AML classification in the year 2023: How to avoid a Babylonian confusion of languages

AML diagnoses – from WHO 2017 to WHO 2022

According to WHO 2022, 746 patients were diagnosed as AML and 705 patients as MDS (Fig. 1A, Supplementary Table S2). Within the AML cases, genetically defined AML (excluding here AML-MRC/AML-MR for comparability with WHO 2017) was the largest subgroup with 65% (477/734) and 67% (502/746) of AML cases in both WHO classification systems, respectively. However, the composition of the genetically defined AML changed. Notably, APL, core binding factor AML, and AML with DEK::NUP214 fusion did not change at all. Major additional contributors were AML with KMT2A-r (n = 45) now including 19 cases (42%) with a different partner gene but MLLT3 (Supplementary Fig. S1) and AML with MECOM-r (n = 69) now including 33 cases (48%) not comprising GATA2 (Supplementary Fig. S2). In addition, the newly recognized entities included 6 cases, 5 belonging to AML with NUP98 rearrangement (partner genes KDM5A: n = 2, NSD1: n = 2, STIM1: n = 1) and one case to AML with another defined genetic aberration (KAT6A::CREBBP). In contrast, the now abandoned entity AML with mutated RUNX1 was mainly reclassified as AML-MR (37/48; 77%) based on a large overlap with ASXL1 and splicing factor mutations (Supplementary Fig. S3). Only 7 cases of this former category were not otherwise genetically defined and moved to AML defined by differentiation. In addition, 10 further cases were classified as AML with mutated NPM1 (according to WHO 2017: AML-MRC: n = 4; MDS-EB-2: n = 4; MDS-EB-1: n = 1; MDS-MLD: n = 1) and 5 cases as AML with mutated CEBPA (former AML-MRC due to the superior hierarchical status of a previously documented MDS or MDS/MPN history or showing MR cytogenetic abnormalities in the WHO 2017).

Fig. 1: Changes in specific MDS and AML diagnoses compared to WHO 2017.figure 1

Changes in diagnoses according to WHO 2022 (A) or ICC (B). P::R = PML::RARA; C::M = CBFB::MYH11; R::R = RUNX1::RUNX1T1; MR(C) Myelodysplasia-related (changes), NOS Not otherwise specified, EB Excess blasts, SLD Single lineage dysplasia, MLD Multilineage dysplasia; 5q/del(5q) Isolated 5q deletion, RS Ring sideroblasts; -r rearrangement; ODGA Other defined genetic alterations, IB Increased blasts, biTP53 biallelic TP53 inactivation, LB Low blasts, abn Abnormalities.

Myelodysplasia-related AML substantially increased from 22% (158/734) AML-MRC to 28% (208/746) AML-MR in WHO 2022 (Supplementary Fig. S4A; 122/208 former AML-MRC, 49/208 former AML-NOS, 37/208 former AML-RUNX1). The largest contributor to this increase were mutations in the defining genes solely leading to this classification in 44% (92/208) of cases (Supplementary Fig. S4B). Notably, cyto- and molecular genetics without medical history were sufficient for AML-MR classification in all patients. In addition, 23% (36/158) former AML-MRC patients were not re-classified as AML-MR: 33 harbored defining genetic abnormalities (55% with MECOM-r: n = 18) and three were defined by differentiation as the morphologic dysplasia had been the only MRC-defining criterion according to WHO 2017 (Fig. 1A). Complementary to these findings, the morphologically defined group was reduced from 13% (99/734) AML-NOS to 5% (36/746) AML with differentiation (Supplementary Fig. S5). When stratified into morphologically defined subgroups, the decrease was particularly striking for acute monoblastic and monocytic leukemia.

Overall, reclassification from MDS according to WHO 2017 to AML according to WHO 2022 was a rare event affecting < 1% of cases of the total cohort (2% of the MDS cohort; Supplementary Table S3). In total, 12 former MDS samples, 8 of them EB-2, were upstaged to AML based on DGA (MECOM-r: n = 5; KMT2A-r: n = 1; NPM1: n = 6).

