American Society of Hematology (ASH) 2010 Conference
ASH is the industry-wide club that you want to belong to if you are a hematologist. The annual ASH conference is a truly amazing event – many thousands of hematologists, general oncologists, industry representatives, regulatory agency folks, the odd patient or patient advocate who snuck in when no one was looking – all gathered in one place. Unlike ASCO (American Society of Clinical Oncology) which caters to all types of different cancers, ASH is limited to blood cancers only. So the papers are likely to be more relevant for our guys.
You can really sense the excitement at ASH conferences. Reputations and careers are made (or un-made), company stock price can plummet or rocket up, depending on how their ASH presentations are received. I am not particularly interested in those aspects of ASH. But there is no doubt that if you want to hear about cutting edge stuff, the latest information about clinical trials that can make life or death difference to our guys, ASH is the place to be.
Patients are not really encouraged to attend ASH conferences. I wonder why. I guess more of that respect stuff we were talking about awhile back. Since you can’t all attend ASH conference, I will try my best to give you a snapshot view of some of the more interesting abstracts. First out of the gate, I would like to review a couple of lenalidomide (Revlimid) papers. I am going to try and bunch these reports so that you are not swamped under a whole lot of “new article alert” emails from us.
FR + Lenalidomide in chemo naïve patients
Is FCR better than FR? I hear that question a lot. As usual, the answer is not a clear yes or no, it depends on what you are looking for. “C” (cyclophosphamide) adds oomph and toxicity. FCR is better if you have 11q deletion. But there is increased risk of myeloid cancer by combining all three of these drugs (more on this topic in a future review coming right up folks). Since we do not have a truly kosher two arm clinical trial comparing FR with FCR head to head, the arguments will continue and the answers will depend on the perspective of the person talking.
Since lenalidomide (aka Revlimid) is the new game in town, it makes sense to ask the question – what if we combine FR with lenalidomide? We have plenty of clinical data on how FCR behaves: very high response rates, impressive number of MRD negative (no trace of minimum residual disease) responses and majority of patients get long remissions with tolerable toxicity. (Yeah, I know, one person’s view of tolerable toxicity is another person’s version of kiss of death). You know what I mean, the reward is pretty good and the cost is not too high – hence the mantle of “gold standard” for FCR. So, here is the trial looking at substituting lenalidomide for nasty old cyclophosphamide, see if we can do better on the response side and decrease the toxicity while we are about it. The abstract is below; my two cents follow right after.
Preliminary Results From a Phase I/II Study of Fludarabine, Rituximab, and Lenalidomide In Untreated Patients with Chronic Lymphocytic Leukemia (CLL)
Ian W. Flinn, MD, PhD1, Jesus G. Berdeja, MD1,Jamie K. Waselenko, MD*,2, R. Seth Cooper, MD3,Jia Bi, MD*,3, Kent Shih, MD*,3, Habib H. Doss, MD*,3,Natalie Dickson, MD*,3, Dana S. Thompson, MD*,3,Howard A. Burris, III, MD*,1 and John D. Hainsworth, MD*,1
Abstract 2461
Background: Fludarabine, rituximab, and cyclophosphamide combinations have shown high CR rates in CLL, but concerns remain about both short and long term toxicity. Lenalidomide has emerged as a potential alternative addition to the fludarabine/rituximab backbone that may increase anti-tumor activity. The purpose of this Phase I/II study was to determine optimal lenalidomide dosing and to evaluate its potential benefits when used in combination with fludarabine/rituximab.
Methods: Eligible patients (pts) had untreated Rai stage III/IV or symptomatic stage 0-II B cell CLL with no CNS involvement, ECOG PS 0–2, and adequate organ function. The Phase I portion of this trial (n=19) explored fixed doses of fludarabine (25mg/m2/IV on days 1, 2, and 3 every 28-day cycle) and rituximab (375mg/m2/IV in divided dose days 1 and 2 cycle 1, followed by 500mg/m2/IV day 1 cycles 2–6) while receiving one of two dose levels (DLs) of lenalidomide. Pts on DL1 received 2.5mg PO on days 8–28 of cycles 1–6; those on DL2 received 2.5mg PO on days 8–28 of cycle 1 and 5.0mg on days 8–28 of cycles 2–6. Tumor lysis syndrome prophylaxis was administered to all pts throughout the first 2 cycles (allopurinol, 300mg PO daily). Disease assessment (NCI WG Guidelines) occurred post-cycle 3 during active treatment, 2 months after completion of the last treatment cycle ( 6 cycles), and every 6 months in follow-up until disease progression.
Results: Between 2/2008 and 5/2010, 28 pts were enrolled; the first 26 are included in this analysis. Pts were all untreated, and 64% male with median age 66.5 yrs (range: 48–82 yrs) and Rai stage 0/I/II/III/IV of 2/10/7/4/3. For the Phase I portion of the trial, the original lenalidomide dosing schedule specified that treatment begin on day 1 concurrently with fludarabine/rituximab, continuing for 21 days. Of the first 4 pts enrolled, 2 experienced persistent grade (g) 3 rash and/or dose-limiting toxicity (DLT), including g4 febrile neutropenia. Only 1 pt completed all 6cycles of therapy but still 3 achieved PR; 1 came off study prior to disease evaluation (DLT). Due to concerns about toxicity in these first 4 pts, the protocol was amended to delay lenalidomide until days 8–28. Results for DL1 pts (n=6) from the Phase I portion of the amended protocol are as follows: 5 pts completed 6 cycles of therapy and achieved an objective response rate (ORR) of 83% (CR, 4; PR, 1); the remaining pt had SD. Median time-to-CR was 34.0 weeks (range 32.4–35.4). Of these 6 pts, the most common DL1 g3/4 toxicities included neutropenia (4), leukopenia (4), and rash (1); 1 pt was hospitalized for g3 upper respiratory infection (possibly-related).
