surprise, was anger. I love animals, and I like dogs, but I have seen too many friends and acquaintances die of this disease. I have seen too many struggle with impossibly difficult choices. For every great remission I have seen great disappointment. I have spent almost six years struggling with CLL, not always successfully. If I thought the last six years were bad, the next six promise to be worse. So pardon me if I don't have a lot of energy left over to counsel people whose dogs have leukemia.

Sometimes I think I'm being a little hard-hearted about this, but I cannot bring myself to call her back. I know she means nothing by it, that she's probably not aware that a CLL patient might develop some emotional baggage after awhile. Is she being a little insensitive? Or am I being oversensitive?

I empathize with her and her dog, but all I want to say to her is "Use your freakin' Google."

Am I right or am I wrong?

The runaway shopping cart CLL fitness test

2009-08-01T12:11:00.012-07:00

On Tuesday night we were at Bashas', our favorite local supermarket, which is built on a sloped lot. After we loaded the car with groceries, our shopping cart, to make a long story short, escaped. It was heading downhill, and at first looked like it would come to rest against a metal railing. But the gimpy wheel that had annoyed us during our trek through the store came into play, setting the cart on a subtle curve right toward someone's car, and it was picking up speed as it went.

It would not be right, I thought, to allow it to bang up someone's vehicle, so I took off after it, running as fast as I could. I caught up with it about three feet from the car it was heading for, which I saved from a scratch or a dent. I was not so lucky. As I grabbed hold of it, both it and I fell, me on my left side.

I bruised my shoulder, got some long scratches on my leg, and the bumpy asphalt was particularly unkind to the area just below and to the left of my knee. This was not helped by the fact that I was wearing shorts, leaving bare skin to come in contact with the ground. I came away with a bloody sore about 2" by 2", part of it black.

Nurse Marilyn drove us home, I took a shower, and she administered Neosporin and a bandage to the wound. The next day we saw our primary care doctor, just to make sure everything was OK. This is where the CLL comes in, because if I did not have lowered immunity -- made worse by my neutrophils being at their nadir due to recent chemotherapy -- it's unlikely that we would have felt the need to be so cautious.

The doctor complimented Marilyn on her bandaging ability, and the black spot was determined to be asphalt, which had embedded itself in the skin, and which we were told would gradually work its way out as the wound healed. He was pleased to hear that I was on prophylactic Bactrim, which is one of the precautions I am taking while doing RCD (Rituxan, Cyclophosphamide, and Dexamethasone) therapy for CLL and AIHA (autoimmune hemolytic anemia). Apparently, Bactrim is used to fight staph infections, among other things. I was sent away with a clean bill of health, or as clean as a CLL patient with a bloody sore can get.

One of my first reactions to the incident, besides "ouch," was to put it in the context of CLL. It was as if I had been subjected to an impromptu physical fitness test: Did I have enough hemoglobin to run at full speed and tackle a shopping cart? Were my platelets numerous enough to insure proper clotting of the wound? Was my immunity good enough to avoid infection? Have my bones survived steroid therapy well enough to avoid breaking or fracturing when my 200-pound body hits the ground?

I was pleased to have passed on all counts, and to know that I can still endanger myself by stopping speeding metal objects. After awhile, one learns to take nothing for granted about life with CLL, especially after having lived with periods when the disease, in the form of its AIHA complication, has impacted my ability to do things like I used to.

There is a fitness scale for cancer patients, called the ECOG performance status, named after the Eastern Cooperative Oncology Group. The scale runs from 0 to 5, with 0 being the best, "Fully active, able to carry on all pre-disease performance without restriction." For most of my CLL life, I have been at that level. But the AIHA, with its red-blood-cell-destroying hemolysis, has put me at ECOG 1 or 2 at times. Two, for example, is ""Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours."

I suppose I am lucky that I am generally a 0, as the shopping cart chase demonstrated. I hope to avoid ECOG performance status level 5, which is described succinctly in the chart as "Dead." Those at level 5 don't put in much of a performance, evidently.

There's no toxin like Cytoxan

2009-07-18T16:08:00.015-07:00

Well, there probably is, but new lyrics are running through old songs in my post-chemo haze. “There’s no business like show business” is the tune, and I suppose that having had a round of RCD last week was getting down to business, so that’s why it turned into a rather annoying song looping through my head.

RCD is Rituxan + Cyclophosphamide (aka Cytoxan) + Dexamethasone, which is a protocol used by Dr. Kanti Rai and his group to combat autoimmune disorders, such as AIHA and ITP, in CLL patients. I, of course, am graced with the AIHA (autoimmune hemolytic anemia), a side effect of CLL gumming up the immune system, which periodically leads to bouts of hemolysis, in which macrophages destroy my red blood cells.

I had a variant of RCD for three rounds at the end of 2007 -- click on "AIHA" under "Posts by Topic" on the right for the whole saga -- which held me pretty well. But it did not involve the same steroid program as used in the protocol, which is 12 mg of dex given over seven days. I entered treatment then in a severe hemolytic crisis, made worse by the failure of my hapless Dr. O’Leary to see the depth of the problem, which necessitated a change of doctors in the middle of the red blood stream. Fortunately for me, my beloved Dr. Belle had just resumed her practice. For a couple of weeks there, I was on my own, doctorless, taking 72 mg of methylpredisolone daily in a desperate attempt to slow the loss of hemoglobin, which fell to 6.6 at its worst.

As we began the treatments — first with a little vincristine, which we quickly dropped due to side effects — we stepped down the methylprednisolone. The Cytoxan was doing the work.

Well, chronic disease is chronic disease. And like an annoying, insistent, door-to-door missionary, CLL is always capable of ringing the bell. It did that again shortly before Christmas 2008, which I wrote about here. I was put on 4 mg of dex, upped to 8 mg when that stopped working so well, to control the AIHA over the holidays, then given Rituxan and Cytoxan in January to nail it.

Readers know that Dr. Belle and I have been experimenting with treatments since then, starting with the rather useless R-FFP. I noticed that my red counts were beginning to head south again at some point not too long after R-FFP concluded, so seeking to nip hemolysis in the bud, we did a week of pulsed dexamethasone (four days of 40 mg/day — quite a dose, but similar to what is given to ITP patients) and one round of standard-dose 375mg/m2 Rituxan. It did wonders, for a month, but while the numbers held, the nodes began to creep back. Then we decided to try more pulsed steroids -- this time, a gram of methylprednisolone by IV on one day, plus that standard-dose Rituxan.

The theory, which has been demonstrated in studies, is that there is a synergy between the methylprednisolone and Rituxan that seems to be more powerful than that between Rituxan and dex. But, then again, there's the real world of the particular patient. I have had a lot of methylprednisolone since my AIHA diagnosis in March 2007, with the resulting time to grow refractory to it. We tried the pulsed dose recently to see how I would respond, this being a sort of trial run at the idea of maybe doing R-HDMP.

Well — surprise, surprise — just a couple of weeks afterward the red counts began to show a subtle drop again, I was alerted to this by more-orange-than-average urine (hemolysis warning sign No. 1) that I have described in the past. The conclusion: methylprednisolone is not going to do much for me, and neither is Rituxan along with it.

The RCD protocol no doubt involves the “D” for a reason, and this time we followed it close to religiously, other than my starting the seven days of dex a little ahead of schedule to keep the hemolysis in check over the weekend. I am pleased to report that Friday’s CBC shows a remarkable recovery of the red counts — heck, my hemoglobin went from 12 to 14 in a week, and the overall RBC jumped from 3.91 to 4.43.

Some conclusions

Part of the purpose of this post, which I am dashing off during what is laughingly referred to as a “day off” around here, is to put forward some insights on steroids, AIHA, and treatment based on my experiences. They come with that anecdotal warning, as well as that internet adage, YMMV:

AIHA patients often face a progressive order of attempting to control the condition. First steroids are usually given, but those can cease to work. Rituxan may be next (or may be given with the steroids), and that can cease to work. At that point, you’re looking at heavier-duty chemo. R-CVP is similar to RCD but involves vincristine, which can lead to neurological problems and which by my experience should be avoided unless truly necessary. RCD is gentler and (for me, so far) quite adequate to the task.

It does involve Cytoxan, which is a venerable old toxic drug used in many cancers, and which may be somewhat better than average at getting at 11q-deleted CLL, which I have. Cytoxan (good PDF here, and yes, the more powerful the drug the more fire you play with; this beggar can't be as choosy as he used to be) gives me few side effects, at least that I can see or feel anyway. Lord knows if it's setting up some mutagenic condition that could lead to another cancer, or to further disease resistance on the part of my CLL clones, but remember that line about beggars.

I don't lose my hair, but I don’t have much left to lose anyway. The drug tends to destroy rapidly-reproducing cells, taxing the stomach lining, but it has not given me nausea, only the desire to eat bland food for a few days. I do get GERD, which I find to be easily controlled with Prilosec OTC.

Speaking of food, with all those steroids as well as the Cytoxan, be aware of your glucose. I avoid sugary, carby things as much as possible during the treatment window and I have no hint of diabetes. Still, my glucose, when tested, goes higher than the norm.

I also get more easily fatigued by the changes the drugs wreak in my body, especially when Cytoxan is part of the equation. I have lost at least 15 pounds in a week, much of which appears to be lymph node weight. (People say I look wonderful after chemo.) The neck nodes, which were brought down nicely by the pulsed steroids without the Cytoxan, were brought down much more dramatically with the Cytoxan. I have a lot of abdominal nodes, and for the last couple of nights have been able to sleep comfortably on my stomach — a sign that progress has been made in these unseen areas, too.

Because of tumor lysis — CLL cell kill, with all the dead cells making their way through your kidneys — it is important to stay well hydrated. I drink at least a gallon of water the day before, of, and after my treatment. (And I use allopurinol -– a commonly-given drug that helps control uric acid -– a few days before, and continue it as long as the cell kill remains.) Then I keep on drinking as much water as I can stand. Even with all that, Friday’s blood test showed my BUN was high, not untypical considering all the cell-kill my body had been through.