AML diagnoses – from WHO 2017 to ICC

When following ICC, the cohort comprised 742 AML, 572 MDS, and 137 MDS/AML cases (Fig. 1B; Supplementary Table S4). This new category of MDS/AML overlap is the largest change from WHO 2017 to ICC affecting 9% of all patients. Focusing on AML cases, 69% (515/742) were genetically defined AML (excluding here again AML-MR). The increase from 65% based on WHO 2017 to 69% following ICC was mainly mediated by introducing the new entity AML with mutated TP53 comprising 52 cases of which the majority was former AML-MRC (48/52; 92%). Within TP53 mutated AML we observed a high fraction of cases with complex karyotype and biallelic TP53 mutations but only a weak overlap with MR mutations (Supplementary Table S5). In addition, AML with other KMT2A-r but MLLT3 and other MECOM-r but GATA2 were introduced including 14 and 21 cases, respectively (Supplementary Fig. S1 and S2).

Regarding AML-MR, in our cohort, 174 cases harbored MR gene mutations while 19 showed certain MR cytogenetics (in total 193/746, 26% of AML cases). AML with MR gene mutations mainly composed former AML-MRC (n = 69), AML-NOS (n = 52) and AML-RUNX1 (n = 46). As in ICC – in contrast to WHO 2022 – RUNX1 mutations were qualifying mutations for AML-MR, 46 of the previous 48 (96%) AML-RUNX1 cases were classified as AML-MR while two had other MECOM-r. In line, AML-NOS was reduced from 99 to 34 cases (5%) not further characterized with respect to morphology (Supplementary Fig. S5). In addition, according to ICC criteria, 8 former MDS-EB-2 cases were upstaged to AML due to NPM1 or in-frame bZIP CEBPA mutations (Supplementary Table S3).

Survival analysis of AML entities according to different classification systems

Kaplan-Meier analyses of overall survival (OS) revealed marked differences between AML entities classified according to WHO 2017, WHO 2022 and ICC. For all classifications prognostic significance was confirmed (Fig. 2; overall p < 0.001). Across the different classifications, major changes regarding OS were observed for AML-CEBPA and AML-MR both entities present in all classification systems but with different inclusion criteria. CEBPA mutated AML showed a median OS of 5.0 and 4.1 years based on WHO 2017 and WHO 2022, respectively, while it was not reached according to ICC. Notably, based on WHO 2017 this entity comprised cases with biallelic CEBPA mutations (n = 56), WHO 2022 additionally considered single CEBPA mutations located in bZIP region (n = 61; in our cohort all with biallelic mutation; 5 additional biallelic CEBPA mutated cases were former AML-MRC due to differences in entity hierarchy) and ICC only included in-frame bZIP mutations (n = 47). Concerning myelodysplasia-related AML, AML-MRC based on WHO 2017 had the shortest median OS with 0.4 years compared to AML-MR according to WHO 2022 with a median OS of 0.5 years and AML-MR according to ICC with a median OS of 1.0 years. The later was mediated by excluding TP53 mutated cases which showed the worst OS (0.1 years) within all AML entities. Within TP53 mutated cases we observed a trend towards effects of TP53 mutation status (mono- vs. biallelic) on OS (Supplementary Fig. S6). When differentiating AML with MR cytogenetic abnormalities from AML with MR gene mutations according to ICC, no difference in OS was observed (median OS: 0.71 vs 0.98 years; p = 0.958; Supplementary Fig. S7).

Fig. 2: Overall survival (OS) of AML patients according to different classifications.figure 2

A OS of AML patients according to WHO 2017 (n = 734). B OS of AML patients according to WHO 2022 (n = 746). C OS of AML patients according to ICC (n = 742). NOS: not otherwise specified; MR(C): myelodysplasia-related (changes); -r rearrangement, ODGA other defined genetic alterations, *comprises MR gene mutations and MR cytogenetic abnormalities; **comprises GATA2::MECOM and other MECOM-r; **comprises KMT2A::MLLT3 and other KMT2A-r.

