Longer Term Follow-up of a Multicenter, Phase 2 Study of Ibrutinib Plus Fludarabine, Cyclophosphamide, Rituximab (iFCR) As Initial Therapy for Younger Patients with Chronic Lymphocytic Leukemia

Introduction FCR remains the only therapy other than allo transplant proven to provide a significant chance of functional cure with very long term follow-up for young, fit patients with mutated IGHV CLL. Given the excellent efficacy and tolerability of ibrutinib in a broad population of young, fit CLL patients, we designed the frontline iFCR study to investigate whether time-limited novel agent plus chemoimmunotherapy could provide durable remission for CLL patients irrespective of IGHV status. We previously reported that with a median follow-up of 16.5 months, the rate of CR with bone marrow undetectable minimal residual disease (BM-uMRD) 2 months post-FCR (primary endpoint) was 33%, and that 84% of patients achieved BM-uMRD as best response (Davids et al., Lancet Haem, 2019). Here, we report updated data with longer follow-up, with all patients having had the opportunity to complete 2 years of ibrutinib maintenance following iFCR. Methods This is a multicenter, single arm, phase 2 investigator sponsored trial (NCT02251548) which enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL treatment criteria. Ibrutinib 420 mg daily was given for 7 days, then combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM-uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity by CTCAE v4.03 and iwCLL criteria. The primary objective was to determine the rate of CR/CRi with BM-uMRD 2 months after iFCR combination. Secondary objectives were to assess response rates, PFS/OS, rates of BM-uMRD after 2 years of ibrutinib maintenance, and safety/tolerability. Results Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites.As previously reported, the median age was 55 years (range 38-65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1-6). Median follow-up is now 40.3 months (range 3.1-76). Median number of ibrutinib maintenance cycles is 24 (range 0-81). By ITT analysis, the rate of CR with BM-uMRD at any point on study is now 55% (47/85 patients), and best rate of BM-uMRD remained 84% (71/85). After 2 years of ibrutinib maintenance, the rates of CR/CRi, BM-uMRD, and PB-uMRD in patients with available d