Originally published as JCO Early Release 10.1200/JCO.2008.17.7980 on September 21 2009

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Multicenter Randomized Phase II Study of Weekly or Twice-Weekly Bortezomib Plus Rituximab in Patients With Relapsed or Refractory Follicular or Marginal-Zone B-Cell Lymphoma

Sven de Vos, André Goy, Shaker R. Dakhil, Mansoor N. Saleh, Peter McLaughlin, Robert Belt, Christopher R. Flowers, Mark Knapp, Lowell Hart, Dipti Patel-Donnelly, Martha Glenn, Stephanie A. Gregory, Charles Holladay, Tracy Zhang, Anthony L. Boral

From the Division of Hematology/Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA; Hackensack University Medical Center, Hackensack, NJ; Cancer Center of Kansas, Wichita, KS; Georgia Cancer Specialists, Atlanta, GA; The University of Texas M. D. Anderson Cancer Center, Houston, TX; Kansas City Cancer Care, Kansas City, MO; Winship Cancer Institute, Atlanta, GA; Mid Ohio Oncology/Hematology Inc, Columbus, OH; Florida Cancer Specialists, Fort Myers, FL; Fairfax Northern Virginia Hematology/Oncology, Fairfax, VA; Huntsman Cancer Institute, Salt Lake City, UT; Rush University Medical Center, Chicago, IL; Charleston Cancer Center, Charleston, SC; and Millennium Pharmaceuticals, Inc, Cambridge, MA.

Corresponding author: Sven de Vos, MD, PhD, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, 9-631 Factor Building, 650 Charles E. Young Dr, Los Angeles, California, CA 90095; e-mail: devos{at}mednet.ucla.edu.

Purpose To determine overall response rate (ORR), time to progression (TTP), and duration of response (DOR) with twice-weekly/weekly bortezomib plus rituximab, and evaluate safety/tolerability, in patients with relapsed or refractory CD20⁺ follicular lymphoma (FL) or marginal-zone lymphoma.

Patients and Methods Patients were randomly assigned (minimization method) to bortezomib 1.3 mg/m² twice weekly (days 1, 4, 8, and 11; 21-day cycle, five cycles; arm A) or bortezomib 1.6 mg/m² weekly (days 1, 8, 15, and 22; 35-day cycle, three cycles; arm B) plus rituximab 375 mg/m² weekly for 4 weeks (both arms). Response/progression was determined by International Workshop Response Criteria using oncologist/radiologist-adjudicated data from independent radiology review and investigator assessment.

Results Eighty-one patients (arm A, n = 41; arm B, n = 40) were enrolled. Dose-intensity was higher in arm A; mean total bortezomib received was similar between arms (18.5 and 17.1 mg/m²). In arm A, ORR was 49% (14% complete response [CR]/CR unconfirmed [CRu]), median TTP was 7.0 months, and median DOR was not reached. In arm B, ORR was 43% (10% CR/CRu), and median TTP/DOR were 10.0/9.3 months. The weekly combination regimen seemed better tolerated. Grade 3 or worse adverse events seemed more common in arm A (54%) versus arm B (35%), including thrombocytopenia (10% v 0%) and peripheral neuropathy (10% v 5%), but diarrhea seemed less frequent (7% v 15%). No grade 4 toxicities were reported in arm B.

Conclusion Both bortezomib plus rituximab regimens seem feasible in relapsed or refractory indolent lymphomas. The more convenient weekly combination regimen is being compared with single-agent rituximab in an ongoing phase III study in relapsed FL.

S.d.V. and A.G. contributed equally to the conduct of the study, analysis of the data, and writing of the manuscript.

Supported by Millennium Pharmaceuticals and Johnson and Johnson Pharmaceutical Research & Development LLC.

Presented in part at the 2006 Annual Meeting of the American Society for Hematology, December 9-12, 2006, Orlando, FL; the 2005 Annual Meeting of the American Society for Hematology, December 10-13, 2005, Atlanta, GA; the 9th International Conference on Malignant Lymphoma, June 8-11, 2005, Lugano, Switzerland; and the 11th Congress of the European Hematology Association, June 15-18, 2006, Amsterdam, the Netherlands.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00085696 [ClinicalTrials.gov] .

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