1. In this phase I trial, gradual dose escalation with selective BCL2 inhibitor, venetoclax, showed a manageable safety profile and significant antitumor activity for treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL).
2. Venetoclax was safe and active at all dose levels, with no maximum tolerated dose identified.
Evidence Rating Level: 2 (Good)
Study Rundown: Patients with relapsed or refractory CLL have elevated expression of anti-apoptotic BCL2 proteins, resulting in accumulation of clonal cells. Ventoclax is a highly selective and potent inhibitor of BCL2, inducing apoptosis in vitro and in vivo models. Based on these models, this first-in-human phase I trial in patients with relapsed or refractory CLL or SLL aimed to establish a safety profile, pharmacokinetic profile, maximum tolerated dose, and dosing schedule for a phase II trial. The majority of patients had multiple prior treatments and poor prognostic factors. Results indicated venetoclax was active at all doses with associated patient response in the majority of cases, but no maximum tolerated dose was identified. Clinical tumor lysis syndrome occurred in a small number of patients in the dose escalation cohort, but not in the dose expansion cohort. Minor toxicities included nausea, diarrhea, upper respiratory tract infection and neutropenia. Limitations of this study include the small sample size, and lack of blinding and randomization, making results difficult to generalize. However, given the challenge in managing relapsing and recurrent CLL, venetoclax represents a promising treatment option for such patients, and its toxicity profile is manageable.
In-Depth [prospective cohort]: This phase I dose-escalation study of oral venetoclax, a BCL2 anti-apoptotic inhibitor, aimed to assess its safety, pharmacokinetic profile and efficacy in patients with relapsed or refractory CLL or SLL. In the dose escalation cohort, there were 8 dose groups (150-1200mg) spread across 56 patient participants. In the dose expansion group, a weekly dose increases were given to 60 patients.
There were a total of 116 patients, 89% of whom had poor prognostic clinical or genetic features. Tumour lysis syndrome occurred in 18% of patients in the dose escalation cohort. In the dose expansion cohort, 1 patient had laboratory evidence of tumor lysis syndrome, but none had clinical symptoms. Other side effects included: mild diarrhea (52%), upper respiratory tract infection (46%), nausea (47%) and neutropenia (41%; grade 3/4). The pooled overall response rate for the 116 patient participants was 79%, with a 20% complete response rate. In patients with a 17p CLL deletion, the response rate was 71%, with a 16% complete response rate. In the dose escalation cohort, the median duration of progression-free survival was 25 months (95% CI, 17-30). No similar data was obtained in the dose expansion cohort due to short follow up (median follow up duration, 17 months; range <1-26).
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