The water also helps protect your bladder from the Cytoxan, and you should go with the flow, pee whenever you need to just to keep the stuff moving through. Watch the serum sodium results on your metabolic panel, as well — this can dip, so you may want to consider drinking salty water or eating salty foods for a week or so after treatment.

Keep in mind also that steroids are immunosuppressive and that Cytoxan is immunosuppressive, so staying on prophylactic meds -- acyclovir, diflucan, Bactrim -- during this period are part of the tools of the trade of the appropriately cautious doctor and patient.

RCD (dex pills in photo below) works for me where Rituxan alone, and Rituxan with pulsed methylprednisolone (HDMP), do not.

I have been around the steroid block enough now to have some feel for how I react to them. Steroids are excellent though transient reducers of lymph nodes. But they come with enough bad side effects — osteoporsis for one — especially when given in smaller, long-term doses, that they should be used sparingly. (Big, pulsed doses appear to be safer, based on information from UC San Diego and elsewhere, but that's still powerful stuff going into your veins.)

I find that node reduction in steroid-Rituxan combinations still rests largely with the ability of the steroids. (The Rituxan helps more with the cell kill, providing a somewhat deeper, though still shallow, remission.) Once you add Cytoxan, the game changes, at least in me. The nodes reduce as much again as before, and the remission lasts far longer.

Another thing I have noticed along the way is that the mental effects of the 'roids (such as sleeplessness) seem more pronounced when I am on smaller doses than when I have undergone the big pulses. Methylprednisolone at 72 mg and less tended to make me worry things a little, but not at 1 gram. Forty milligrams of dex over four days had the mental effect of drinking water, but give me 12 mg and my brain shoots into overdrive, getting very detailed about things, and I have trouble sleeping. (It should go without saying that dose equivalencies among steroids vary greatly -- this converter can come in handy.)

I expect to be undergoing more rounds of RCD, then perhaps to have a CT scan to see where the nodes stand abdominally, where they are worse than neckly and underarmly, to coin some medical phrases.

Right now I look like a slimmed down picture-of-health, ready to absorb all those laudatory comments from friends and acquaintances who wonder what kind of a marvelous crash diet I've been on.

Living the not-so-good life in Sedona

2009-07-11T13:36:00.009-07:00

Our little city of Sedona, nestled amid the red rocks of Northern Arizona, is a resort community and tourist destination. A lot of people retire here to live the good life, or choose to live and work here for the same reason.

It's reasonably affordable, as such places go -- unless you come down with a catastrophic illness and are subject to the whims and foibles of our health care system. I am not talking about myself here. I am talking about a couple in town who lost pretty much everything in a futile attempt to battle the wife's colon cancer. This was reported recently in our local newspaper, the Sedona Red Rock News. Here's a link to the story, entitled "Health system fails Sedona couple." Here are some excerpts:

It wasn’t long before all of the DiMarcos’ days were consumed with medical appointments, arguing with insurance companies and pleading for help from state agencies.

By 2007, their lifelong savings had dwindled to nothing, exhausted by treatments and drugs deemed ineligible for coverage by their insurance company. With no money left, Joseph turned to credit cards to pay for hotel rooms near hospitals, for co-pays and for pain medication.

. . . In spite of hundreds of thousands of dollars of tests and treatment, painful procedures and mind-numbing drugs, by 2008 Andrea’s doctors held little hope for her recovery and she was referred to RTA Hospice and Palliative Care in Sedona. She passed away two months later.

Joseph is left with the memories of a woman he describes as his soulmate, a twin flame with whom he wanted to grow old. He is also left with a mountain of bills, having to choose which one to pay each month.

In the latest print edition is another story (not online), this time about a patient with heart problems who faced the unfairness of the system first-hand. This involves the "churning" of insurance applications, in which private insurers look for an old condition or treatment you may have forgotten to mention and use it as an excuse to cancel your plan rather than pay for the care you desperately need.

My point here is that in any community -- even one of 15,000 people -- there is story after story like this. Health care reform is needed not only for the 50 million uninsured, but also for the many millions more who are insured, only to find that the system fails them when they need it most.

Here's a letter I just wrote to the editor of the News:

I’d like to commend the Red Rock News for its recent series of articles on how failures in our health care system have caused heartache and pain for local residents who are the victims of cancer and other serious diseases.

I am one of those stories. In 2003, I was diagnosed with chronic lymphocytic leukemia. Mine is a fairly aggressive form of the disease and I have required several rounds of chemotherapy. Fortunately, this has been covered by my health insurance, a state-sponsored program for small businesses. But the plan has its limits. It specifically excludes adult stem cell (bone marrow) transplants. I am 52 years old and the expert doctors I have traveled to see out of state (at my own expense, since my plan only covers a limited in-state network), have told me that I am unlikely to see 60 unless I get a transplant. These can run upwards of a million dollars out of pocket, well beyond my capacity to pay.

As you might imagine, private plans that cover transplants want nothing to do with me. Unless there is health care reform in Washington that requires all insurers to take patients with preexisting conditions, I face a bleak future.

I am all for keeping private insurers, but I also strongly favor a public option. Some mechanism has to be put in place to keep private providers honest, as your most recent article about the “churning” of health care applications demonstrates. If people cannot rely on their private insurance in a pinch, then they deserve an option where care is truly guaranteed.

To those who were recently seen protesting here against “Obamacare” and who argue that they don’t want the government managing their health care, I have this to say: What is so offensive about creating a system that preserves your sacred private insurance but also gives people like me a chance to receive life-saving care? Is it really preferable to have penny-pinching private insurance bureaucrats finding excuses not to give you the procedures and drugs you need? I’d take a government bureaucrat any day -- I’ve been dealing with them at the state level for years -- since they don’t have that vested interest in finding ways to deny me, or my doctor. Finally, if you really hate “socialized medicine,” then give up your Medicare coverage on principle. I’d gladly take it.

Sincerely,
David Arenson

THE COMPANY WE KEEP

Counties in blue have some sort of universal health care system. Countries in green are trying to institute one. Countries in orange -- Iraq and Afghanistan -- have universal systems instituted by the United States after they were invaded. Perhaps we have to declare war on ourselves to get universal care?

Two thumbs down on Rituxan + fresh frozen plasma

2009-06-07T14:50:00.006-07:00

I came. I saw. I wasted my time.

That’s my verdict on Rituxan + fresh frozen plasma. Make that two thumbs down — mine and that of a patient who posted to the ACOR CLL List that his experience with it was “arduous and ineffective.” Better words to describe it I cannot find.

Our two anecdotal cases fly in the face of the results reported by Klepfish et al. in their paper Adding fresh frozen plasma to rituximab for the treatment of patients with refractory advanced CLL, about which I wrote here. The positive results reported on the five patients in the study might as well have come from an alternate universe as far as my experience goes.

R-FFP did nothing for my red counts or platelets. It was completely ineffective on even the smallest of lymph nodes. Indeed, once Rituxan was added it seemed to lead to a mild case of tumor flare, which eventually subsided with the nodes back at baseline. My lymphocyte count did drop, perhaps at a slightly faster clip than it did the last time I used single agent Rituxan. But the difference was not especially significant and, as my oncologist pointed out, the CLL cells could just as well have been seeking refuge back in the lymph nodes. As time has gone on, my disease has become more node-centric, to coin a phrase.

I underwent two rounds before we abandoned ship, pivoting to another treatment. I am now on monthly high-dose pulses of steroids accompanied by Rituxan, and we’ll probably add some cyclophosphamide. This is essentially a steroid-heavy version of the RCD protocol that got me through my hemolytic crisis in the fall of 2007 and gained me a pretty good remission for the following year.

It's also as close as I'm willing to get to R-CHOP, which is known for its effectiveness on bulky nodes. R-CHOP is probably as much fun as it sounds, and stands for Rituxan + cyclophosphamide; Hydroxydaunorubicin (aka adriamycin or doxorubicin); Oncovin (vincristine); and prednisone. I can't see doing vincristine again, and have no desire to subject my heart muscle to adriamycin (aka "the red death") if I can avoid it.

I'd rather go the FCR route than the HO route; perhaps, with final approval of Arzerra (HuMax-CD20) by the FDA expected soon, I'll be doing FCH when the time comes. In the meantime, steroids have a proven track record of reducing nodes. Eventually I’ll have another CT scan to see how we’re doing on the abdominal nodes, and we’ll consider following up with something more powerful to deepen and consolidate the remission. We might use Campath if we can get my abdominal node mass down to less than 5 cm. It’s a work in progress.

At least it’s working. The R-FFP involved a great deal of effort for no gain. The FFP was infused at the hospital, which was followed by a short trip to the oncologist’s office for the Rituxan. The hospital took forever to get the job done, forcing me to abandon plans to get two units of FFP and 375 mg/m2 of Rituxan in one day. In the first round there were delays because the hospital took three hours to type and match my blood. I did one unit that day, followed by half the Rituxan. The next day I did the second unit and finished the Rituxan. In the second round it took from 7 a.m. to 3 p.m. for the hospital to get two units in me (note the happy expression on my face in the photo above); by then it was too late to do the Rituxan, which was infused the following morning.

Marilyn and I learned a few things about FFP. One is that premeds generally are not given prior to its administration. Two is that a type and match is good for 21 days. Three is that you can add a second filter to the IV setup if you want to be as thorough as possible in catching any errant white blood cells. We insisted on the addition of a leukopoor filter (the circular jobby in the photo) so all the FFP was double-filtered. Four is that nobody seems to know how long the complement gained from the FFP lasts in your body -- could be hours, could be days. Marilyn spoke to the director of the blood bank and he said nobody knew, that no study had ever been done.

Hopefully these details will be of no use to you as you will sensibly avoid undergoing this protocol. I might add here that my CLL is not as advanced as those in the study, nor can it be called refractory. Although I have had a lot of Rituxan in my time (two of the patients in the study were refractory to the drug), I should have been a fairly easy patient, as it were. Of course, one thing we know in CLL is that some people respond better to a particular treatment than others, and this may just not have been my cup of tea, or bag of plasma.

