Home > Proceedings in Hematology > Proceedings of the 4th European Congress Controversies in Leukemia > Definitions of acute myeloid leukaemia and their clinical significance according to the WHO 2022 and ICC classification

Definitions of acute myeloid leukaemia and their clinical significance according to the WHO 2022 and ICC classification

Donata Backhaus (email)× Donata Backhaus (orcid) (email)

1 Department for Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University of Leipzig Medical Center, Leipzig, Germany
Jacob Jendro (email)× Jacob Jendro (orcid) (email)

1 Department for Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University of Leipzig Medical Center, Leipzig, Germany
Uwe Platzbecker (email)× Uwe Platzbecker (orcid) (email)

1 Department for Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University of Leipzig Medical Center, Leipzig, Germany
Dominic Brauer (email)× Dominic Brauer (orcid) (email)

1 Department for Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University of Leipzig Medical Center, Leipzig, Germany
Madlen Jentzsch (email)× Madlen Jentzsch (orcid) (email)

1 Department for Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University of Leipzig Medical Center, Leipzig, Germany

acute myeloid leukaemia, AML, WHO, ICC, classification

In 2022, two concurrent classification systems for acute myeloid leukaemia (AML) were introduced, replacing the 2016 version of the World Health Organization (WHO). While the WHO 2022 and the International Consensus Classification (ICC) exhibit significant overlap, distinctions arise in certain key aspects of AML definition and specific subgroups. Notably, the blast threshold defining AML differs between the two systems, with the new entity MDS/AML replacing the 2016 WHO myelodysplastic syndrome with elevated blasts-2 according to the ICC, but not in the WHO 2022 classification. Moreover, in the WHO 2022 system, AML-defining genetic aberrations still permit the diagnosis of AML regardless of the blast count in bone marrow or blood. In contrast, the ICC introduces a 10% threshold for this category. Consequently, in a small number of cases, the diagnosed myeloid neoplasm may differ between the two classifications. The most notable distinctions in subgroup definitions involve AML with myelodysplasia-related aberrations, including TP53, as well as AML with CEBPA mutations. This review examines the significant changes from the 2016 to the 2022 classification systems, highlighting their similarities and differences and discussing the ensuing implications for clinical practice.



For many years, acute myeloid leukaemia (AML) has been classified according to the World Health Organization (WHO) classification of tumours, which integrates clinical features, morphology, immunophenotyping, and genetics.1–5 Our understanding of the biology of hematologic neoplasms continuously evolves, leading to revisions of the classification every 5 to 10 years.6 To ensure widespread use and acceptance of the third edition, released in 2001, the WHO collaborated with the Society for Hematopathology, the European Association for Haematopathology and a Clinical Advisory Committee (CAC) comprising leading pathologists, oncologists, haematologists, and geneticists. This collaboration extended for the fourth (2008) and revised fourth (2016) edition.7 In an effort to streamline the selection of editors and authors for the fifth edition, released in 2022, the WHO opted for a process called informed bibliometrics instead of the CAC.6 However, some contributors to earlier editions deemed the CAC still necessary and organised one in September 2020. The findings of this CAC were not included in the fifth WHO edition but were published separately in the International Consensus Classification of Myeloid and Lymphoid Neoplasms (ICC).7,8 Consequently, there are now two competing classification systems for myeloid neoplasms, which complicates accurate patient diagnoses.2,8 In this context, we discuss the similarities and differences between the two 2022 classifications for AML, and provide a summary of previously published data assessing both classifications in real-world cohorts. Finally, we address their implications for the European LeukemiaNet (ELN) 2022 risk classification, the most commonly used risk stratification system in AML.