The maximum tolerated dose of lenalidomide (5.0mg, DL2) is currently being studied within the Phase II portion of this study. Currently, the findings for DL2 (Phases I/II pooled, n=16) are as follows: 5 pts were unevaluable (2 too early for assessment; 3 due to toxicity). Two pts achieved CR; 5 pts are PR, 2 of which are still currently receiving treatment. Four pts are stable, including 2 who are still on-study. In DL2 pts the most common g3/4 toxicities were neutropenia (10), leukopenia (5), fatigue (3), anorexia (2) and rash (2). Five pts on DL2 were hospitalized, including1 with g3 tumor lysis syndrome while receiving prophylaxis (related) and another with g3 allergic reaction/hypersensitivity (possibly-related); 1 pt later expired from g5 diarrhea (possibly-related).
Conclusion: The activity of lenalidomide, when added to fludarabine/rituximab, appears promising, despite notable toxicity. The dosing schedule of lenalidomide in combination with fludarabine/rituximab appears to influence the overall toxicity of the three-drug regimen, as evidenced by the improvement in tolerability with sequential dosing. Phase II study is ongoing which will further characterize the toxicity and efficacy of this regimen in pts with CLL.
Disclosures: Flinn: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: This study useslenalidomide off-label, in combination with fludarabine/rituximab, as an investigational treatment for patients with chronic lymphocytic leukemia. Cooper: Bristol-Myers Squibb: Consultancy.
Patients:
This is an early stage I/II clinical trial, they were trying to figure out how to do it right. I was surprised that in a little over 2 years, they managed to enroll 28 patients (26 of them are in included in this analysis). Just goes to show, it is not easy recruiting volunteers for clinical trials.
Patients were around 66 years old, all previously untreated. Fully two thirds of them were Rai Stage II or lower – not your end-of-the-road basket cases by any stretch of imagination. The authors did not give any prognostic information, a real pity in this day and age. Let us hope they will publish this information in later more elaborate articles.
Drug Dosages, Schedules
The fludarabine and Rituxan dosages were pretty much what I would expect to see in a typical FR regimen, neither more nor less (25 mg/m2 of F on days 1,2 and 3 of each 28 day cycle; a single 500 mg/m2 of Rituxan infusion each cycle)
The original protocol had patients taking lenalidomide on days 1 through 21 of each cycle, overlapping with the administration of F and R. OOPS! Toxicity was too high in the first 4 patients on this schedule. Two of the four patients had grade -3 rash (ouch!) and grade-4 neutropenia with fever to match (double ouch). One dropped out of the trial because of toxicity.
Based on this sobering clinical data, the protocol was changed to postpone the lenalidomide to days 8-28 of each cycle, so that there was a break between the FR part of the drug administration and the lenalidomide in each 28 day cycle. Furthermore, lenalidomide was given in two different doses. First group (6 patients) took a 2.5mg tablet on days 8-28 of each cycle. The second group (16 patients) got a larger dose, 5mg instead of the 2.5mg.
Risks and Rewards
I am not too impressed by the responses – and I am blown away by the toxicity encountered even at the 2.5 mg dose level of lenalidomide. For the larger group at the 5mg/day dose level, two patients got CR. Five are in PR, hoping things will get better over time. Four patients got nothing more than “stable disease”, meaning things did not get any worse than they were to begin with. The remaining five patients are still in limbo, too early to tell. While the numbers are small and it is hard to do apples to oranges comparison, I am pretty convinced this is not anywhere as good as FCR response statistics reported in many earlier trials.
How about the “cost” side of the equation, the wear and tear on the old body as a result of FR + lenalidomide? Authors report only grade 3-4 toxicities, I suppose on the assumption only sissies worry about lower grade 1-2 toxicities. Here are the scary statistics:
- Neutropenia – 10 patients
- Leukopenia – 5 patients
- Hospitalizations – 5 patients
- Tumor lysis syndrome requiring hospitalization – 3 patients
- Allergic hypersensitivity – 1 patient
- “Grade 5” diarrhea – 1 patient.
Folks, these were all grade 3-4 toxicities, pretty serious stuff and nothing to laugh about. I am particularly concerned about the 3 patients with tumor lysis syndrome – even when all patients got allopurinol as prophylactic medication, specifically to try and prevent TLS. And don’t forget that ever so cute “Grade -5” diarrhea. Grade-5 is another way of saying the patient died. If I had to die, I would not choose to die of diarrhea, I guess I am picky that way.
So, how do the researchers rate this combination of FR + Lenalidomide? They call it promising. With a little more fiddling with the dosages and the sequence of drug administration, they feel it should be possible to reduce the toxicity. I am glad to see they did classify the toxicity seen thus far as “notable”. Wow. I would have used more dramatic words to describe the toxicity, with more than a couple of exclamation points to drive home the message.
