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 ( 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.