One of the bags was especially murky and yellow, causing the nurse to comment that the donor must have had a fatty steak dinner before they gave plasma. Perhaps the donor should also have had some jalapenos, which might have given the protocol more kick.

Beyond living "la vida leuko"

2009-05-23T13:01:00.018-07:00

The house is a mess. I don't have time for much of anything except what absolutely must be done, which explains why I'm not blogging a lot lately. Marilyn and I are living our lives inside a turbo-charged hamster wheel consisting of treatment for CLL; renovating the house and paying for renovation of the house so that we can sell it; and keeping our business ramped up to pay for as much of the above without going into even more enormous debt than we already find ourselves in (Thank you, Bernie Madoff! May you live to be a hundred -- in jail, of course).

It’s a three-ring circus with lots of elephants plotzing around. Sometimes the building shakes. And yet this morning, as I poured a cup of coffee into my Far Side mug in the beautiful new kitchen I won’t own much longer (we hope), I felt a sense of calm and optimism that I had almost forgotten had once been part of my life.

Call it a flashback to pre-CLL, when the mere weight of the world hung around my shoulders -- as opposed to the mere weight of the world plus the prospect of death and how to avoid the latter for as long as possible.

Here I stood in a half-done house, enjoying what for us Arizonans is a delicious morning of overcast, drizzly, and cool Memorial Day weekend weather. I could look through the mess around me and see that there was a future somewhere. A move sort of impending, an adventure even, a next step that despite being in large part about CLL is not all about CLL.

The CLL part, as I have alluded to in this blog many times, has much to do with the health insurance I have. Thank God I have it, but it’s Arizona-based only and it’s restrictive and won’t pay for a stem cell transplant when and if the time comes. So unless something miraculous finally happens in Washington requiring insurers to cover people with pre-existing conditions, I will have to follow the four winds to a place where there is a high-risk insurance pool that will take me. Let’s see what moves faster -- health care reform or the sale of this house. I am hoping for both by the end of the year.

The non-CLL part has something to do with getting one’s life back in order. A lot of things have been let slide around here since I was diagnosed in 2003. Plans and projects shelved, everything deferred to matters of disease and, gradually, economics. Spin it as much as I like, it’s basically been a depressing, unhappy time. After almost six years, I have decided that you can’t truly make a silk purse out of the CLL sow’s ear. Perhaps the mistake is in trying too hard.

Now things are changing. There are physical signs of it wherever I look. And maybe as time goes on I have developed less propensity to worry. Maybe I’m sick of living la vida leuko. Maybe standing in a new kitchen amid old debris symbolizes the ability to get things done, to get moving, to somehow take a powerful step beyond the inertia that followed the gut-punch of a cancer diagnosis.

Who knows, maybe I’m just responding to negative ions in the atmosphere. I’m not expecting the CLL road to get easier. I am just hoping that my ride along it -- Marilyn’s and mine -- might be somehow less bumpy, perhaps more focused on the scenery. It’s a beautiful world, really. Sedona is a beautiful place, but I have lived in beautiful places before.

Another one, I hope, awaits. Physical, metaphorical, lyrical. I’ll take what I can get.

Perhaps, I hope, I have taken a step and am just a little bit there already.

Might as well jump (?)

2009-05-13T12:23:00.009-07:00

I don’t usually quote Van Halen songs in this blog. But then again I don’t usually run across a nurse who says deciding whether to have a stem cell transplant is like deciding whether to jump out of a burning building.

That’s what Theresa Brown, R.N., does today in a blog on The New York Times website. The title of her post is sobering: “When Cancer Treatment Might Kill You.” She tells the story of a young multiple myeloma patient who had an allogenic stem cell transplant and is now on a ventilator, having survived four surgeries in the last eight days following a bowel perforation. Doctors have removed his colon. This is all the result of Graft vs. Host Disease, aka GvHD.

What’s interesting here is the feeling that the nurses have about transplants: Mixed at best.

“It’s tough, and among ourselves there’s a strong feeling of “I would never get an allo,” because we know how bad it can be,” writes Brown.

Nonetheless, they don't think it's entirely hopeless.

“On my floor we have a book, an old-fashioned photo album filled with pictures of the transplant patients who are still alive. To many of the nurses on this floor, the specific details of these patients’ lives are irrelevant; all we care about is that they’re alive. They talk, eat, see their grandchildren, nurture their kids, love their spouses and enjoy their friends. They fill the place in the world that is uniquely theirs.

“For me, the book of transplant patients has a magical feeling. I sample its treasures by looking at a few photographs and then I put it away. I don’t need to read the whole book; just knowing it exists is enough. 'All these people survived,' I think. 'All these people are alive because of the work we do.' ”

I find that medical personnel speaking candidly can give you the best idea of what something is really like, or of what to avoid, what to do, what limits to accept, when to push harder. My oncologist, for example, absolutely recommends against staying in the hospital if it can possibly be avoided. The reason: too many germs. “If you have to go, bring your own pillow,” she told me once. “You don’t know what’s been living in the one they give you.”

Transfusion nurses have given me knowing looks indicating that I didn’t really need a transfusion. An ER doc, during the height of my October 2007 hemolytic crisis, told me that my instincts were right, that I was better off living with low hemoglobin until chemotherapy two days later than risking what I might pick up in a transfusion of non-irradiated blood. This went against the textbook, given that my hemoglobin was 6.6, but it was the voice of experience talking.

The point is, when medical people speak honestly, I listen. So I was quite interested in Brown’s conclusions about transplants.

“I compare his choice with deciding whether to jump from a burning building. Staying in the building means certain death. But if you jump, you might break both legs and take months to heal or sustain injuries serious enough that the complications eventually kill you. But you would be alive when you hit the ground. Maybe it will only buy you a few more rough years. But you might just walk away and live.

“When it comes down to cancer patients making the choice, a few decide to stay in the building. They opt for the quicker, surer death of cancer. Others, for different reasons, don’t have the option of a transplant. But even knowing the risks, I’m pretty sure I would make the leap, endure the free-fall, feel the impact, and hope to be one of the lucky ones who survives to walk back into the life that is waiting for me.”

That is, perhaps, the best metaphor I have run across when it comes to the transplant choice.

I know people who have jumped. Some survived and walked away, others managed with the equivalent of a broken leg. Some didn’t make it, or made it but faced difficult, often life-threatening challenges later on. Right now, one of them, a patient with aggressive CLL who sailed through transplant, is dealing with severe GvHD of the gut.

“This has easily been the hardest three weeks of our lives,” writes his wife. “Not knowing the plan or what was in store was and is so hard for us. . . . (He) isn't out of the woods yet by far.”

This patient was a textbook success until things started to go wrong. His case, not unlike the patient described in Brown's post, are potent reminders. They tell us, to take the metaphor in a slightly different direction, that we patients are playing with fire whenever we make a major decision, and especially when we decide to undergo transplant.

So, what will you do when the building starts to burn?

I will jump, but probably only when the flames get as close as I can stand them.

Rituxan + fresh frozen plasma

2009-04-04T13:12:00.005-07:00

"Here I come to save the day!" -- Mighty Mouse

Modern-day alchemists have been trying to turn rituximab into Mighty Mouse for years now. The partially murine-derived monoclonal antibody, best known by its trade name Rituxan, can be used alone or in combination with chemotherapy to treat chronic lymphocytic leukemia. It doesn’t work too well as a single agent, but that hasn’t stopped some of us from using it that way because it is considerably less toxic than the alternatives.

When Rituxan attaches itself to B lymphocytes, including literally billions of CLL clones, it creates antibody-antigen complexes; it is the immune system’s response that determines to a great degree the effectiveness of the cell kill. That response involves activation of complement (more below) as well as the onslaught of our immunity army — macrophages, neutrophils, natural killer cells, and the like. Finding ways to boost the attack, through means that are also comparatively benign, has a been a focus of research.

At MD Anderson, they added Leukine to Rituxan in a study of elderly patients. Leukine is a Granulocyte-Macrophage Colony Stimulating Factor, which means it encourages the growth of granulocytes (neutrophils, eosinophils, and basophils) and monocytes, which mature into macrophages. This booster was somewhat effective, according to the researchers, and had the added benefit of upregulating CD20 expression. CD20 is what the Rituxan gloms onto on the surface of the B cells — the more CD20 you have, the better. (CLL cells don’t have that much CD20 when compared to those of, say, non-Hodgkins Lymphoma, on which single-agent Rituxan is much more effective and for which it was first approved by the FDA.)

Neupogen, which stimulates the growth of granulocytes but not macrophages, was advanced as a booster some time ago by CLL Topics. Despite a few mouse studies and the like, the idea never made it to clinical trial in humans, which means the evidence we have is anecdotal. I tried it in 2004 and 2005 and it didn’t do much for me, either in terms of lowering my lymphocyte count or, more importantly, reducing stubborn lymph nodes. It did allow me to experience the unusual sensation of rodents running around in my bones, which was actually the sensation of cells reproducing madly, not unlike that crazed Octomom we’ve been hearing about of late.

Similarly, I tried adding Beta-glucan to Rituxan in October 2006; there is an open clinical trial on this based on some evidence that it might encourage activation of the complement system. In my experience, this was, again, more theoretical than real.

The bottom line on all these boosters is that they are pretty mild, and therefore unlikely to do much for anyone except those who have mild CLL. Those like me, with progressing disease, need a little more mighty with our mouse.

+++

A promising area of booster research focuses on complement. Complement, a system of proteins circulating in blood plasma, forms our innate immunity. It is what gives some of us CLLers a fighting chance against infection long after our immunoglobulins have declined to frighteningly low levels.