Boundary between MDS and AML

According to the WHO 2016 classification, AML was defined if the blast percentage in peripheral blood (PB) or bone marrow (BM) was equal to or exceeded 20%. Exceptions were defined for genetic abnormalities like core-binding factor AML or acute promyelocytic leukaemia (APL), which have been previously considered as AML regardless of the blast count.9 If the blast proportion exceeded 5% in PB or 10% in BM, but did not reach the 20% cut-off, an MDS with excess blasts 2 (MDS-EB2) was diagnosed, especially when BM dysplasia or PB cytopenias were present.1

Because of the increasing recognition of shared common pathogenic mechanisms between MDS and AML, and the high observer-dependency of blast enumeration,2 the blast cut-off that defines the boundary between both diseases was re-assessed in the WHO 2022 classification and the ICC. In the end, both classifications retained 20% blasts to define AML, but highlighted the biologic continuum between MDS and AML, and the need to offer patients a broader range of therapeutic approaches.2,7 Therefore, the ICC introduced the new category of MDS/AML (defined by a blast proportion of 10-19% in PB or BM), replacing the former MDS-EB.2,7 This group is further divided into MDS/AML with mutated TP53, MDS/AML with myelodysplasia-related (MR) gene mutation, MDS/AML with MR cytogenetic abnormalities and MDS/AML not otherwise specified (NOS). In contrast, the WHO 2022 classification rejected to lower the blast cut-off to define AML with the argument of the risk of overtreatment and the mere replacement of one arbitrary cut-off by another.2 Subsequently, the WHO 2022 retained the previous blast thresholds of 5-19% in PB and 10-19% in BM for MDS-EB2, but renamed it to myelodysplastic neoplasm with increased blasts 2 (MDS-IB2) to acknowledge the neoplastic behaviour of the disease.2

With the newly defined ICC entity MDS/AML, the question arose whether these patients should be risk-stratified according to the MDS (i.e. Molecular International Prognostic Scoring System [IPSS-M]) or AML risk classification (i.e. ELN 2022), which was assessed by Huber et al. in a cohort of 137 MDS/AML patients.10 For both classifications, there was a clear tendency towards higher risk groups with 10% of patients having moderate high, 29% high, and 45% very high IPSS-M risk, and 9% of patients having intermediate, and 91% adverse ELN 2022 risk, driven by the high incidence of MR gene mutations defining ELN 2022 adverse risk. According to the IPSS-M, there was a clear outcome separation, and overall survival (OS) was comparable to that of a published MDS cohort. In contrast, while OS still differed according to the ELN 2022, outcomes were significantly better than in a published AML cohort. The authors concluded that in MDS/AML patients, the IPSS-M should remain the preferred risk stratification system.10
AML defined by genetics

With the growing understanding of the pathogenesis and biology of AML the WHO 2022 classification as well as the ICC extended the list of AML-defining genetic abnormalities (Table 1).2,7 In comparison to the defined sub-classification of AML in the WHO 2016, the WHO 2022 classification broadened existing groups with defined gene fusions to also incorporate rare fusion partners. This affects APL with t(15;17)(q24.1;q21.2)/PML::RARA (now APL with PML::RARA fusion), as well as AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A (now AML with KMT2A rearrangement) and AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM (now AML with MECOM rearrangement). All may have a variety of fusion partners and can be cryptic on conventional karyotyping.2 Additionally, the WHO 2022 classification now recognizes AML with RBM15::MRTFA fusion (formerly RBM15::MKL1) and AML with NUP98 rearrangement as independent subgroups.2 In contrast, the ICC still retained the cytogenetically defined WHO 2016 subgroups, but added subgroups of APL with other defined RARA, and AML with other KMT2A, or MECOM rearrangements.7 Furthermore, both classifications introduced a new subgroup of “AML with other defined genetic alterations” (WHO 2022)2,7 or “AML with other rare recurring translocations” (ICC),7 providing a place for previously unknown AML entities.

With regard to molecular abnormalities, both classifications acknowledge AML with NPM1 mutation and AML with CEBPA mutation as distinct entities. However, the latter was changed from AML with bi-allelic CEBPA mutations in the WHO 2016 classification,1 to AML with CEBPA mutations in the WHO 2022 classification,2 which comprises bi-allelic mutations as well as single mutations in the basic leucine zipper (bZIP) region of CEBPA. Within the ICC, this group only includes AML with in-frame bZIP mutations and is named accordingly.7

