It's chemo time

Treatment starts Tuesday. I have decided to go with bendamustine and rituximab (aka Treanda and Rituxan), the first round of which will be given in the hospital so I can be monitored for tumor lysis.

As readers of this blog know, I have been looking for a kinase inhibitor trial for some time. A series of events out of my control has kept me out of trials, and my clinical condition now demands something bigger and stronger.

I was invited into the CAL-101 plus ofatumumab trial at UCLA last August, only to be told that there was a mistake by the company that organizes the trials and that the slot didn't actually exist. Had this worked out, it would have been ideal, since I was still at Stage 2 with ample hemoglobin and platelets. It would probably have been a seamless transition from the lenalidomide (Revlimid) I was on, and it probably would have forestalled the situation I now find myself in. At last count, hemoglobin was 7.9, platelets were 96, and the lymph nodes are bigger than ever. My spleen is 6 cm below the costal margin and the liver is, in the words of my oncologist, Dr. Droll, "pronounced."

In March, I was invited into the ABT-199 trial at the University of Arizona Cancer Center. I went there for the testing that is required before entering the trial, only to find out that there was now a problem between the drug company, Abbott, and UA. Since then I have been able to piece together some of the story; it appears that a failure to do something right at UA lead to the suspension of recruitment there. Which left me with nothing other than the promise that I would have first crack when a slot opened in the AVL-292 trial, in which UA was also participating.

The slot for AVL-292 finally opened, and I was faced with a difficult fact: Hemoglobin of 9.0 is required for admission, and while mine had been a steady 9.2 for months, it dropped to 8.5 and now 7.9. So I wasn't going to get in the trial regardless.

The cart before the horse

This all dragged on much longer than anticipated, and as it did my hemoglobin began to head south. It became apparent to me that between my failing marrow and disease bulk, using a kinase inhibitor would be like trying to stop a house from burning down with a garden hose. Even if it addressed the nodes to some extent, it was almost assuredly not going to address the marrow, or do so with much depth and rapidity, and that is probably the worst problem I have at the moment.

I went in for a bone marrow biopsy on Thursday; I haven't heard the official results, but the person who did the BMB -- and all she does is BMBs, day in and day out -- said my marrow was "packed." I'm not surprised.

(For BMB fans, of which there are none, it is worth noting that they put me under for the procedure with propofol, as well as using lidocaine on my hip. This is the way to go as far as I'm concerned. I woke up a few minutes early and felt her digging the needle around in my hip bone; it was much more pleasant being knocked out.)

Ultimately, it makes a lot more sense to deliver as big a blow as I can to the disease now, and then follow up with a trial, probably a kinase inhibitor, as maintenance afterward. I might also consider using lenalidomide as maintenance; perhaps at a low dose I could tolerate it, and with less disease burden it might not be as overreactive in terms of tumor flare as it proved to be last November.

The choice

Basically, there are two choices for Big Chemo these days: FCR or BR. In my case, given the low hemoglobin and the fact that I had autoimmune hemolytic anemia from 2007 to 2010, FCR is just too risky. While the CR can moderate fludarabine's ability to trigger AIHA, it is still a risk, and one that someone with a hemoglobin of 7.9 should not take.

Bendamustine is newish, at least in practice in the U.S., and is supposed to be less myelosuppressive than FCR. Reading anecdotal case histories, one finds that most patients get through it with good results. There are exceptions, usually when neutrophils crash, triggering bad reactions, which is why using Neulasta during treatment makes some sense.

The most reputable paper on BR comes from the German CLL Study Group, which examined the treatment in a tough group of relapsed and refractory patients. The abstract is available here. For those who don't know, bendamustine was developed in East Germany. After reunification, it attracted the interest of researchers and drug companies. An alkalyting agent like cyclophosphamide, it also seems to have properties similar to purine analogues like fludarabine.