Through a complex series of events, these proteins can be brought into action, focusing the body’s attack on the offending Rituxan-CLL complexes; macrophages play a close, interactive role with complement and even create some of the proteins found in complement. Derived from the Greek for “big eaters,” macrophages are powerful tools, capable of gobbling up huge numbers of CLL cells — or, if misdirected, as in autoimmune hemolytic anemia, red blood cells. (If there were a way to get macrophages to destroy CLL cells with the same efficiency that they go after red cells in AIHA, my CLL would be cured in a few weeks.)

It is this process — known as Complement Dependent Cellular Cytotoxicity — that accounts for much of the cell kill when Rituxan is used, so finding ways to tweak it has been a focus for researchers.

One thing they have found is that complement tends to be depleted rather quickly after Rituxan is infused. Typically, there is a cell-killing frenzy in the first 24-48 hours, which declines as time goes on. Successive Rituxan infusions are accompanied by less dramatic results as complement gets used up and has little chance to recover.

This has been my pattern. For example, when I was on Dr. John Byrd's thrice-weekly Rituxan regimen in October 2006, I reported the following in this blog:

The plan was to do Rituxan three days a week for two weeks, 375 mg/m2 each time. To this I added 2000 mg of Beta-glucan daily, the same product being used in a clinical trial of CLL patients at the University of Louisville, Kentucky. My CBC was done before each infusion, so I had the opportunity to see what was happening more frequently than in the past.

The treatment opened with a bang. My absolute lymphocyte count of 153,600 dropped to 48,200 within 48 hours. My chipmunky neck began to slim down. Another 48 hours put my count at 26,600. And that’s about where it stopped. By the middle of the second week I was reaching my Rituxan plateau, both in terms of nodes and counts. . . . My doctor suggested, and I concurred, that there was little point in doing the sixth infusion.

Aside from depletion, complement deficiencies have been identified in some CLL patients, especially those with more advanced disease. It is also thought that these deficiencies may be the cause of autoimmune problems.

+++

So what if we give the patient more, possibly healthier complement from an external source?

That leads us to the latest booster in the news, fresh frozen plasma (FFP), used in a small study of Stage 4 patients by doctors in Israel and Greece. The results were published last year under the title Adding fresh frozen plasma to rituximab for the treatment of patients with refractory advanced CLL. (The study appeared in QJM: An International Journal of Medicine, a peer-reviewed publication of the Oxford University Press.) The idea was to take FFP, filled with all those complement proteins, and give it to patients along with Rituxan.

Five patients with “severe, treatment-resistant CLL,” including three who had failed Rituxan, were given two units of FFP, followed by the standard dosage of 375mg/m2 of Rituxan. Treatment was repeated every one to two weeks for two to five cycles. The authors reported that “a rapid and dramatic clinical and laboratory response was achieved in all patients. Lymphocyte counts dropped markedly followed by shrinkage of lymph nodes and spleen and improvement of the anaemia and thrombocytopenia. This could be maintained over 8 months (median) with additional cycles if necessary. Treatment was well tolerated in all cases.”

The full paper provides some useful detail; I have a hard copy, purchased by my hem/onc, who finds the R-FFP idea intriguing.

All patients showed an improvement in hemoglobin and platelets. Rituxan usually improves these figures on its own, so it is hard to say how helpful the FFP was in this regard. But since we are dealing with a group of treatment-resistant salvage patients, my guess is that the progress is meaningful. Here are the before-and-after results for each patient: Hemoglobin — 9.0/11.1; 9.7/13.0; 6.4/11.0; 9.7/14.2; 10.2/14.7. Platelets — 40,000/92,000; 75,000/128,000; 13,000/58,000; 70,000/83,000; 117,000/140,000.

Of particular interest to bulky-disease-me are results on lymph nodes. Certain nodes were measured in each patient, with these before/after results: 7cm/2cm; 1.5 cm/normal; 6 cm/3 cm; 2 cm/normal; 2.5 cm/normal. Of course, CT scans would have provided a much more accurate measurement, especially since Rituxan — like most treatments — tends to be less effective on deep abdominal nodes, which cannot be palpated (measured by hand). While I would not expect R-FFP to perform miracles in node reduction, it does seem to be more effective than Rituxan alone.

The patients were followed for a median of eight months (range 4-24) and were described as having “durable” responses, “already well over a year in two of the patients.”

The authors discuss how FFP may work by correcting “qualitative and quantitative abnormalities of the complement system reported in patients with advanced disease. Even normal complement may be rapidly depleted as a consequence of RTX therapy. Thus, supplying complement and enhancing complement-dependent cell lysis by the FFP/RTX combination may be the crucial factor. However, this is not the only mechanism possible. FFP would have provided immunoglobulins which are frequently very low in most patients with CLL and could affect the kinetics of RTX metabolism. These postulates require further study.”

The authors understand that the results of their study need to be “confirmed in larger series of patients and in controlled settings.”

But they conclude, “Our initial observations in the treatment of five patients with advanced, treatment-resistant CLL suggest that the concurrent administration of plasma with RTX may afford a remarkable clinical response that can be maintained. The clinical and hematological improvement was observed within days and occurred even in three of the patients who had failed standard RTX treatment. The administration of plasma may have corrected complement abnormalities associated either with the CLL or with RTX action and appears to be safe. Further controlled studies are required, but even now, the possibility that RTX action may be enhanced by this simple, cost effective method should be noted.”

+++

Before we do our R-FFP happy dance, it is worth remembering that nothing we put in our bodies to treat cancer is risk-free. FFP has some potential side effects worth noting.

Since it is a blood product, FFP carries a small risk of viral transmission similar to that of red blood cell and platelet transfusions. While red blood cells are sometimes irradiated to kill viruses, this is not done to FFP. Donor-retested FFP is probably the safest form available; this involves holding the plasma in quarantine for a minimum of 112 days until the donor can be retested to check for viruses that may not have shown up during initial screening. This is a cumbersome process, which makes donor-retested FFP difficult to come by.

An easier “fix” is for FFP to be given through a filter that should catch any errant white blood cells that may be carrying an infection such as CMV. (The plasma is supposed to be free of white cells, but a few may sneak in.)

Upon infusion, allergic reactions occur in a small number of patients, usually consisting of urticaria (hives), a rash that can be mild to severe.

Antibodies in donor plasma can also wreak havoc. According to the UCSD Laboratory Services Guide, “Antibodies in the plasma may react with the recipient's red cells, causing a positive direct antiglobulin [Coombs] test.” In other words, it could open the door to AIHA. I should point out, though, that one patient in the Israeli study had AIHA, that his HGB rose from 9.7 to 14.2, and that he was described as “asymptomatic” after treatment.

Wikipedia reports that “the potential for alloimmunization is present, as demonstrated by the infrequent formation of Rh antibodies.”

One rare, unintended side effect is the possible development of Human Anti-Mouse Antibodies — in other words, the FFP might create an allergy to Rituxan! This can happen over time anyway, as this link explains, and it doesn't necessarily mean Rituxan can't be used again. Dr. Terry Hamblin once wrote, "HAMA responses can inactivate the effect of the rituximab, but not always. Sometimes giving more antibody overcomes the response."

Another problem, UCSD adds, is that “In rare instances, noncardiogenic pulmonary edema (transfusion-related acute lung injury) may develop due to antibodies in donor plasma that react with recipient leukocytes.”

I discussed some of these issues with my doctor, who noted that FFP is a commonly-used product that seldom results in a worst-case scenario. Two units, she added, is a relatively small amount. Patients need to be watched for blood clots, which can be warded off by taking enteric-coated aspirin. (Indeed, FFP has been given in cases of ITP since it helps with clotting.) Fluid retention is also a concern, and can be relieved by diuretics such as Lasix. Those issues, and possibly a mild rash, are more likely to present themselves than exotic antibody problems.

I am left to conclude that FFP is relatively low-risk as these things go, probably on the order of Rituxan itself. Rituxan, of course, is not benign for everyone; it can cause anaphalactic shock during infusion, and later on can cause severe skin problems, lead to viral reactivation, and so on. This doesn’t happen to most people, but it does happen. Similarly, FFP appears to be easily tolerated by most, and a real problem for a few.

+++

I am going to try it. I need to do something to keep my disease in check, and I have long been fascinated by the possibilities of this combination. I enter the protocol with my eyes wide open, knowing that it is experimental and that it may not work. If it were a run-of-the-mill Rituxan booster, I wouldn't even consider it; the potential of FFP to deliver a much more powerful punch has convinced me to go ahead.

My best-case scenario is a response similar to the patients in the study, especially in terms of lymph nodes. If the protocol can make a reasonable dent in my lymphadenopathy, it will have done so at minimal cost in comparison to the alternatives. Giving R-FFP a try is unlikely to burn any bridges, and I will know in fairly short order whether it works on me.

The most likely worst-case scenario is that FFP, like the other Rituxan boosters I have used, simply won’t do much. Outside the Israeli study, I know of one patient in the USA who tried R-FFP, every two weeks for three cycles. He reported to the ACOR CLL List that he found it “arduous and ineffective.”

In which case, should my results mirror his, it may well be time for me to go a more traditional route — perhaps high-dose steroids accompanied by Rituxan and Campath, or else Revlimid.

It is worth stepping back here for a little perspective as supplied by Dr. Hamblin. "Monoclonal antibodies," he once wrote, "are not the magic bullets that people hoped they would be." Cancer cells have defenses against attack, and the way Rituxan works is not completely understood, which is why so many booster ideas are better on paper than in real life. Perhaps there is no way to create a Mighty Mouse that is truly strong enough to save the day.

Nonetheless, FFP is the most promising idea to date. The theory behind it is sensible. The study results, limited though they may be, are encouraging. And you never know what your body might respond to. My doctor and I figure it is worth a shot. Based on my history, I expect to tolerate the protocol well. I have used Rituxan extensively, with no problems, and the one time I had a blood product (IVIg), it went smoothly.

A final note: All this Rituxan-boosterism may be rendered a moot point within the next year as HuMax-CD20 presumably gains approval from the FDA under the trade name Arzerra. HuMax, a fully humanized monoclonal — no mouse! — works much better with the complement system than Rituxan does. If I could wait for it, I would. But my CLL moves faster than the government.

