IDH2 Mutation Is Associated with Favorable Outcome Among Older Adults with Newly Diagnosed Acute Myeloid Leukemia Treated with Lower-Intensity Therapy

Background: Mutations of isocitrate dehydrogenase (IDH) are recurrent in acute myeloid leukemia (AML) and the prevalence increases with age. The prognostic impact of IDH1 and IDH2 mutations remains controversial. IDH inhibitors are small molecules that bind within the IDH enzymatic active site, blocking aberrant 2-hydroxyglutarate production and inducing myeloid differentiation. While they can lead to differentiation syndrome, they generally have a more favorable side-effect profile, making them an attractive option for older patients. We aimed to describe the prevalence and prognostic impact of IDH mutations in newly diagnosed (ND) AML patients ≥ 60 years in a large cohort of patients treated on a Leukemia and Lymphoma Society-sponsored trial.

Methods: We performed a retrospective observational analysis including patients ≥ 60 years with ND AML who were enrolled on the Beat AML clinical trial (NCT03013998) before May 10, 2023. Patients were treated with a variety of treatment regimens. Cytogenetic analysis and next-generation sequencing (FoundationOne®Heme) were obtained. Mutations were considered present at any detectable VAF. Cox proportional hazard models were used to describe the relative risk of each variable on death over time from the date of trial inclusion.

Results: A total of 1023 patients with ND AML were identified. Patients had a median age of 72 (range 60-92) years and the majority were non-Hispanic White (83.2%), and male (57.6%). Ninety-nine (9.7%) patients were IDH1^MUT, 193 (18.9%) patients were IDH2^MUT including 10 (1.0%) patients with a co-occurring IDH1 and IDH2 gene mutations.

Both IDH1^MUT and IDH2^MUT were associated with 2022 ELN favorable-risk (26.3% and 22.3% for IDH1 and IDH2 respectively, vs 15.5% overall (P<0.001)). IDH1^MUT significantly co-occurred with DNMT3A^MUT (42.4%), NPM1^MUT (44.4%) and less frequently with TP53^MUT (10.1%) (P<0.001 for all). IDH2^MUT was associated with DNMT3A^MUT (35.8%), NPM1^MUT (31.1%), SRSF2^MUT (38.3%), and less frequently with TET2^MUT (6.7%) and TP53^MUT (9.3%) (P<0.001 for all). Normal karyotype was higher in IDH1^MUT (P<0.001) and IDH2^MUT (P<0.001), whereas complex karyotype (P<0.001 for both) and core-binding factor AML (P=0.047, P=0.015) were lower in IDH1^MUT and IDH2^MUT.

To evaluate the impact of IDH mutations in patients ≥ 60 years, we focused on patients evaluable for outcome treated with lower-intensity therapy (LIT) (N=674), and intensive chemotherapy (IC) (N=178), separately. Among the LIT treated patients, 96 patients received treatment with an IDH inhibitor, and 237 patients received a hypomethylating agent (HMA) plus venetoclax. For patients treated with LIT, the hazard ratios (HRs) of death over time were 0.58 [95% CI 0.47-0.72; P<0.002], 0.81 [95% CI 0.59-1.13; P=0.214] and 0.56 [95% CI 0.44-0.72; P<0.001] for IDH^MUT, IDH1^MUT, IDH2^MUT respectively. Among patients receiving IC, the HRs were 1.05 [95% CI 0.68-1.69; P=0.777], 0.70 [95% CI 0.31-1.61; P=0.406] and 1.27 [95% CI 0.77-2.1; P=0.352] for IDH^MUT, IDH1^MUT, and IDH2^MUT respectively. The HR of death for IDH1^MUT patients treated with LIT with the addition of an IDH1 inhibitor (N=24) was significantly lower (HR 0.47 [95% CI 0.24-0.92; P=0.027] vs IDH1^MUT patients treated without an IDH1 inhibitor, while an IDH2 inhibitor did not change survivial outcomes in patients with IDH2^MUT (N=71).

Discussion: To our knowledge this is the largest retrospective study characterizing the prevalence of IDH mutations in patients ≥ 60 years with AML. We demonstrated that IDH mutations were detected in ~27% of older patients with AML. Although there could have been selection bias as the Beat AML study had separate IDH^MUT study arms, these findings are concordant with other studies showing an increase in frequency of IDH mutations with age. IDH2^MUT was associated with a lower HR of death among patients treated with LIT, which was not seen in patients receiving IC. The high prevalence of IDH mutations suggests that IDH inhibitors used as single agents or in combination with lower-intensity therapies are an important class of drugs for this older patient population as they are generally well tolerated, that need further investigation.

