Genetic risk classification for adults with AML receiving less-intensive therapies: the 2024 ELN recommendations

European LeukemiaNet (ELN) genetic risk classifications have been used widely in clinical practice and in clinical trials.^1,2 These classifications were based exclusively on data from patients who received intensive chemotherapy and were not intended for prognostic stratification of older and/or unfit patients receiving less-intensive therapeutic options. Recent attempts to validate the 2017 and 2022 ELN risk classifications in older patients treated with less-intensive regimens have proven suboptimal, with most individuals classified as adverse risk.^3,4 This supported the need for a new genetic classifier relevant for stratifying prognostic outcomes in patients receiving hypomethylating agent (HMA)–based regimens alone or in combination with either the B-cell leukemia/lymphoma 2 inhibitor venetoclax (VEN) or azacitidine (AZA) with the IDH1 inhibitor ivosidenib (IVO) for IDH1-mutated acute myeloid leukemia (AML).^5,6 

Regarding the prognostic impact of genetic factors in patients treated with HMA monotherapy, analysis of cytogenetic data from the phase 3 clinical trial evaluating AZA vs standard of care indicated a 31% to 46% reduced risk of death for patients with adverse-risk karyotype treated with AZA compared with conventional care.⁷ Gene mutation analyses were only available in one-third of patients and were largely inconclusive.

A recently published analysis of 604 patients treated in a randomized clinical trial evaluating guadecitabine vs treatment with either AZA, decitabine, or low-dose cytarabine demonstrated that both the 2017 and 2022 ELN risk classifications had suboptimal utility in predicting clinical outcome.³ Remodeling and multivariable analysis identified 3 distinct prognostic risk groups based on the genomic status of 3 genes: a low-risk group identified by DDX41^mut (germ line in 61% cases); a high-risk group characterized by the presence of either FLT3-ITD^pos or TP53^mut; and an intermediate-risk group defined by the absence of DDX41^mut, FLT3-ITD and TP53^mut.

There has been a steady increase in the number of studies investigating the role of genomic factors in determining response and survival outcomes after HMA/VEN-based therapy.^4,8-16 Similar to the HMA monotherapy study,³ a pooled analysis of 279 patients treated with AZA/VEN in phase 1b and phase 3 trials demonstrated an inability of either the 2017 or 2022 ELN risk classifications to clearly stratify prognostic outcomes.⁴ Reanalysis using a bioinformatic-based approach delineated 3 novel risk groups based on a 4-gene classifier: a higher-benefit group defined by TP53^wt, KRAS/NRAS^wt, and FLT3-ITD^neg (52% patients); an intermediate-benefit group by FLT3-ITD^pos and/or KRAS^mut and/or NRAS^mut (25.4%); and a lower-benefit group defined solely by TP53^mut (22.6%).⁴ The median overall survival (OS) times for the 3 risk groups were 26.5 months, 12.1 months, and 5.5 months, respectively. The adverse prognostic impact of TP53^mut or FLT3-ITD^pos after treatment with AZA/VEN and failure to improve survival above AZA alone has been reported previously.^9,10 Importantly, an external validation of this 4-gene predictive signature was provided recently by a single-center study of 159 patients treated with HMA/VEN.¹⁵ 

Within these newly defined higher- and intermediate-benefit groups, the most frequently occurring International Consensus Classification disease entities were AML with myelodysplasia-related (MR) gene mutations (corresponding to AML, MR in the World Health Organization fifth edition classification¹⁷), followed by AML with mutated NPM1, and AML not otherwise specified.⁴ In patients with NPM1- or IDH2-mutated AML, exploratory analyses identified a negative prognostic impact in the setting of concomitant signaling gene mutations (FLT3-ITD^pos, KRAS^mut, and NRAS^mut), which is consistent with their biological associations as mediators of VEN resistance. For example, NPM1^mut AML without signaling gene mutations had a median OS of 39 months compared with only 9.9 months in the presence of a co-occurring FLT3-ITD^pos, KRAS^mut, and/or NRAS^mut. Similar trends were found for IDH2^mut (median OS, 36.9 vs 12.2 months), RUNX1^mut (median OS, 32.5 vs 9.3 months), and AML with MR gene mutations (median OS, 22.9 vs 12.9 months), if an activated kinase pathogenic variant was absent or present, respectively.