You want my two cents, possibly worth less than that on the open market? Don’t sign up for this combination of FR + Lenalidomide, at least not until they have worked out the bugs and can demonstrate to your satisfaction that the risk / reward picture is a bit more to your advantage. Until then, if you want a real high impact therapy with “tolerable” toxicity, you might be better served by good old FCR. As the saying goes, the devil you know etc.
Revlimid + Arzerra
This next abstract is also focused on lenalidomide. The difference is there is no fludarabine to ramp up toxicity. The combination here is lenalidomide + ofatumumab (Humax-CD20, “Arzerra”). Since ofatumumab is a monoclonal antibody and lenalidomide is an immune modulating drug – neither of them is what you would call standard issue chemotherapy drugs – this combination may be pleasing to the anti-chemo crowd.
A number of “R +R” (Rituxan + Revlimid) trials are under way, some have shown decent results with the R&R combination. This one substitutes the new kid on the block, ofatumumab instead of good old Rituxan. It is also very important for you to understand relapsed patients were recruited for this trial, not the chemo naïve group looked at in the previous abstract. This study of Revlimid + ofatumumab comes from our friends at M. D. Anderson, heavy weight authors all.
Combination of Ofatumumab and Lenalidomide In Patients with Relapsed Chronic Lymphocytic Leukemia: Initial Results of a Phase II Trial
Xavier Badoux, MD1, Susan O’Brien, MD2,William G. Wierda, MD, PhD3, Stefan Faderl, MD3,Zeev Estrov, MD2, Kimberly Yerrow, BSN*,2,Hagop M. Kantarjian, MD2, Michael J Keating, MD2 and Alessandra Ferrajoli, MD2
Abstract 2464
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 xULN). 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
Patients
Patients recruited for this trial had already been around the block and flunked fludarabine (or pentostatin) containing therapy. Bear that in mind as you evaluate the results. Basic liver and kidney function was needed, as also platelet count of over 30K. There were no restrictions on neutrophil counts. Prudently, they ruled out folks with HIV, hepatitis (B or C) and recent history of TB. Which reminds me, I got to remember to review for you later on a very recent article on the role of Rituxan in hepatitis viral reactivation. And here you were thinking Rituxan and Arzerra were the proverbial free lunch. But I digress.
Drug Dosages, Schedules
Arzerra was given at 1,000mg per infusion, once weekly for 4 weeks. Then one infusion per month for the next 5 months, and finished off with alternate month infusions of the monoclonal up to two years. Long term protocol, indeed.
Lenalidomide was given at a pretty hefty dose of 10 mg/daily (I expect this was adjusted as needed, depending on how individual patients tolerated the drug), starting on day 9 and presumably continued for the duration of the two year trial. Someone should calculate the dollar cost of such a long term therapy with these two pretty expensive drugs. I can hear the insurance companies groaning already. Oh yes, before I forget, allopurinol was given for the first two weeks to try and finesse tumor lysis syndrome.
Risks and Rewards
This abstract reports on 16 patients who have completed at least 3 months of this protocol. Unlike the previous abstract, the authors give at least some of the prognostics of the patients going in. Besides being post-fludarabine poster children, these guys were around 62 years old, high B2M (4.4mg/DL), nine of the 16 were IgVH Unmutated, 5 had 17p deletion and 3 had 11q deletion. Tough crowd to treat.
10 out of the 16 responded, a pretty impressive overall response rate of 63% in this group of refractory patients with poor prognostics. There were 2 CRs, 8 PRs. The remaining four patients had stable disease. Not bad at all.
Grade 3-4 toxicity was limited to neutropenia (8 patients) and anemia (2 patients). One guy had grade 2 superficial thrombosis. The dreaded “tumor flare reaction” was limited to grade – 1 variety in just 2 patients – this is hardly worth the mention. And there was not one patient with dangerous tumor lysis syndrome!
None of the patients were on routine antibiotic prophylaxis and sure enough there were three grade 3 infections, two of them pneumonia. The trial continues and I expect we will get more data on important stuff such as how long the remissions last and overall survival as the trial matures.
Bottom-line
All in all, I am pretty pleased both with the responses achieved and the toxicity price paid by this combination. Patients who have relapsed after fludarabine based therapies have few good options, especially if they also have poor prognostic indicators such as unmutated IgVH and high risk FISH (17p and / or 11q) deletions. This combination of lenalidomide + ofatumumab may be a good choice for them.
I worry about the 2 year length of the protocol. That is a long, long time for patients to stay engaged, stay in therapy and keep everything else in life on a back burner. The good news is that the ofatumumab infusions are the only ones done in the doctor’s office. Daily lenalidomide pill is taken in the comfort of your own home – so maybe that reduces the wear and tear on your nerves a little. All in all, this combination is worth keeping in mind and you can be sure I will be giving you updates as more results become available.
