Combination of Venetoclax and Azacytidine As First-Line Induction Therapy for Acute Myeloid Leukemia in Patients Younger Than 60 Years: A Tertiary Care Center Experience from Our Low Middle Income Country

Abstract

INTRODUCTION: Anthracycline- and cytarabine-based “7+3” induction chemotherapy has been the frontline treatment option for acute myeloid leukemia (AML) in the non-elderly and fit patient population. Sixty percent of these patients (pts) achieve Complete remission (CR). However, an estimated 30-40% of pts relapse (Tara L. Lin & Livio Pagano et al., Expert Review of Hematology, 2021). In addition, based on a large US database study and studies from India, the “7+3” regimen is associated with high rates of induction mortality, intensive care unit (ICU) admission, and duration of hospital stay. BCL2 inhibition with venetoclax has been a new paradigm for the treatment of AML. Herein, we present our institutional experience in treating AML in pts younger than 60 years (yrs) old with a combination of venetoclax (ven) and azacytidine (aza). METHODS: We conducted a retrospective review of patients aged 18-60 who were newly diagnosed with AML between May 2020 and May 2023, and in this study, we included all pts, who met the WHO criteria for AML, did not have APML, had no prior history of treatment for other malignancies, and had not received prior induction treatment. Pts received aza 75 mg/m2 on days 1-7 and ven, which escalated from 100 to 200 to 400 mg on days 1-3. Ven continued at 400 mg without posaconazole or 100 mg with posaconazole from days 4-28, and bone marrow aspiration and biopsy were performed after day 28. Patients who achieved morphological remission without count recovery had up to 14 days off therapy before subsequent cycles. Non-responders received up to 1-2 additional cycles. Post-response (defined as a complete remission [CR] ), and patients with measurable residual disease (MRD) negative by multiparameter flow cytometry (MFC) with the residual blast cutoff being < 0.1% proceeded to further cycles. The primary objective of the study is to focus on the induction mortality rate and complete remission in younger, newly diagnosed AML pts who received aza and ven in the induction period. Responses to induction and subsequent post-remission therapy were recorded. RESULTS: A total of 17 patients with AML aged ≥ 18 years and ≤60 years were treated with a combination of aza and ven from May 2020 to May 2023. The median patient age was 47 yrs (interquartile range [IQR]: 30-56 yrs, 52.9% age <50 yrs ), and 52.9% of the pts were males. According to the European Leukemia Network (ELN) guidelines for 2022, using FISH and next-generation sequencing (NGS), 5 out of 17 pts (41.2%) were categorized as having favorable risk, 3 out of 17 patients (17.6%) were categorized as having intermediate risk, and 9 out of 17 pts (41.2%) were categorized as having adverse risk. During their inpatient stay, none of the pts required renal replacement therapy (RRT), and 1 out of 17 (5.8%) pts required mechanical ventilation. The dose of ven was 400 mg in 8 out of 17 patients (47%). One pt was on sertraline and received 200mg of ven. The remaining pts (8/17) received 100 mg of ven with posaconazole, which reduced the cost of the treatment to 50%. The median pretreatment white cell count (WCC) was 11.49 x 10^9/L (IQR: 6.25 to 39.74 x 10^9/L). The platelet count took a median of 31 days to recover above 50 x 10^9/L (IQR: 28-43 days), while the median time for the absolute neutrophil count (ANC) to recover above 1 x 10^9/L was 52 days (IQR: 47-60 days). 11 out of 17 (64%) of our patients achieved complete remission (CR1) after the first cycle. Additionally, 5 out of 17 (29.4%) were MRD-negative when compared to a large US study database and an Indian study (see table1). The median duration of hospital stay was 16 days (IQR: 10-20 days), and the induction mortality rate was 1/17 (5.8%) (see table1). This death occurred in a patient with adverse risk. CONCLUSIONS: The response to induction therapy with venetoclax and azacytidine in young adults with AML was similar to the standard “7+3” induction therapy, with around 64% of pts achieving CR after the first cycle. The median duration of hospital stay, frequency of ICU admission, and especially induction mortality have been lower than the “7+3” regimen. BCL2 inhibition has indeed resulted in a paradigm shift in the treatment of AML. Therefore, it may be the right time to consider the combination of ven and aza as the standard first-line induction therapy for all pts with AML.