As mentioned before, both classifications re-assessed the blast threshold to define AML, which was also done for the group of AML with defining genetic abnormalities. Within the WHO 2022, no blast count is necessary to diagnose AML with defining genetic abnormalities, with two exceptions: AML with BCR::ABL1 (to avoid an overlap with chronic myeloid leukaemia in myeloid blast phase), and AML with CEBPA mutation (due to insufficient data).2 According to the ICC, a blast count of at least 10% was kept for AML with defining genetic abnormalities - again except for AML with t(9;22)(q34.1;q11.2)/BCR::ABL1, which still requires 20% for AML diagnosis.7

Table 1. Comparison of AML with defining genetic abnormalities according to the WHO 2022 classification and the ICC, as defined in the published recommendations.2,7
AML with defining genetic abnormalities*
APL with PML::RARA fusionAPL with t(15;17)(q24.1;q21.2)/PML::RARA

APL with other RARA rearrangements**
AML with RUNX1::RUNX1T1 fusionAML with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1
AML with CBFB::MYH11 fusionAML with inv(16)(p13.1q22) or (16;16)(p13.1;q22)/ CBFB::MYH11
AML with DEK::NUP214 fusionAML with t(6;9)(p22.3;q34.1)/DEK::NUP214
AML with BCR::ABL1 fusion*AML with t(9;22)(q34.1;q11.2)/BCR::ABL1*                                                 
AML with KMT2A rearrangementAML with t(9;11)(p21.3;q23.3)/MLLT3::KMT2A

AML with other KMT2A rearrangements**
AML with MECOM rearrangementAML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1)

AML with other MECOM rearrangements**
AML with NPM1 mutationAML with mutated NPM1
AML with RBM15::MRTFA fusion-
AML with NUP98 rearrangement-
AML with other defined genetic alterationsAML with other rare recurring translocations
AML with CEBPA mutation*AML with in-frame bZIP CEBPA mutations
AML, MR*AML (≥ 20%) and MDS/AML (10-19%) with mutated TP53

AML (≥ 20%) and MDS/AML (10-19%) with MR gene mutations

AML (≥ 20%) and MDS/AML (10-19%) with MR cytogenetic abnormalities
AML, defined by differentiationAML, not otherwise specified
AML with minimal differentiation-
AML without maturation-
AML with maturation-
Acute basophilic leukaemia-
Acute myelomonocytic leukaemia-
Acute monocytic leukaemia-
Acute erythroid leukaemia-
Acute megakaryoblastic leukaemia-
Relevant differences are highlighted in bold. Abbreviations: AML, Acute myeloid leukaemia; ICC, International Consensus Classification, MR, Myelodysplasia-related; WHO, World Health Organization.

* In patients with defining genetic abnormalities, no blast cut-off (WHO 2022) or a 10% cut-off (ICC) is sufficient to diagnose AML. Exceptions remain the marked cases, i.e. AML with BCR::ABL1 fusion and AML with CEBPA mutation (according to WHO 2022) as well as AML with t(9;22)(q34.1;q11.2)/BCR::ABL1 (according to ICC), in which at least 20% blasts have to be present to diagnose AML.

** In these subgroups the ICC defines specific rearrangements:

For APL with other RARA rearrangements: t(1;17)(q42.3;q21.2)/IRF2BP2::RARA; t(5;17)(q35.1;q21.2) /NPM1::RARA; t(11;17)(q23.2;q21.2)/ZBTB16::RARA; cryptic inv(17q) or del(17)(q21.2q21.2) /STAT5B::RARA,STAT3::RARA; Other genes rarely rearranged with RARA:TBL1XR1 (3q26.3), FIP1L1 (4q12), BCOR (Xp11.4).

For AML with other KMT2A rearrangements: t(4;11)(q21.3;q23.3)/AFF1::KMT2A; t(6;11)(q27;q23.3)/AFDN::KMT2A; t(10;11)(p12.3;q23.3)/MLLT10::KMT2A; t(10;11)(q21.3;q23.3) /TET1::KMT2A; t(11;19)(q23.3;p13.1)/KMT2A::ELL; t(11;19)(q23.3;p13.3)/KMT2A::MLLT1.