The news hole

2009-03-12T11:22:00.024-07:00

The "news hole" is a term from my newspaper days, meaning that gaping maw of blank space that has to be filled with stories for each edition. The news hole is like a black hole, except you have to fill it with something.

Living in an information society, we are constantly in need of, um, information. I remember when Marilyn and I walked into a Borders after our first book was published. There it was, Disco Nixon, taking up an entire table, gleaming under spotlights and screaming, “Here I am!” And after not too long it was gone from its prominent place, lost on a shelf on the second floor, just another of the 50,000 books published in 1995. Fifty thousand! Who has time to read 50?

In the world of 24-hour news, including TV and cable TV as well as website after website, there is also a news hole. Madoff victims are helping fill it (and hey, I’m glad to see Bernie was led off to jail today). I have had some interesting requests for interviews -- French television, a chain of German newspapers, Fox News, Inside Edition, and Geraldo, among others. I've been turning them down, though a free trip to France might have swayed me on the first one, but it was not in the offing. My stepmother Cynthia is so tired of media requests that she doesn’t even reply to them any more. CBS News, who cares? Katie who?

I don’t particularly enjoy seeing myself on television, unless there is a larger point to be gained from it, and that mostly doesn't seem to be the case. It’s interesting to be in this position, fielding these sort of calls and requests, getting a feel for what it’s like to be on the opposite end of the news hole. It involves a lot of inconvenience, with the added risk of being misquoted or portrayed inaccurately. The opportunities it creates are largely opportunities to be interviewed by more reporters.

But that’s not the big news around here. Marilyn and I are swamped with our home remodeling project, which is in one of the circles of Hell. While this will net us a nicer place to live, that’s not the purpose. We are preparing our home for sale. Bernie Madoff is making us free up our equity, such as it is. The contractor is here every day, creating noise and dust and requiring us to make a thousand decisions about everything, including the kitchen sink. So what’s more important to us than Geraldo is finding the right shower valve for the new tub in the master bath, running to Home Depot to pick up pavers for the downstairs patio, deciding whether the reverse osmosis faucet in the kitchen should be brushed nickel or brushed stainless steel.

Oh, yes. CLL is in there somewhere. I need to schedule a visit with my hem/onc in Scottsdale but that has to be coordinated with the arrival of our special-order shower pan for the hall bath, which we have to pick up down there next week sometime.

This house is our news hole. The remodel monster needs to be fed. And did I mention, speaking of feeding, that mice had chewed through the insulation and some of the wiring in our carport ceiling?

These are the issues I am living with front and center, surrounded by a jumble of boxes and furniture covered with dust, topped with that cherry known as sleep deprivation. Geraldo can wait.

A tip for fellow remodelers

If you want 10% off at Lowe's (and by extension Home Depot, since they accept competitors' coupons) get thee to a US Post Office and find a "moving kit." Inside there will be a Lowe's coupon for 10% off, good until June 30. (It's amusing to see that people are selling these on eBay, raiding post offices from coast to coast and making upwards of 20 bucks for lots of 10 coupons.)

Me and Madoff in the media

2009-03-06T12:55:00.006-07:00

For those following my Bernie Madoff saga, here is a link to the piece that ran this morning on ABC's Good Morning America. You'll see me in the video report, as well as in a web story entitled "Madoff Scam Could Cost Cancer Patient His Life."

If you are visiting this blog for the first time and are interested in my original post on Madoff, which was read by a producer at ABC News and which led to all this attention, do take a look at Bernie Madoff Screws Leukemia Patient.

And if you're a CLL patient or caregiver, a special welcome. I hope my posts and the useful links on the right side of the page are helpful to you.

Besides the report on GMA, as they call it, here are some other links of interest: Madoff's World is an excellent article in Vanity Fair that quotes from my blog. ABC's World News Tonight ran a story on March 4 called Mrs. Madoff's Money, which included my 1991 video of Ruth Madoff's parents, Sol and Sarah Alpern, at our Catskills hotel, Sunny Oaks. Bloomberg.com interviewed me for this January report entitled Madoff’s Tactics Date to 1960s When Father-in-Law Was Recruiter.

All he needs is a red clown nose.

20/20 interview delayed

2009-02-20T17:27:00.007-07:00

A few hours before tonight's 20/20 segment on Bernard Madoff was to air, I received a call from the producer and was told that my interview had been cut for time reasons, although they do plan to use it in a future broadcast. (Apparently there's a whole section they had to cut out, plus Diane Sawyer was given more time for an update on another story.) I'll hear more from the producer next week. So stay tuned -- I'll post an update here when I know with greater certainty when the interview might be aired.

As to the segment itself: It was predictably heavy on the sexy (as they say in the news biz) Palm Beach rich-who-got-burned angle and the celebrities-who-lost-a-lot (Zsa Zsa Gabor, Kevin Bacon) angle. And let's face it, Donald Trump is always going to get more air time than me.

My family's connection goes back to Madoff's early years and 20/20 didn't have time to get into how he got his start, how his father-in-law Sol Alpern (our hotel guest) got us involved in it, and so on. That really is another story for another time.

But part of that story is that many Madoff investors were not rich or famous. My father is a retired high school teacher, for example. My stepmom made money in the real estate boom in her neighborhood during the 1980s, buying and selling a couple of properties. Our family and the guests at the hotel who had Madoff accounts were, by and large, middle class to upper middle class people. Most people I know who lost money lost in the tens or hundreds of thousands, not in the millions. That element of the story deserves to be told, including, I hope, the way it impacts the life of your average chronic lymphocytic leukemia patient who doesn't have a Picasso to sell to make ends meet.

The report featured footage of Bernie sitting at his computer in his penthouse, presumably whiling away his hours of house arrest on the internet. One wonders if he is trying to scam those infamous Nigerian scammers.

I do appreciate the fact that 20/20 was willing to raise direct questions about who else might have been involved, who might have known that this was all a Ponzi scheme. Madoff's wife Ruth (my stepmom's classmate) and his sons and brother all received a mention. As someone who has been part of running a family business, it always made me feel more secure that Madoff had brought his family into the operation. But then again, come to think of it, people in the Mafia have families, too.

I'll be on ABC's 20/20 this Friday

2009-02-19T08:19:00.008-07:00

I was interviewed this week by ABC News correspondent Brian Ross for a special two-part investigation into Bernie Madoff, the man behind the $50 billion Ponzi scheme. The first part will air this Friday on ABC's 20/20.

Readers of CLL Diary are already familiar with my family’s longstanding acquaintance with Madoff and his wife Ruth. A producer at 20/20 read my post Bernie Madoff screws leukemia patient and one thing led to another. The post goes rather heavily into the leukemia angle, and that is part of the interview as well. I discuss how my losses in Madoff and my family’s losses impact my health care, including a possible stem cell transplant. I also talk about the perspective that my CLL diagnosis has given me on life, which affects how I feel about the Madoff mess.

Part of my motivation for doing the interview was as a patient advocate -- to get CLL into the national media, however briefly or obliquely (and also to be living proof that you can be a younger person with the disease). If people find my blog through the story -- perhaps patients and caregivers who are not familiar with the online resources available -- then they will also find the useful links I have selected on the right side of the blog page.

The producers offered to fly me and Marilyn to New York City for the interview but it was on too short notice, so ABC sent a film crew here to Sedona. Besides me sitting in a chair talking to Ross via satellite, they also took some atmospheric shots -- me looking over old Madoff statements, me standing on my deck looking at the red rocks, and me walking across Highway 89A, which is the main four-lane road through town. It's a bit odd walking for the camera -- I was reminded of Monty Python's Ministry of Silly Walks as I tried to nonchalantly navigate my way down the street. I was also thinking about Miss America starting down the runway and tried not to walk like that.

I don’t know yet what will end up on the cutting room floor, or how the story will be handled -- I am a very minor part of the report, but perhaps a human face on the scandal. I do feel that the producers and Ross are dedicated to doing a proper, investigative job when it comes to digging into the Madoff affair, and that is long overdue.

Another transplant twist, in which I learn my chances of getting a good donor match

2009-02-13T21:02:00.011-07:00

Many months after my visit to the NCI/NIH to discuss a stem cell transplant trial, I received a call from the clinical nurse in charge of finding donors for trial participants. In the 15 or so minutes we talked, Jennifer Wilder could not have been more helpful.

While I was rejected for the trial, one of the benefits of applying for it was that I was able to get a much better handle on my donor match situation. Before the trial, all I had to go on was a preliminary search of the National Marrow Donor Program (NMDP) database, which indicated there were 22 potential 6/6 matches at low resolution on the microscope.

That’s like looking through Mr. Magoo glasses and saying there are objects in the sky twinkling at night without knowing which are stars, which are planets, and which are airplanes passing by.

For their part, the NIH needed to do enough searching at high resolution to see what the prospect of a 10/10 matched unrelated donor would be, as that level of match is required for participation in the trial. It is also generally accepted as the desirable standard at all transplant centers. Their effort would have cost me thousands of dollars had I been paying for it out of pocket.

* * *

More on the results in a minute, but first a little background:

The bottom line when it comes to adult stem cell transplants is what sort of match you can get, and not all matches are created equal.

Sibling matches, for example, can mean less Graft vs. Host Disease (GVHD), which is what can happen when your new immune system comes into contact with your old one. But this also tends to mean less Graft vs. Leukemia effect (GVL), in which the new immune system takes on the CLL cells. Engraftment is harder since the CLL cells stick around, and relapse is more likely. Statistics show that if you are rolling the dice on a cure, your brother’s or sister’s stem cells are not the best way to go.

Matched unrelated donors are preferred -- those wonderful people who volunteer to help others in need. You’d think that out of some six billion people on earth there would be more than 10 million such donors, but those who need transplants are small in number and the need for donors does not get much publicity. (That prospective donors are often charged a small fee for testing does not help; one wonders what would happen if people were paid a small fee to agree to enlist, but that is another post for another day.)

