Continuous venetoclax for relapsed chronic lymphocytic leukemia (CLL) – characteristics and outcomes of long-term responders

Abstract Aim: Venetoclax was initially approved for continuous use in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), but the potential for truly durable responses with continual BCL2 inhibition are unclear and long-term toxicity not yet defined. We describe the frequency, characteristics and outcomes of patients with R/R CLL achieving a long-term response (>5 years) to continuous venetoclax. Methods: We identified 86 patients with R/R CLL treated with continuous venetoclax (+/- initial rituximab) within four early phase clinical trials (M12-175, M13-982, M13-365, M15-889) at two institutions. “Long-term responders” were defined by > 5 years of continuous venetoclax without progressive disease (PD). Progression-free survival (PFS) and overall survival (OS) from treatment onset and from the 5-year landmark were analyzed using Kaplan Meier methods. Two and 5-year landmarks for undetectable minimal residual disease (uMRD) status (10-4by flow cytometry in peripheral blood) were used to assess associations with PFS. Next generation sequencing was performed at PD for BCL2 mutations. Adverse events were graded according to the national cancer institute common terminology for adverse events, version 4.0. Results: Twenty-nine (33%) patients were “long-term responders”. Median age at venetoclax commencement was 67, median number of prior lines of therapy was 3 (1-8) and 41% had TP53 aberrant disease. Long-term responders were more likely to have IGHV-M CLL (44% vs. 15%, p =0.03), non-complex karyotype (89% vs. 65%, p = 0.04) and have achieved uMRD status (76% vs. 28%, p=0.04) than those with PD within 5 years of commencing venetoclax. At a median additional follow-up of 4.2 years, 18 (62%) long-term responders had ceased venetoclax, mostly due to PD (10/18) or the development of therapy-related myeloid neoplasm (3/18; all prior recipients of fludarabine). Eleven patients (38%) remained on treatment, including 3 patients with enduring uMRD. Median additional PFS post the 5-year landmark was 2.9 years and median OS was not reached. Of the 10 PD patients, two had Richter's transformation (RT) and BCL2 mutations were detected in 3/7 patients assessed. Nine patients received subsequent therapy, with an overall response rate of 50% (4/8 response-evaluable), including 80% response rate to BTKi in those without RT (4/5). In a land-mark analysis including all patients continuing venetoclax beyond 2 years (43/86), 5-year PFS for those with uMRD at 2 years was 87% and 45% for those without (HR 0.72, 95% CI 0.34-1.52, p=0.39). MRD status at 5-year landmark was significantly associated with PFS (HR 0.16, CI 0.04-0.71, p = 0.03). The frequency of grade ≥3 infection observed beyond 5 years (1.2 infections per 100 patient months) was similar to that observed in the first five years of venetoclax treatment (0.8 infections per 100 patient months). Patients who experienced grade ≥3 infection after 5 years had a significantly higher rate of grade ≥3 neutropenia compared to those who did not (66.7% vs 20%%, p=0.032). After 5 years, grade ≥3 neutropenia occurred in 34% and grade ≥3 thrombocytopenia in 17% of patients. Conclusion: Long term responses to continuous venetoclax occurs in approximately one third of patients with R/R CLL and are more common in patients with good risk genomics. Amongst this cohort, patients with sustained uMRD have the most favourable outcome but all patients show a continuous risk of relapse, infection and cytopenias.