[Long-term outcomes of first-line iFCR regimen in chronic lymphocytic leukemia/small lymphocytic lymphoma and the role of MRD].

Objective

This study aimed to investigate the clinical significance of measurable residual disease (MRD) in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) regimen.

Methods

Data of 34 patients with treatment-naive CLL/SLL treated with the iFCR regimen in the Department of Hematology of The First Affiliated Hospital of Nanjing Medical University from February 2019 to June 2025 were retrospectively collected and comprehensively analyzed. Data included MRD detected with flow cytometry (FCM) and NGS, efficacy evaluation, progression-free survival (PFS), and overall survival (OS). UMRD4 was defined as MRD of <10(-4) detected with FCM. According to peripheral blood MRD (PB-MRD) kinetics, patients were categorized into three groups: sustained uMRD4 (n=13), MRD relapse (n=4), and sustained MRD positive (n=7) .

Results

Median follow-up was 60.2 (95% CI: 53.9-66.5) months, and the median PFS and median OS times were not reached. The 5-year PFS and OS rates were 58.6% (95% CI: 35.6% -96.6% ) and 94.4% (95% CI: 84.4% -100% ), respectively. Compared with patients with unmutated immunoglobulin heavy chain variable (IGHV) and TP53 aberration, patients demonstrating mutated IGHV (median PFS time: not reached vs 59.3 months, P= 0.019) and the absence of TP53 aberration (median PFS time: not reached vs 38.6 months, P=0.011) were associated with a longer PFS. After 2 months of combination therapy completion, patients with PB-uMRD4 achieved a higher rate of complete response (CR) compared with those with positive PB-MRD (73.3% vs 20.0%, P=0.015) and demonstrated a longer PB-uMRD4 duration during long-term follow-up (36.3±16.2 months vs 4.6±4.7 months, P<0.001). A good concordance was observed between PB-MRD and bone marrow MRD (BM-MRD) detected with FCM (P<0.001, r=0.739) and NGS (P<0.001, r=0.869). Further, the concordance of PB-MRD detection (P=0.003, r=0.439) between FCM and NGS was superior to that of BM-MRD (P=0.033, r=0.299). Treatment was either actively discontinued (those achieving uMRD4) or continued (those with detectable MRD) according to the BM-MRD level after 2 years of iFCR treatment. Furthermore, disease progression occurred in 1 (1/9, 11.1% ) patient who discontinued therapy and 7 (7/19, 36.8% ) patients who continued treatment. Among them, 7 patients who actively discontinued treatment and kept PB-uMRD4 and CR demonstrated no del (17p), del (11q), and TP53 mutations. The proportion of patients with complex karyotypes (7.7% vs 57.1%, P=0.031), del (17p) (0 vs 42.9%, P=0.031), and TP53 mutations (0 vs 42.9%, P=0.031) was lower in the sustained uMRD4 group compared with the sustained MRD-positive group.

Conclusion

Unmutated IGHV and TP53 aberration remained adverse factors for PFS in patients with CLL/SLL who received the first-line iFCR regimen. After 2 months of combination therapy completion, patients with PB-uMRD4 were more likely to maintain PB-uMRD4 for an extended period, whereas patients with high-risk factors, including complex karyotype, del (17p), and TP53 mutation, were less likely to achieve uMRD and discontinue treatment. Furthermore, the ibrutinib maintenance strategy can be adjusted based on the BM-MRD level at 2 years. Monitoring PB-MRD dynamically was crucial in detecting MRD conversion and progression.