For AML with other MECOM rearrangements: t(2;3)(p11~23;q26.2)/MECOM::?; t(3;8)(q26.2;q24.2)/MYC,MECOM; t(3;12)(q26.2;p13.2)/ETV6::MECOM; t(3;21)(q26.2;q22.1)/MECOM::RUNX1

The WHO 2016 entity of AML with myelodysplasia-related changes (MRC), whose diagnosis was made by detection of at least 50% dysplastic cells in more than one cell line, a history of antecedent MDS or the presence of MR cytogenetic abnormalities, was also refined.1 Both WHO 2022 and ICC removed morphology as a diagnostic criterion, but added a panel of MR gene mutations to define AML-MR.2,7 In addition, the WHO 2022 retained the history of MDS or myelodysplastic/myeloproliferative neoplasm overlap (MDS/MPN) as a diagnostic criterion for this group, which the ICC did not.

While in the WHO 2022 classification AML-MR represents a single category summarizing cytogenetic and molecular abnormalities,2 the ICC further subcategorizes into three groups – AML with mutated TP53, AML with MR gene mutations, and AML with MR cytogenetic abnormalities.7 Because of its aggressive behaviour and dismal prognosis, AML with mutated TP53 is recognized as a separate entity by the ICC, for which a mutation with a variant allele frequency (VAF) ≥10% must be present.7 In contrast, the WHO 2022 does not include TP53 mutations as a diagnostic criterion for AML-MR.

Several other gene mutations, i.e. in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2 are now acknowledged to define AML-MR and included in both classifications.2,7 Additionally, the ICC incorporated RUNX1 mutations into AML-MR, replacing the provisional WHO 2016 entity AML with mutated RUNX1.7 The WHO 2022 completely omitted this entity because of the lack of sufficient unifying characteristics.2 However, due to the frequent co-occurrence of other MR gene mutations, the majority of RUNX1 mutated cases remain in the category AML-MR.11

With regard to cytogenetic abnormalities, both classifications updated their definition criteria, which are summarized in Table 2.2,7 Of note, only the WHO 2022 recognized monosomy 13 or del(13q), as well as del(11q) as aberrations justifying the diagnosis of AML-MR,2 whereas only the ICC acknowledged trisomy 8 and del(20q).7

While MR gene mutations were included in both 2022 classifications based on their ability to more precisely define this specific subgroup than morphology alone, they also seem to have a prognostic significance in AML. In general, a shorter event-free survival and OS for individuals with these mutations was described,12 especially within the ELN 2017 intermediate risk group.12 Further analyses suggested that also the number and VAF of gene mutations are relevant, as patients with one MR gene mutation or lower VAFs had longer OS compared to patients with more than one MR mutation or higher VAFs.13–15 However, the adverse prognostic impact of MR gene mutations might be abrogated by an allogeneic hematopoietic stem cell transplantation (HSCT). In this context, a longer OS and relapse-free survival (RFS) was observed in de novo AML patients with at least one MR gene mutation who underwent HSCT, compared to patients after chemotherapy consolidation.16 Other studies suggested a benefit for HSCT in a time-dependent Cox regression analysis,15 or a very favourable 2-year OS of 77% in SRSF2 mutated AML patients after HSCT.17 In addition, in patients that underwent an allogeneic HSCT, those classified as adverse ELN 2022 risk due to the presence of an MR gene mutation had the most favourable outcome within the adverse risk group, which rather resembled that of patients classified as intermediate risk.18

While overall, TP53 mutations were recognized to provide adverse risk in myeloid neoplasm, recent data in MDS suggested especially dismal outcomes in the presence of a TP53 multi-hit status (defined as ≥2 TP53 mutations, a single TP53 mutation together with a cytogenetic deletion of the TP53 locus, a VAF ≥ 50%, or a copy-neutral loss of heterozygosity at the TP53 locus).19 Therefore, the WHO 2022 and ICC only included multi-hit TP53 mutations in the group of MDS with bi-allelic TP53 inactivation or MDS with mutated TP53, respectively.2,7 In contrast, in AML, also the presence of monoallelic TP53 alterations showed poor outcomes,20,21 which was only worsened by a co-occurring complex karyotype.20,21 Finally, patients with mutant TP53 seem to have dismal outcomes, irrespective of whether MDS-IB or AML was the underlying myeloid neoplasm, which again underlines the biologic continuity between both diseases.20,21

