{"doi":"10.1002/ajh.26146","title":"The prognosis and durable clearance of <scp>RAS</scp> mutations in patients with acute myeloid leukemia receiving induction chemotherapy","abstract":"The RAS oncogenes, NRAS and KRAS are frequently mutated in AML, occurring in 11% and 5% of patients, respectively.1 These gain-of-function mutations produce altered RAS-GTPase proteins locked in an active GTP-bound state resulting in constitutive activation of the mitogen activated protein kinase (MAPK), and phosphoinositide-3 kinase (PI3K) pathways that impact cell proliferation and survival. Although among patients receiving induction chemotherapy, the presence of RAS mutations do not significantly impact prognosis,1 mounting evidence suggests that RAS-pathway mutated leukemic clones are more likely to be cleared. Targeted next generation sequencing performed at diagnosis and at time of complete remission (CR) after induction chemotherapy revealed that RAS-pathway mutations including NRAS, KRAS, NF1, PTPN11 had higher clearance rates relative to other mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), DNA methylation, and RNA splicing.2, 3 The addition of intensive chemotherapy represents a promising strategy in combination with non-intensive therapies, including targeted therapies of IDH and FLT3 and venetoclax-based regimens, where RAS mutations have emerged as a common mechanism of resistance.4-6 In order for this strategy to be effective additional sequencing at time of relapse is necessary to determine if RAS mutations are persistently cleared after treatment with induction chemotherapy. Here, we performed a single center retrospective study in an unselected adult (age > 18 years) AML population receiving induction chemotherapy. This was to determine the prognosis of NRAS or KRAS mutations and analyze paired NGS at diagnosis and relapse, to evaluate the persistence of RAS-mutant clones after treatment with induction chemotherapy. There were 232 patients with a diagnosis of AML, who were treated with intensive induction chemotherapy from April 1, 2014 to May 15, 2019 and had next-generation sequencing performed prior to treatment were included for analysis [Figure S1]. Over the duration of the study, NGS was performed using one of three sequencing panels: 30-gene panel, 49-gene panel or a 400-gene panel. The details of these assays including the minimum variant allele fraction for mutation calling are reported in the supplemental material [supplemental methods]. A total of 196 patients were WT, 20 patients (9%) were NRAS-mutated, 11 patients (5%) KRAS-mutated, and five patients (2%) were both NRAS and KRAS-mutated. A total of 510 mutations were detected including 27 NRAS mutations (mutation frequency 5%) and 19 KRAS mutations (mutation frequency 4%). The RAS mutations occurred at typical hotspot locations: G12, G13, Q61 [Figure S2]. Baseline characteristics of RAS and WT AML are listed in Table S1. When compared to WT patients, NRAS-mutated patients were associated with a higher proportion with at least four co-mutations (WT 13%, NRAS 30%) and AML with myelodysplastic related changes (WT 28%, NRAS 55%). Characteristics of the KRAS-mutated patients included older median age (WT 60 years, KRAS 64 years), higher median WBC (WT 3 x 109 cells/L, KRAS 13 x 109 cells/L) secondary AML or therapy-related AML (WT 41% vs KRAS 73%), inversion 16 (WT 3%, KRAS 18%), and KMT2A or 11q23 rearrangements (WT 2%, KRAS 36%) at baseline. We also observed that WT1 mutations were more prevalent among RAS-mutated patients, occurring in six out 36 patients (17%). Induction regimens consisted of intravenous cytarabine 100 mg/m2 on days 1–7 and an anthracycline on days 1–3 (idarubicin 12 mg/m2 (6%), daunorubicin 60 mg/m2 (47%), daunorubicin 90 mg/m2 (33%)) or in a liposomal formulation of CPX-351 (14%). Forty patients received combinations of targeted therapy and induction chemotherapy, including midostaurin (n = 12), crenolanib (n = 7), gilteritinib (n = 1), ivosidenib (n = 10), and enasidenib (n = 10) for Flt3, IDH1-, and IDH2-mutated AML, respectively. The type of induction or proportion of patients receiving targe","journal":"American Journal of Hematology","year":2021,"id":181033,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":417844,"name":"Meier Hsu","orcid":"0000-0002-9519-8560","position":1,"is_corresponding":false},{"id":90690,"name":"Sean M. Devlin","orcid":"0000-0002-6801-720X","position":2,"is_corresponding":false},{"id":15539,"name":"Maria E. Arcila","orcid":"0000-0001-5824-6554","position":3,"is_corresponding":false},{"id":55985,"name":"Mikhail Roshal","orcid":"0000-0002-9585-0790","position":4,"is_corresponding":false},{"id":275374,"name":"Yanming Zhang","orcid":"0009-0006-0610-9463","position":5,"is_corresponding":false},{"id":731873,"name":"Chris Famulare","orcid":null,"position":6,"is_corresponding":false},{"id":284255,"name":"Aaron D. Goldberg","orcid":"0000-0002-2892-2643","position":7,"is_corresponding":false},{"id":523571,"name":"Sheng F. Cai","orcid":"0000-0002-2708-887X","position":8,"is_corresponding":false},{"id":259769,"name":"Andrew Dunbar","orcid":"0000-0003-0339-4220","position":9,"is_corresponding":false},{"id":275371,"name":"Zachary D. Epstein‐Peterson","orcid":"0000-0002-5942-2502","position":10,"is_corresponding":false},{"id":668435,"name":"Kamal Menghrajani","orcid":"0000-0002-6357-6475","position":11,"is_corresponding":false},{"id":560355,"name":"Jacob L. Glass","orcid":"0000-0003-0363-7763","position":12,"is_corresponding":false},{"id":309200,"name":"Justin Taylor","orcid":"0000-0003-4407-6325","position":13,"is_corresponding":false},{"id":238128,"name":"Aaron D. Viny","orcid":"0000-0001-7039-0110","position":14,"is_corresponding":false},{"id":731874,"name":"Sergio S. Giralt","orcid":null,"position":15,"is_corresponding":false},{"id":108871,"name":"Boglarka Gyurkocza","orcid":"0000-0002-2933-2119","position":16,"is_corresponding":false},{"id":352732,"name":"Brian C. Shaffer","orcid":"0000-0003-3433-9179","position":17,"is_corresponding":false},{"id":268584,"name":"Roni Tamari","orcid":"0000-0002-2386-0850","position":18,"is_corresponding":false},{"id":35287,"name":"Ross L. Levine","orcid":"0000-0002-7884-1905","position":19,"is_corresponding":false},{"id":108822,"name":"Martin S. Tallman","orcid":"0000-0002-4367-6102","position":20,"is_corresponding":false},{"id":284249,"name":"Eytan M. Stein","orcid":"0000-0001-8992-9390","position":21,"is_corresponding":false},{"id":660620,"name":"Brian Ball","orcid":"0000-0001-8625-7023","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-18T23:48:01.257885Z","pmid":"33650111","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":[]}