Off and on

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

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

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

“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

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

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

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

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

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

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