Durable Clinical Benefit Is Associated with Objective Response and Not Lack of Progression in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL): Results from the Genasense/Flu/Cy Phase 3 Study.

Major objective response (durable complete remission [CR]) is considered evidence of clinical benefit in acute or chronic leukemias. Time-to-progression has recently been proposed as an endpoint for therapeutic trials in CLL, but includes patients who do not achieve objective partial response (PR).

Methods: We prospectively collected data regarding clinical benefit in a phase 3 trial of fludarabine (Flu) plus cyclophosphamide (Cy) with or without Genasense (oblimersen sodium), an anti-Bcl-2 agent. Extent of symptom relief was then correlated with the level of objective response, as assessed by blinded review of clinical data, radiology (including CT scanning), and bone marrow histopathology. Patients who had relapsed from or failed to respond to prior fludarabine-based treatment were eligible for this study. After baseline assessment, they were randomized to receive either Flu/Cy alone (n = 121; Flu, 25 mg/m²/day IV 30–60 min; Cy, 250 mg/m²/day IV 30–60 min) on days 1–3, or continuous infusion of Genasense (3 mg/kg/day) on days 1–7 in combination with the same doses of Flu/Cy given on days 5–7 (n = 120). Treatment was repeated every 4 weeks for up to 6 cycles. The primary endpoint was the proportion of patients achieving a CR or nodular PR (nPR). Symptoms evaluated included: fever; night sweats; fatigue; abdominal discomfort or early satiety due to hepatosplenomegaly; impaired cosmesis or mobility due to lymphadenopathy; and other complaints. “Durable benefit” was defined as a minimum of 6 cumulative months without these disease-related symptoms in patients who were initially symptomatic, up to the date of recurrent symptoms, objective disease progression, or introduction of non-protocol therapy for CLL.

Results: The addition of Genasense to Flu/Cy increased the confirmed Cr/nPR rate from 7% to 17% (P =0.025). Safety profiles for both treatment arms were tolerable. Grade 5 tumor lysis syndrome and infusion reaction (1 pt. each), and an increase in thrombocytopenia, were observed in the Genasense group, whereas neutropenia and anemia were not increased. With 2 years of minimum followup, the duration of CR/nPR was significantly longer in the Genasense group (median, NR vs. 22 mo. for Flu/Cy; P = .03). Durable benefit closely correlated with the level of objective response. Irrespective of treatment assignment, 94% of patients who achieved CR/nPR also attained durable clinical benefit, compared with 59% of patients whose best response was PR. Only 6% of patients whose best response was less than PR attained durable symptomatic relief.

Conclusions: The results of this prospective trial strongly suggest that objective response, in particular CR/nPR, is associated with meaningful symptomatic relief in patients with relapsed/refractory CLL. We confirm that PR can confer meaningful benefit, but we observed durable relief in only 59% of patients with this level of response. In contrast, meaningful benefit occurred infrequently in patients whose best response was less than PR. These results suggest that lack of progression (or measurement of time-to-progression) may not represent a primary or surrogate measure of patient benefit in patients with relapsed or refractory CLL.