Safe Accelerated Venetoclax Escalation: a phase 1b study of obinutuzumab plus venetoclax with daily ramp-up in CLL.

Although venetoclax-based regimens are highly effective for patients with chronic lymphocytic leukemia (CLL), initiation is complex because of the requirement of a 5-week dose ramp-up used to mitigate the risk of tumor lysis syndrome (TLS). We report the results of the first prospective study of venetoclax initiation using an accelerated 5-day inpatient dose ramp-up in CLL. Forty patients were treated, including 15 (37.5%) with relapsed or refractory disease and 13 (32.5%) with medium (n = 11 [27.5%]) or high (n = 2 [5%]) TLS risk at enrollment. All except 1 (97.5%) received obinutuzumab in combination with venetoclax. All patients completed an accelerated daily venetoclax ramp-up from 20 to 400 mg in the inpatient setting. None had clinical TLS. One (2.5%) patient with Bruton tyrosine kinase inhibitor-refractory CLL and high TLS risk developed laboratory TLS after the 200 mg dose of venetoclax, which normalized within a day with a 1-day dose hold and supportive care. The median inpatient time was 7 days. In intention-to-treat analyses of efficacy at 3 months, the overall response rate was 78.0%. Our data support the feasibility of accelerated venetoclax ramp-up in select patients in experienced centers and warrant further exploration of this approach in broader clinical settings. This trial was registered at www.clinicaltrials.gov as NCT04843904.