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.