CLL-506 Clinical Outcomes Beyond Progression on Ibrutinib in Patients With Chronic Lymphocytic Leukemia

Context: Patients with chronic lymphocytic leukemia (CLL) with disease progression on ibrutinib have worse outcomes compared to patients stopping ibrutinib due to toxicity. Objective: To analyze survival estimates of patients with CLL following true disease progression (per iwCLL 2018 criteria) on ibrutinib. Design: Retrospective. Setting: Academic. Patients or Other Participants: Patients with CLL who received ibrutinib therapy for CLL at a Mayo Clinic Cancer Center site (Arizona, Florida, Minnesota) between 4/2012-6/2021. Main Outcome Measures: Treatment-free survival (TFS) was analyzed as the duration from the start of treatment immediately after ibrutinib failure to the start of the subsequent line of therapy or death, whichever occurred earlier. Overall survival (OS) was analyzed as the time from date of progression while on ibrutinib and from subsequent therapy start date until date of death or last known to be alive. OS was analyzed using the Kaplan-Meier method (with comparisons of OS by characteristics analyzed by the log rank test). Results: Among 144 patients with CLL identified to have disease progression on ibrutinib, the median age was 68 years and 74% were male. Unmutated IGHV (90%) and TP53 disruption (50%) were common in evaluable patients at the time of progression on ibrutinib. The median OS for the entire cohort following progression on ibrutinib was 25.5 months; 29.8 months and 8.3 months following CLL progression (n=104) and Richter's transformation (n=38), respectively. Longer OS was observed among patients with CLL progression who had received ibrutinib in the frontline (n=23) compared to relapsed/refractory setting (not reached versus 28.5 months; p=0.04), but was similar amongst patients treated with 1, 2, or ≥3 prior lines (18.5, 30.9, and 26.0 months, respectively, p=0.24). Among patients with CLL disease progression on ibrutinib, next-line treatment with chimeric antigen receptor T-cell therapy or venetoclax-based treatment was associated with significantly longer median OS and TFS compared to other approved treatments (OS: not-reached, 29.8 months, and 9.1 months, respectively, p=0.034; TFS: 30.4 months, 20.1 months, and 4.4 months, respectively, p<0.001) Conclusions: These findings suggest an unmet need for this growing patient population while supporting the current practice of next-line venetoclax and participation in clinical trials.