Tolerability in Transplant-Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Based Combination Therapy: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction

Therapeutic challenge remains in older patients with acute myeloid leukemia (AML) with significant comorbidities who are not fit for induction chemotherapy and haemopoietic stem cell transplantation. Leukemic cells depend on BCL-2 protein (anti-apoptotic protein) for their survival. Venetoclax is a selective small-molecule BCL-2 inhibitor which binds to BCL-2 resulting in apoptosis of leukemic cells. In recent years, venetoclax has been approved in combination with azacitidine or low dose cytarabine in transplant-ineligible patients with newly diagnosed AML (ND AML). However, there are notable toxicities. The purpose of our meta-analysis is to determine tolerability, rates of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI), dose reduction and 30-day mortality in transplant-ineligible patients with ND AML treated with venetoclax based combination therapy.

Methods

We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30^th, 2023. Phase III RCTs utilizing venetoclax in transplant-ineligible patients with ND AML that mention tolerability, rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, 30-day mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied.

Results

A total of 637 transplant-ineligible patients with ND AML from 2 phase III RCTs (VIALE-A and VIALE-V) were eligible. VIALE-A and VIALE-V compared azacitidine + venetoclax vs azacitidine + placebo, and venetoclax + low dose cytarabine vs placebo + low dose cytarabine respectively. The randomization ratio was 2:1 in both studies. TD due to treatment emergent adverse events (TEAE) was noted in 104 (24.5%) of venetoclax group vs 45 (21.2%) in control group with RR of 1.15 (95% CI: 0.85 -1.57; P = 0.37). TI due to TEAE was higher in the venetoclax group (68.9%) compared to control group (55.6%) with RR of 1.24 (95% CI: 1.08 -1.42; P = 0.002). 21 (4.9%) of patients in venetoclax group and 10 (4.7%) in the control group required dose reduction of treatment due to TEAE, RR 1.03 (95% CI: 0.50 -2.16; P = 0.93). Treatment emergent SAEs were reported in 77.4% in the venetoclax group vs 60% in control group (RR, 1.30; 95% CI: 1.15-1.46; P <0.0001). 30-day mortality was reported in 39 (9.1%) of patients in the venetoclax group and 20 (9.4%) in the control group with RR of 0.96 (95% CI: 0.58 -1.60; P = 0.89).

Conclusions

Our meta-analysis showed that there was no significant difference in the rate of treatment discontinuation and dose reduction due to adverse events in transplant-ineligible patients with ND AML treated with venetoclax combination regimens, compared to control arm although rates of treatment emergent SAEs and treatment interruption were considerably higher in the venetoclax-treated arm. However, the 30-day mortality rate was similar between the two groups. Longer follow up and timely supportive care are required to improve treatment emergent SAEs and treatment interruption.