{"doi":"10.1002/ajh.27366","title":"Combination therapy with hypomethylating agents and venetoclax versus intensive induction chemotherapy in <i>IDH1</i>‐ or <i>IDH2</i>‐mutant newly diagnosed acute myeloid leukemia—A multicenter cohort study","abstract":"Intensive induction chemotherapy followed by consolidation therapy with additional chemotherapy and/or an allogeneic hematopoietic stem cell transplant (allo-SCT) is the standard of care for younger and fit patients with acute myeloid leukemia (AML).1 For older AML patients or those deemed unfit for intensive chemotherapy, the addition of the BCL2 inhibitor venetoclax to hypomethylating agents (HMA + VEN) has been shown to improve overall survival (OS) compared with HMA monotherapy and become the standard of care in this population.2 Furthermore, HMA + VEN use has expanded in real-world to patients younger than 75.3 Mutations in Isocitrate Dehydrogenase (IDH)1 and IDH2 occur in ~20% of cases of newly diagnosed AML.4 While the prognostic implications of IDH mutations among AML patients receiving intensive chemotherapy appear to depend on the pattern of concurrent mutations, HMA + VEN is associated with high rates of durable responses in IDH1 and IDH2-mutated AML.5, 6 While intensive chemotherapy remains the preferred option for young patients (i.e., <60 years old) and HMA + VEN in older patients (>75 years old), it remains unclear whether AML patients 60–75 years old carrying an IDH1/2 mutation and who are eligible for both intensive chemotherapy and HMA + VEN should be treated with one modality over the other. We included consecutive patients ≥60 years old with newly diagnosed IDH1- and IDH2-mutant AML who were treated at four academic centers in the United States (Dana-Farber Cancer Institute, Memorial Sloan Kettering Cancer Center, City of Hope National Medical Center and Yale Cancer Center) with either conventional or liposomal cytarabine/daunorubicin (intensive chemotherapy group) or HMA + VEN. The study was conducted with the approval from the institutional review boards at the respective institutions with need for informed consent waived due to the retrospective nature of the study. Patients in the intensive chemotherapy group could receive concurrent treatment with an FDA-approved third agent (i.e., midostaurin, quizartinib, or gemtuzumab ozogamicin). Patients who had received HMA + VEN-based triplet therapies were excluded from this analysis. Detection of IDH1 and IDH2 mutations, as well as other mutations, was performed at diagnosis by next-generation sequencing per local standards. Mutations that were prevalent in more than 5% of patients were included in the analyses. Responses were assessed at the end of induction treatment in the intensive chemotherapy group and at the time of best response in the HMA + VEN group. Responses were classified according to the European LeukemiaNet 2022 criteria.1 Composite complete remission (cCR) was defined as complete remission (CR) + CRi (CR with incomplete count recovery). OS was calculated from the date of first treatment until death or last follow-up by the Kaplan–Meier method. Time-to-event outcomes were compared using the log-rank test. Analyses were performed in the entire cohort, as well as in prespecified subgroups of patients 60–75 years old, patients who underwent an allo-SCT, and in patients with IDH1 and IDH2 mutations separately. Patients with concurrent IDH1 and IDH2 mutations were excluded from subgroup analyses comparing IDH1 and IDH2-mutant patients separately. For all analyses, two-sided p-values of <.05 were considered statistically significant. We constructed a uni- and multivariable Cox proportional hazards regression model to evaluate the hazard ratio (HR) of specified covariates on OS, with allo-SCT as a time-varying covariate. All covariates with a p-value of <.1 from the univariable model as well as the pre-defined covariate of treatment group were included for the selection of a final model using a backward elimination approach. Due to collinearity between complex and monosomal karyotypes with TP53 mutations, as well as incomplete availability of cytogenetic information at baseline, we only included molecular disease characteristics in the multivariable m","journal":"American Journal of Hematology","year":2024,"id":453057,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":830326,"name":"Shai Shimony","orcid":"0000-0001-7245-9652","position":1,"is_corresponding":false},{"id":284242,"name":"Rory M. Shallis","orcid":"0000-0002-8542-2944","position":2,"is_corresponding":false},{"id":1231120,"name":"Yiwen Liu","orcid":"0000-0002-7982-7996","position":3,"is_corresponding":false},{"id":1242660,"name":"Guillaume Berton","orcid":"0000-0001-8810-7117","position":4,"is_corresponding":false},{"id":670322,"name":"Eva J. Schaefer","orcid":null,"position":5,"is_corresponding":false},{"id":280996,"name":"Amer M. Zeidan","orcid":"0000-0001-7017-8160","position":6,"is_corresponding":false},{"id":284255,"name":"Aaron D. Goldberg","orcid":"0000-0002-2892-2643","position":7,"is_corresponding":false},{"id":284249,"name":"Eytan M. Stein","orcid":"0000-0001-8992-9390","position":8,"is_corresponding":false},{"id":108574,"name":"Guido Marcucci","orcid":"0000-0002-3983-5908","position":9,"is_corresponding":false},{"id":1242661,"name":"Rebecca P. Bystrom","orcid":"0000-0003-4407-4389","position":10,"is_corresponding":false},{"id":489016,"name":"R. Coleman Lindsley","orcid":"0000-0001-9822-806X","position":11,"is_corresponding":false},{"id":287951,"name":"Evan C. Chen","orcid":"0000-0002-9218-215X","position":12,"is_corresponding":false},{"id":1275611,"name":"Jorge Ramos","orcid":"0000-0002-3377-1683","position":13,"is_corresponding":false},{"id":89270,"name":"Anthony S. Stein","orcid":"0000-0002-1786-1398","position":14,"is_corresponding":false},{"id":387643,"name":"Vinod Pullarkat","orcid":"0000-0001-9129-3424","position":15,"is_corresponding":false},{"id":233349,"name":"Ibrahim Aldoss","orcid":"0000-0001-9564-4498","position":16,"is_corresponding":false},{"id":284245,"name":"Daniel J. DeAngelo","orcid":"0000-0001-7865-2306","position":17,"is_corresponding":false},{"id":3266,"name":"Donna Neuberg","orcid":"0000-0003-2566-3145","position":18,"is_corresponding":false},{"id":34476,"name":"Richard M. Stone","orcid":"0000-0002-7526-2633","position":19,"is_corresponding":false},{"id":1242662,"name":"Sylvain Garciaz","orcid":"0000-0002-0081-1255","position":20,"is_corresponding":false},{"id":660620,"name":"Brian Ball","orcid":"0000-0001-8625-7023","position":21,"is_corresponding":false},{"id":282263,"name":"Maximilian Stahl","orcid":"0000-0002-1299-5901","position":22,"is_corresponding":false},{"id":280995,"name":"Jan Philipp Bewersdorf","orcid":"0000-0003-3352-0902","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T02:02:58.784290Z","pmid":"38751104","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}