The full paper from the German group is worth reading. Bendamustine can work on those who are fludarabine-refractory, with 45.5% responding. It can also work on those who have had  rituximab, and I have had plenty in years past. Of seven patients who had previously received rituximab, five responded with a partial remission.

A disturbing fact involves Richter's Transformation. Four of 78 patients were diagnosed with Richter's Transformation after the end of treatment. The authors imply this was unrelated to treatment, but I'm not so sure. Richter's can be set up by profound immunosuppression resulting from treatment; just because it doesn't show up until later doesn't mean treatment had nothing to do with it.

The bottom line is that all therapy comes with risks; kinase inhibitors are not risk-free, as Chaya Venkat makes clear in a recent report at CLL Topics Updates.

What I can expect

Based on the German data and my clinical situation, I am hoping for a partial remission that significantly reduces the nodes and clears out the marrow to a great extent. I am not anticipating a CR, despite the optimistic words of Dr. Daruka Mahadevan at UA, who said BR would "clean me out."

This is why maintenance should be initiated soon after I complete BR in December. I need to keep the disease in check through some means; if there has been a lesson for me in my experience since November, it is "don't let up."

I will report on BR in some detail as I experience it; little has been written, even anecdotally, about patient experiences with the drug, and it is here to stay as a major player in CLL.

I'll be doing the first round in the hospital so I can be monitored 24/7 for tumor lysis. In someone with my disease bulk, so many CLL cells could die so quickly that my kidneys might be at risk. Both Dr. Mahadevan and Dr. Droll thought this was a good idea, and I can't argue. As much as I don't like the hospital, I like my kidneys. I also expect that Dr. Droll will go with a lower-than-usual dose of bendamustine in the beginning, another way to guard against potential problems.

And so the next chapter begins in my CLL Diary. I am looking forward to the treatment, which I hope will restore some of the quality of life that I have lost. I had seven years of relatively easy CLL; when things head south, one is reminded of how difficult (and, yes, how potentially deadly) this disease can be.

Revlimid, in retrospect

Now that my year-and-a-half experiment with Revlimid -- aka lenalidomide -- is likely done for good, I think it's appropriate to sum up what I've learned.

Blogs tend to blurt out information that gets disconnected after awhile; my training as a feature writer tells me to sum up and provide context. For those chronic lymphocytic leukemia patients considering Revlimid, I hope my anecdotal experience might be of some use, which is why I am writing this.

I say "anecdotal" with all the usual warnings, as in YMMV -- Your Mileage May Vary -- and with this drug, it probably will. 

Pills are small and easy to take, but this one is not, on so many levels. For a little capsule that's supposed to be an "immunomodulator," it can easily provide more grinding fits and challenges than regular chemo. In CLL, lenalidomide comes with a wide degree of patient tolerance issues. One of them ultimately derailed the drug for me, but until it did, this stuff was almost golden.

Today, it is being eclipsed by the buzz about kinase inhibitors with license-plate names: CAL-101, ABT-199, AVL-292, PCI-32765, and so on. These drugs are in trials with promising results; while they may end up being a first choice over lenalidomide for many patients, in some cases they may not. Revlimid is here to stay for CLL, and it is a useful option to have. I used it from March 2010 until November 2011, with three months off starting in March 2011.

Revlimid modulates the immune system. Somehow. And in people with weakened immunity, such as CLL, this can do a couple of great things. One, it can cut down on infections, sinus and otherwise. In fact, it has been suggested that low doses of lenalidomide can be given to older people -- not necessarily CLLers, just older people who tend to get sicker easier -- as a means of keeping the immune system more functional. I have been fortunate in my CLL career not to have been especially infection-prone, despite my immunoglobulins being in the tank for nine years. While on Revlimid I was infection free -- not even a sinus minus clogging up my yap.

Revlimid normalized my blood counts, and it has done this for a lot of people. My absolute lymphocyte count wasn't too high to start with, as most of my disease is located in my 11q-deleted lymph nodes. But at one point my CBC became picture-perfect, frame-able even. You couldn't tell by the numbers that anything was wrong.

