Welcome to March/April, 2010 edition of OncoFacts. We are continuing our coverage of the important and potentially practice changing data from the 2009 Annual Meeting of the American Society of Hematology (ASH). This month, we will look at presentations concerning chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), and lymphoma.

Chronic Lymphocytic Leukemia

Abstract 205
Kirsten Fischer from the German Chronic Lymphocytic Leukemia (CLL) Study Group reported the results of a phase II trial of bendamustine 90 mg/m² days 1 & 2 and rituximab day 1 of a 28 day cycle in the front-line management of advanced CLL. One hundred seventeen newly diagnosed patients were treated. Eleven percent were Binet A, 41% Binet B, and 48% Binet C. A median of 5 cycles was administered. Toxicity was primarily myelosuppression and infections, with 2.6% treatment related mortality. Overall response rate was 91% with 32.7% complete response (CR), 2.7% nodular partial response, and 55.5% partial response (PR). Median progression-free survival (PFS) had not been reached with 80% of patients in remission at 18 months. The German CLL Study Group is moving forward with this bendamustine-rituximab regimen and currently has accrued approximately 200 patients to its phase III comparison (GCLLSG-CLL10) of bendamustine-rituximab with fludarabine-cyclophosphamide-rituximab (FCR) as front-line therapy.

Abstract 535
Michael Hallek reported updated results from the German CLL Study Group CLL8 trial in which newly diagnosed patients with advanced CLL were randomized for initial therapy to FCR versus fludarabine-cyclophosphamide (FC) alone. Eight hundred seventeen treatment naive patients with CLL were randomized 1:1 to FCR or FC alone. Of the patients, 4.9% were Binet A, 64% Binet B, and 31% Binet C. A median of 5 cycles were received by both groups. Dose reductions of >10% occurred in 47% of the patients who received FCR and 27% of the patients who received FC. The mean observation time was 38 months.

Results are noted below:

ORR, overall response rate; PFS, progression-free survival

The greatest benefit from the FCR regimen was seen in the patients with Binet A and B. The statistically significant differences in OS were only seen in the patients with Binet A and B. Overall survival was not significantly different in the patients with Binet C receiving FCR versus FC. The authors expressed the concern that FCR may not have provided as much benefit for the patients with Binet C because of insufficient treatment intensity in these patients with a higher tumor burden. The CLL8 is the first phase III study to demonstrate a statistically significant improvement in clinical benefit with FCR compared to FC in a randomized trial. The German CLL Study Group now considers FCR to be the standard of care for front-line management of advanced CLL.

Abstract 206
The Leukemia Department at the M. D. Anderson Cancer Center has participated in a number of trials with lenalidomide in CLL demonstrating response rates of 32% to 47% in relapsed disease. At the ASH Annual Meeting, Alessandra Ferrajoli presented the results of a phase II study of lenalidomide plus rituximab in relapsed CLL. The investigators in this study hypothesized that since lenalidomide stimulates natural killer (NK) and T-cell function, it might enhance rituximab-mediated cytotoxicity in CLL. Eligible patients with CLL were those previously treated with purine analog-based therapy. All patients had previously received rituximab, and 24% were purine-analog refractory. Rituximab was given weekly x 4 and then once every 4 weeks. Lenalidomide was give at 10 mg daily starting on day 9 of cycle 1. Patients received prophylactic allopurinol for 14 days. Sixty patients accrued, and 44 were evaluable at the time of presentation. After 6 cycles, 28 patients responded to the combination for an ORR rate of 64%. There were 21 PRs and 7 nodular PRs. Overall survival at 1 year was 95%. Overall response rate in the poor prognostic groups of del17p and del11q were 67% and 70%, respectively. Grade 3-4 neutropenia occurred in 31%, fatigue in 27%, and thrombocytopenia in 5%. Infectious complications occurred in 18% and tumor lysis syndrome in 5%. Tumor flare reactions were less frequent than with lenalidomide alone in previous studies.

Abstract 207
Bill Wierda, also from the M. D. Anderson Cancer Center, presented the results of another phase II study. He combined ofatumumab, a novel anti-CD20 monoclonal antibody, with fludarabine and cyclophosphamide (O-FC) in previously untreated advanced CLL. Patients were randomized to receive ofatumumab either 500 mg or 1000 mg on day 1 of each cycle. Overall response rates were 77% and 73% with CR rates of 32% and 50%. Progression-free survival and OS had not been reached at 8 months of follow-up. Response rates were somewhat lower among patients who had β2M >4 or who received <6 cycles of therapy. This compares to ORRs of 95% with FCR in both the M. D. Anderson Cancer Center trial and the German CLL8 trial with CR rates of 72% with FCR at M. D. Anderson Cancer Center and 44% in the German CLL8 study. The most common grade 3-4 adverse events seen with O-FC were infections and hematologic toxicity.

Abstract 209
Thomas Elter from the University of Cologne presented the final analysis of the German CLL2 study of alemtuzumab plus fludarabine-cyclophosphamide in relapsed or cytogenetic high-risk CLL. Patients had a median of 1 (0-4) prior regimens. The overall response rate in 56 evaluable patients was 68%, with 22% CR, 11% unconfirmed complete response (CRu), 35% PR, 15% stable disease (SD), and 17% disease progression (PD). Twelve out of 56 patients died during or within 6 months after their last dose of therapy. Five deaths were related to therapy, 3 to concomitant disease, and 4 to progressive disease.

References
Fischer K, Cramer P, Stilgenbauer S, et al. Bendamustine combined with rituximab (BR) in first-line therapy of advanced CLL. A multicenter phase II trial of the German CLL Study Group (GCLLSG). Blood. 2009;114(22). Abstract 205 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Hallek M, Fingerle-Rowson G, Fink AM, et al. First-line treatment with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) improves overall survival (OS) in previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL): Results of a randomized phase III trial on behalf of an international group of investigators and the German CLL Study Group. Blood. 2009;114(22). Abstract 535 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Ferrajoli A, Badoux XC, O’Brien S, et al. Combination therapy with lenalidomide and rituximab in patients with relapsed chronic lymphocytic leukemia (CLL). Blood. 2009;114(22). Abstract 206 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Wierda WG, Kipps TJ, Dürig J, et al. Ofatumumab combined with fludarabine and cyclophosphamide (O-FC) shows high activity in patients with previously untreated chronic lymphocytic leukemia (CLL): Results from a randomized, multicenter, international, two-dose, parallel group, phase II trial. Blood. 2009;114(22). Abstract 207 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

Elter T, James R, Stilgenbauer S, et al. Chemoimmuno-therpay with fludarabine, cyclophosphamide and alemtuzumab (FC-Cam) in patients with relapsed or genetic high-risk CLL: Final analysis of the CLL2L trial of the German CLL Study Group. Blood. 2009;114(22). Abstract 209 and oral presentation at: American Society of Hematology Annual Meeting; December 5-8, 2009; San Francisco, CA.

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