Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: New Approaches to Combination Chemotherapy and Venetoclax Plus Hypomethylating Agent Therapy in AML
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, adult, Non-Biological therapies, elderly, Clinical Research, Combination therapy, Diseases, real-world evidence, Therapies, Adverse Events, Myeloid Malignancies, Study Population, Human
Methods. We retrospectively analyzed data from untreated AML patients ineligible for IC who received AZA for 7 days associated with VEN for only 7 days from the 1st cycle every 28 days. Response to therapy was evaluated according to ELN-2022 criteria’s and comparisons between cohorts were determined using Chi2 test. Time-to-event analysis were assessed using the log-rank method, with logistical regression analysis and Cox proportional hazard modeling to determine the effect of variables.
Results. Charts from 82 treatment-naïve AML patients from 7 french centers who received AZA-VEN 7+7 scheme from the 1st cycle were retrospectively analyzed (Table 1). Median age was 75.2 years and 56% had secondary AML (including 26 patients with therapy-related AML). Performance status (PS) was altered (i.e. PS 2-4) in 37% of patients and 29% presented at least 1 exclusion criteria to VIALE-A protocol. Forty percent of patients presented normal karyotype while 22% had complex cytogenetic. Myelodysplasia-related genes mutations were found in 48%, TP53 mutations in 21.3% of patients while NPM1 and IDH2 mutations were found in 14.6% and 13.4% respectively. Overall, 69.5% of patients presented adverse risk as defined by ELN-2022 classification.
Patients received a median of 4 cycles (range 1-28). After cycle 1, 49% presented febrile neutropenia grade III/IV and 88% required at least 1 transfusion. Early death rate at 60 days was 6.1%. Neutrophil (>1G/L) and platelet (>100G/L) recoveries were observed after a median of 36 and 31 days respectively. Forty-eight percent of patients required a median delay of 13 days to start the 2nd cycle. Overall response rate (ORR; complete remission (CR) and complete remission with incomplete hematologic recovery (CRi)) were 41.5%, 53.9% and 68.3% after 1, 2 and all cycles respectively. Univariate analysis revealed that complex karyotype, TP53 mutations (VAF≥10%) and adverse risk ELN-2022 were correlated with a worse ORR. With a median follow-up of 4.8 months (0.3–25.8), estimated event-free survival (EFS) and overall survival (OS) were 7.5 months (IC95: 5.1–17.1) and 12.8 months (IC95: 9.2–19.2) respectively. Univariate analysis revealed that OS and EFS were significantly improved in patients without VIALE-A protocol exclusion criteria’s, ≥75 years, with PS 0-1, normal karyotype and in absence of TP53 mutation. Thus, estimated median EFS and OS in patients without VIALE-A protocol exclusion criteria's were 11.4 and 13.8 months respectively (Fig 1).
Among 56 CR/CRi patients, 61% had dose reduction mainly due to grade III/IV cytopenias: reduced treatment duration to 5 days in 97%, VEN dose reduction to 200mg/d in 50% and a 5-weeks interval between cycles in 29% of patients. Estimated median OS in patients with reduced dose was 25.8 months.
Discussion. Limiting VEN exposure to the concurrent days of AZA administration (7+7 scheme) induced similar response rates than the recommended VEN administration for 28 days. The 7+7 scheme, applied to the same population than VIALE-A trial, compared favorably to the 7+28 usual dose. Even with reduced VEN exposure, significant toxicity occurred during cycle 1 and subsequent cycles. In responders, subsequent dose reduction of VEN seems associated with favorable outcome. Our results provide rationale for reduced AZA-VEN scheme used in current clinical trial evaluating triplet combination.
Disclosures: Willekens: Abbvie: Honoraria. Bonnet: Abbvie: Honoraria. Micol: AstraZeneca: Honoraria; Abbvie: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria. Marzac: Astellas: Honoraria. Jourdan: BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Bouscary: Abbvie: Honoraria. de Botton: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; AURON: Research Funding; FORMA: Research Funding; SYNDAX: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Other: Travel / accommodation, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel / accommodation, Speakers Bureau; Jazz pharmaceutical: Honoraria, Speakers Bureau.
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