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Significant Survival Benefit From Adding Oblimersen to Fludarabine-Cyclophosphamide Combination Therapy in Relapsed/Refractory Chronic Lymphocytic Leukaemia: Presented at EHA

By Chris Berrie

BERLIN -- June 9, 2009 -- Adding oblimersen to combination fludarabine plus cyclophosphamide (FC) has a safety profile similar to that of FC alone, increases the rate of durable complete responses, and provides significant long-term survival benefit for patients with chronic lymphocytic leukaemia (CLL) who initially respond to fludarabine treatment, according to research presented here at the 14th Congress of the European Hematology Association (EHA).

This analysis of the 5-year follow-up of a randomised, phase 3 trial was led by Susan O'Brien, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, and presented here on June 5 by coinvestigator Thierry Cousin, MD, Genta Incorporated, Berkeley Heights, New Jersey.

Oblimersen was tested in association with FC treatment in patients with relapsed/refractory CLL, in a total of 241 patients who had previously received 2 or more cycles of a fludarabine-containing regimen.

These patients were randomised to receive up to six 28-day cycles of FC alone (n = 121; median age, 63 years; male, 74%) or in combination with oblimersen (oblimersen-FC; n = 120; median age, 63 years; male, 74%). The doses were as follows: fludarabine 25 mg/m²/day plus cyclophosphamide 250 mg/m²/day for 3 days, either without or with oblimersen 3 mg/kg/day for 7 days as a continuous intravenous (IV) infusion beginning 4 days before FC.

The baseline demographics and signs and symptoms of disease were similar across these FC and oblimersen-FC treatment arms, with 67% overall showing an Eastern Cooperative Oncology Group performance status of 1 or greater. Their disease-related histories were also similar for median diagnosis to randomisation time (58 vs 70 months), Rai stage (3/4, 50% vs 45%), baseline lactate dehydrogenase (elevated, 43% vs 44%), and history of splenectomy (3% vs 9%).

The primary endpoint of complete response rate was significantly greater for patients with oblimersen-FC over FC alone (17% vs 7%, respectively, P = .025), and duration of response at 2 years follow-up was significantly better for oblimersen-FC (hazard ratio [HR], 0.29; log rank P = .03). The aim of the current analysis, therefore, was to determine whether long-term follow-up to 5 years demonstrated a survival benefit for oblimersen over FC alone.

Information was available for 97% of the original randomised patients, and the post-study CLL treatments were balanced between all arms.

Of those subjects who showed complete or partial responses, 24% of patients receiving FC and 47% of patients receiving oblimersen-FC were still alive at this long-term follow-up. Among these patients, oblimersen-FC promoted significantly improved 5-year survival (HR, 0.60; log rank P = .038). No difference was seen for survival of the originally nonresponding patients.

When compared with FC, oblimersen-FC treatment improved complete response rates in a manner that was consistent with the proposed Bcl-2 down-regulatory action of oblimersen, targeting relapsed patients (6% vs 25%, respectively, P = .016) with only 1 or 2 prior regimens (6% vs 23%, P = .016) who responded to their last therapy over 6 months ago (6% vs 22%, P = .032).

The greatest survival benefit was seen in the fludarabine-sensitive relapsed population with oblimersen addition to FC (HR 0.50, log rank P = .004). "It is a well-tolerated, good drug in these patients," Dr. Cousin concluded.

Funding for this study was provided by Genta Incorporated.

[Presentation title: Five-Year Follow-Up of Heavily Pretreated Patients With Relapsed/Refractory CLL in Phase 3 Study: Significant Survival Benefit With Oblimersen Plus Fludarabine/Cyclophosphamide in Responding Patients. Abstract 0357]

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