A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL

Nitin Jain, Kumudha Balakrishnan, Alessandra Ferrajoli, Susan M. O'Brien, Jan A. Burger, Tapan M. Kadia, Jorge E. Cortes, Mary L. Ayres, Francesco Paolo Tambaro, Michael J. Keating, Varsha Gandhi, William G. Wierda

Research output: Contribution to journalArticle

Abstract

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. Bendamustineelicited 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.

Original languageEnglish (US)
Pages (from-to)22104-22112
Number of pages9
JournalOncotarget
Volume8
Issue number13
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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B-Cell Chronic Lymphocytic Leukemia
Cyclophosphamide
DNA Damage
Phosphorylation
Phase II Clinical Trials
Clinical Trials, Phase I
Maximum Tolerated Dose
Therapeutics
Standard of Care
fludarabine
Bendamustine Hydrochloride
Rituximab
Disease-Free Survival
Patient Care
Survival

Keywords

  • Bendamustine
  • Chemoimmunotherapy
  • CLL
  • Fludarabine
  • Rituximab

ASJC Scopus subject areas

  • Oncology

Cite this

Jain, N., Balakrishnan, K., Ferrajoli, A., O'Brien, S. M., Burger, J. A., Kadia, T. M., ... Wierda, W. G. (2017). A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL. Oncotarget, 8(13), 22104-22112. https://doi.org/10.18632/oncotarget.12054

A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL. / Jain, Nitin; Balakrishnan, Kumudha; Ferrajoli, Alessandra; O'Brien, Susan M.; Burger, Jan A.; Kadia, Tapan M.; Cortes, Jorge E.; Ayres, Mary L.; Tambaro, Francesco Paolo; Keating, Michael J.; Gandhi, Varsha; Wierda, William G.

In: Oncotarget, Vol. 8, No. 13, 01.01.2017, p. 22104-22112.

Research output: Contribution to journalArticle

Jain, N, Balakrishnan, K, Ferrajoli, A, O'Brien, SM, Burger, JA, Kadia, TM, Cortes, JE, Ayres, ML, Tambaro, FP, Keating, MJ, Gandhi, V & Wierda, WG 2017, 'A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL', Oncotarget, vol. 8, no. 13, pp. 22104-22112. https://doi.org/10.18632/oncotarget.12054
Jain N, Balakrishnan K, Ferrajoli A, O'Brien SM, Burger JA, Kadia TM et al. A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL. Oncotarget. 2017 Jan 1;8(13):22104-22112. https://doi.org/10.18632/oncotarget.12054
Jain, Nitin ; Balakrishnan, Kumudha ; Ferrajoli, Alessandra ; O'Brien, Susan M. ; Burger, Jan A. ; Kadia, Tapan M. ; Cortes, Jorge E. ; Ayres, Mary L. ; Tambaro, Francesco Paolo ; Keating, Michael J. ; Gandhi, Varsha ; Wierda, William G. / A phase I-II trial of fludarabine, bendamustine and rituximab (FBR) in previously treated patients with CLL. In: Oncotarget. 2017 ; Vol. 8, No. 13. pp. 22104-22112.
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