Predictive significance of early bone marrow MRD response assessment in Acute Myeloid Leukemia patients treated with venetoclax plus decitabine induction therapy: Real-world data from India

Abstract

Abstract INTRODUCTION The intensive 3+7 regimen is the standard induction therapy for acute myeloid leukemia (AML). However, a significant proportion of newly diagnosed AML patients are often ineligible for 3+7 induction therapy and are being treated with venetoclax (VEN) plus hypomethylating (decitabine/azacitidine) therapy. AIMS & OBJECTIVES To study treatment outcomes, including early bone marrow assessment at day 14 of VEN+decitabine induction, using a generic venetoclax in newly diagnosed AML patients who were ineligible for intensive induction chemotherapy. METHOD Newly diagnosed AML patients considered ineligible for intensive induction chemotherapy were treated with generic venetoclax plus decitabine. The Venetoclax dose range was 50-100 mg/day for 14 days per 28-day cycle for at least two cycles, with concomitant azole antifungal therapy/prophylaxis as indicated. Bone marrow morphology & flowcytometric measurable residual disease (flow-MRD) analysis were done for response assessment on day 14 of 1st cycle, and after completion of the first two cycles of VEN + decitabine therapy. All patients received prophylactic G-CSF in cycle 1 after day 14 marrow assessment. Patients who achieved CR after two cycles received either high-dose cytarabine consolidation or continuous VEN+decitabine therapy. RESULTS A total of 72 patients were treated between February 2023 & June 2025. Median age was 42.5 (IQR 25.5) years; male: female ratio was 1:1.5. As per European LeukaemiaNet 2022 risk stratification, 27 %, 54 % and 19 % patients had favourable-, intermediate-, and adverse-risk AML, respectively. AML multiplex PCR was performed in all patients, and NGS could be performed in 14 % of the patients. The most frequent genetic abnormalities were FLT3 (24%), NPM1 (23%), RUNX1:RUNX1T1(13%), CBFB-MYH11 (6%), DNMT3A (6%), and NRAS (5%). Normal karyotype was noted in 50% of the patients, and the most frequent cytogenetic abnormality was t(8;21)(q22; q22.1)(9.73%), Monosomy 5(5.56%), Monosomy 7(4.17%), and inversion (16)(p13.1q22)(2.78 %). All patients had an ECOG performance status of 3 or 4. At presentation, the median hemoglobin, Total leucocyte counts, and platelets were 7.15 (g/dL), 37.39 x 109/L, and 47.16 x 109/L, respectively. At day 14, 22% of evaluable patients had marrow blasts <5 % & 8% had negative flow-MRD status. Ten percent of patients required a switch to intensive chemotherapy (7+3) based on day 14 marrow response. Either CR or CR with incomplete hematologic recovery (CRi) was achieved in 46% patients after two cycles of VEN+decitabine therapy, and 29% & 38 % achieved MRD negative status after cycle 1 & 2, respectively. Median time to nadir of hemoglobin, total leucocyte count, and platelet count from day 1 of VEN+decitabine therapy was 10, 13, and 9 days, respectively. The median interval between two consecutive cycles of VEN+HMA therapy was 40 (IQR 9) days. Thirteen percent of patients died in 1st cycle & another 4% died in 2nd cycle of VEN+decitabine. Thirty percent of patients required intensive chemotherapy after failure of VEN+decitabine, 29 % patients received high-dose cytarabine consolidation, and 25% patients opted for continuation of VEN+decitabine therapy. Matched sibling donor allogenic stem cell transplant was performed in three (4.2%) of the study population. Major leukemia-related complications at presentation were invasive fungal infection (77.8%), followed by tumor lysis syndrome (24%). Incidence of grade 4 anemia, thrombocytopenia, and febrile neutropenia in cycle 1 was 89%, 91%, and 64% respectively. The commonest non-hematological toxicity in cycle 1 was pneumonia (84%), septic shock (70%), & acute kidney injury (53%). After a median follow-up duration of 9 (IQR 4-14) months, 53 % patients are alive & 48 % continue to remain in complete remission. Twelve percent of patients had AML relapse. The median overall survival duration of the study was 17 months (95 % confidence interval (CI), 9-25 months). CONCLUSIONIn our single-centre experience, venetoclax plus decitabine induction therapy using generic preparations of venetoclax was observed to be highly effective & relatively safe in newly diagnosed AML patients who were considered ineligible for intensive induction regimens. VEN+decitabine therapy was associated with significant myelosuppression & delayed haematological recovery, but this could be effectively managed with intensive supportive treatment.