A 10/10 match -- or better -- means the stage is set for a pretty good chance of engraftment and possibly cure. At the low end, Dr. Steven Pavletic of the NCI told me, an 8/8 match is acceptable. But it’s not desirable, and it’s something I would think twice about if it were all I could muster.

Then there’s the cord blood transplant, in which the rules change a bit: The level of match is not as important since the stem cells are pretty much unformed and adaptable to your system. Double cord blood transplants are a new thing, performed in adults at only a few centers. Dr. Paveltic described them as being riskier than unrelated, which indeed appears to be the consensus as of now.

A word is in order here about the mysteries of HLA -- Human Leukocyte Antigen -- typing, the complexities of which have caused smoke to come out of my ears as well as several other orifices on more than one occasion. For those of you who want to focus on the locus, the following are some links that provide further information, one from Wikipedia, one from CLL Topics and two from the NMDP, the first one for patients, the second one for professionals. (And aren’t we patients professional researchers at this point?)

* * *

Despite the statistics on CLL outcomes, the reflexive procedure at transplant centers seems to be to look for a sibling match first and then to look for an unrelated donor if that fails. I’ve got two brothers and a sister but each of them is a half-sibling. All are willing to donate their stem cells to my cause, none of which would be helpful. So thank you Rick, Dan, and Julie, but a sibling match is out.

Wilder told me that they found 15 6/6 unrelated matches at high resolution, looking at loci A, B, C, DRB1, DRB3, and DQB1. Two potential matches “would probably fall off for ethnic or other reasons," leaving me with a pool of 13.

(Ethnicity is important in all this, and I am a bit of an odd combination. My paternal grandparents were Russian Jews, who escaped the rule of Tsar Nicholas II and came to America shortly before the Russian Revolution. My mother was adopted, which I only learned following her death in 1977; after much searching, I narrowed her birthplace to the Irish immigrant community around Crown Point, New York. So I am something of an Irish Jew, evidently, which explains my demented sense of humor but which also puts me in a distinct ethnic minority.)

Of those 13 potential matches, they had additional data on four -- enough to get close to determining a 10/10 match. Of those, there is a 50% chance of one perfect match, Wilder said. The other three would be about a 10% chance of a 10/10 match. What lurks in the “mystery nine" would have to be determined through further testing.

Beyond this, there were 10 mismatched donors, probably only one of which might be as high as a 9/10 match.

Wilder said the odds of a successful transplant with a 9/10 match are “fairly decent.” The rule of thumb is that for every mismatch, successful outcomes drop by 9%.

A mismatch of one number at a locus is called an allele mismatch, she said, which is what I appear to have in three places when compared to the usual results for Caucasians. A mismatch of both numbers is called an antigen mismatch. Wilder said that an allele mismatch is not as bad as an antigen mismatch (fun reading here.)

“Do some mismatches matter more than others?” I asked.

The consensus is “yes,” Wilder said, but nobody agrees on what they are. For example, studies suggest that a mismatch at locus A-0205 is important but these studies are from Japan and could be important only within the confines of the Japanese ethnic group.

I have three “less common alleles,” she said, which means “a less common combination of numbers.” But she described my alleles as “nothing that’s all that rare.”

Obviously they’re rare enough to turn finding a 10/10 match into a bit of work.

One of my uncommon alleles is that A-0205. If you HLA-type 100 Caucasians, most will have 0201. Another uncommon allele that I have is at locus DRB1; I have 1305, and most would be 1302. Each of these counts as a mismatch. So a mismatch on the A-0205 alone means a 9/10 match, a mismatch on both the above means 8/10, etc. Transplanters do have an order of preference for where the mismatches are, but I didn’t get into the details.

Wilder said the bottom line for me is that with continued searching and typing of more donors, I would have a pretty good chance of finding a 10/10 match, with the prospect of a 9/10 in the background.

She searched databases worldwide. Wilder noted that people do join databases and a search in another year or two could “pop up some perfect matches.”

Which was polite of her to say, but my one perfect match, if there is one, could also get hit by a truck.

* * *

I have a case of CLL in which nothing is easy. I don’t have indolent disease. I don’t have horribly aggressive disease. I have progressing disease with fairly mild clinical symptoms, if you discount episodes of hemolysis due to AIHA, which isn't exactly easy to do. But my marrow is still pretty healthy, I don't have B symptoms such as fatigue and night sweats, and I am not prone to frequent or severe infections.

Alas, I have three out of four poor biological markers -- IgVH mutational status, ZAP-70 and FISH are all bad; CD38 remains good.

December's FISH test showed no new deletions beyond the 11q, and my 11q deletion appears to be stable when compared to results from 2007 -- the deletion shows up on just over half of cells tested. It also appears that I still have some ATM (programmed cell death) functionality. ATM is located on the long arm of chromosome 11, hence the tag of 11q. (It is not present on the short or “p” arm of the chromosome.) Monoallele deletion -- which is what I have -- means the relevant bit is broken off of the long arm of one of the set of two chromosomes #11. Biallele deletion means that both of the chromosomes 11 have lost the ATM gene. It stands to reason, and appears to be born out clinically, that the monoallele deletion is the half a loaf that is better than none; how long it will stay that day, given the vagaries of clonal evolution, is anyone's guess.

The downside of my 11q is that I also have extensive abdominal lymph nodes, as my CT scan of last month made clear. They're not impinging on anything important, but they have grown into a 13 cm by 15.5 cm mass, helping driving the disease, and a mass of that size is an indicator for treatment, according to the NCI guidelines.

I know where all this eventually leads -- transplant or die -- but it is not a pell mell rush, and so there is a little wiggle room along the way in terms of the what and when of treatment.

And what I learned from Wilder is that I’m not on Easy Street when it comes to finding a 10/10 donor, either. Still, she made it clear that there's a realistic chance. So let’s hope the one or maybe two or three people in the world’s donor databases who qualify enjoy quiet evenings at home with their air purifiers and heart-healthy diets.

Is this a slim reed on which to plan a long-term strategy?

The way I see it, the alternatives do not change because of the donor match situation. Basically, I can ride along doing chemo until nothing works on me anymore and I earn my scarlet “S” for “Salvage patient,” at which point I can make my peace with the world and go out gracefully.

Or I can go for a transplant at the best level of match I can get, even if it is not ideal: 9/10 perhaps, or cord blood, or maybe that 10/10 after all.

There is an anonymous quote I ran across that sums up my opinion: “There are always two choices. Two paths to take. One is easy. And its only reward is that it's easy.”

Dragging out the chemo is the “easy” choice here, but in a way it is also the hardest. It is a personal statement that “I accept that CLL will shorten my life, and that I will live three, five, maybe eight more years.”

Making the “hard” choice to go for transplant is saying, “I know there is a reasonable chance that I could be cured of CLL and I am willing to accept the risk of getting killed in the process, or living with inconvenience afterward, in order to have a longer life.”

In my humble opinion, and it is only that, so long as transplant is a viable alternative with a reasonable chance of success, the “easy way out” is akin to writing a suicide note.

* * *

But knowing that finding a perfect match will be a bit dicey does make me wonder about the advisability of jumping sooner rather than later. In making this decision, I am juggling a lot of balls in the air, or twirling a lot of plates on sticks, or tap dancing on the backs of several hungry alligators -- pick your metaphor.

As Dr. Pavletic told me, people don’t get healthier with age. I have no comorbidities (other cancers or diseases) that might reduce my chances of success. My heart and lung function are good. I am still chemosensitive, so my chances of getting a CR, or close, are decent, though hardly guaranteed. There will never be a better time than now, Pavletic said. As a reminder, he estimated that I have a 70% chance of a cure or long-term remission, perhaps a 15-20% chance of death, based on a 10/10 match. This tracks with everything I have heard for a patient in my situation.

Then again, despite my CLL and AIHA, I am enjoying pretty good quality of life. I’m 52. I can wait until I’m 55 or even a bit older before taking the leap. This guarantees me a few more years, time to enjoy life before risking that life. What I risk in waiting is the arrival of a comorbidity, watching the disease grow more stubborn and resistant to therapy, things that might ultimately reduce my chances of transplant success. What I gain in waiting is knowing that, barring a flying anvil with my name on it, I will probably be alive in three years. I am not risking a one in five chance of death.

This is a tough one. Push is starting to come to shove. Your thoughts are welcome.

Dopey, dopey, dopey

2009-02-05T17:30:00.015-07:00

Reading CLL discussion groups, and reading between the lines in those discussion groups, I am very much aware that some people deal with the stress of leukemia by taking drugs. And by drugs I mean alcohol and prescription antidepressants as well as illegal substances such as marijuana.

What is causing me to write about this is the tempest-in-a-bong over Olympic champion Michael Phelps. The 23-year-old swimmer was photographed smoking pot; from the overreaction of some people, you’d think he had been caught strangling mermaids with one of those ribboned gold medals.

Well, give me, and Michael Phelps, a break.

Somehow the United States managed to come into existence and prosper for its first 150 years without any restrictions on what you could put into your body. Alcohol, pot, laudanum, opium, cocaine, magic mushrooms, you name it -- all were there and ready for the taking as this country built itself into something ever more prosperous and successful.

But American respect for individual liberty has always had a counterbalance: our Puritan heritage, which entered the 20th century in the form of the temperance movement that brought us the Prohibition of alcohol.

Big success that was, of course. Since then we’ve been on a bender Prohibiting just about everything else, and that hasn’t been working, either. Our last three presidents all used illegal drugs in their youth. Our drug laws are a joke, which is hardly funny because of the enormous waste of lives, money, and resources involved.

Within the past 15 years or so, medical marijuana has gained a foothold in some states. It’s obvious that anyone with a flimsy excuse -- I do believe painful bunions were once used -- can get a doctor to prescribe pot in California. At least when it comes to marijuana, the absurdity of Prohibition is starting to break down. Gone are the days, and they were real, when people were sentenced to years in jail for possessing a joint.

