Long-term outcomes with continuous venetoclax for relapsed chronic lymphocytic leukemia

Venetoclax was first approved for continuous use in relapsed-refractory chronic lymphocytic leukemia (RR CLL), but the efficacy and consequences of very long term BCL2 inhibition are unknown. We describe the frequency, characteristics and outcomes of patients with RR CLL treated with >5 years of continuous venetoclax. Long-term responders (>5 years of continuous therapy without progressive disease [PD]), were identified from a cohort of 86 RR CLL patients treated with continuous venetoclax± rituximab. Landmark analyses at 2 and 5 years assessed association between undetectable measurable residual disease (uMRD; 10-4 peripheral blood flow cytometry) and progression free survival (PFS). Next generation sequencing (NGS) was performed at PD for BCL2 and TP53 mutations. Twenty-nine (33%) patients were long-term responders. Compared to those with PD within 5 years, they were more likely to have mutated IGHV(44% vs. 14%, p =0.029), non-complex-karyotype (89 vs. 50%, p=0.043) and uMRD (79 vs. 30%, p<0.001). At median follow-up of 11.1 years, 76% had ceased venetoclax, mostly due to PD. In a landmark analysis of patients continuing venetoclax beyond 2 years, 5-year PFS was 87% for those with uMRD vs. 45% without (HR1.30, 95% CI 1.12-1.52, p=0.001). BCL2 mutations were detected in 4/8 patients at PD. Grade ≥3 toxicities - including infection (51%), neutropenia (20%) and thrombocytopenia (10%)- occurred at consistent frequency throughout treatment. Long-term responses to continuous venetoclax occur in approximately one third of RR CLL patients. Sustained uMRD confers the most favorable outcome, though all patients show a continuous risk of relapse, infection and cytopenias.