Outcomes of Adult Patients with Newly Diagnosed IDH-Mutated Acute Myeloid Leukemia Receiving Intensive Chemotherapy Plus Venetoclax
Authors: Croden Jennifer , Marvin-Peek Jennifer , Konopleva Marina , Borthakur Gautam , Daver Naval , Abbas Hussein A. , Takahashi Koichi , Sasaki Koji , Garcia-Manero Guillermo , Jain Nitin , Pemmaraju Naveen , Short Nicholas J. , Hammond Danielle , Jabbour Elias , Masarova Lucia , Chien Kelly S. , Issa Ghayas C. , Montalban-Bravo Guillermo , Yilmaz Musa , Maiti Abhishek , Alvarado Valero Yesid , Kornblau Steven M. , Ravandi Farhad , Kantarjian Hagop , Kadia Tapan M. , DiNardo Courtney D. 
Published: December 2024

Background: Isocitrate dehydrogenase (IDH) 1 or 2 mutations are present in ~20% of patients with acute myeloid leukemia (AML). The availability of new agents, including venetoclax and the targeted IDH1 and IDH2 inhibitors, have improved the outcomes of patients with IDH-mutated AML, especially in the relapsed/refractory (R/R) setting, and for newly diagnosed intensive chemotherapy (IC)-ineligible patients. However, the optimal induction regimen for IDH-mutated patients who are eligible for IC is not established. Ivosidenib and enasidenib, potent IDH1 and IDH2 inhibitors, have been evaluated in combination with standard 7+3 chemotherapy (Stein EM, Blood 2021), and have led to robust remission rates leading to an ongoing randomized phase 3 clinical trial. Similarly, venetoclax (VEN)-containing regimens have demonstrated improved remission rates in newly diagnosed AML patients eligible for IC (Lachowiez CA, Lancet Haematol 2022), including IDH-mutated AML. However, limited data exists regarding outcomes of AML patients with IDH1 and IDH2 mutations receiving IC regimens including VEN.
Methods: We performed a retrospective single-center study of patients with newly diagnosed IDH1- and IDH2-mutated AML treated between January 11, 2019, and February 18, 2023. Eligible patients aged 18-70 were treated with IC+VEN during the study period. Regimens used were cladribine, idarubicin, and cytarabine + VEN (CLIA+VEN) and fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + VEN (FLAG-IDA+VEN), as part of ongoing prospective clinical trials (NCT02115295, NCT03214562). Key endpoints included overall response rate (ORR), rate of complete remission (CR), and rate of complete remission with incomplete hematologic recovery (CRi) after induction therapy, as well as overall survival (OS). Survival analysis was performed using the Kaplan-Meier method and differences between groups were assessed using the log-rank test.
Results: Median follow-up was 37.3 months. During the study period, 124 patients with AML were treated with frontline IC+VEN. Of these, 99 (80%) were IDH wild type, 10 (8%) were IDH1-mutated, and 15 (12%) were IDH2-mutated. Ages of these cohorts were 46 years (range 19-67), 56 years (45-65), and 54 years (29-64), respectively. The majority of IDH1- and IDH2-mutated patients had de novo AML (96%), and most were adverse risk (44%) per ELN 2022 classification. Seventy-three (59%) patients were treated with CLIA+VEN: 58 (59%) IDH wild type, 6 (60%) IDH1-mutated, and 9 (60%) IDH2-mutated, and 51 (41%) received FLAG-IDA+VEN: 41 (41%) IDH wild type, 4 (40%) IDH1-mutated, and 6 (40%) IDH2-mutated. No patient received targeted IDH inhibition as part of their induction.
After IC+VEN induction, the ORR was 96% (95/99) in IDH wild type, 80% (8/10) in IDH1-mutated, and 100% (15/15) in IDH2-mutated (p=0.134). CR/CRi was achieved in 92 (92%) of IDH wild type, 8 (80%) of IDH1-mutated (including 7 of 8 MRD negative), and 15 (100%) of IDH2-mutated patients (12 of 15 MRD negative) (p=0.173). Of these patients, 3 (38%) IDH1-mutated and 4 (27%) IDH2-mutated transitioned to HSCT in CR1. OS at 3 years for IDH wild type, IDH1-mutated, and IDH2-mutated patients was 76% (95% CI 67-85%), 60% (95% CI 36-84%), and 61% (95% CI 36-86%), respectively.
Conclusions: Venetoclax combined with intensive induction chemotherapy results in a high rate of MRD-negative remissions and impressive 3-year OS in newly diagnosed, IDH-mutated AML. Further study and randomized trials are needed to determine the optimal induction regimen for patients with IDH-mutated AML.