31 comments on "Lenalidomide (Revlimid) in the News"
Coy been on lenalidomide for over a year with very good results–he takes 10 mg daily for several weeks at a time-then-depending on blood report-stops for 2 to 4 weeks-he also receives IVIG every 6 weeks and neupogen as needed-we also watch liver function closely to monitor revlimid dosage time–his white count and Hg were in the normal range last week after being off revlimid for 4 wks–only plat.stay low-about 30–His main problem currently is many skin cancers this past year with repeated mohs surgeries–what is the indication that revilmid is contributing to the skin cancer?? He was a stage IV patient before beginning revilimid-
Thanks and keep them coming!
How many of the abstracts are “abstract” and how many are adding to the advancement science at ASH?
Your two cents is worth a lot more on the open market; we recognize the value even if the doctor’s don’t and are annoyed by your advocacy!
Keep the information flowing so we can make informed decisions and not have to just rely on what the good doctor tells us.
Kind of reminds me of the studies done between chimpanzees throwing darts at the financial page and highly paid educated brokers making picks. The overall result was about the same over time. Is there any real scientific game plan going on here or they just throwing the kitchen sink at patients and hoping one day to get lucky? This can best be described as very slow, hopeful, expensive, and painful progress. God bless the guinea pigs & those in trenches looking for solutions- we owe them a lot. I recommend the new book “The Emperor of all Maladies” by Siddhartha Mukherjee. The long biography of cancer shows what a tough battle this this is. It seems to me there is an awful lot of productive basic research going on now that is having a hard time making it to the bedside.
Thank you for your reviews and comments, Chaya. They are very helpful to me. I laughed out loud at your lack of enthusiasm for dying from diarrhea.
My husband is in a different clinical trial with these drugs. He received FR for 4 rounds and will begin the revlamid pill after a 4 month ‘waiting period’. That will start in January.
He did have neutropenia from just the 4 rounds, so the last two were not given according to the trial protocol. However, all of his blood counts rebounded tremendously within 6 weeks of the last treatment, and he is feeling great. His overall WBC is now ‘low normal’, and the lymphocytes are low as a % overall. He is IGvh unmutated, and will begin the revlamid in Mid January. We don’t know what the dose will be, but were told it can be adjusted, just as the IV chemo was.
I couldn’t imagine trying to give all these meds ‘at the same time’. We chose this trial because the option of 6 months of the revlamid as a maintenance med after the chemo ended seemed like a reasonable course to take with the higher risk unmutated CLL. He just turned 50, and we are happy with the progress. A bone marrow prior to the start of the Jan. treatment will determine if he has had a CR.
I’m picky that way too, having once survived a bout of dysentery that required a month long hospital stay. That’s not the way I want to go either.
As a chemo naive, stage II patient, I always look forward to your reviews. I bought the CLL book Susan O’brien edited as soon as I learned two years ago that I had CLL. It was a hard slog for a neophyte, but well worth the effort.
Thanks and Happy Holidays to All
Jim
Hi Chaya and thank you for your reviews and comments. You are so concise and insightful, with a great touch of humanity. Is there a link that you can share that would take us to the web site where all of the presentations and papers of the conference are?
Also are you aware of any high level type papers that would lay out the pros and cons of chemo versus non-chemo paths for treatment? It seems that the science and research in and around CLL is dynamic, causing such a paper to need constant updating. However, given the state of the science surrounding CLL today and all that we know as to the probable outcomes of treatments based on each patient’s factors and staging, a high level treatment road-map, with chemo and non-chemo paths, and pros and cons, would seem to be a useful tool for both patients and their oncologists. The more I think through this, the longer and more detailed the document becomes, however, it seems someone, somewhere, in the industry or in the universities and treatment centers, should be thinking through this and summarizing it in a readily usable and consumable format for both patients and oncologists. Were there any hints of this type of information at the ASH?
Hi, Chaya! I too have been “cruising” the ASH abstracts since last week, and have found a couple of interest to me. My take on your paper and others I have been reading is that if you go down the lane of purine analogs and akylates, and you are over 70, you do so at your own peril. I found out last week I am not eligible for the Len/Rit studies at MDA so I am back to square one with Dr. K. I have said “No” on both types of shotgun therapies. I did not see the abstract on ofatumumab and lenalidomide so it gives me more hope. Perhaps I can plead “compassionate use” with Dr. K. Been quoted $7000/week for Len which would do some big time damage to my financial situation.
Again, thanks for all your help. Pleast stick with your effort.
Barry
Thanks for the Info from the ASH conference.
Chaya,
Thank you for the updates. They are all very educational.
Stay well and Happy Holidays to all.
Monique
Chaya
Having just been newly diagnosed at the age of 43 I am happy to have found your site so that I can stay well informed. At this point I don’t know my what “bucket” I may fall into but I am now much more informed for when I meet my oncologist next week. I will be reading alot now and trying to stay healthy (although I kind of thought I was already). Right now I would love to read about peoples success stories so I can lift my spirits.Does anyone know where people might write about their happy endings?
thanks diane
Chaya
Thanks so much for your continued efforts. Having been diag. about 8mos ago, I’m still riding a roller coaster of emotion. At one point the(GP MD) sent me to an Oncologist who had me see their PA. She diag. me w/Lymphoma! After I was done “Freaking out”(both my parents died from that) I find that she was wrong and shouldn’t have told me that? That’s when they said I have CLL!