Table 2. Comparison of AML-MR defining cytogenetic abnormalities according to the WHO 2022 classifcation and the ICC, as defined in the published recommendations.2,7
WHO 2022ICC 2022
complex karyotype ( ≥ 3 abnormalities)
del(5q) or t(5q)del(5q), t(5q) or add(5q)
-7, del(7q) or t(7q)-7, del(7q)
del(12p) or  t(12p)del(12p), t(12p) or add(12p)
-13 or del(13q)-
del(17p) or t(17p)-17, del(17p) or add(17p)
Relevant differences are highlighted in bold. Abbreviations: AML, acute myeloid leukaemia; ICC, International Consensus Classification, MR, Myelodysplasia-related; WHO, World Health Organization.
AML not defined by genetics

Due to the increasing knowledge regarding the genetic abnormalities in AML, this subgroup gradually decreased over time. However, there are still some AML cases without a defined genetic driver. According to the WHO 2016, these cases were regarded as AML-NOS and subcategorized based on the degree and type of differentiation.1 In the WHO 2022 classification this was retained, and only the term AML-NOS was replaced by AML, defined by differentiation (Table 1).2 In contrast, in the ICC the term AML-NOS was kept, but the subcategorization was omitted due to its limited prognostic significance.7

Of note, acute erythroid leukaemia (AEL), previously named pure erythroid leukaemia,1 remains an entity in the WHO 2022 classification, because of its aggressive phenotype with a high prevalence of bi-allelic TP53 mutations. In contrast, in the ICC, AELs are usually included in the newly introduced subcategory of AML-MR (with mutated TP53).7

In the WHO 2022 classification, AML with defining genetic abnormalities supersedes AML defined by differentiation with the exception of AEL, which is prioritised over AML-MR due to its distinctive morphologic feature, regardless of de novo or secondary origin.2 Similarly, in the ICC, AML with defining genetic abnormalities take precedence over AML-MR and AML-NOS. In addition, the group of AML-MR is further divided and prioritised as follows: AML with mutated TP53, AML with MR gene mutations, and AML with MR cytogenetic abnormalities (Figure 1).7

Figure 1: Hierarchical classification of AML according to WHO 2022 and ICC.

Abbreviations: AML, acute myeloid leukaemia; MR, myelodysplasia-related; NOS, not otherwise specified; VAF, variant allele frequency.
Diagnostic qualifiers

In the WHO 2016 classification, myeloid neoplasm (i.e. AML, MDS, MDS/MPN) occurring therapy-related or with germline predisposition were regarded as separate entities.1 In the WHO 2022 classification, these categories are re-named into “post cytotoxic therapy” and “associated with germline variant”, respectively,2 and now re-considered as disease qualifiers that should be added to the disease type and classification. In this way, the substantial overlap to genetically defined AML subgroups, which better reflect the disease biology and individual risk, becomes more emphasized. Furthermore, exposure to PARP inhibitors was introduced as a qualifying criterion for AML post-cytotoxic therapy due to its link to complex karyotypes and mutations in DNA damage repair genes like TP53 or PPM1D. 22

Also, the ICC eliminated the prior stand-alone entities therapy-related myeloid neoplasm and myeloid neoplasm with germline predisposition, but recognizes them as a qualifier to the diagnosis, naming them “therapy-related” and “germline predisposition”.7 In contrast to the WHO 2022, also the history of MDS or MDS/MPN is highlighted as a qualifier and named “progressing from MDS” and “progressing from MDS/MPN”.7

To further underline the importance of this more genetically based classification, OS of chemo-consolidated patients with secondary and therapy-related AML was generally shorter compared to de novo AML patients,23 which was attributed to a higher incidence of adverse cytogenetics. However, when outcomes were analyzed within distinct cytogenetic or ELN risk groups, this impact was less present, especially in patients with intermediate and adverse risk,23,24 and patients consolidated by HSCT.24


