Use of hypomethylating agents and anti-BCL-2 in elderly and/or unfit AML patients: A single-center experience

Acute myeloid leukemia (AML) is a type of hematologic cancer characterized by the clonal proliferation of myeloid precursor blast cells in the peripheral blood, bone marrow, and/or other tissues. The median age at diagnosis is 68 years. Approximately 70% of newly diagnosed AML cases occur in individuals aged 55 years and older (1). The incidence of AML is steadily increasing due to the aging population and the use of chemotherapy and/or radiotherapy in the treatment of other malignancies. In general, prognosis is poor in AML patients aged 65 years and older; in this age group, the five-year survival rate ranges between 5% and 10% (2). In elderly patients, an increased burden of comorbidities, the severity of these conditions, and low performance status contribute to a higher incidence of treatment-related morbidity and mortality. Furthermore, AML in older individuals is often associated with several biological features linked to chemoresistance, such as a higher frequency of adverse cytogenetic findings, increased expression of drug resistance genes, and the presence of preexisting hematologic disorders (3). Therefore, the management of treatment in elderly AML patients remains both challenging and controversial. While the 3+7 induction chemotherapy regimen is the standard approach for newly diagnosed younger AML patients, this regimen is not always the first-line option in older patients. In medically frail elderly individuals, intensive chemotherapy may result in early mortality. Hence, treatment protocols based on hypomethylating agents have become increasingly prominent for this patient group. In recent years, the addition of the BCL-2 inhibitor venetoclax to low-intensity treatment regimens has been shown to significantly improve survival in elderly AML patients (4). This study aims to investigate whether the addition of the BCL-2 inhibitor venetoclax to hypomethylating agents (azacitidine, decitabine) in patients who are unable to tolerate high-dose induction chemotherapy, have poor performance status, or are of advanced age, has a positive impact on overall survival in AML, improves treatment response, affects relapse rates, and how the chosen treatment regimen and response vary based on mutation analysis. Additionally, the study aims to contribute to future research on targeted therapies. Materials and Methods: This single-center retrospective study was conducted at the Hematology Department of Dicle University Faculty of Medicine Hospital and includes data from elderly and/or unfit patients diagnosed with AML who received hypomethylating agents and Anti-BCL2 therapy between January 1, 2019, and December 31, 2024. A total of 40 AML patients were included in the study. These patients were either aged 60 years or older at the time of diagnosis or considered unfit for intensive induction chemotherapy due to poor performance status (ECOG >2), comorbidities, or organ dysfunction, and had received combination therapy with a hypomethylating agent and an Anti-BCL2 agent. Patients with secondary AML, aged 0–18 years, relapsed/refractory cases, and those with incomplete medical records were excluded from the study. Data were obtained retrospectively from the hospital information management system and patient medical records. Recorded data included demographic characteristics (age, sex), hematologic and biochemical parameters at diagnosis, cytogenetic/molecular risk classification, administered treatment protocols, treatment responses (complete remission, partial response, refractory disease), and survival data (overall survival and event-free survival). Findings: According to the findings of our study, the mean age of the patients was 71.25 ± 5.24 years. It was determined that 47.5% of the patients were male and 52.5% were female. The mean hemoglobin level was found to be 8.82 ± 1.68 g/dL, the mean platelet count was 142.43 ± 130.46 x10³/mL, and the mean neutrophil count was 3.68 ± 4.55 x10³/mL. There was no statistically significant difference in treatment response according to patients' gender (p>0.05). Based on the study findings, 40% of the patients achieved remission, 7.5% achieved partial remission, 25% did not respond to treatment, 12.5% died after the first cycle, and in 15% of the cases remission status could not be evaluated. There was no statistically significant difference in the incidence of FLT3, NPM1, IDH1, IDH2, CKIT, t(8;21), and Inv(16) mutations between patients based on their treatment response (p>0.05). Overall survival (OS) was evaluated in the patients. The mean follow-up duration was 9.60 ± 9.92 months, and the mean overall survival was determined to be 14.145 ± 2.298 months. The 1-year OS rate was 78.5%, the 2-year OS rate was 51%, and the 3-year OS rate was 21%. The 1-year progression-free survival (PFS) rate was 79.9%, the 2-year PFS rate was 56.8%, and the 3-year PFS rate was 24.8%. Overall survival was also evaluated based on whether the patients had secondary AML. The mean OS for non-secondary patients was 15.650 ± 2.746 months, while for secondary AML patients it was 8.619 ± 2.518 months. Among non-secondary patients, the 1-year OS rate was 44.9%, the 2-year OS rate was 32.1%, and the 3-year OS rate was 12.8%. For female patients, the 1-year OS rate was 27%, the 2-year OS rate was 13.5%, and the 3-year OS rate was 13.5%. There was no statistically significant difference in survival rates between secondary and non-secondary AML patients (LogRank=1.518; p>0.05). Results: The management of treatment in elderly acute myeloid leukemia (AML) patients remains clinically challenging and is still a matter of debate. In this patient group, 1-year overall survival (OS) rates generally remain below 30%. In our single-center study, which analyzed elderly and/or unfit AML patients who were unable to tolerate intensive chemotherapy and received combination therapy with hypomethylating agents (azacitidine, decitabine) plus venetoclax, the median overall survival times were found to be consistent with real-world data reported in the literature. Our study focused on patients receiving HMA+venetoclax treatment. In the literature, when patient groups receiving HMA+venetoclax are compared with those receiving HMA alone, the group receiving the combination therapy has shown longer median survival. However, the survival durations in the HMA+venetoclax group are comparable to those observed in our study. To reduce early mortality and improve survival in this patient population, treatment strategies combining venetoclax with hypomethylating agents should be preferred. Nonetheless, there remains an ongoing need for more effective and safer treatment options in elderly AML patients, both in terms of efficacy and tolerability.