This site has been invaluable to me! However could someone please tell me something about where I am in this? The Dr. was very vague to say the least? My White count it seems has been “creeping up”(my GP’s words)for awhile. Turns out “awhile” has been at least 5 yrs! When it all came out the count was 15K. 7 mos later it’s at 17K. No one seems to want to tell me anything! Did a marrow test. “Inconclusive”?
HELP!
JR
Thanks Chaya for a great review. When looking into lenalidomide, have you come across any profiling data for those who are most at risk for tumor flare? It would seem logical that folks with a profile weighted to SLL would be at higher risk but knowing the complexity of all the potential variants possible in each patient I am not sure this is even predictable at this time and not sure it is solely based on dosage amounts. Is the danger from tumor flare the real issue, say, from internal nodes or is the issue of flare more confined to the pain and discomfort from experiencing it?
To JR,
Info you gave is way too incomplete for detailed advice but given the low peripheral blood count you state (15k increasing to 17k in 7 months)and assuming you are not suffering from infections or severe anemia DON’T PANIC. In early stage CLL with the white count as low as you describe and without autoimmune complications, testing by BMB is a waste, if not a painful waste of money and effort. CT & PET scans should not be done and some of the more important prognostic testing like IgVH mutation status will likely fail for lack of enough clone to obtain results.
Use your time to learn by reading Chaya’s CLLTOPICS articles and specifically know how to interpret your blood lab reports so you know when it is appropriate to act, go enjoy a picnic or panic.
This advice comes from the desk of the uncredentialed so take it as that and no more. There are generous Docs on the ACOR web Listserv and the Website CIG who can professionally address your concerns but supply them with the minimum of the following from your labs: 1)Absolute Lymphocyte Count (ALC) if given, 2)Absolute Neutrophil Count (ANC)if given, Forget the % of the former, 3)platelet count, HgB, RBC,and anything on your reports that say Immunophenotype which will list things like “CD19+, CD5+”(CD38+ or – is a good one to know)
WWW
dynajim:
I am sorry we cannot tell you where you are in this. You have come to the wrong place if you are looking for a diagnosis or an instant prognosis. May i suggest you get a second opinion at a really good cancer center with a really good CLL expert? Most insurance companies are quite willing to pay for a second opinion.
I am not being hard nosed about this, but one lesson you have to learn is that the internet is full of well meaning folks who are willing to practice medicine without a license. I wonder how much harm we do with our efforts to help in this way. On this site we try to give information, education, some amount of solidarity with other patients. I hope we try to refrain from CLL diagnosis and prognosis based solely on a white count of 15K.
If it is any consolation, most people freak out when told they have cancer, even if it is couched as “a good cancer”. Your reaction is quite human, nothing to be ashamed of. When you get over the fright, then it is time to settle down, learn more about this disease so that you can make smart choices in taking care of yourself. We have a collection of useful articles in the “Just diagnosed?” section that might help you. Much of it will sound like a foreign language at first. But trust me, it will get better over time, you will become more familiar with the terminology. With knowledge comes sense of control. I find I can deal with stuff a lot better when it is out in the open, not just scary things that go bump in the night.
Welcome to our website, I hope we can help you regain a sense of control over your own life and health.
Hi Diane,
Even though your life course has forever been changed with the diagnosis of CLL, there is very good reason for hope. As for the happy ending, it all depends on your perspective and outlook for life.
I consider myself lucky. The biggest challenge I faced after being diagnosed with CLL was coming to grips with the fact that, like every human before me, I will not be immortal. I was 45 when I was diagnosed with CLL. At that time it was easy to get trapped into playing the “will I make it to x event” mind game. X was defined by any significant family life event that might occur at some distant point in the future. Eventually I realized it was a game that could not be won. While it was important to make time to grieve for the loss of immortality, experience the fear of the diagnosis of cancer, and express rage and every other emotion that goes along with being a cancer patient, there are only so many hours in the day. If I spent too much time concerned with what might happen in the future, I could not feel, see, and experience the joy, love, happiness, and life that surrounded me each day. It helped me to see that happiness is a way of life that I can choose rather than a goal to achieve at the end of a long life. If I could find a little love and happiness each day, I would be happy and at peace at the end of the journey, no matter where it took me or how long it lasted.
That being said, my effort to find happiness is still a work in progress. Like everyone, some days are much better than others. I will be the first to admit that it is not always an easy task to accomplish. Like most skills, it takes awareness, practice, and the support of others to become better at finding daily happiness. My daughter introduced me to a simple exercise she learned during college orientation based on the image of a rose. At the end of each day, take a few minutes to review the events of the day with a friend or family member. Take turns reflecting on the day’s events. Start with an image of the thorns on the stem. They represent something unpleasant that happened that day. It is good to acknowledge an unpleasant event and how it made you feel. This is meant to be a reflective exercise and not a drawn out bitch session. Limit you thought to one unpleasant event that has ended rather than reliving every moment of the experience. Next imagine the rose bloom. It represents something good that happened during the day. Just like bad events, we also need to acknowledge good things to remind us that if we look, we can find goodness in every day. Finally, think of the rose buds. They represent hope for the coming day. The exercise is meant to help identify things that you can do each day to increase happiness in your life. It also allows you to let go of the unpleasant events and makes it easier to leave them in the past.