And this is a really big deal -- while using Revlimid, my very nasty, recurring case of autoimmune hemolytic anemia resolved. From the moment that the AIHA was diagnosed in March 2007, until Revlimid put a stop to it, I was bedeviled by serious hemolysis and treatments that began to fail, one after another, until I was left getting pretty heavy chemo (Rituxan, dexamethasone, and cyclophosphamide) as frequently as every three months. And there was some question about how long that could continue before a splenectomy became a necessity.

Dr. Asher Chanan-Khan, probably the country's leading lenalidomide-CLL researcher, told me in an e-mail before I started the drug that he had seen two actively hemolyzing patients -- hemolysis means your macrophages are eating your own red blood cells, which they will continue to do until you have none left and die --  whose hemolysis resolved while on Revlimid.

My own experience has led me to prosthelytize on these pages more than once, and so let me shout it out again for all my AIHA fellow-sufferers to hear: Please, please, consider Revlimid, especially if you are finding that the usual treatments (steroids, rituximab) are failing. If it does for you what it did for me, you'll have enough red blood cells to do some serious dancing in the streets. After a year of Revlimid, my hemoglobin was back up to 15.1 -- the exact number it was at on the day of my CLL diagnosis in 2003. I turned Coombs negative and remain so at this moment.

Revlimid also reduced my lymph nodes to a noticeable degree. I would say -- and I am guessing, since some nodes are more palpable than others -- by up to about half. In a nodey guy like me, that is great news. It took a long time. But it was slow and steady. And in CLL, slow and steady is often all you need to win the race, or at least to stay where you need to be when in competition with the growth of the disease.

Now, here's a real Revlimd success story. I have a friend with 11q-deleted CLL who went into a Revlimid clinical trial as frontline treatment. His lymphocyte count had reached a half-million (that's not a typo). In the trial, patients are upped from 5 mg daily to 25 mg daily over time, if they can tolerate it. And my lucky friend proved able to tolerate it, and to get the benefit from the maximum dosage. 

By the end of his two-year stint, his counts had normalized, what nodes were left were barely palpable, his hemoglobin was high, and a bone marrow biopsy showed improvement. Platelets were a bit low, but you can't have everything, and he's been told they should recover. He had found himself an excellent way to start out controlling his CLL without burning any bridges. He has had treatment, but not chemotherapy, which sets up disease resistance. From all indications, he can go on to do any other treatment out there, or take advantage of a new treatment that comes along, and he can expect it to work as well on him as if he had never been treated. (And, of course, he can always do more Revlimid at relapse.)

That is great news in the Second Chance department, which is so important in CLL,  and which cannot be understated. Preserving a second chance is what I was trying to do with single-agent Rituxan back in the days before Revlimid. That turned out not to work. Once you've done single-agent Rituxan, you have diminished your response to future treatments. It's not a free ride. But since Revlimid is an immunomodulator and works on totally different principles from chemotherapy, it does not appear to set up disease resistance. (Not that it won't make changes in the immune system, and only time will tell if there's something important about it that researchers and patients have been missing so far.)  But if I were starting out and needing treatment, I would seriously consider Revlimid for the Second Chance reason, as well as for its potential to do the job in the blood, nodes, and marrow that needs to be done.

And if I had been through the chemo mill, and was pretty much out of Second, Third, and Fourth chances, I would also look into Revlimid. There are some CLLers out there who have been kept alive for years now with daily doses of Revlimid. Fate has allowed them to tolerate it, and it works as well on the nasty 17p-deleted CLL clones that are left after the Chemo Wars as on the "nice" ones you tend to find more of at the start. For these people, Revlimid truly is golden.  

Dosages are tricky. Not everyone can tolerate 25 mg. Celgene, the drug's maker, has recommended that as a routine matter, CLLers not be given more than 10 mg daily. Some patients are coasting along at 5 mg, in maintenance. Some can tolerate 10, some higher. Some can't tolerate it at all.

