Oblimersen for the treatment of patients with chronic lymphocytic leukemia - PubMed (original) (raw)

Oblimersen for the treatment of patients with chronic lymphocytic leukemia

Bruce D Cheson. Ther Clin Risk Manag. 2007 Oct.

Abstract

Among adults in Western countries, chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia. CLL primarily affects the elderly and may be associated with multiple comorbidities. A cure has not been identified, and new treatment options are needed. Expression of Bcl-2 protein is associated with the pathogenesis of CLL and chemotherapy resistance. Oblimersen, a Bcl-2 antisense phosphorothioate oligonucleotide, is being evaluated in patients with CLL and other cancers; trials through Phase III have been completed. In the setting of relapsed/refractory CLL, single-agent oblimersen demonstrates modest activity, whereas the addition of oblimersen to fludarabine/cyclophosphamide significantly improves the rate of complete and nodular partial responses; moreover, these responses are durable and associated with clinical benefit. Oblimersen is more efficacious in relapsed rather than refractory patients. The side effect profile of oblimersen, alone or in combination with standard chemotherapy, is favorable compared with currently available chemotherapies. In the first cycle, an infusion reaction with or without tumor lysis syndrome is uncommon, and transient thrombocytopenia is observed. Catheter-related complications are associated with the need for continuous intravenous infusion of oblimersen over several days; other routes of administration are under clinical investigation. Oblimersen is a promising therapeutic approach for patients with relapsed CLL and should be further evaluated in the front-line setting.

Keywords: Bcl-2 antisense; G3139; Genasense®; chronic lymphocytic leukemia; oblimersen.

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Figures

Figure 1

Figure 1

Bcl-2 response in peripheral blood mononuclear cells from pediatric patients with solid tumors by oblimersen dose: change from baseline (Day 0) on Day 5 (No Day 5 sample for 2 patients; response on Day 6 shown. Copyright © 2007. Reprinted with permission from the American Society of Clinical Oncology from Rheingold SR, Hogarty MD, Blaney SM, et al. 2007. A Phase I trial of G3139, a bcl-2 antisense oligonucleotide, combined with doxorubicin and cyclophosphamide in children with relapsed solid tumors: A Children’s Oncology Group study. J Clin Oncol, 25 1512–18.

Figure 2

Figure 2

Overall response in previously untreated and previously treated patients with CLL: Phase II study.

Figure 3

Figure 3

Duration of response (from date of first response) during and following protocol therapy among patients achieving a CR or nPR by treatment group: Phase III Study (Copyright © 2007. Reprinted with permission from the American Society of Clinical Oncology from O'Brien S, Moore JO, Boyd TE, et al. Randomized Phase 3 trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol, 25:1114–20).

Figure 4

Figure 4

Duration of response from date of best response by treatment group: Phase III study, intent-to-treat population (data on file, Genta Incorporated).

Figure 5

Figure 5

Survival with 3 years of follow-up by response and treatment group: Phase III study, intent-to-treat population (Copyright © 2007. Reprinted with permission from the American Society of Clinical Oncology from O’Brien S, Moore JO, Boyd TE, et al. Randomized Phase 3 trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol, 25:1114–20).

Figure 6

Figure 6

Kaplan-meier survival curves by treatment group: Phase III study, intent-to-treat population, fludarabine-responsive patients (Copyright © 2007. Reprinted with permission from the American Society of Clinical Oncology from O’Brien S, Moore JO, Boyd TE, et al. Randomized Phase 3 trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol, 25:1114–20).

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