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

Stephen Mulligan, Paul Turner, Devinder Gill, Maya Latimer, William Renwick, Rosemary Harrup, Gavin Cull, Cecily Forsyth, Naomi Mackinlay, Leanne Berkahn, Phillip Campbell, David Simpson, Constantine Tam, Melanie Sulda, Giles Best, Mathias Bressel, Juliana Di Iulio, Bryone Kuss

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Abstract

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.
Original languageEnglish
Article numberAbstract 31
Pages (from-to)23-25
Number of pages3
JournalLeukemia and Lymphoma
Volume56
Issue numberSup1
DOIs
Publication statusPublished - 19 Jan 2016
EventXVI International Workshop on Chronic Lymphocytic Leukemia 2015 - Sydney, Australia
Duration: 6 Sep 20159 Sep 2015

Keywords

  • final statistical analysis
  • Dose-reduced FCR
  • fit elderly CLL patients
  • 12 month follow-up
  • ALLG CLL5 randomised dose

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    Mulligan, S., Turner, P., Gill, D., Latimer, M., Renwick, W., Harrup, R., Cull, G., Forsyth, C., Mackinlay, N., Berkahn, L., Campbell, P., Simpson, D., Tam, C., Sulda, M., Best, G., Bressel, M., Di Iulio, J., & Kuss, B. (2016). 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. Leukemia and Lymphoma, 56(Sup1), 23-25. [Abstract 31]. https://doi.org/10.3109/10428194.2015.1080893