Excellent Clinical Outcomes in Deeply Mutated IGHV Chronic Lymphocytic Leukemia upon Fludarabine and Cyclophosphamide Plus Rituximab

Introduction: Frontline fludarabine and cyclophosphamide plus rituximab (FCR) has until recently been considered the standard of care for fit younger patients (<65 years [y]) with chronic lymphocytic leukemia (CLL), who are immunoglobulin heavy chain variable gene (IGHV) mutated. Established 25 years ago, the IGHV germline identity (ID) of <98% vs ≥98% has defined IGHV mutational status mutated (M) vs unmutated (U), respectively (Hamblin et al., and Damle et al., Blood 1999). FCR leads to long-term progression-free survival (PFS) for patients with IGHV-M (median PFS 14.6 y; Thompson et al, Blood 2024) also described as a potential functional cure, although the risk of secondary malignancy and therapy-related myeloid neoplasms is significant (da Cunha-Bang et al., BJH 2021). In recent years, targeted treatments have largely replaced chemoimmunotherapy (CIT). Thus, it is debated whether FCR is still a relevant treatment option possibly providing a clinical cure for a subset of patients. Here, we investigated whether patients with deeply mutated (D) IGHV may indeed benefit from FCR.

Methods: We retrospectively included patients diagnosed with CLL between Jan 2008 and Apr 2021 in the Danish CLL register, who were up to 65 years of age when they received frontline FCR. Information on IGHV germline identity (ID) was collected nationwide from three central laboratories. Patients were grouped according to IGHV germline ID: IGHV-U (≥98%) vs IGHV intermediately mutated (IGHV-I; 94-98%) vs IGHV-D (<94%). With real world data missing consistent information on CLL progression, we analyzed treatment-free survival (TFS) as time to next treatment or death (composite event) using the Kaplan-Meier method and followed patients until next treatment, death, or end of follow-up. The log-rank test was used to compare 10-y overall survival (OS) and TFS.

Results: In total, 269 patients received frontline FCR including 255 (94.8%) with information on IGHV status, while information on IGHV germline ID was available for 178 patients (66.2%): 120 (67.4%) 36 (20.2%), and 22 (12.4%) patients were IGHV-U, IGHV-I, and IGHV-D, respectively. At time of diagnosis, the 269 patients had a median age of 55 years (interquartile range [IQR] 50-60), the median age was similar between patients with IGHV-D, IGHV-I and IGHV-U (56 [IQR 48-61] vs 55 [IQR 50-59] vs 56 [IQR 50-60], respectively), 67.7% were male, 45.0% were Binet stage A at diagnosis, 60.2% were IGHV-U, and 5.6% had a 17p deletion, which was exclusively seen among IGHV-U patients.

OS upon FCR was numerically longer in patients with IGHV-M compared to IGHV-U (10-y OS 74.6% vs 67.9%, respectively; P=0.13). As expected, patients with IGHV-M demonstrated longer TFS as compared to those with IGHV-U (10-y TFS 64.0% vs 33.6%, respectively; p=0.00019). Subdividing the IGHV-M group into IGHV-I and IGHV-D, patients who were IGHV-D demonstrated longer OS (10-y OS 100% vs 79.7% vs 67.2%, respectively) and longer TFS (10-y TFS 100% vs 73.5% vs 28.8%, respectively) compared to both IGHV-I and IGHV-U. A significant difference was found between IGHV-D and IGHV-I regarding both OS (P=0.030) and TFS (P=0.022) using the pairwise log-rank test.

Conclusion: In this population-based real-world study, younger CLL patients treated with frontline FCR demonstrated excellent long-term OS and TFS in a smaller subset of patients (12%) with deeply mutated IGHV (IGHV-D) with germline ID below 94%. Upon external validation, IGHV-D – rather than IGHV status alone – could identify patients with a high likelihood of being cured with FCR. By contrast, less than 3 of 4 patients with intermediately mutated IGHV (94-98% germline ID) remained alive and without second line treatment after 10 years follow-up; these patients should thus be offered targeted therapies.