As far as CLL is concerned, it is hard to know what might lead to a happy ending. I was diagnosed before treatment was necessary so we hoped for a long watch and wait period. My wife hoped that I wouldn’t need treatment until the kids were out of high school. Two and one half years later when my lymphocyte count went from 12000 to 42000, we initially hoped that I wouldn’t need chemotherapy for another year or two. My follow up CT identified a football-sized mass of mesenteric lymph nodes. I ended up in the in the infusion center only a couple of months later and was reassured not to worry because those nodes will melt like butter with the treatment. One year later I was considered double resistant (unresponsive to fludarabine and campath). I started a new protocol. I also found a journal article reporting the response of double resistant patients to this new protocol or any other chemotherapy protocol. Of the 100 patients reviewed in this retrospective study, four patients also had a stem cell transplants in addition to chemotherapy treatments. Only two of the patients were still alive. Both were from the stem cell transplant group.
My son is a senior in high school this year. I had a transplant 21 months ago. Six years ago I could not imagine that the previous two sentences would describe my life’s path. At this point I have no detectable disease. Graft versus host disease is evident but well controlled. I will probably continue to take immune suppression medication for several more years. My new immune system is showing signs of progress but is still very immature. It will probably be several more years before we can determine how effective it will be at protecting me.
Given my miserable response to everything prior to transplant, I guess you could say I saved my luck for when I needed it the most. It also shows that even when things look pretty bleak, there is reason for hope.
I wish you well in your journey to find a happy ending.
Steven
Has anybody seen this “Shares in Celgene fell approximately 10 percent Monday after the company presented data at the ASH annual meeting that showed that patients receiving the company’s multiple myeloma drug Revlimid (lenalidomide) as a maintenance therapy had a higher incidence of certain types of secondary malignancies compared to patients receiving placebo.” The article was dated Dec 06 2010,from the ASH conference. They(patients) may be living long enough for this to become an issue or it may be peculiar to multiple myeloma or it may be statistically unrelated, just not what I wanted to read. I am currently taking 10mg Revlimid as a maintenance therapy.
Thomas
to dynajim:
First let me repeat Chaya’s advice — go to a good cancer center. I was diagnosed with CLL 22 years ago at age 48 and was referred to M.D. Anderson in Houston, which just happened to be in a neighboring state. I have been through four treatment protocols since then with first Fludarabine, then (10 years later) with Rituxan, then with FCR, and currently with Arzerra. I almost signed up for the A+L trial Chaya describes, but my doctor at MDA recommended we try just the Arzerra by itself first. That’s not to say clinical trials are always to be avoided — I was on the original Fludarabine trial in 1991 (which turned out well with a long remission) and later an interferon-beta trial (which was abandoned after several years). I must admit that I have been lucky with my prognostic indicators and my brand of CLL has remained controllable. The reason that I describe this, however, is to illustrate that CLL does not have to take over your life. My primary advice to you is to watch out for infections as Chaya’s many articles describe. Letting these get out of control can hurt you more than the CLL itself (although of course they are related). I get IVV infusions once a month, which has made a big improvement in my overall wellness.
Bob
Correction: I mean’t to say “IGG (immune gamma globulin) infusions” or sometimes called IVIG (intravenous immune globulin). I might add that I have been receiving these since a viral infection got into my brain (viral encephalitis) in 1996 and caused quite a bit of damage to my optic nerves. These are the sorts of infections you have to watch out for.
number72:
This news made quite a stir in the multiple myeloma contingent at ASH2010. Here is a link that describes the various Revlimid maintenance trials and the results reported:
http://www.medpagetoday.com/MeetingCoverage/ASHHematology/23819
Basically, these were large scale multiple myeloma trials where Revlimid was being used as a maintenance drug over many years. As hoped for, Revlimid maintenance (compared to no maintenance) decreased the number of deaths due to disease progression. Here is a quote:
“After a median follow-up of 34 months, 185 patients in the placebo group had progressive disease or died compared with 117 in the lenalidomide arm. Lenalidomide-treated patients had a median progression-free-survival of 42 months versus 24 months in the placebo group”
The other side of the coin, several trials showed there was a slight but unmistakable increase in the number of secondary cancers in the Revlimid maintenance arm.
Hard to extrapolate how this would play out for CLL patients. Multiple myeloma is a very different kind of cancer compared to CLL. But I think this much we can take home. Each and every one of these drugs has some level of risk, there is no free lunch folks. Higher doses and longer duration protocols are likely to increase the risks – hence my concern about the 2 year duration of one of the studies reviewed above.
At the same time, if Revlimid maintenance sharply decreases the overall number of patient deaths due to disease progression – at the risk of “tolerable” increase in the number of secondary cancers – we are back to choosing between the lesser of two evils. I will be keeping an eye out for any reports about secondary cancers in CLL patients treated with long term Revlimid maintenance therapy
Thanks for catching this Number72.
Linda Myers
Ithaca NY
I was diagnosed with CLL 16 years ago (in the pre-Internet, pre-FCR days), and also was fortunate to have connected with Dr. K at MD Anderson Cancer Center. I live in upstate New York, so going to Texas was quite a leap back in 1995. I’ve been treated three times since diagnosis and am currently in my third remission with some minimal residual leukemic cells remaining. I can no longer tolerate FCR. I’ve been in two clinical trials — currently with Revlimid, which I’m trying to take in pill form daily for a year — hopefully to wipe out the remaining leukemic cells and perhaps give me a longer remission. I’m learning how to tolerate diarrhea every few days. We’ve had to stop treatment twice for non-life-threatening challenges (very discomforting gastrointestinal reflux; head and chest cold with an enduring nighttime cough)and now neutropenia. Each time when I’ve returned to treatment, we’ve lowered the dosage a little.
