Type: Oral
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Molecular Features and Response to Treatment in AML
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research, survivorship
Methods: The total cohort (N=3142) included patients from <1 month to 88 years old. Pediatric and young adults were treated on multiple AML trials including CCG-2961 (n=23), AAML03P1 (n=54), AAML0531 (n=733), AAML1031 (n=1062), (total peds, n=1872) and adult patients on SWOG (n=359), BEAT AML (n=333), TCGA (n=180), and ECOG-ACRIN (n=398) (total adults, n=1270). Mutational profiling was performed by whole-genome, transcriptome, and targeted sequencing and prevalence of gene mutations were analyzed based on age groups. Prevalence of DNMT3A mutation, co- occurring mutations as well as the outcomes were analyzed based on cooperating mutations.
Results: While the prevalence of DNMT3A mutation among the entire cohort was 8.4% (N=264), only 2 cases were identified in pediatrics and young adult patients (0-18 years old) and prevalence of DNMT3A mutation amongst the adult cohort was 20.67%. The mutational prevalence was correlated with increased age (p value <0.05). Missense mutations at residue 882 were most prevalent (n=165) while other missense, nonsense and frameshift mutations were identified throughout the gene (n=99). A comparison of canonical R882 vs other mutations found no difference in overall survival (p=0.7924).
DNMT3A centric oncoprint analysis demonstrated that DNMT3A mutation commonly co-occurred with NPM1 mutation (60%), followed by FLT3-ITD (37%), IDH1/2 (29%) and FLT3-TKD mutations (12%) (Figure 1). Based on the DNMT3A and cooperating mutations, the patients were divided into 8 groups and the overall survival was analyzed (groups A-H). Although majority of DNMT3A positive patients had adverse outcome, those with DNMT3Amut/NPM1mut and DNMT3Amut/NPM1mut/IDHmut groups without other commonly associated mutations did well (p value <0.0001, 54.2% and 62.9% 5 year OS estimates, respectively). Specifically, presence of other mutations including FLT3-TKD with DNMT3Amut/NPM1mut results in a lower OS (group C, 18.1% 5-year OS estimate). DNMT3Amut co-occurring with any other gene mutations (other than NPM1) including DNMT3Amut/FLT3 ITDmut have the lowest OS with 5 year OS estimates of 13.7%, 13.9%, and 18.4%, groups F-H, respectively (Figure 2). The most dismal outcomes were observed in the DNMT3Amut/NPM1mut/FLT3 ITDmut patients with 5 year OS estimates of 11.8%.
Conclusion: This large cohort study confirms that prevalence of DNMT3A gene mutation increases with age and is a rare event in pediatrics and young adult patients. While DNMT3A mutation doesn’t have an independent prognostic factor by itself, we demonstrated that co-occurring NPM1 mutation has a favorable outcome even in the presence of IDH1/2 mutation. However, co-occurring DNMT3Amut with IDH1-2 mutation without NPM1 has an inferior OS, highlighting the prognostic impact of NPM1 mutation. Presence of FLT3 ITDmut has an unfavorable OS, regardless of NPM1 and/or IDH1/2 mutations.
Disclosures: Othus: Daiichi Sankyo: Consultancy; Glycomimetics: Consultancy; Biosight: Consultancy; Merck: Consultancy; Celgene: Consultancy. Appelbaum: Jasper Biotherapy: Membership on an entity's Board of Directors or advisory committees. Erba: Janssen Oncology: Consultancy; Covance (Abbvie): Consultancy, Other: Independent Review Committee, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Glycomimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other, Speakers Bureau; Pfizer: Consultancy; ALX Oncology: Research Funding; PTC therapeutics: Research Funding; Gilead/Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Kura Oncology: Consultancy, Research Funding; Takeda: Consultancy; Trillium Therapeutics: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman: UpToDate: Patents & Royalties: Royalties; Abbvie: Research Funding; Orsenix: Research Funding; Biosight: Research Funding; Glycomimetics: Research Funding; Rafael Pharmaceuticals: Research Funding; Amgen: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; KAHR-Adv Bd: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Innate Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Ipsen Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Atallah: Blueprint: Speakers Bureau; Takeda: Research Funding; BMS: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy; Novartis: Consultancy, Research Funding. Luger: Onconova, Celgene, Biosight, Hoffman LaRoche, and Kura: Research Funding; Syros, Agios, Daiichi Sankyo, Jazz Pharmaceuticals, Brystol Myers Squibb, Acceleron, Astellas, and Pfizer: Honoraria. Abdel-Wahab: Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder: Membership on an entity's Board of Directors or advisory committees; H3B Biomedicine, LOXO Oncology, and Nurix Therapeutics: Research Funding; H3B Biomedicine, Foundation Medicine Inc, Merck, Prelude Therapeutics, and Janssen: Consultancy. Levine: Astra Zeneca and Kura: Other: honoraria for invited lectures ; Qiagen: Other: supervisory board member; Syndax, Incyte, Janssen, Astellas, Morphosys and Novartis: Consultancy; Ajax, Abbvie, Constellation, Zenalis, Celgene, Roche, and Prelude: Other: research support; Imago, Mission Bio, Bakx, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics and Isoplexis: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Gilead and Novartis: Other: Grant reviews.
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