Outcomes with Venetoclax and Hypomethylating Agents in Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Cell Transplantation: A Systematic Review and Meta-Analysis

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Introduction This systematic review and meta-analysis aimed to evaluate the effectiveness of Venetoclax, a BCL-2 inhibitor, with hypomethylating agents (HMA) for relapsed acute myeloid leukemia (AML) post-allogeneic hematopoietic stem cell transplantation (HSCT). Methods Following PRISMA guidelines, a comprehensive search was conducted in PubMed, Cochrane, and ClinicalTrials.gov databases until April 2024. Keywords used included relapsed acute myeloid leukemia, hematopoietic stem cell transplant, and venetoclax. Thirteen studies met the inclusion criteria. We assessed heterogeneity in the meta-analysis with the I 2 statistics. Proportions and 95% confidence intervals (CI) were extracted to compute pooled analysis using the ‘meta’ package in the R programming language (version 4.3.3). Results We included 337 AML patients from 13 studies who relapsed after HSCT and were treated with venetoclax and HMA. Ten (77%) studies were retrospective, and 3 (23%) were prospective. The median age of patients was 58.5 years (35.2-66) and 50% were male (163 out of 326). The median follow-up duration was 15.3 months (2.7 to 20.1). The median time to relapse after HSCT, reported in 9 studies, was 7 months (1.6-9). The median overall survival was recorded at 8.58 months. Among the 8 studies reporting ELN risk categories, favorable (n=26), intermediate (n=65), intermediate-high risk (n=18), and adverse risk (n=123) were observed. Donor types for HSCT were available for 142 patients, with the distribution as follows: matched related/sibling donor (MRD/MSD, n=38), haploidentical donor (Haplo, n=31), matched unrelated donor (MUD, n=63), and mismatched unrelated donor (MMUD, n=10). Venetoclax was combined with HMA in all patients, with azacitidine (AZA) in 62% and decitabine (DEC) in 38%. Donor lymphocyte infusions (DLI) were utilized in 27% of the patients. The pooled overall response rate (ORR) was 52% (95% CI 40-64%, I²=73%, p<0.01), and the pooled complete response (CR) and CR with incomplete count recovery (CRi) was 39% (95% CI 28-50%, I²=70%, p<0.01). The pooled 6-month overall survival (OS) was 51% (95% CI 24-77%, I²=77%, p<0.01), while the 1-year OS was 29% (95% CI 11-58%, I²=82%, p<0.01). The pooled mortality rate was 29% (95% CI, 9-64%, I²=89%, p<0.01). Our study analyzed the incidence of three common (grade III-IV) adverse events including neutropenia (73%, 95% CI 63-82%, I²=13%, p=0.33), thrombocytopenia (71%, 95% CI 62-79%, I²=33%, p=0.20), and infections (31%, 95% CI 14-56%, I²=89%, p<0.01). Conclusion Venetoclax, in combination with HMA, showed promising efficacy in treating relapsed AML post-HSCT. However, the significant heterogeneity and high mortality rate observed underscores the need for further research and novel therapeutic strategies, such as chimeric antigen receptor T-cell therapy followed by a reduced intensity allogeneic HSCT, to achieve better outcomes.

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