Reading people’s entries here, I see how different one person’s CLL can be from another’s.
The big question for me is, presuming I get a few more good years of remission, whether to risk a stem cell transplant within the next couple of years when I’m healthy and still relatively young (I just turned 68) — or hope that some new treatment will come along for relapsed patients like me within the next few years.
And of course everyone’s (not just CLL patients’)enduring question: what to do with one’s life to make meaning and be useful — to be a full human being, not merely a perennial patient. I’m still working on that one.
I send cheers, hope, and happy holidays to my fellow CLL patients and supporters like Chaya.
To all who responded
Thanks to you all for your advice and info. And Thanks especially to Chaya. I’m reading more on this every day. Yes. It is a little difficult to understand even though I’d like to think I’m fairly intelligent. But I’m getting there.
Thanks again,
JR
I was diagnosed last year at the age of 47. As prognostic markers are not available in Scotland I took myself to London and had them done in June this year. I have found out that I have the bad kind of CLL 11q del, CD38 20% and the unmutated gene (my ALC count last year was 7.3K now it is 18.5K). I recently wrote to Prof Hamblin regarding Revlimid and he told me there is a trial for early stage CLLers with bad prognostic markers but after reading all this I am not so sure in taking part.
My 3 sisters and brother have recently been tested to see who would be a good tissue match to me and luckily my sister at 51 was a match. So rather filling my body up with toxins too early Chaya do you think I should stay on w&w?
A most grateful reader on your topics
Jacqueline
Chaya and Jacqueline,
Thank you for providing such a wonderful resource for CLL patients and their families. We are so lucky to have someone like you to provide a forum to learn and exchange ideas. Every time I log on to the site I have to pause and marvel at the persistent dedication and countless hours you have devoted to make this wonderful resource possible.
I wish we had the ability to take a sample of CLL cells from the body and test them against various agents similar to the way antibiotics are tested against bacteria cultures to determine the best antibiotic to treat the infection. Unfortunately, this test does not exist and we are forced to make an educated guess as to what might work.
Although statistical risks are present at every decision point, we are all individuals and do not always respond in line with the statistics. As Chaya often reminds us, we must keep those risks in perspective and not them to prevent us from initiating treatment when it is indicated.
I was in a similar position that you now face. We both were diagnosed at a young age and have a related donor to fall back on as a last hope if the other treatments fail. When I first started chemotherapy, I was concerned about the relationship of cyclophosphamide to cystitis and bladder cancer. After discussions with my oncologist, I learned that the effect was proportional to the concentration and length of time that the drug remained in the bladder. She informed me that the dose in FCR was small compared to protocols for other cancer treatments. She also said that the risk could be managed by remaining well hydrated throughout treatment days and evenings that cyclophosphamide was administered. Cyclophophamide is primarily eliminated from the body through renal excretion. Given the amount of IV fluid given during administration of FCR, most patients are relatively hydrated during treatment. However, for my own piece of mind, I also drank a fair amount of extra fluid during the infusion and throughout the evening. The price of having to go to the bathroom every hour was well worth the satisfaction of knowing that my bladder concentration of cyclophosphamide was low and not hanging around for an excessive amount of time. It also gave me a reason to get up and walk around during the infusions.
I was also concerned about the risk of agents causing myeloid cancers. Although I hoped for a long remission from chemotherapy, given my age, prognostic factors, and disease progression, it was likely that I would require a stem cell transplant. I found some solace in the fact that the risk of a myeloid cancer forming was not much higher than the risk quoted of developing a stroke or dying during coronary artery bypass surgery, roughly around 5%. I also reasoned that since myeloid cancers usually presented several years after treatment, if I ended up with a transplant, my risk of agent induced myeloid cancer would go away when my old blood cells were destroyed and replaced with the new graft during transplant.
I ended up getting a significant amount of chemotherapy before the transplant. Even though I only achieved a partial remission prior to the transplant, it ended up being worth the risk and effort. My graft remains 100% donor and I have no detectible CLL following the transplant.
I was fooled by a relatively low ALC into thinking I might not need treatment. I was in good shape and symptom free. I had some small, stable lymph nodes in the neck and axilla and assumed the nodes that I could not feel would also be small. However, a beta-2-globulin level greater than 7 (normal < 2) alerted my oncologist to the possibility that my disease was more advanced than the ALC and peripheral nodes indicated. A CT scan showed very significant mesenteric adenopathy. I was thin but no one was ever able to palpate the mesenteric nodes. The bone marrow was reported to be 97% infiltrated even though my hemoglobin level was still in the low normal range. My CD38 level was much higher than yours. The q11 del was seen on my initial lymph node biopsy but never detected on peripheral blood or bone marrow samples. Patients with 11q del often have a disproportionate amount of mesenteric lymph nodes compared to other CLL patients. You might consider discussing the merits of getting a beta-2-globulin level, abdominal ultrasound, or CT scan with your oncologist to help answer the question of when to watch and when to treatment.
