A Randomised Dose De-Escalation Study of Oral Fludarabine, ±Oral Cyclophosphamide and Intravenous Rituximab As First-Line Therapy of Fit Patients with Chronic Lymphocytic Leukaemia (CLL) Aged ≥65 Years: Final Analysis of Response and Toxicity

BACKGROUND: Fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free (PFS) and overall survival (OS) versus (vs) FC in the CLL8 Study. The median age in CLL8 was 61 years compared to 72 years for CLL overall. We aimed to assess the safety, tolerability and efficacy of FCR based therapy in elderly patients (pts).METHODS: Previously untreated pts 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 all at 4 weekly intervals for an intended 6 cycles. Cycles could be delayed up to 2 weeks for grade 3+ toxicity, and if unresolved by 2 weeks, pts were taken off study. All analyses were by intention to treat (ITT) and adjusted for pre-treatment Binet stage.RESULTS: Recruitment of 120 pts was completed in July 2012. 117 fulfilled eligibility and 1 had no treatment or follow-up reducing the cohort to 116. Median age was 71 (range 65-82) years; 78 males (67%) and 39 females (33%). Binet stage was progressive A - 19 (16.2%), B – 55 (47.0%), C – 43 (36.8%). Response data are shown in table 1 and grade 3+ toxicity in table 2. All 6 protocol cycles were completed in 69% but less on FCR5 44% vs FR5 89% and FCR3 76% (p<0.001). FCR3 vs FR5 was not statistically significant (NSS).Reasons for non-completion were death, intercurrent illness, withdrawn consent, stable or progressive disease, unacceptable toxicity and doctor decision.