Heterogeneity of AML entities between new classification systems

A direct comparison of the ICC with the WHO 2022 highlighted several differences (Fig. 3A). Overall, the classification of the disease subgroup differed in 14% (104/746) of AML cases (not taking the category of MDS/AML into account; Fig. 3B). While some of these changes arise from minor differences in subtype definitions, others reflect major differences in the two classification systems – including an additional biological subgroup in the ICC (AML with mutated TP53).

Fig. 3: Changes in AML diagnoses between WHO 2022 and ICC.figure 3

A Changes in specific MDS and AML diagnoses between WHO 2022 and ICC. B Major differences in AML diagnoses between WHO 2022 and ICC. P::R = PML::RARA; C::M = CBFB::MYH11; R::R = RUNX1::RUNX1T1; MR Myelodysplasia-related, NOS Not otherwise specified, EB Excess blasts, SLD Single lineage dysplasia, MLD Multilineage dysplasia, 5q/del(5q) Isolated 5q deletion, RS Ring sideroblasts, -r rearrangement, ODGA Other defined genetic alterations, IB Increased blasts, biTP53 Biallelic TP53 inactivation, LB Low blasts, abn Abnormalities.

KMT2A- and MECOM-rearranged cases formed two entities in WHO 2022 but were split into four different entities following ICC separating other partner genes than MLLT3 or GATA2. However, there was no significant difference in OS between KMT2A::MLLT3 and other KMT2A-r cases (Supplementary Fig. S1). The same was true for the survival of GATA2::MECOM and other MECOM-r cases (Supplementary Fig. S2). Major differences also affected myelodysplasia-related AML (Supplementary Fig. S8). TP53 mutations were detected in 23% (48/208) of AML-MR leading to a classification as AML-TP53 according to ICC. Notably, AML-TP53 showed shorter OS compared to AML-MR according to WHO 2022 (median OS: 0.1 vs 1.0 years, p < 0.001; Supplementary Fig. S9).

The different definitions for the upstaging from MDS to AML according to genetics and blast cutoffs led to 12 patients with differences in the main diagnosis – AML or MDS – between the two new classifications (Supplementary Table S3). Thus, the upstaging from MDS to AML was not consistent between WHO 2022 and ICC. Only 4 of total 16 cases were concordantly upstaged to AML in both new classifications.

The largest difference between WHO 2022 and ICC was mediated by the introduction of the new category MDS/AML including mainly MDS-IB2, but also MDS and AML cases (MDS-biTP53 and AML with MECOM-r; Supplementary Fig. S10). MDS/AML separated into those with TP53 mutations (19/137; 14%), with MR gene mutations (99/137; 72%), with MR cytogenetic abnormalities (6/137; 4%) and MDS/AML, NOS (13/137; 10%).

Risk stratification based on ELN 2017 and ELN 2022

In line with AML disease classification according to ICC, also AML risk classification has been adjusted in ELN 2022 guidelines. In our cohort, favorable and intermediate groups shrunk from 256 to 229 and from 155 to 125 cases, respectively, while in contrast the adverse risk group increased from 275 to 332 cases (Supplementary Fig. S11, Supplementary Table S6). These changes within the criteria for the different risk groups did not only affect the group size, but were also to some degree reflected in the outcome data (Fig. 4). This impacted mainly the favorable risk category with a median OS of 6.6 years in ELN 2022 compared to 4.2 years in ELN 2017. The median OS of the intermediate groups was comparable (0.81 and 0.80 years), whereas of adverse groups slightly increased from ELN 2017 to ELN 2022 (0.66 and 0.71 years, respectively). However, c-indices (calculated to assess the correlation between predictions according to ELN 2017 and ELN 2022 with real outcomes) were similar between both ELN 2017 and ELN 2022 with 0.5967 and 0.5961, respectively.

Fig. 4: OS of AML patients according to ELN risk classifications.figure 4

OS of AML patients based on WHO 2017 (n = 686; excluding AML with PML::RARA) according to ELN 2017 (A) or ELN 2022 (B) risk classifications. C-indices: 0.5967 for ELN 2017; 0.5961 for ELN 2022.

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