Best wishes in your journey,
Steven
Steven
I hope you are well!
Thank you for the time you took to let me know some facts. I have found out just today that my beta-2 globulin level is 2.2 (normal range here is 1.2 – 2.4).
Apart from having a cheast infection, an ongoing sinus condition and funilly enough a bout of cystitis I am/was like you slim and reasonably fit with no other symptoms.
My question is why if I have a matching sibling as a donor they wait until your body can no longer tolerate chemo. I would prefer to have a transplant as soon as I need treatment for the fist time.
My best wishes
Jacqueline
Jacqueline,
Although the numbers have been dropping steadily as clinicians get better at stem cell transplants, there are still significant risks. About 5 years ago it was still about a 50-50 shot at cure or survival. Some clinicians I know love to point out this is the only “curative strategy” for this incurable cancer while others point out a stem cell transplant gone bad, even if not fatal, will make the person wish they had their old CLL back. Some doctors are not very good with keeping up with the literature and hold onto their beliefs despite much evidence to the contrary. This site is very good about telling people when it is time to speak up for your own care.
As is almost always the case, there have been some very good articles on the subject here: http://updates.clltopics.org/2641-mini-allo-stem-cell-transplants-who-should-get-them
The point that having a relative provides a huge leap in the numbers in your favor is made. You will also not have to face the possible choice to use cord blood as your source of stem cells. I have been directly involved for the past decade and they have cured many people of many things, including cancers, but in CLL it is not widely used because of the believed lesser graft vs leukemia effect from matched unrelated donors (MUD).
Good luck whatever you choose.
Jacqueline:
I will be blunt in my response to your question: the reason why they wait is that stem cell transplants – even the mini-allo variety with well matched sibling donor – still carry a substantial penalty of death and long term morbidity. Please read an article we had on http://www.clltopics.org titled “Catch-22”, probably one of the more important reviews we did. We discussed some of these issues in the context of a patient named “Richard” making therapy choices.
Richard had high risk prognostic indicators and went into a transplant in his first remission. That was the right thing to do in his case since his chances of getting a second good remission were not all that great. He did everything by the book, he was in great shape, athlete, he had a terrific transplant team and great support at home, young and lots to live for. I regret to tell you he passed away after a lot of GVHD complications. He was my friend and I miss him dearly.
One of the Hutch experts put it this way, why they will not transplant patients unless they fall within the present guidelines of high risk CLL or a patient refractory to several lines of chemotherapy. If he were interviewing a patient that did not meet the criteria set forth, without the transplant the patient is almost 100% sure of being alive three months from that point in time. With a transplant, there is a 30% (more or less) chance that the patient will be dead in the same time frame. Pretty blunt statistics, but they are true. Until and unless that mortality figure goes down substantially, mini-allo transplants will continue to be dangerous options to be handled with great care.
Bottom line, I am very glad we have the option of mini-allo transplants, I am very glad they are slowly improving survival and cure statistics, I am very glad mortality and GVHD issues are slowly getting better, I am relieved our high risk patients have the choice of a transplant, now that expert consensus is on the side of transplanting sooner rather than later in such cases.
But all said and done, these are still very high risk procedures and not to be taken lightly. Going into a transplant while in good shape is important. But it is also important to understand the fundamental risks involved – they are still pretty substantial. No responsible transplant center will (or should) transplant good risk CLL patients early in their CLL journey. That may change in the future as the technology improves, but that is where we are right now.
Thanks for great information, as always, Chaya! I wonder, I’ve never heard you mention translocations relative to treatment issues. My doc at Mayo says my reverse translocation: t (14:18) is the highest risk feature of my CLL. Otherwise, I have 10% mutated status, no deletions, CD38 positive, 100 % CD49d positive –“atypical” CLL disease. My numbers three years since Dx are suggesting I’m approaching treatment time…
Thank you, dear Chaya. A question: Do you know if India’s new generic Revlimid is available in the U.S. yet?
We just returned from our appt. today, and my husband will begin 5 mg of Revlamid for 21 days of each month for a total of 6 months. He is on extremely close follow-up (weekly blood work and follow up appointments).
The B/M results show 10% residual infiltration with leukemia cells (his B/M prior to the inital chemo was 90%), so we are pleased that the 4 rounds of I/V chemo (F/R) done this past summer/fall knocked it back this far. He was not able to continue with the other two rounds due to grade IV neutropenia.
Now, 4 months later, all of the rest of his blood work is well within normal ranges. Because he has the igvh unmutated aspect of the disease, we are willing to take the risks with the revlamid. He will be taking allopurinol, bactrim, and acyclovir as support meds.
Because he is on study, the revlamid will be free, which is a huge blessing in all this. We are looking forward to eliminating that last 10%!
Jan:
Generic Revlimid from India or any place else is a long way from becoming available to consumers. You can bet Celgene (owner of Revlimid) will fight it tooth and nail, citing patent protection, safety issues etc. We live in a complicated world.
Just read Budgie’s post and I had the thought that it would be great if everyone who is talking about a clinical trial could please include the trial number found on the clinicaltrial.gov website. That would be really helpful to those of us who are exploring those trials.
Thanks
Lynn
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