Rituximab, Fludarabine, and Cyclophosphamide (R-FC) Prolongs Progression Free Survival in Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) Compared with FC Alone: Final Results from the International Randomized Phase III REACH Trial

The addition of rituximab to a variety of chemotherapy regimens for the treatment of patients with CLL has yielded promising results in phase II trials. The R-FC regimen demonstrated particularly high rates of overall response (ORR), complete remission (CR), progression-free survival (PFS) and overall survival (OS) in relapsed/refractory CLL (Wierda, et al, JCO 2005). REACH was an open-label, multicenter, randomized, phase III study to evaluate the efficacy and tolerability of R-FC versus FC in relapsed or refractory patients with CD20 positive CLL. The primary endpoint of the study was progression free survival.

Five hundred and fifty two patients from 17 countries were randomized (1:1) to receive either R-FC or FC. Rituximab was administered IV before the FC infusion for a total of 6 treatment cycles at intervals of 28 days (Cycle 1: 375 mg/m2 IV; Cycles 2–6: 500 mg/m2 IV). Fludarabine (25 mg/m2 IV/day) and cyclophosphamide (250 mg/m2 IV/day) were administered over 3 days for 6 cycles. Baseline demographics, disease characteristics, and prognostic factors were well balanced between the two arms. Median age was 63 years. All Binet stages were represented (A 10%, B 59%, C 31%). A median of one prior treatment had been administered, consisting of single-agent alkylator therapy (66%), purine-analogs (16%), or combination treatments (CHOP, COP, F-containing, 18%). Patients with prior FC combination treatment or prior rituximab were not eligible. Median observation time was 25 months.

The primary endpoint PFS was significantly prolonged by median 10 months in the R-FC arm (30.6 months) compared to FC (20.6 months, p =0.0002, Hazard Ratio (HR) 0.65 [95% CI 0.51; 0.82]). Secondary endpoints EFS, TTNT, DR showed similar results. ORR were higher for R-FC vs. FC (70% vs. 58%, p=0.0034), due to superior CR rates (24% vs. 13%, p=0.0007). Multiple subgroups were analyzed applying a Cox-regression model: all Binet stages experienced similar incremental benefits in PFS (HR Binet A 0.75, B 0.65, C 0.61). Mutational status and cytogenetic subgroups remained prognostic and benefited from the addition of rituximab to FC (HR IgVH unmutated 0.62, mutated 0.7; del17p pos 0.75, neg 0.63; del13q pos 0.56, neg 0.77). Median overall survival was not reached for R-FC and was 53 months for FC, (p=0.29, HR 0.83). Of 47 patients that relapsed and were treated in the R-FC arm, 30% received rituximab again. Sixty-nine patients were treated at relapse in the FC arm, and 49% received rituximab.

Grade 3/4 Adverse Events were higher in the R-FC arm (80%) vs. FC (74%), but serious adverse events were similar (50% vs. 48%, respectively). Grade 3/4 neutropenia and febrile neutropenia were only marginally increased for R-FC (42% and 15%) vs. FC (40% and 12%, respectively), the same was seen for thrombocytopenia (R-FC 11% vs. FC 9%). Grade 3/4 infections (R-FC 18%, FC 19%) were similar, and there was no difference in bacterial, viral, or fungal infections between the two arms. Grade 3/4 anemia was slightly increased in the FC arm (R-FC 2%, FC 5%). Slightly higher Fatal Adverse Events were seen with R-FC (13%) vs. FC (10%). Fatal SAEs were mainly due to infections, secondary neoplasms, and cardiac disorders. Summary and conclusion: In this large randomized trial in relapsed or refractory CLL, with 10 months improvement in PFS and a doubling of CR rates, R-FC was statistically significant and clinically meaningful superior to FC in the primary analysis. Improvement in PFS was seen across most subgroups, including all Binet stages. Fatal AEs were relatively high in both arms. However, overall, the addition of rituximab to FC in REACH showed a very favorable risk-benefit profile and did not reveal any new or unexpected safety signals.