DDX41 mutations identify a particularly favorable-risk group among patients treatment with HMA therapy³ and similarly appear to demonstrate a favorable prognosis in patients treated with AZA/VEN, with 2 recent studies reporting a high response rate and favorable outcome for patients with DDX41^mut AML.^13,14 At 2 years, DDX41-mutated AML was associated with an OS probability of 60.1% (median OS, 27.8 months) after HMA monotherapy³ and 91.1% (median OS, not reached) after HMA plus VEN–based therapy.¹³ 

A randomized phase 3 study established AZA/IVO as a new treatment standard for patients with IDH1^mut AML, with improved OS for AZA/IVO, compared with AZA/PBO (24.0 vs 7.9 months).⁶ With additional follow-up, the median OS in the AZA/IVO arm has extended to 29.3 months.¹⁸ Although this compares favorably with 10.2 months for IDH1^mut patients treated with AZA/VEN,¹⁹ such uncontrolled crosstrial comparisons should be interpreted cautiously. Genes frequently comutated with IDH1 include DNMT3A, SRSF2, and RUNX1.²⁰ Ad hoc subgroup analyses suggest that AZA/IVO has favorable outcome in IDH1^mut AML even if co-occurring with either these or receptor tyrosine kinase mutations.²⁰ Therefore, based on the available data, it is appropriate to categorize all patients with IDH1^mut AML as favorable in the context of AZA/IVO therapy.

Table 1 outlines a proposed ELN genetic risk classification framework for patients with newly diagnosed AML receiving less-intensive HMA-based therapies (2024 ELN Less-Intensive). The 2024 ELN Less-Intensive genetic risk classification is applicable to patients receiving HMA monotherapy, HMA/VEN, or AZA/IVO (for IDH1^mut AML). For patients with favorable-risk disease, the median OS times have been reported to be >24 months. For adverse-risk patients, OS ranges between 5 to 8 months, whereas the remaining patients are categorized as intermediate risk. Table 2 gives an overview of reported survival times for selected genetic subgroups.

Although patients with NPM1^mut or IDH2^mut AML appear sensitive to VEN treatment,⁸ favorable clinical outcome appears limited to cases lacking activated signaling gene comutations. DDX41^mut (two-thirds of germ line origin) has increasingly been linked to favorable outcomes in AML, after both HMA monotherapy or VEN-based combination therapies.^3,13 Finally, all patients with IDH1^mut have favorable outcomes after AZA/IVO.

TP53^mut are universally associated with adverse clinical risk, with poor outcomes for HMA therapy alone or in combination with VEN.^3,4,10,14-16 Complex karyotype is present in the majority (80%-90%) of TP53^mut cases. Although the median OS for cytogenetic adverse-risk AML without concurrent TP53^mut treated with AZA/VEN is 23.4 months,¹⁰ additional confirmatory studies in the setting of less-intensive therapies are needed.

AML with MR mutations as defined by the International Consensus Classification has established specificity for secondary AML.²¹ A recent study indicates that patients with AML and MR mutations are particularly responsive to HMA/VEN²²; consistent with other reports linking splicing factor variants or ASXL1 mutations to improved outcomes after HMA/VEN.^23,24 However, even within this category, the copresence of signaling gene mutations is associated with inferior prognosis.⁴ 

This iteration of the 2024 ELN Less-Intensive AML classification was based on currently available genetic data from less-intensively treated patients, which still remain limited. For AML subgroups with specific gene rearrangements (eg, translocations and inversions), characterization of their impact on prognosis was not possible, owing to their rarity in older age patients, resulting in a paucity of available data. The current classification also has limited relevance to patients with prior myeloproliferative neoplasm or prior exposure to HMA therapies, including AML after an antecedent myelodysplastic syndrome, because such patients were generally excluded from clinical trials of VEN in AML. In terms of low-dose cytarabine/VEN-based treatment and genomic determinants of outcome, we have not included specific comments in the current ELN Less-Intensive classification, because these analyses have yet to be published.

