1209 - Ibrutinib plus fludarabine, cyclophosphamide and rituximab (iFCR) as initial treatment in chronic lymphocytic leukemia/ small lymphocytic leukemia with or without TP53 aberrations: A prospective real-world study in Chinese cohort

Background
Bruton tyrosine kinase inhibitors (BTKi) monotherapy has introduced the concept of continuous treatment in chronic lymphocytic leukemia/small lymphocytic leukemia (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 (CIT) 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 (Jiangsu Province Hospital) 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 minimal residual disease (uMRD) 2 years after iFCR initiation were feasible to discontinue ibrutinib maintenance.

Results
Thirty-four previously untreated, young fit CLL/SLL patients who received iFCR regimen between January 2019 and Match 2021 were retrospectively 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%). 35.3% (12/34) patients experienced at least one dose FC regimen reduction and 47.1% (16/34) patients experienced at least once ibrutinib dose-hold with a median duration of 7 days.

Conclusion
The iFCR regimen could achieve high response rate and proportion of uMRD 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.