In my case, doses as low as 5 mg have caused problems. I'll get into that in a minute. Suffice it to say that the higher the dose you can take, the more the drug will probably be able to do for you. Finding that right dose, and watching out for symptoms that could indicate drug intolerance, requires a great deal of patience. It helps to have a doctor who has used the drug in CLLers, or at least in those for whom it was originally intended, patients with MDS. You need to be aware of your body and on top of symptoms if you are going to experiment with it, and let's face it -- in CLL, Revlimid is still experimental.

Revlimid can also make you feel kind of out of it. Before I get into more serious tolerance issues, one thing my friend and I both noticed, and that some others have noticed, too, is that lenalidomide can bring a certain dullness to your life. I wouldn't say fatigue, necessarily. But this drug is the enemy of multi-tasking. It can lead to a lack of focus or sharpness. You can operate heavy machinery, you can go to work, you can do all the things you normally do, but somehow you do these things slower, or somewhat more detached, or in a somewhat foggy world involving less concentration. This is not a good-time, party drug. When Marilyn and I flew back East for my step-mom's big 70th birthday bash, I stopped taking Revlimid a few days before. I knew that if I were off of it, I'd be enjoying the party and making conversation. If I were on it, I'd be sitting in a corner trying to remember who so-and-so was from a distance. Suffice it to say that lenalidomide is no help with libido, either. While not everyone reports these sorts of symptoms, It's ongoing use could lead to a somewhat lower quality of life in some respects. That's not enough to make it not a choice, but it's potentially part of the experience (and for some it does get better over time.)

Revlimid can lead to serious clotting issues. This is one of those things that Celgene is very up-front about, and that the nurses who dispense the drug are always reminding you of.

By now, if you've read CLL Diary, you know that clotting was my problem, and that this shifted the risk-reward scale in favor of abandoning lenalidomide. To recap, I have a family history of clotting troubles. My mother died of a pulmonary embolism at 57,  just two years older than I am now. Her older son -- my older half-brother -- suffered several strokes, one of which took his life this past July at the age of 66. I saw him become bedridden and incontinent, barely able to move one hand, hardly able to swallow, eventually surviving through a stomach plug. I saw him decline, both physically and mentally. One night, a few weeks before he died, in a moment of frightening clarity, he shouted something from the hospital bed that had been set up in his living room: "What a miserable existence!"

It is possible to live with CLL and have good quality of life. In the QOL department, there are many worse conditions to have, not all of them cancerous. Staring my brother's fate in the face, I was ever reminded that worse things could await me if I were not careful.

I had two transient ischemic attacks, aka mini-strokes, while on lenalidomide, and then a third incident that probably qualified as something of the same. The first incident came about four months in, while I was on 10 mg daily, and involved about ten minutes of aphasia, or language difficulty. It resolved completely, and I ignorantly chalked it up to "chemo brain" and put it out of my mind. 

The second attack came some some months later, after things had been going so well that my oncologist gave me the go-ahead to up the dose to 15 mg daily. We wanted to go in and get at those nodes. After a week or so, the same language difficulty appeared again, also for about ten minutes. This time I went to see the doc, and she put two and two together, and clotting issues took center stage.

Which is why, like my lucky friend, who underwent a supervised trial in which Coumadin was required prophylaxis, I would not advise anyone to go on Revlimid without also going on Coumadin, or warfarin. Even if you don't think you have a clotting problem, it is wise to guard against it. If it is good enough for Dr. Chanan-Khan's patients, it should be good enough for your doctor's, too. Like any prophylactic drug we CLLers take -- such as allopurinol, acyclovir, or Bactrim -- it is designed to guard against a problem occurring. And at a low dose, such as 2 mg daily, it should not present a problem for most people. It is insane not to do it, IMHO.