The 2022 ELN recommendations additionally emphasize the role of measurable residual disease (MRD) assessment for comprehensive risk assessment, which has become integral to the management of patients treated with intensive chemotherapy. In patients treated with HMA-based therapies, MRD data are just emerging, and they suggest that MRD monitoring also plays an important and complementary role in informing prognosis.^25,26 

Acknowledging its limitations, this ELN genetic risk classification provides a basis for consensus stratification of patients receiving less-intensive therapies. It will be important for these 2024 ELN Less-Intensive recommendations to be validated in future clinical trials, as well as large real-world data sets. With the treatment landscape in older/unfit patients continuing to evolve (eg, with addition of FLT3 and menin inhibitors), it is expected that this classification will continue to undergo iterative future refinement.

The authors acknowledge Rüdiger Hehlmann for his continuous generous support of these recommendations on behalf of the European LeukemiaNet.

H. Döhner is supported by Sonderforschungsbereich 1074 “Experimental models and clinical translation in leukemia” and Forschungsgruppe 2674, project A02 “Genetic landscape of acute myeloid leukemia in older patients,” both funded by the Deutsche Forschungsgemeinschaft. A.H.W. is supported by the Australian National Health and Medical Research Council, Victorian Cancer Agency, Metcalf Family Fellowship, and the Medical Research Future Fund. C.D.D. is supported by the Leukemia & Lymphoma Society Scholar in Clinical Research Award.

Contribution: H. Döhner, C.D.D., A.H.W., and B.L. wrote the draft version of the manuscript; and all authors reviewed and approved the final version of the manuscript.

