Clinical Research Papers:
A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL
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Nitin Jain1, Kumudha Balakrishnan2, Alessandra Ferrajoli1, Susan M. O’Brien3, Jan A. Burger1, Tapan M. Kadia1, Jorge E. Cortes1, Mary L. Ayres2, Francesco Paolo Tambaro4, Michael J. Keating1, Varsha Gandhi2,* and William G. Wierda1,*
1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3 The UCI Chao Family Comprehensive Cancer Center, Orange, CA, USA
4 S.S.D. TMO, AORN Santobono, Pausilipon, Napoli, Italy
* These authors have equal contribution as senior authors
William G. Wierda, email:
Keywords: chemoimmunotherapy, fludarabine, bendamustine, rituximab, CLL
Received: May 29, 2016 Accepted: August 13, 2016 Published: September 15, 2016
Chemoimmunotherapy regimens have been the standard first-line therapy for patients with chronic lymphocytic leukemia (CLL). For young, fit patients the standard of care is combination of fludarabine, cyclophosphamide, and rituximab (FCR). Based on the preclinical work demonstrating that bendamustine combined with fludarabine resulted in increased DNA damage, we designed a phase I-II clinical trial with fludarabine, bendamustine, and rituximab (FBR) for patients with relapsed/refractory CLL. Treatment consisted of fludarabine 20 mg/m2 daily x 3 days and rituximab 375-500 mg/m2 x 1 day. Phase I included bendamustine at increasing doses of 20, 30, 40, or 50 mg/m2 daily x 3 days; phase II was with FR, and B at the selected dose. DNA damage response (H2AX phosphorylation) was evaluated in a subset of patients. Fifty-one patients were enrolled. The median age was 62 years; median number of prior therapies was 2; 40% had del(11q); and 41 patients had received prior FCR-based therapies. Hematologic toxicity was more common in ≥40 mg/m2 dose cohorts. Maximum tolerated dose (MTD) was not identified. Bendamustine-elicited H2AX phosphorylation was not dose-dependent, but markedly increased after fludarabine. We identified bendamustine 30 mg/m2 as the safe dose for phase II. The overall response rate (ORR) was 67% with 36% complete response (CR) / CR with incomplete count recovery (CRi). Younger patients (<65 years) had significantly higher ORR (81% vs. 50%; p=0.038). The median progression-free survival was 19 months, and the median overall survival was 52.5 months. FBR is an effective and tolerable CIT regimen for patients with relapsed CLL.
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