Ibrutinib alternating with three cycles of interval fludarabine, cyclophosphamide, and rituximab (FCR) in adults with untreated chronic lymphocytic leukaemia as time-limited regimen: a single-arm, multicentre phase 2 trial in China.

Background: Effective time-limited therapies remain an unmet need in chronic lymphocytic leukaemia (CLL). We evaluated a novel regimen combining ibrutinib with intermittent fludarabine, cyclophosphamide, and rituximab (FCR) in patients with CLL. Methods: This single-arm, multicentre, phase 2 trial was conducted at three centres in China. Eligible participants were adults (aged 18-65 years) with previously untreated CLL requiring therapy according to the International Workshop on Chronic Lymphocytic Leukaemia criteria. The regimen consisted of ibrutinib (420 mg daily) combined with three cycles of FCR administered on days 1-3 of cycles 1, 5, and 9. After the completion of induction therapy, among patients who had achieved complete remission (CR) with undetectable minimal residual disease (uMRD): those without TP53 deletion or mutation could discontinue treatment; those with TP53 deletion or mutation continued maintenance therapy for 6 months before discontinuing treatment; all other patients continued ibrutinib until they achieved CR-uMRD, followed by an additional 6 months of treatment. The primary endpoint was CR rate at best response. This trial is registered with ClinicalTrials.gov, NCT03980002. Findings: Between June 1, 2019, and July 30, 2023, 50 patients were enrolled with a median follow-up of 55 months (IQR 40-65). The median age of participants was 57 years (IQR 48-62), and 36 (72%) were male. Among 47 patients with available IGHV data, 18 (38%) had unmutated IGHV. TP53 deletion/mutation were present in four (8%) patients. The CR rate, the primary outcome, was 70% (35/50) at best response. 18 patients (36%) achieved CR with undetectable MRD in both bone marrow and peripheral blood, discontinuing treatment post-induction. Four deaths occurred; one due to Richter's transformation, two from COVID-19, and one from cerebral infarction. Grade 3/4 neutropenia occurred in 13 (26%) patients, leucopenia in 11 (22%) patients, and lymphocytopenia in 12 (24%) patients. No therapy-related cases of myelodysplastic syndrome or acute myeloid leukaemia were observed. Interpretation: This regimen achieved deep remissions with manageable toxicity. Whilst acknowledging study limitations and that pathway inhibitors are the current standard of care, these findings provide proof-of-principle that this regimen could be a feasible, time-limited treatment option for CLL. Particularly in resource-limited healthcare systems where continuous novel agents are less accessible. Future studies should explore long-term durability beyond 5 years and validate MRD thresholds for treatment cessation. Funding: National Nature Science Foundation of China, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Beijing Xisike Clinical Oncology Research Foundation.