Originally published as JCO Early Release 10.1200/JCO.2006.07.1191 on February 12 2007
Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1114-1120
© 2007 American Society of Clinical Oncology.
Randomized Phase III Trial of Fludarabine Plus Cyclophosphamide With or Without Oblimersen Sodium (Bcl-2 antisense) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
Susan O'Brien,
Joseph O. Moore,
Thomas E. Boyd,
Loree M. Larratt,
Aleksander Skotnicki,
Benjamin Koziner,
Asher A. Chanan-Khan,
John F. Seymour,
R. Gregory Bociek,
Steve Pavletic,
Kanti R. Rai
From The University of Texas M. D. Anderson Cancer Center, Houston, TX; Duke University Medical Center, Durham, NC; Yakima Regional Cancer Care Center, Yakima, WA; Cross Cancer Institute, Edmonton, AB, Canada; Klinika Hematologii Collegium Medicum Uniwersytetu Jagiellonskiego, Cracow, Poland; Instituto Argentino de Diagnostico y Tratamiento SA, Buenos Aires, Argentina; Roswell Park Cancer Institute, Buffalo; Long Island Jewish Medical Center, New Hyde Park, NY; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; and University of Nebraska Medical Center, Omaha, NE
Address reprint requests to Susan O'Brien, MD, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: sobrien{at}mdanderson.org
Purpose Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL.
Patients and Methods Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m2/d plus cyclophosphamide 250 mg/m2/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR).
Results Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups.
Conclusion The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.
published online ahead of print at www.jco.org on February 12, 2007.
Presented in part at the annual meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004, and at the XI International Workshop on CLL, New York, NY, September 16-18, 2005.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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