The third incident occurred in September of last year, and came and went over the course of a week. By that time, I was on higher doses of warfarin, which were not improving my clotting time much at all, and lower doses of Revlimid, such as 5 mg three times a week. I felt a transient numbness on the left side of my mouth, sort of the way you feel after you've been to the dentist and the Novocaine has started to wear off. Simultaneously, I also felt this numbness in my left hand. This resolved after about 15 minutes, but it came and went for short periods during the following week.

Finally, of course, there is the story of my lenalidomide gotterdammerung and the abscessed lymph node, catalogued a few posts back complete with messy photos. Despite a year-and-a-half of being on the drug (and sometimes off of it), resuming it at 5 mg just four days in a row caused such unholy tumor flare as to land me in the hospital.

Which leads me to a final point: Revlimid can do unanticipated things to the immune system. In my case, it appeared to goose it up over time. There was a three-month period, starting in March 2011, when I was off the drug. I was, in part, expecting to get a slot in a kinase inhibitor trial, which did not pan out, and I needed to be "drug free" for 28 days before starting the trial.

Just before resuming Revlimid after this hiatus, I came down with a case of hives. This was unusual, since my allergies don't usually take that form. It resolved with Benadryl (speaking of Zombie drugs) and I went on to restart Revlimid at a general course of 5 mg three days a week. Over the course of the last summer, I was constantly getting hives, several times a week. Move me to a spot with a new allergen, and it would start. Let me get a little sweaty in Arizona in the summer -- which is impossible not to do -- and the the hives would come again. It was all easily controlled; in fact I began taking Allegra every other day just to keep it away. But something in my immune reaction was more hair-trigger, way more prone to act quickly than it had been in the past.

My theory -- and, again, this is anecdotal guesswork -- is that Revlimid, which had rewritten my immune system in some good ways, also rewrote it in some more dangerous ones. A recent paper by Dr. Chanan-Khan and others discusses mechanism of action at some length, and basically points out that lenalidomide works best when there are lots of NK and T-cells present. (The latter, little marvels, also surveil against squamous cell skin cancer, another problem I've had, and something common to CLLers; Revlimid appears to have kept a lid on those, too.)

The paper, Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response, is worth reading if you're thinking of taking the lenalidomide leap. It appeared in the May 15, 2011 issue of Cancer, which is published by the American Cancer Society. Now, here is where I teach you to fish. Most journals that usually charge for articles will provide one free for the personal use of a patient if you just write and ask. In this case, contact canceredoff at cancer.org. 

Tumor flare, the paper explains, predicts response in Revlimid. There is a two-thirds chance that you will encounter it. From the very beginning, tumor flare was always a challenge for me. It came on big when I first started the drug, then remained at a lower but tolerable level during treatment as the ongoing battle with the nodes was engaged. What happened at the end with the abscess was one for the record books. Again, just a guess, but I wonder if the Revlimid had created in me a condition by which my immune system overreacted when the Revlimid itself was re-introduced at a 5 mg sustained dose, higher than I had been taking for some time.

Talk about ironic. In many ways, I responded very well to Revlimid, perhaps a little too well. It created too much fire to play with.

But it got me through a rough patch when I needed it, and it saved my ass in 2010 and much of 2011, getting me in a bumpy fashion to the great hope of 2012, kinase inhibitors.

So, thank you Celgene. And if you, fellow patient, are in the right position to tolerate it, Revlimid could be an important option for treatment. Just consider that it may not be easy, and do expect the unexpected.

(A final note: readers will recall that I began my Revlimid regimen in 2010 along with infusions of ofatumumab, aka Arzerra. The Arzerra was stopped after September's dose as the Revlimid appeared to be doing most of the work; I was on (and off) Revlimid for another eleven months after the Arzerra ended, so I do not think it clouds the story much. The one thing it may have done is mitigate the tumor flare I experienced at the beginning; perhaps it also served to keep the immune-goosing effects of the Revlimid somewhat in check.)

Hang on

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.

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

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.

My little OL protocol: ofatumumab and lenalidomide

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.

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

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.

My visit to the NCI, Part 3 - An enlightening meeting

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?