Dose-reduced FCR first-line therapy in fit elderly CLL patients is safe, tolerable, and highly effective: first report of final statistical analysis from end of study and 12 month follow-up of ALLG CLL5 randomised dose de-escalation study

Background: The CLL8 Study showed fludarabine, cyclophosphamide and rituximab (FCR) provided significant benefit in progression free (PFS) and overall survival (OS), but the median age was 61 years, 10-years younger than typical CLL. We conducted a randomised dose de-escalation study to assess the safety, tolerability, and efficacy of FCR based therapy in fit elderly patients with CLL. Methods: Previously untreated, fit (CIRS 6) patients with progressive CLL aged 65 were randomised to one of 3 therapy arms: (i) FR5: F-24mg/m2 po D1-5 + R (375mg/m2 cycle 1, 500mg/m2 cycles 2-6) iv D1, (ii) FCR3: F-24mg/m2 po and C-150mg/m2 po D1-3 + R iv D1 or (iii) FCR5: F-24mg/m2 po+ C-150mg/m2 po D1-5 + R iv D1 ( = full dose FCR) at 4 weekly intervals for planned 6 cycles. Early stopping for toxicity was mandated: treatment could be delayed for 2 weeks for grade 3 + toxicity, but if unresolved by 2 weeks, patients were taken off study. The primary end-point was tolerability defined as the proportion of patients completing all 6 cycles of planned therapy. Results: Patient characteristics: Of 120 recruited patients, 116 were assessable. Median age was 71 (range 65-82) with 77 (66.4%) males and 39 (33.6%) females. Binet stage at registration was stage A-16.4%, B-46.6% and C-34.5% and CIRS 0-2: 53.4%, 3-4: 31.9%, 5-6: 14.7%. Tolerability: FCR5 was less tolerable (p < 0.001) with 34% completing all 6 cycles compared to FR5 86% and FCR3 74% which were not statistically different (NSD) (Table 1). Safety: Due to the early stopping rule, all 3 arms were safe, but more patients came off protocol with “unacceptable” toxicity in FCR5 arm (p < 0.001); 3 with fatigue, and 8 cytopenia (Tables 1 and II). Toxicity: Grade 3/4 toxicity was more common with FCR5 than FR5 or FCR3 (p = 0.004) (FCR3 vs FCR5 NSD). Most toxicity was haematological and manageable (Table 2). Dose delay occurred in 43 patients (37%): FR5 12 (32%), FCR3 14 (34%), FCR5 17 (44%) (p = 0.653). 11/13 patients stopping early due to toxicity received 3 cycles of therapy (mean 3.5). Intention to treat FCR5 minimum residual disease (MRD)-negative rates were higher with FCR5 (79%) (p < 0.001) vs FCR3 and FR5 (FCR3 vs FR5 NSS), and hence an MRD-dose intensity effect may exist but FCR5 had more incomplete marrow recovery, toxicity and earlier cessation of therapy. Response rates: Overall response rates (ORR) were high (95%) in all 3 arms. FCR5 and FCR3 had higher complete remission (CR-BM-confirmed) than FR5 but not significant (p = 0.203 and p = 0.802 respectively) (Table 3). PFS and OS at 12 months were 83% and 95%, and 18 months 69% and 90%. At 18 months, PFS was FR5 65%, FCR3 75%, FCR5 65% and OS 97%, 90%, 83% respectively (Figures 1&2, all NSD). Conclusion: Dose-reduced FCR is safe, very tolerable and highly effective. Response rates are very high. Full dose FCR is also effective but early cessation with toxicity appears important.