Conflict-of-interest disclosure: H. Döhner reports advisory role with honoraria for AbbVie, AstraZeneca, Gilead, Janssen, Jazz, Pfizer, Servier, Stemline Therapeutics, and Syndax and clinical research funding (to institution) from AbbVie, Astellas, Bristol Myers Squibb (BMS), Celgene, Jazz Pharmaceuticals, Kronos Bio, and Servier. C.D.D. reports honoraria/consulting fees from AbbVie, Agios/Servier, Astellas, Celgene/BMS, Cleave, Foghorn, Genentech, GenMab, GSK, Novartis, Notable Labs, and Takeda and research grants (to the institution) from AbbVie, Agios/Servier, Astex, Calithera, Celgene/BMS, Cleave, Foghorn, Immune-Onc Therapeutics, and Loxo. A.H.W. reports advisory role with honoraria for AbbVie, Agios, Amgen, Astellas, AstraZeneca, Roche, BMS, Celgene, Gilead, Pfizer, Janssen, Jazz, Novartis, and Servier; clinical research funding (to institution) from AbbVie, Servier, Celgene/BMS, AstraZeneca, Amgen, and Novartis; and receives a fraction of royalty payments from the Walter and Eliza Hall Institute of Medical Research related to venetoclax. B.L. reports advisory role with honoraria for AbbVie, Astellas, BMS, Stemline Pharmaceutics/Menarini, Syndax Pharmaceuticals, Ryvu Therapeutics, Wugen Inc, and CureVac and royalties from UpToDate. F.R.A. reports consulting for Jasper Biote. C.C. reports advisory role with honoraria for AbbVie, Amgen, Astellas, AstraZeneca, Berlin-Chemie, BMS, Celgene, Daiichi Sankyo, Eurocept Pharmaceuticals, Gilead, Janssen, Jazz, and Novartis and clinical research funding from AbbVie, BMS, Celgene, and Jazz Pharmaceuticals. H. Dombret reports honoraria/consulting fees from AbbVie, Amgen, Astellas, Celgene/BMS, Daiichi Sankyo, Incyte, Jazz Pharmaceuticals, Pfizer, and Servier and research funding from Amgen, Astellas, Celgene/BMS, Incyte, Jazz Pharmaceuticals, and Pfizer. B.L.E. has received research funding from Novartis and Calico; has received consulting fees from AbbVie; and is a member of the scientific advisory board and shareholder for Neomorph Inc, TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. P.F. reports honoraria and, as French Myelodysplastic Syndrome group chairperson, research support from Celgene/BMS, Novartis, AbbVie, Jazz, Janssen, and Agios. R.A.L. reports receiving consulting or advisory fees from AbbVie, Amgen, Ariad/Takeda, Astellas, Celgene/BMS, Curis, CVS Caremark, Epizyme, Function Oncology, ImmunoGen, Jazz Pharmaceuticals, Kling Biotherapeutics, Medpace, MorphoSys, Novartis, and Servier; clinical research support to his institution from Astellas, Biomea, Celgene, Cellectis, Daiichi Sankyo, Forty Seven/Gilead, Novartis, and Rafael Pharmaceuticals; and royalties from UpToDate. R.L.L. reports supervisory board fees from Qiagen; scientific advisor fees from Mission Bio, Zentalis Pharmaceuticals, Ajax, Auron, Prelude, and C4 Therapeutics, for which he receives equity; research support from Calico, Zentalis Pharmaceuticals, and Ajax; consultation fees from Incyte and Janssen; and honoraria from AstraZeneca for invited lectures. Y.M. reports honoraria from Nippon Shinyaku, BMS, Novartis, Sumitomo Pharma, Kyowa Kirin, AbbVie, Daiichi Sankyo, Takeda, Janssen Pharmaceutical, Astellas, Pfizer, Eizai, Otsuka Pharmaceutical, and Sumitomo Dainippon and research funding from Chugai. G.O. reports advisory role with honoraria for AbbVie, Astellas, BMS, Celgene, Gilead, Servier, Jazz, and Novartis. C.R. reports advisory role with honoraria for AbbVie, Amgen, Astellas, BMS, Celgene, Jazz, Novartis, Pfizer, and Servier and clinical research funding from AbbVie, Novartis, and Pfizer. J.S. reports advisory role with honoraria for AbbVie, Astellas, Jazz Pharmaceuticals, and BMS and clinical research funding from AbbVie, Astellas, Jazz Pharmaceuticals, and Jose Carreras International Leukemia Foundation. E.M.S. reports advisory board fees from Novartis, Pinotbio, Janssen, BMS, Agios, Jazz, Menarini, Genentech, Genesis, AbbVie, Neoleukin, Gilead, Syndax, OnCusp Therapeutics, CTI BioPharma, Foghorn, Servier, Calithera, Daiichi Sankyo, Aptose, Syros, Astellas, Ono Pharma, and Blueprint; honoraria from Kura; safety monitoring roles with Epizyme and Cellectis; research funding from Eisai and BMS; and equity from Auron. M.S.T. reports advisory board fees from AbbVie, Daiichi Sankyo, Moleculin, Orsenix, KAHR, Oncolyze, Jazz Pharma, Roche, BioSight, Novartis, Innate Pharmaceuticals, Kura, Syros Pharmaceuticals, Ipsen Biopharmaceuticals, and Cellularity; research funding from AbbVie, Orsenix, BioSight, GlycoMimetics, Rafael Pharmaceuticals, and Amgen; royalties from UpToDate; and serving as Chair of Differentiation Adjudication Committee at Foghorn (Foghorn259) and chair of data safety monitoring board for HOVON150. H.-F.T. reports advisory role with honoraria for AbbVie, Alexion, Celgene, Daiichi Sankyo, Novartis, and Roche and research funding from Celgene. J.W. reports advisory role with honoraria for AbbVie. A.W. reports advisory role with honoraria for AbbVie, Astellas, BMS, Celgene, Gilead, Janssen, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier and clinical research funding from Jazz Pharmaceuticals. The remaining authors declare no competing financial interests.

Correspondence: Hartmut Döhner, Department of Internal Medicine III, Ulm University Hospital, Albert-Einstein-Allee 23, Ulm 89081, Germany; email: hartmut.doehner@uniklinik-ulm.de.