Friday, December 17, 2010

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.

Saturday, December 11, 2010

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.

Sunday, November 21, 2010

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.

Saturday, October 30, 2010

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.


Sunday, October 10, 2010

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.

Tuesday, September 28, 2010

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

Sunday, September 05, 2010

The OL protocol after six months

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

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

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

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

Are they?

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

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

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

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

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

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

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


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

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

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

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

There are always more questions than answers in CLL.

Tuesday, June 01, 2010

At last, progress on the nodes

“Good news, everyone!”

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

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

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

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

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

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

* * *

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


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

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

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

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

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

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

* * *

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

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

* * *        

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

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

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

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

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



Monday, May 24, 2010

Rash decisions, and other Revlimid news

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

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

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

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

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

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

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

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

* * *

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


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

* * *

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

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

Tuesday, May 11, 2010

Life in the slow lane

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

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

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

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

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

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

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

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

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

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

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

Sunday, April 04, 2010

Take two aspirin and call Obama in the morning

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

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


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

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

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

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

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

Sunday, March 28, 2010

Post Secret CLLer?

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

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


Saturday, March 27, 2010

The fog lifts

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

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

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

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

Tuesday, March 23, 2010

Finally

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

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


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

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

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


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

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

Sunday, March 14, 2010

Lenalidomide lets loose

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

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

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

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

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

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

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

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

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

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

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

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

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