Ibrutinib plus fludarabine, cyclophosphamide and rituximab (iFCR) as initial treatment for chronic lymphocytic leukemia/ small lymphocytic leukemia: a single‐arm study

Abstract

Introduction: BTK inhibitors (BTKi) monotherapy has introduced the concept of continuous treatment in CLL/SLL until disease progression, leading to several concerns like lack of deep remission, increasing risk of toxic effects and substantial cost. Therefore, time-limited treatment strategies as first line treatment of CLL/SLL were comprehensively explored and BTKi combined with chemoimmunotherapy was one of these options which could induce durable responses in young fit patients. Methods: CLL/SLL patients who were treated with iFCR as initial therapy in the First Affiliated Hospital of Nanjing Medical University were included without any genomic restrictions. Ibrutinib (420 mg daily) was given continuously for 2 years and intravenously rituximab (375 mg/m2 in day 0 of cycle 1; 500 mg/m2 in day 0 of cycle 2–6), fludarabine (25 mg/m2, days 1–3) and cyclophosphamide (250 mg/m2, days 1–3) were administered every 28-day cycle, up to maximal 6 cycles. Patients who achieved complete remission or complete remission with incomplete recovery (CR/CRi) and bone marrow (BM) undetectable MRD (uMRD) 2 years after iFCR initiation were feasible to discontinue ibrutinib maintenance. Results: 34 previously untreated, young fit CLL/SLL patients who received iFCR regimen between January 2019 and March 2021 were included in our cohort. The median age was 55 years (IQR: 48–56). IGHV was unmutated in 21 of 34 (61.8%) patients; complex karyotype was present in 11 of 34 (32.4%) patients; TP53 mutation or del(17p) was detected in 6 of 34 (17.6%) patients. CR/CRi rate and BM uMRD rate was 35.3% (12/34) and 41.2% (14/34) after 3 cycles of iFCR and increased to 55.9% (19/34) 2 months after 6 cycles in both patients who received 3 or 4 and 6 cycles of iFCR. The best CR/CRi and BM uMRD rate were both 73.5% (25/34). With the median follow-up of 33 months (range 7–42 months), the 3-year PFS and OS rate was 80.0% and 95.5% respectively. CR/CRi rate and BM uMRD rate was comparable between patients with IGHV mutated and unmutated status without TP53 aberration, while all patients with TP53 aberration failed to achieve sustainable CR/CRi or BM uMRD. Patients who achieved MRD 10-6 negative post 3 cycles of iFCR sustained remission and discontinued ibrutinib maintenance. The most common hematological adverse events were neutropenia (25/34, 73.5%) and thrombocytopenia (24/34, 70.6%), grade 3–4 neutropenia and thrombocytopenia occurred in 67.6% (23/34) and 35.3% (12/34) patients respectively. The most common non-hematological adverse events were nausea (21/34, 61.8%), fatigue (16/34, 47.1%) and vomiting (15/34, 44.1%). Conclusion: The iFCR regimen could achieve high response rate and uMRD rate as initial treatment for young fit CLL/SLL patient without TP53 aberrations with acceptable tolerability. MRD-guided iFCR courses adjustment in patients who achieved early phase remission could achieved sustainable response and reduced toxicity. Encore Abstract - previously submitted to regional or national meetings (up to <1’000 attendees) The research was funded by: This study was supported by National Natural Science Foundation of China (Grant No. 82170166, No. 82100207, No. 82170186, No. 81970146, No. 81900167), Translational Research Grant of National Clinical Research Center for Hematology (2020ZKZB01), Six Talent Peaks Project in Jiangsu Province 2019 (Grant No. WSN-001) and Youth Talent support Project in Jiangsu Province Hospital (Grant No. YNRCQN035). Keywords: Chronic Lymphocytic Leukemia (CLL), Combination Therapies No conflicts of interests pertinent to the abstract.