Venetoclax With Hypomethylating Agents in Newly Diagnosed AML Unfit for Intensive Chemotherapy

Background and rationale

Acute myeloid leukemia (AML) is predominantly a disease of older adults, in whom adverse disease biology, comorbidity, and poor performance status frequently preclude intensive induction chemotherapy. Hypomethylating agents (HMAs) combined with the selective BCL-2 inhibitor venetoclax have become a standard lower-intensity option for patients unfit for intensive therapy. In Bangladesh, a second and distinct group of patients is unable to receive intensive chemotherapy: younger, medically fit patients for whom the cost of conventional induction and its supportive care is prohibitive. Real-world outcome data for venetoclax plus HMA are absent from Bangladesh and sparse from comparable low-resource settings, and the financially ineligible younger population is under-represented in published trial and registry data. This study was undertaken to evaluate the short-term outcome of a single cycle of venetoclax plus an HMA in both of these groups at a public tertiary care hospital.

Design and setting

This was a prospective, single-arm, open-label interventional (pre-post) study conducted in the Department of Haematology and Bone Marrow Transplantation Unit, Dhaka Medical College Hospital (DMCH), Dhaka, Bangladesh. Participants were recruited from both inpatient and outpatient services by purposive sampling of consecutive eligible patients.

Participants

Adults aged 18 years or older with newly diagnosed AML were eligible if the treating physician judged them ineligible for intensive chemotherapy on the basis of age (60 years or older), performance status, or comorbidity, or if they were unable to receive intensive chemotherapy for financial reasons, or were unwilling to receive it. Patients with acute promyelocytic leukemia and patients previously treated with a hypomethylating agent were excluded. Written informed consent, in English or Bangla, was obtained from every participant or legal guardian before enrolment.

A sample size of 15 was calculated for an estimated 2-log reduction in leukemic burden with an assumed standard deviation of 2, a precision of 2, and 95% confidence. During the recruitment period nine additional consecutive eligible patients presented who were unable to afford conventional AML chemotherapy; with the approval of the study supervisor these patients were also enrolled, giving a final enrolled sample of 24.

Baseline assessment

Before the first dose, all participants underwent history and clinical examination recorded on a semi-structured questionnaire, including sociodemographic data, presenting symptoms and signs, and comorbidity. Baseline investigations comprised complete blood count with differential and blast percentage, peripheral blood film, and bone marrow examination with blast percentage.

Intervention

Each participant received one 28-day treatment cycle. The hypomethylating agent was administered as intravenous azacitidine 75 mg/m² daily on days 1 to 7, or intravenous decitabine 20 mg/m² daily on days 1 to 5, at the discretion of the treating physician. Oral venetoclax was given as 100 mg on day 1 and 200 mg on day 2, and was continued at 100 mg daily from day 3 to day 28; the dose was not escalated further because all participants received concomitant oral voriconazole 200 mg twice daily from day 3 to day 28 as antifungal prophylaxis, a strong CYP3A4 inhibitor requiring venetoclax dose reduction. Tumour lysis syndrome prophylaxis and supportive care, including transfusion and antimicrobial therapy, were given according to institutional practice.

Some participants were admitted for part of the cycle while others were managed on an outpatient basis. All participants managed outside hospital were given an emergency contact number for the study team and were reviewed for intercurrent complications, which were managed as they arose.

Outcome assessment

On day 28, all participants underwent repeat complete blood count, peripheral blood film, and bone marrow examination. Response was categorised as complete remission (CR), complete remission with incomplete haematologic recovery (CRi), partial remission (PR), stable disease, or death in aplasia, using European LeukemiaNet 2017 response criteria. CR required bone marrow blasts below 5 percent, absence of circulating blasts and blasts with Auer rods, absence of extramedullary disease, absolute neutrophil count of 1000/µL or more, and platelet count of 100,000/µL or more. CRi required all CR criteria except for residual neutropenia or thrombocytopenia. Adverse events occurring at any point during the cycle were recorded, as was all-cause mortality to day 28.

Statistical analysis

Data were entered and analysed using SPSS version 25.0 for Windows. Categorical variables were summarised as frequency and percentage, and continuous variables as mean with standard deviation. Pre- and post-treatment haematological parameters were compared using the paired t-test, with a two-sided p value below 0.05 considered statistically significant.

Ethics

Ethical clearance was obtained from the Ethical Review Committee of Dhaka Medical College (memo number ERC-DMC/ECC/2022/318, dated 27 June 2022). Participants were informed of their right to withdraw at any time without prejudice to their routine care, received no financial incentive, and were assured that identifying information, medical records, and laboratory results would remain confidential and be used for research purposes only. Access to collected data was restricted to the investigator.

Inclusion criteria

Newly diagnosed acute myeloid leukemia Age 18 years or older Deemed ineligible for intensive chemotherapy by the treating physician on the basis of age (≥60 years), performance status, or comorbidity; or unable to receive intensive chemotherapy for financial reasons; or unwilling to receive intensive chemotherapy Written informed consent

Exclusion criteria

Acute promyelocytic leukemia Previous treatment with a hypomethylating agent