Swords:Disc Medicine: Consultancy. Traer:Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Servier Laboratories: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Schrödinger: Research Funding; Incyte Corporation: Research Funding; AstraZeneca: Research Funding. Stein:Celgene: Consultancy, Other: consulting fees; Agios Pharmaceuticals: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Consultancy, Other: consulting fees; AstraZeneca: Consultancy, Other: consulting fees; Servier: Consultancy, Other: consulting fees; Genentech: Consultancy, Other: consulting fees; Astellas Pharmaceuticals: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; Abbvie: Consultancy, Other: consulting fees; Gilead: Consultancy, Other: consulting fees. Lin:Aptevo; Bio-Path Holdings; Ciclomed; Cleave; Jazz; Jazz Pharmaceuticals; Leukemia & Lymphoma Society; Kura Oncology; Trovagene: Research Funding; Jazz Pharmaceuticals; Servier: Consultancy. Patel:Servier: Current Employment. Arellano:Syndax Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board meeting 5/31/24, Syndax pharmaceuticals, role of menin inhibition in treatment of acute leukemias. Stock:Adaptive: Consultancy, Honoraria; Kura: Research Funding; Kura, Servier, Newave, Adaptive, Jazz, Asofarma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Odenike:AbbVie (Inst); Agios (Inst); Aprea AB (Inst); Astex Pharmaceuticals (Inst); AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); CTI BioPharma Corp (Inst); Daiichi Sankyo (Inst); Incyte (Inst); Janssen Oncology (Inst); Kartos Therapeutics (Ins: Research Funding; AbbVie; Blueprint Medicines; BMS; Bristol-Myers Squibb/Celgene (Inst); Celgene; CTI; Impact Biomedicines; Kymera; Novartis; SERVIER; Taiho Pharmaceutical; Treadwell Therapeutics: Honoraria. Deininger:SPARC: Research Funding; Leukemia & Lymphoma Society: Research Funding; Fusion Pharma: Consultancy; DisperSol: Consultancy; Takeda: Honoraria, Other: Part of a study management committee, Research Funding; Sangamo: Consultancy, Honoraria; Medscape: Honoraria, Other: Case Author ; Incyte: Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Other: Part of a study management committee, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grants, Travel, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grants, travel, clinical trial support, Research Funding. Olin:Cellectis: Research Funding; Servicer: Consultancy; Riger: Consultancy. Smith:Revolution Medicines: Research Funding; Biomea: Other: Clinical Trial Funding; Cellgene: Other: Clinical Trial Funding; Abbvie: Honoraria, Research Funding; ERASCA: Research Funding; Genentech: Honoraria. Curran:Servier: Honoraria; Dava Oncology: Honoraria; Pfizer: Consultancy; Clincal Care Options: Honoraria; Jazz Pharmaceuticals: Consultancy; Kite Pharmceuticals: Consultancy. Stefanos:Eilean Therapeutics: Consultancy. Levine:Qiagen: Membership on an entity's Board of Directors or advisory committees; Anovia: Consultancy; Auron: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Ajax: Membership on an entity's Board of Directors or advisory committees; Bakx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Scorpion: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy; Zentalis: Membership on an entity's Board of Directors or advisory committees; Epiphanes: Membership on an entity's Board of Directors or advisory committees; Jubilant: Membership on an entity's Board of Directors or advisory committees; Bridge Bio: Consultancy; Bridge Medicines: Consultancy; Mission Bio: Membership on an entity's Board of Directors or advisory committees. Burd:Eilean Therapeutics: Current Employment. Borate:Ryvue: Other: IDMC; Sumitomo: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Rigel: Consultancy; Incyte: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Abbvie: Consultancy; Takeda: Other: IDMC. Mims:Foghorn Therapeutics: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society Beat AML Study: Other: Senior Medical Director; Treadwell Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Daiichi Saynko: Membership on an entity's Board of Directors or advisory committees. Byrd:Abbvie, AstraZeneca, and Syndax: Consultancy; Vincerx Pharma, Eilean Therapeutics, and Kurome Therapeutics: Current equity holder in private company. Madanat:Sierra Oncology, Stemline Therapeutics, Blueprint Medicines, Morphosys, Taiho Oncology, SOBI, Rigel Pharmaceuticals, Geron, Cogent Biosciences, and Novartis: Other: Advisory Board; BMS, Kura Oncology, Blueprint Medicines, Geron: Consultancy; Blueprint Medicines, MD Education and Morphosys: Other: Supporting or attending meetings and/or travel.