Abstract
Background: Despite a typically indolent course observed in chronic lymphocytic leukemia (CLL), 2-8% of patients will develop an aggressive B-cell lymphoma, termed RT. Treatment of RT with a diffuse large B-cell lymphoma-like histology (RT-DLBCL) is typically with CIT regimens used for de novo DLBCL. However, historical data suggest these regimens are associated with poor response rates and survival outcomes. The dismal prognosis observed in RT-DLBCL has spurred interest in novel regimens incorporating targeted therapies. Whether BTKis may enhance outcomes observed with CIT is of particular interest given their activity in CLL and RT-DLBCL, but minimal data exist to describe this combination in the frontline setting.
Methods: We conducted a retrospective investigation of consecutive patients diagnosed with RT-DLBCL between January 1st, 2012 and June 30th, 2024 at the University of California, San Francisco (UCSF). We reviewed the medical record for patient demographics, CLL treatment history, RT-DLBCL characteristics, and treatments received for transformed disease. We defined specific treatment subgroups based on receipt of frontline CIT with or without BTKi coadministration or as maintenance therapy; these cohorts excluded patients who had previously received BTKis for management of CLL. Patients were followed until death or last contact date. Primary endpoints of this study included metabolic complete response (CR) rate to frontline therapy as assessed by Lugano classification of PET/CT and overall survival (OS) as estimated by the Kaplan-Meier method and compared using the log-rank test. Secondarily we examined objective response rates (ORR), duration of response, and progression-free survival (PFS). This study was approved by the UCSF institutional review board.
Results: We identified 56 total patients with RT-DLBCL during the study period, of whom 14 received CIT combined with BTKi in the frontline and/or maintenance setting (CIT+BTKi), and 24 received CIT-only after excluding previous BTKi-exposed patients. The median age across the cohort was 72 years, and the median time from CLL to transformation was 5.8 years. Across the overall cohort, ORR was 62.5%, CR rate 57.1%, and median OS was 57.2 months. In an analysis of survival by prior CLL-directed therapy, lower median OS was observed among patients who received prior CLL-directed CIT (N=15, 12.3 months) and targeted therapy (N=12, 8.9 months) compared to patients without prior CLL-therapy (N=29, not reached, p = 0.005). Across the entire study cohort, median OS was not reached in germinal center B-cell (GCB) cell-of-origin RT-DLBCL and 29 months in non-GCB origin (p = 0.07).
Across the CIT+BTKi and CIT-only groups, 27 (71.1%) received no prior CLL-directed therapy. R-CHOP was the most common (57.9%) CIT regimen received. All CIT+BTKi patients continued maintenance BTKi after completion of frontline therapy, and median duration of maintenance was 7.8 months. All 14 CIT+BTKi patients achieved CR compared to 14 (58.3%) of the CIT-only group (p = 0.01). With a median follow-up of 28.3 months, median OS was not reached in the CIT+BTKi group and 75 months among CIT-only recipients (p = 0.66). Only 1 death in the CIT+BTKi group was due to lymphoma – 3 other deaths occurred due to cardiac arrythmia, sarcoma, and an unknown cause in patients who otherwise remained in CR. Median PFS was not reached with CIT+BTKi treatment and 11.8 months with CIT-only (p = 0.04). In contrast to the overall cohort, recipients of CIT+BTKi had numerically worse median OS with GCB (46.4 months) vs non-GCB origin (not reached, p = 0.17).
Conclusion: In this single-institution retrospective cohort of patients with RT-DLBCL, we observed median OS and CR rates that compare favorably against historical cohorts. Prior CLL-directed therapy was associated with inferior survival among RT-DLBCL patients compared to patients with no prior therapy, consistent with previous reports. The addition of BTKi to frontline CIT was associated with higher CR rates and longer PFS, though this did not translate to a statistically significant difference in OS. Notably, these response rates and survival outcomes exceed those previously reported with an alternative novel combination of CIT and venetoclax. CIT+BTKi may be associated with improved survival in non-GCB RT-DLBCL. Future studies in larger, prospective cohorts should be undertaken to identify which patients may benefit most from this combination therapy.
