Bendamustine Produces Durable Responses with An Acceptable Long-Term Safety Profile in Patients with Rituximab-Refractory Non-Hodgkin's Lymphoma: A Pooled Analysis.

Abstract Abstract 2681 Poster Board II-657 Background: Although initially very responsive to therapy, indolent non-Hodgkin's lymphomas (NHLs) are generally incurable. Therefore, it is important to identify active and tolerable treatments for patients (pts) with relapsed or refractory disease. Bendamustine (B, Treanda®), a mechlorethamine alkylator with novel mechanisms of action, is approved in the US for the treatment of indolent B-cell NHL that has progressed during or after rituximab (R) or an R-containing regimen. Methods: Data from 2 North American, multicenter studies with similar design and enrollment and response assessment criteria were pooled to examine safety and durability of response and allow meaningful comparisons between groups receiving prior therapies. B 120 mg/m2 was given IV on D 1, 2 q 21 days × 6-8 cycles to pts with R-refractory indolent NHL. Pts with transformed disease were excluded from efficacy analyses. Endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. Results: The primary analysis set consisted of all randomized pts (N=176; median 61 yr; 81% stage III/IV; median 2 prior chemotherapy- and 2 R-containing courses) and comprises the population for safety analyses. Histologies included follicular (68%), small lymphocytic (20%), marginal zone (11%), and lymphoplasmacytic (1%) lymphomas. Fifty-four (35%) pts were refractory to their last chemotherapy; 49 (28%) were refractory to their last alkylator-based regimen. Sixty-six (38%) pts received prior purine analogs (PA); 22 (33%) of these pts were PA refractory. Ninety-four (53%) pts received ≥6 cycles of B; early withdrawals were primarily due to adverse events (AEs, 28%, mostly myelosuppression [18%]) or disease progression (14%). Dose reduction occurred in 14% of cycles; 18% of cycles involved a treatment delay. Common nonhematologic AEs, primarily grade 1/2, were nausea (75%), fatigue (57%), vomiting (40%), and diarrhea (37%). 97% of pts received antiemetic therapy during study treatment. Grade 3/4 hematologic AEs included neutropenia (58%), thrombocytopenia (25%), and anemia (11%). Overall, 50 opportunistic infections in 48 pts were reported: herpes zoster (HZ, 18), herpes simplex (7), candidiasis (16), cytomegaloviral infection (5), Pneumocystis jiroveci pneumonia (2), atypical mycobacterial infection (1), and tuberculosis (1). HZ reactivation tended to be higher in pts with prior PA exposure (13% vs 8 %, P=NS); pts receiving prophylactic antivirals (n=18) did not experience HZ outbreaks, while an 11% incidence of outbreaks was observed in those not prophylaxed. Second malignancies occurred in 6 pts: 3 MDS, 1 CMML, 1 squamous cell carcinoma, and 1 AML. Two pts had tumor lysis syndrome (1 each grades 3 and 4) in the first cycle. Grade 3/4 AE frequencies were similar by prior PA exposure, except for neutropenia (41% vs 29%) and infection rate (26% vs 14%), which were higher in PA-pretreated pts. Grade 3/4 AEs were higher in pts '60 yr vs <60 yr (78% vs 63%), mainly due to fatigue (15% vs 6%), thrombocytopenia (23% vs 6%), and cardiac disorders (8% vs 2%). In 161 pts evaluable for efficacy (i.e., without transformed disease), B produced a 76% ORR (23% complete response [CR]/unconfirmed complete response [CRu]); in 75% of responders, the best response was recorded during cycles 1 to 3. Median (range) follow-up was 17 (11.5–24) months and DOR was 9 (7.1–10.5) months. At 1 and 2 years, 34% and 24% of responders continued to respond. Stratified by FLIPI, ORR was 77%, 75%, and 79% for low-, intermediate-, and high-risk groups, respectively; corresponding median DOR was 7.8, 9.0, and 7.0 months. Among 127 pts previously treated with alkylators, ORR was 88% (28% CR/CRu) in sensitive and 59% (12% CR/CRu) in refractory populations; corresponding median DOR was 9.3 and 7.7 months. Overall PFS was 9.0 (95% CI: 8–10.9) months; median PFS for alkylator-sensitive and -refractory pts was 10.9 (8.4–12.5) and 7.1 (4.0–9.3) months, respectively. Among 66 pts previously treated with PA, ORR was 81% and 64% for sensitive and refractory PA groups, respectively. ORR and DOR were similar by age (< or >65 yr), gender, histology, prior chemotherapy (' or >1). Conclusions: Durable responses and acceptable safety support the use of bendamustine in R-refractory pts with indolent NHL, even those who were refractory to prior alkylator- and PA-based treatments. PFS will be updated and pooled, and presented at the ASH meeting. Disclosures: Cheson: Cephalon, Inc.: Consultancy, Honoraria. Friedberg:Cephalon, Inc.: Research Funding. Kahl:Cephalon, Inc.: Consultancy, Research Funding. van der Jagt:Cephalon, Inc.: Research Funding. Tremmel:Cephalon, Inc.: Employment, Equity Ownership. Zaks:Cephalon, Inc.: Employment, Equity Ownership.

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