* * *

I’m not a druggy personality. I like the occasional glass of red wine, but I find that being fully awake and aware in the here and now is more trippy than living in a haze. I experimented with the usual stuff in high school and college, but it’s been 30 years since I’ve smoked pot.

The only drug that I ever truly liked was LSD, which I took a half-dozen times in college. Sometimes it was revelatory, sometimes merely enjoyable, sometimes a bit of both. I recall laying on my back in the organic garden at UC Santa Cruz, watching as passing clouds smiled at me. Another time I was listening to the music of Johann Sebastian Bach, which wove itself into something resembling a complex Persian carpet right before my eyes. Never once, despite hysterical media reports that indicated it might be a real danger, was I tempted to jump off a building to see if I could fly.

In life, the Darwin Awards apply, whether you’re on drugs or not. Some people can handle drugs and some can’t.

I think we’ve all seen what happens to friends and family when people can’t cope with them, or when they take undue risks to get high. A family that has always been quite close to ours lost its sensitive and talented middle child to some bad heroin one night in New York City; he was in his 30s. Another kid I knew and worked with many a summer led a life of drugs and dissolution, stealing from his own parents as an adult, until he managed to ruin his body to the point that it killed him.

And I know many more stories involving our legal drug. alcohol; I have seen it bring heartache and pain, emotional and physical, to people who could have and should have had happier and longer lives.

I also know people in their 70s who have smoked pot their entire lives and seem none the worse for wear. Just about everyone I was close to growing up has violated our Prohibition laws on multiple occasions and most of them are quite happy and successful today.

Which leads me back to my point: Our drug laws are dopey. They’re not respected and they don’t work.

People will do what people will do, whether they’re 23-year-old swimmers or 60-year-old cancer patients. Perhaps some day American society will be ready for an adult discussion of drugs -- why they should be legal (or at least managed more sensibly) and why you should make the choice to use them sparingly.

Until then, let’s drop the hypocrisy. Let’s zip the flimsy moral outrage. Drugs are everywhere. They always have been, they always will be, and in a free society Prohibition will always fail.

My visit to the NCI, Part 3 - An enlightening meeting

2009-01-25T16:01:00.013-07:00

Readers will recall that Marilyn and I took a road trip from Arizona to Maryland last July. Our destination was the National Cancer Institute/National Institutes of Health, where we were to discuss a clinical trial for a matched unrelated donor stem cell transplant. We had contacted the NCI/NIH in January, following completion of my R-C(V)P treatment for CLL and AIHA. I’d had a rough time in 2007; we didn’t know how well the chemo would work, and we were looking at the prospect of moving to transplant sooner rather than later if the chemo didn’t hold. The NCI trial, besides being well designed, had the advantage of being free of charge, and my health insurer specifically forbids stem cell (“bone marrow”) transplants. There was a possibility of a big win-win here, if the time was indeed right and a donor could be found.

As we made our way from Hagerstown to Bethesda, the last 70 miles on our journey to the NCI/NIH, we had no idea that the question of my participation in the study had already been decided. Marilyn and I had concluded, after a day of reading and reflection while sequestered in our hotel room, that perhaps I might be jumping the gun, all things considered; we were about to find out that, for somewhat different reasons, there would be no trial for me, whether it was needed or not.

The NIH Clinical Center is shoehorned onto a cramped campus not too far off the Capital Beltway. One is greeted at the entrance by a phalanx of bored security officers who check your ID and your car, rather lackadaisically on the lookout for terrorists. This continues as you enter the parking garage of the Mark O. Hatfield Clinical Research Center, which is part of a 40-acre complex that makes up the largest clinical research hospital in the world. A guard places an orange cone in your path as you head in, checking your visitor passes to again make sure that you are who you say you are.

The Hatfield Center is big and new; navigating through it involves a lot of sign-following and direction-taking. After being set up with an NCI patient number and file -- which was done incorrectly and led to delays -- we were sent to the 12th floor for our meeting with Dr. Steven Pavletic, the protocol chair.

It was past 5 o’clock and Pavletic was running late; the place was practically empty, but had obviously gone through some heavy use earlier in the day. We couldn't help but notice how dirty and unkempt the seating area was. Lunch had happened. Not that this is the bottom line when choosing a transplant facility, but it added to our impression of a big, somewhat impersonal operation. Gone were the legion of senior citizen hospital volunteers we were used to seeing in Arizona, people who straightened the magazines, primped the cushions, and handed out complimentary fruit.

We were finally ushered into a tiny conference room by the transplant coordinator, a uniformed officer of the US Public Health Service. We chose the chairs without the potato chip remnants and awaited the good doctor.

Steven Zivko Pavletic originally hails from Croatia and is the head of the Graft-versus-Host and Autoimmunity Unit in the Experimental Transplantation and Immunology Branch at the center. In other words, he knows his way around a transplant and has a specialty in graft vs. host issues. He’s a few years older than me; Pavletic graduated from medical school in Zagreb in 1979, the same year I earned my anthropology degree at UC Santa Cruz. His head of brown hair is starting to gray, he retains a gentle Slavic accent, and he has an easygoing if businesslike manner.

* * *

Our interview began with some questions about how I was doing since my treatment had ended in December. This included a discussion of what lymph nodes can be palpated and a review of my latest CBC, which was about as picture-perfect as my CBCs get, and which elicited an “It’s wonderful!” from the doctor.

Pavletic asked if I had a history of other serious illnesses (no), allergies to medications (no), whether I smoked (briefly years ago), had any siblings (three half sibs, which means they may as well be strangers for transplant donor purposes), a history of cancer or leukemia in the family (not that I know of, but my mother was adopted), children (no), and what current medications I was on (2 mg of methylprednisolone plus Nasonex).

We discussed my treatment history, during the course of which I told Pavletic I was Coombs positive -- a sign that I might be prone to AIHA -- at diagnosis in 2003.

“So you never received fludarabine because they were concerned about the Coombs test?” he asked. Single-agent fludarabine has been shown to trigger AIHA in some cases, as many as 23% in one study.

I explained my story: At first we didn’t know my disease was as bad as it is, so we didn’t think we needed to bash it with heavy-duty chemo. We were concerned about fludarabine's T cell suppression leading to squamous cell skin cancers, of which I have a history. Only later, as more prognostic tests became available, did we learn that my biological markers are pretty poor. The positive Coombs had not really been an issue in the beginning -- indeed, my first oncologist had pushed me to use single-agent fludarabine without explaining, or perhaps without knowing, that it might lead to AIHA -- and I had converted to Coombs negativity after using Rituxan.

Pavletic then began what I like to think of as the good news part of our good news/bad news interview (his comments are provided here courtesy of my trusty tape recorder; don’t visit a major medical facility without one):

“The purpose of this visit is to answer your questions. You don’t have siblings so the next choice would be an unrelated donor . . . The preliminary search shows you have a reasonably good chance of a good match. [There will be much more on the donor situation in a later post.]

“You want more than one donor . . . It’s good to have a few choices because it takes a little time to get it set up, and you never know, donors can back out due to medical reasons, private reasons. So we try to have a backup, find two or three so if one falls out we have a backup.

“So I think it’s a reasonable option in your situation. You are relatively young for a transplant, and age is an important prognostic factor for outcomes.”

Here I asked at what point is one too old, or do one’s chances of success become significantly lessened by age.

“It’s linear. Ten years old is better than 35 and 35 is better than 55 and 55 is better than 70. The risk goes up mainly because the risk of Graft vs. Host Disease (GVHD) goes up with age. That’s one of the main complications, although graft vs. host can be beneficial if it’s mild. It is immunologically active against leukemia. A little graft vs. host is good.

“That’s a risk, and then other comorbidities. Right now I don’t see much in your case that you would have other comorbidities -- lung, heart, kidney, liver issues, another autoimmune disease, diabetes, an ongoing infection that’s not under control.” Pavletic said that the echocardiogram and pulmonary function tests that I had been asked to undergo before coming east were both “good.”

* * *

“That doesn’t mean doing a transplant is risk-free,” he went on. “It’s a journey, it’s a process that’s not without certain mortality risks, but the whole objective is to eradicate your disease. It’s not recommended unless somebody has enough high-risk features to justify that approach.

“The main prognostic factor is how the disease behaves. Certainly your biological factors, you know, like ZAP-70, are consistent with this more aggressive type, and clinically it’s been demonstrated with the recurrences of disease . . . I think it’s reasonable to consider transplantation.

“We usually recommend, if someone fails one type of therapy and the disease comes back, you should consider a transplant. Maybe we can still give another cycle of something and see how things go, you know, depends what is the interval between the first and second, but once you fail two attempts for treatment you should consider a transplant.

“In your case, [the possibility of long] life expectancy is still significant, and the likelihood that CLL is going to continue to cause trouble for you in the next year or two is very high.

“You responded well to this cyclophosphamide-based regimen, you are enjoying a good quality of life this last eight months, so you may ask ‘Why transplant?’"

I told him about two friends of mine who underwent transplant. One had terrible refractory disease, couldn’t get anything approaching a CR, but had a 10/10 match and was doing fine almost a year later. The other, PC Venkat, had a double cord blood transplant and did everything right going in but was felled by something unexpected even after he had engrafted.

"I realize there is an element of chance," I said.

“There are two reasons why people may die after transplant. One is called non-relapse mortality (NRM). It means something bad happens from the complication of the transplant procedure -- stirs up your immune system, immune suppression, toxicities, you can get infections when GVHD, or just from drugs.

“Certainly transplants that are mismatched are a little bit more risky. I would say a cord is more risky than unrelated and unrelated is more risky than sibling, though if you have a 10 out of 10 match that we are looking for, it is fairly close risk to doing a sibling transplant. It certainly inches up in terms of risk, but it’s not dramatically different . . . I would say maybe the risk of GVHD, the risk of infection is certainly somewhat higher.

“Non-relapse mortality goes up with organ dysfunction and comorbidities, the performance status -- all these things are pretty good in your case. How good is the donor match. Age as well plays some role. With the regimens we use these days, I would say NRM is between 10% and 15%, depends on the situation.

