Real World Outcomes of Hypomethylating Agents and Venetoclax Combination Therapy in Acute Myeloid Leukemia and Myelodysplastic Syndrome- Single Center Experience from a Resource Limited Country

Background: Management of Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) are challenging in low-middle income countries (LMICs) due to lack of advanced diagnostics for risk stratification, restricted finances and lack of trained manpower and infrastructure for handling patients with intensive chemotherapy. Venetoclax when combined with hypomethylating agents (HMA) such as decitabine or azacitidine inhibit electron transport chain complex II resulting in metabolic disruption and eradication of leukemia stem cells (LSCs). Although widely used globally, limited data is available for its use and outcomes from LMICs. Objectives: In this study, we aim to evaluate the outcomes of AML and MDS patients treated with venetoclax and HMA combination therapy in a tertiary care center of Pakistan. Materials and Methods: We conducted a retrospective analysis on 96 patients of which 54 patients had AML and 42 had MDS. All patients received venetoclax combined with HMA at a single center from January 2020 to December 2024. The primary outcomes measured for AML were overall survival (OS), progression free survival (PFS) and response rates (complete remission [CR], partial remission [PR], stable disease [SD] and no response [NR]) while for MDS response was assessed as per International Working Group (IWG criteria). Secondary outcomes were treatment related toxicity (febrile neutropenia, deaths, tumor lysis syndrome) Results: A total of 96 patients were divided into AML cohort (n=54) and MDS cohort (n=42). AML cohort had a male-to-female ratio of 2:1 and a median age of 52 (IQR:37- 62.2). The overall survival (OS), disease free survival (DFS), overall response rate (ORR) and complete remission (CR) was 77.4%, 52.8%, 50% and 88.8% respectively. Of relapsed patients (n=9), only 1 patient responded to salvage therapy. The median OS and DFS for patients receiving salvage HMA was 75% and 12% respectively. Common treatment related toxicities included febrile neutropenia (FN) in 66.7% patients with no treatment related mortality. A total of 12.9% patients underwent consolidative HSCT and 18.5% received off label venetoclax maintenance. The MDS cohort (n=42) had a male-to- female ratio 9.5:1 with 51 years median age. The OS and DFS in MDS cohort were 59.5% and 44.4% respectively. Disease was relapsed in 21.1% patients and median time to response was 64 days. FN occurred in 54.8% patients. Karyotype analysis showed normal cytogenetics in 90.5%. A total of 17.1% MDS patients underwent consolidative HSCT and 12.2% received venetoclax maintenance. Conclusion: HMA-VEN combination therapy is a feasible and effective treatment for patients with MDS and AML presenting in a resource limited setting. However, the low CR rates and high incidence of febrile neutropenia compared to high-income countries underscores the need for better supportive care, comprehensive molecular testing and individualized treatment approaches.