Incidence of Pneumonia, Sepsis and Febrile Neutropenia 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
Authors: Htut Thura Win , Myat Yin Mon , Zaw Myo Htet , Thein Kyaw Zin 
Published: December 2023

Introduction
Prognosis remains dismal for older patients with acute myeloid leukemia (AML) even after hypomethylation agent or low dose cytarabine. Venetoclax is a highly selective oral BCL-2 inhibitor which induces apoptosis in BCL-2 dependent leukemic cells. In recent years, phase III RCTs have shown that the addition of venetoclax to standard treatment in older patients with newly diagnosed AML (ND AML) significantly improved efficacy with notable toxicities. We conducted a combined analysis of randomized controlled trials (RCT) to determine the risks of pneumonia, sepsis and febrile neutropenia 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 febrile neutropenia, sepsis and pneumonia as adverse effects 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. The incidence of any-grade pneumonia was 22.1% in study group vs 23.6% in control group (RR, 0.94; 95% CI: 0.70 - 1.27; P=0.69). High-grade pneumonia rate was nearly 2.9% lower in the study arm compared to control arm, but RR was not statistically significant at 0.86 (95% CI: 0.62 - 1.21; P = 0.39). High-grade sepsis was reported in the study arm (5.6%) versus 7.5% in control arm with RR of 0.75 (95% CI: 0.41- 1.38; P = 0.35). High-grade febrile neutropenia as hematologic adverse events was noted in 163 (38.4%) of patients in study group compared to 47 (22.2%) in control group with RR of 1.73 (95% CI: 1.31- 2.29; P = 0.0001). Febrile neutropenia as serious adverse events was reported in 107 (25.1%%) of patients in study group compared to 27 (12.7%) in control group with RR of 1.98 (95% CI: 1.34- 2.93; P = 0.0006).
Conclusions
Our meta-analysis showed that venetoclax based anti-leukemic therapy contributed to higher incidence of high-grade febrile neutropenia as hematologic and serious adverse events in transplant-ineligible patients with ND AML, with RR of 1.73 and 1.98. However, the risks of high-grade sepsis and pneumonia were found to be statistically not significant between the two groups. Timely intervention with proper supportive care is required.