Outcome Prediction By the New 2022 European Leukemia Net (ELN) Genetic-Risk Classification for Adult Patients (Pts) with Acute Myeloid Leukemia (AML): An Alliance Study

Background: Since their 1^st edition, published in 2010, the ELN recommendations for diagnosis and management of AML include genetic-risk classifications that have become an integral part of clinical practice guiding assessment of the likelihood of AML pts to respond to therapy and achieve long survival. The updated 2022 ELN include a revised genetic-risk classification that incorporated recent advances in molecular genetics of AML. Major changes from 2017 ELN include 1) addition of 7 myelodysplasia(MDS)-related mutations (mut) to adverse (adv) group; 2) placing NPM1-mutated pts with adv cytogenetic abnormalities in the adv group; 3) consideration of only FLT3-ITD, not allelic ratio; 4) replacing biallelic CEBPA mut with bZIP in-frame CEBPA mut as favorable (fav) markers. Additionally, t(3;v)(q26.2;v)/MECOM and t(8;16)(p11;p13) were added to the adv group and karyotypes with ≥3 trisomies excluded from adv group. The goals of our study were to test how well the 2022 ELN genetic-risk groups associate with treatment response and overall survival (OS), compare performance of the 2022 and 2017 ELN classifications in all pts with AML and in cohorts separated by pt age, and assess the validity of newly introduced features.

Methods: We analyzed outcomes of 1,098 adult pts with AML similarly treated with cytarabine/anthracycline induction on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols between 1986 and 2016 who were categorized according to the 2022 and 2017 ELN genetic-risk classifications. Centrally reviewed cytogenetic and molecular data required by ELN were available for all pts.

Results: According to the 2022 ELN classification, 38% of pts were assigned to fav, 26% to intermediate (int) and 36% to adv groups. This represents a decrease in the size of fav and increase in the size of adv groups compared with 2017 ELN classification (fav: 43%, int: 25%, adv: 32%). CR rates reflected well the risk-group assignments, with 90% for fav, 74% for int and 52% for adv groups (P<.001), as did OS (5y rates: fav, 51%, int, 27%, adv, 13%, P<.001). However, there was no difference in outcome prediction when we compared the 2022 ELN and 2017 ELN classifications for all pts (ROC for CR, 2022 ELN: 0.72, 2017 ELN: 0.74; ROC for OS, 2022 ELN: 0.70, 2017 ELN: 0.69, Fig. A). This was also true for pts age <60y and those ≥60y. A major change in the 2022 ELN was 1) the addition of MDS-related gene mut as a criterion for adv group assignment, unless they co-exist with "favorable-risk AML subtypes". Indeed, pts with MDS-related mut and no fav features had poor outcome similar to the outcome of pts with other adv markers (CR, 49 vs 56%, P=.22; OS, 5y rates: 12 vs 16%, P=.33). The outcome of pts with MDS-related mut without fav features was worse than outcome of pts with MDS-related mut co-occurring with fav markers (CR, 49 vs 80%, P<.001; OS, 5y rates: 12 vs 42%, P<.001). However, the outcome of pts with fav AML harboring MDS-related mut was worse than outcome of pts with fav AML without MDS-related mut (CR, 80 vs 93%, P=.002; OS, 5y rates, 42 vs 53%, P=.009, Fig. B) thus challenging this new hierarchical assignment. 2) We also found that NPM1-mutated pts with adv cytogenetic abnormalities, whom 2022 ELN assigns to the adv group, had similar CR rates (84 vs 79%, P=.99) but better OS (5y rates, 31 vs 14%, P<.001) than pts harboring NPM1 mut and FLT3-ITD, who are classified in the int group. 3) AML with FLT3-ITD is now categorized in the int group, irrespective of the allelic ratio or concurrent presence of NPM1 mut. However, OS of pts with FLT3-ITD was worse than OS of pts without FLT3-ITD remaining in the int group (5y rates: 19 vs 37%, P<.001). 4) Lastly, the 2022 ELN now require only an in-frame bZIP CEBPA mut for classification into the fav group. Indeed, CR rates and OS of bZIP CEBPA-mutated pts were superior to those of pts with non-bZIP CEBPA mut or CEBPA wild-type.

Conclusions: The 2022 ELN genetic-risk classification made changes that acknowledge advances in our understanding of disease biology and AML-associated gene mut. This classification provides guidance for risk stratification with similar efficacy as the previous, 2017 one. Our analyses both confirm and challenge the prognostic relevance of some of the newly added features.

U10CA180821, U10CA180882, U24CA196171; Clinicaltrials.gov Ids: NCT00048958 NCT00899223, NCT00900224; https://acknowledgments.alliancefound.org

Shared authorship, first: KM, JK; last: JCB, A-KE

Blachly:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; INNATE Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; MingSight Pharmaceuticals: Research Funding. Mims:Zentalis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Other: Data Safety and Monitoring Board; Genentech: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Ryvu: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety and Monitoring Board; BMS: Membership on an entity's Board of Directors or advisory committees. Larkin:Gilead: Membership on an entity's Board of Directors or advisory committees. Powell:Ambit Biosciences: Research Funding; Genentech: Research Funding; Hoffman LaRoche: Research Funding; Jazz Pharmaceuticals: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding. Marcucci:Abbvie: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings. Baer:Ascentage: Research Funding; Forma: Research Funding; Kura Oncology: Research Funding; AbbVie: Research Funding; Kite, a Gilead Company: Research Funding; Takeda: Research Funding. Stock:Amgen: Honoraria; Jazz Pharmaceuticals: Honoraria; Kite: Honoraria; Kura Oncology: Honoraria; MorphoSys: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Pluristem: Consultancy, Honoraria; Servier: Honoraria; Newave Pharmaceuticals: Consultancy; Syndax: Consultancy, Honoraria; Agios: Honoraria. Byrd:TG Therapeutics: Honoraria; Vincerx Pharma: Current equity holder in publicly-traded company; AstraZeneca: Consultancy; Xencor, Inc: Research Funding; Novartis: Consultancy, Honoraria; Kura Oncology, Inc: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Syndax: Consultancy; Pharmacyclics LLC: Honoraria, Research Funding. Eisfeld:Karyopharm Therapeutics: Other: Spouse is current company employee.