“Nobody has a crystal ball. What works for one person, if you survive and do well, then 1% is good. Ballpark, looking at your whole features, I would say from doing the procedure there should be a risk of somewhere between 15 and 20% of mortality within two years after procedure from some complication. That would be on the higher end, but I would say the risk is real.

* * *

“The other risk of mortality is from disease progression -- if somebody has refractory disease that’s not in remission, it’s certainly more likely to come back or not go away than if somebody has a chemo-sensitive disease and remission. As you do clearly have a chemo sensitive disease, that improves the odds of staying in remission.

“This is why we do transplants in CLL. We tend to say that it’s an uncurable disease by chemotherapy. It tends to come back.”

Pavletic used his hands to mimic a survival chart.

“This is like 5 years, 10 years, we have those survival curves maybe you have seen. If disease is more aggressive, if someone is diagnosed with disease of your features, I would say the data show the survival is somewhere like seven years. With each subsequent treatment, the disease gets more aggressive, so -- I will make it up -- but your anticipated survival curve is maybe here, two years or something.”

I made a mental note to self: Two years seems awfully pessimistic given my situation -- Dr. Terry Hamblin has pegged survival for patients of my unmutated, 11q-ilk at between 8 and 15 years -- but the general point is well-taken.

“So a transplant kind of fits. You can get all these complications and you can potentially die during the initial phases and then it tends to kind of plateau like this [more hands] where I can’t project exactly, but I would say somebody like you has somewhere around a 70% chance of long-term, disease-free survival. That would be a conservative estimate. These other 30% going to --"

"Relapse or die," I interjected.

“Yes.

“And then you get this immunotherapy portion where we really are with CLL in transplants. You know, we get rid of the disease, but it comes back . . . It can come back, late relapses have been described occasionally, but most of this stuff happens the first years. It doesn’t mean somebody can’t relapse at seven years or fourteen years.

“The other risks of transplant besides the mortality include chronic graft vs. host disease. It could be some interrupted quality of life or disability. Some people can control this, get off all the immunosuppression we give, but there could be some residual damage from GVHD to lungs or some other organs that can be a little bit impaired. But most of the time people can get back to normal function -- I would say in 80 to 90% of cases.

“Late effects are cataracts, second cancers like squamous cancers, the risks go slightly up. They have to be watched for.”

Since we were on the subject, I went through a list of questions I had brought and got some interesting answers:

If someone has a history of squamous cell cancers and a tendency to rashes -- can you extrapolate from this that after transplant they may be more likely to have a graft vs. host skin condition?

“No, no. You still have to watch for skin cancers. That does increase slightly, even for people who have had no skin cancers.”

I had mononucleosis as a kid and still have the Epstein-Barr virus running around in my system. What does that imply?

“Certainly compared to situations where both you and the donor would be negative for that sort of thing, you have potential for reacting the EB virus somewhere during the transplant, but it rarely has major implications. Rarely people can develop what we call post-transplant lymphomas that can be life threatening but usually not in this kind of transplant that you would get; usually that happens in T cell-depleted transplants. Most people are positive for EBV, so it is hard to find a situation where someone is negative.”

Splenectomy is used for refractory AIHA. Would I be shooting myself in the foot, transplant-wise, by having one?

“Not really. Having no spleen theoretically makes patients in the general population a little bit more susceptible to certain bacterial infections. But in transplant the immune system is compromised already, we would do all the necessary prophylaxis, so I would say there’s no major impact on transplant.”

If I have a successful transplant, might I be rid of the AIHA as well as the CLL?

“We don’t ever say 'never' here, but once you get a good engraftment, it would be highly unlikely to have a flare-up of AIHA.”

Pavletic began to sum up:

“So the options in your case: We can say 'Let’s see how long it goes,' maybe re-treat, some other things. Hemolytic anemia -- you never know when it’s going to hit; it could be life threatening -- rarely -- but it is certainly something that complicates this whole picture.

“My point is, you are a good transplant candidate. I think it’s a good consideration. There are reasonably good choices of donors. It’s not without risk. It’s not that you need to rush for a transplant tomorrow; you can see how long it goes. I think some other drug combinations or something can again put you into remission. But it’s your personal decision. You shouldn’t feel being pressed into this. If it’s something you are considering, you’re never going to be at a better point for transplant than you are now, because later the disease may be more refractory, you may get some other medical problems. But it’s not a situation when you have to jump tomorrow, but it is a consideration that is very fair.”

* * *

And then the other shoe began to drop.

“Now, speaking of what we can do here, I have one concern that’s quite serious, because we have only one program and that protocol includes fludarabine, not only for conditioning but for preparing -- the way our protocol is written -- to get you to that conditioning for transplant. If your immune system is not suppressed enough, measuring by lymphocyte count, we give between one and three cycles of chemotherapy called EPOCH-FR [etoposide, prednisone, vincristine, cyclophosphamide, and adriamyacin plus fludarabine and rituximab]. We have found that it improves, accelerates the engraftment. And you get another dose of FC for conditioning, which means chemotherapy that is supposed to finally prepare your immune system. That’s how we do it here, and we don’t have wiggle room changing that protocol."

I made my pitch. I explained that I’m OK with fludarabine if I’m not actively hemolyzing and if the risks are worth the reward. I described data from MD Anderson showing that when used in combination with cyclophosphamide and Rituxan, both of which act against AIHA, the effects of fludarabine appear to be mitigated and AIHA is triggered no more than usual.

Pavletic didn't appear to be impressed by the MD Anderson study.

“I don’t think anybody would give fludarabine as part of FCR to somebody with active hemolytic anemia --"

You’d be surprised, I told him, and there was a fair amount of laughter in the room.

“It may be a consideration if that’s the only option for somebody. Yes, as you say, some people give it or some people don’t even give it with a positive Coombs test and some people, they think it’s nonsense not to give it -- so there’s a little spectrum of opinions there.

“I would personally say, if you have to give it, then give it, but if you don’t have to give it, do something else . . .

“Sometimes hemolysis can be very violent, and nobody can say if it’s going to be mild, moderate, or severe.

“I think your disease is, so far as I understand here, at a good point. I don’t feel like you need anything right now. Maybe I’m wrong on that, but it sounds like you had a good response to your treatment. Maybe they can give you a few more of this CP-Rs. It would probably have a beneficial effect again. I’m not seeing anywhere now written on the wall that you must get fludarabine for any purpose. There’s still wiggle room around that.

“Speaking of our protocol, there are conditioning regimens and there are protocols that don’t use fludarabine. Not too many choices -- fludarabine is very popular as part of conditioning regimens -- but there are options like using total body irradiation in middle-of-the-road doses.

“So if you do a transplant here you are taking a risk, biting the bullet. There are cases we’ve done in transplant situations where nothing bad happens, and there are cases where something bad did happen. But we have this extra layer, we’re asking for more fludarabine before the transplant.

“My bottom line, what I’m saying, is it would not be a good choice to go for this study if you can find one that has no fludarabine in the conditioning. It’s just taking unnecessary risks for us and for you.

“This is a very specific protocol that may not be acceptable either to you or the study to expose you to those risks where we don’t know how it’s going to pan out. If you ask my gut feeling, there’s probably at least a 50% chance you would go through this and have no problem relating to hemolytic anemia, but why take another 50% chance or risk or 30% or 20% that something may go wrong and you say, 'Oh, my god, why did we do that?’

“Why take a 10% risk if you can not take a 10% risk? You have other headaches with a transplant.”

* * *

Pavletic suggested visiting other transplant centers where the induction and conditioning regimens would be more flexible. Much as I was disappointed in being rejected for the NCI study -- it would have been nice to have the option, if I decided I wanted it -- both Marilyn and I agreed that in an ideal world, Pavletic was right. Our plans to get better health insurance, which include moving to a state that has an insurance pool for high-risk patients that will cover a transplant, began to look more like a necessity and less like a theory.

The doctor spoke a little more about where my case stood and what I need to consider:

“It’s your decision entirely. Do you want to move on [to transplant] or not? I think everybody would agree that it would be reasonable to move on. Nobody has a crystal ball saying how your CLL is going to behave, and you have to understand that if you say ‘I’m going to sit and wait,’ you may have some disease progression that is going to make it hard to get in remission for transplant.

“There are no great options, but maybe the same thing [R-CP] would work, maybe high-dose chlorambucil, maybe Campath, maybe investigational drugs. These sort of things could buy another inch of time, maybe a year without symptoms, maybe six months, it’s hard to say. But the more subsequent relapses you get, certainly the likelihood of transplant being effective, it’s going down. And nobody with age gets younger and healthier.

“So I think you have some wiggle room. Go around, think it out, work on your life issues, go some other places and get a consult, stuff like that. It’s not a state of panic, but I would encourage not getting complacent.”

* * *

And so, here I am, in January 2009 having relapsed at last, not getting complacent.

There is another little NCI piece of the puzzle that merits its own post, in which I finally learned in detail what my chances really are of finding a 10/10 donor match. That will be coming soon to a blog near you.

It will, along with recent CT and FISH results and my responsiveness to just-completed R-CD therapy, shed some light on my long-term strategy. I am reviewing that now, given all that I have learned since our visit to the NCI in July. A post summarizing that, and the options as I see them, will eventually follow.

In the meantime, those keeping score will be happy to hear that my one round of R-CD has turned the corner on my hemolysis. Red counts are heading back up, my dexamethasone dose has been reduced to 2 mg a day, I've lost more weight -- another lymph node baby -- and the lymphocyte count is heading down.

It will hold me -- for now.

IRONY DEPARTMENT

I received a call in August from the transplant coordinator with Dr. Pavletic's official recommendation: Enjoy my remission and then use FCR if the disease progresses, which is an interesting turn in his thinking given his objections to giving me fludarabine. FCR would then make me a candidate for a transplant. Relapse after fludarabine therapy is a common step on the way to transplant; must I prove my bona fides at some point by having fludarabine and relapsing? Or is there another path?