Real-World Experience with Generic Venetoclax Plus Hypomethylating Agent Induction Therapy in Newly Diagnosed Acute Myeloid Leukemia Patients in Resource-Limited Setting: A Single-Center Study from India
Authors: Kachhwaha Arjun , Benson Reshma , Satadeve Paras , Gupta Adamya , Shah Bibhant , Dalton Prisla , Ronanki Kavya , Kumar Karthik , Singh Sashi , Nayak Jhasaketan , Nagpal Nikhil , Singh Shalini , Singh Neha , Chandra Harish , Nath Uttam Kumar 
Published: December 2024

INTRODUCTION
The standard induction therapy for acute myeloid leukemia (AML) is the intensive 3+7 regimen. 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 agents (HMA) therapy.
AIMS & OBJECTIVES
To study treatment outcomes with VEN+HMA induction in severely resource-constrained setting, using generic preparation of 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 HMA (decitabine / azacitidine). Venetoclax dose range was 50-100 mg/day for 14 days per 28 days' cycle for at least two cycles, with concomitant azole antifungal therapy / prophylaxis as indicated. Hydroxyurea was used for initial cytoreduction. 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 first two cycles of VEN+HMA 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+HMA therapy.
RESULTS
Total 44 patients were treated between February 2023 & June 2024. Median age was 44.5 (IQR 49) years; male: female ratio was 1:1.5. As per European LeukaemiaNet 2022 risk stratification, 20 %, 55 % and 25 % patients had favourable-, intermediate- and adverse-risk AML respectively. Most frequent genetic abnormalities were FLT3 (22 %), NPM1 (20 %), AML1: ETO (9 %), DNMT3A (9 %), BCOR (7 %), IDH1 (7 %) and CBFB-MYH11 (5 %). Mean hospital stay in cycle 1 & 2 was 23 & 2 days respectively. Mean baseline total leucocyte count, platelet, & hemoglobin was 44.5 x 109/L, 48 x 109/L, & 6.8 g/dl respectively. At day 14, 18% of evaluable patients had marrow blasts &lt;5 % & negative flow-MRD status. Twenty-two percent patients achieved complete remission (CR) plus MRD negative status after cycle 1. Median time to hematological recovery in 1st cycle was 24 (IQR 8) days. Either CR or CR with incomplete hematologic recovery (CRi) was achieved in 45 % patients after two cycles of VEN+HMA therapy. Thirteen percent patients died in 1st cycle & another 4 % died in 2nd cycle of VEN+HMA. Twenty percent patients required intensive chemotherapy after failure of VEN+HMA, 21 % patients opted for continuation of VEN+ HMA therapy (all had CR), and 23 % patients received high dose cytarabine consolidation. Incidence of febrile neutropenia was 100 % in cycle 1 & 18 % in cycle 2, 11 % developed septic shock in cycle 1, & 9 % had neutropenic enterocolitis in cycle 1. None of the patients had tumor lysis syndrome. Commonest non-hematological toxicity in cycle 1 were acute kidney injury (16 %) & hyperbilirubinemia (11 %); 11 % required mechanical ventilation, & 5 % required hemodialysis. Granulocyte transfusion could be done in 5% patients in cycle 1. After median follow-up duration of eleven months, 53 % patients are alive & 48 % continue to remain in complete remission. Nine percent patients had AML relapse. Median survival was 10 months.
CONCLUSION
In our single-center experience, venetoclax plus HMA 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+HMA therapy was associated with significant myelosuppression & delayed haematological recovery, but this could be effectively managed with intensive supportive treatment.