Changes between the WHO 2016 and the 2022 classifications

There are already two published studies comparing patient allocation and outcomes according to both 2022 classifications with the WHO 2016 and with one another.14,25 Huber et al. reclassified 1451 patients (717 with MDS, 734 with AML),25 while Attardi et al. reclassified 1001 patients with AML.14 Here, a significant shift between the WHO 2016 and WHO 2022 (in 23% of cases) or ICC (in 24% of cases) was shown.14 As expected, the number of patients classified as NOS according to WHO 2016 (39% and 13%) decreased to 24% and 5% (WHO 2022, now ‘defined by differentiation’) and 27% and 5% (ICC), respectively.14,25 Matching this, both studies observed an increase in patients classified as AML-MR in the 2022 classifications due to the inclusion of MR gene mutations:2,7 according to WHO 2016, 18% and 22% of patients were classified as AML-MRC, which increased to 35% and 28% according to WHO 2022 and 31% and 26% according to ICC, respectively.14,25

With the elimination of the WHO 2016 provisional entity AML with mutated RUNX1 in both 2022 classifications, 93% and 96% of these patients were reclassified as AML with MR gene mutations according to the ICC (which kept RUNX1 as MR-defining). Still, due to the high co-incidence of RUNX1 and ASXL1 or spliceosome mutations, also 74% and 77% of patients were classified as AML-MR according to the WHO 2022.14,25
Discrepancies in patient allocation according to WHO 2022 and ICC

The classification of most patients was congruent according to WHO 2022 or ICC, with only 14% and 13% of patients classified differently.14,25 The main reasons for discrepant classifications were differences in the definition of AML with mutated CEBPA, KMT2A- and MECOM rearranged AML, and AML-MR between WHO 2022 and ICC.25 While in general, differences regarding the main diagnosis (MDS or AML) between WHO 2022 and the ICC were very rare (<1%), only in 4/16 patients upstaging was concordant in both classifications.25 These rare but relevant events epitomize the problem of having two classifications and show how the choice of classification may critically influence available treatment options.

Lastly, the inclusion of AML with mutated TP53 in the ICC, but not WHO 2022, seems to have the most relevant real-world implications. Attardi et al. demonstrated that 91% of AML with mutated TP53 according to the ICC were reclassified as AML-MR according to the WHO 2022.14 Huber et al. showed the other way around, that 23% of AML-MR patients according to the WHO 2022 harboured a TP53-mutation.25
Prognostic relevance of the WHO 2022 and ICC classification

Although the unique biological – and not prognostic - features of each entity drove disease categorisation in all three classifications, the inclusion of certain genetic features also are of prognostic relevance.25

Huber et al. demonstrated that OS for AML-MR(C) was shorter in the WHO 2016 (median 0.4 years) and the WHO 2022 (median 0.5 years) compared to the ICC (median 1.0 years). This was likely mediated by the exclusion of TP53-mutated patients, whose short OS (median OS 0.1 years) was best shown in the respective category of ICC.25 With the exclusion of patients with MR gene mutations from AML defined by differentiation, long-term OS improved from approximately 10% after 10 years for AML-NOS according to WHO 2016 to approximately 20% after 10 years for AML defined by differentiation according to WHO 2022 and AML-NOS according to ICC.25

In both 2022 classifications, only minor changes within the genetically defined AML groups were made,2,7 which did not translate into a significant change of OS for AML with defined fusion genes, or mutated NPM1.25 Only for AML with mutated CEBPA non-aligning definitions between the three classifications lead to a noticeable difference in OS (median OS 5.0 years in WHO 2016, 4.1 years in WHO 2022, and not reached in ICC).25

ELN 2022

Adjustment of recommendations

The first ELN recommendations for diagnosis and management of AML were published in 2010,26 and later updated - following the WHO 2016 classification - in 2017,1,27 and - following the ICC – in 2022.28 Compared to the ELN 2017 classification, the distribution into three genetic risk groups – favourable, intermediate, adverse – was kept, but some adjustments made following new insights into AML disease biology and prognosis. First, only bZIP in frame CEBPA mutations, now define favourable risk, irrespective of whether they occur mono- or biallelic.28 The former emphasized varied risk depending on a high or low FLT3-ITD allelic ratio (AR) has been omitted, and now the presence of a FLT3-ITD defines intermediate risk irrespective of the AR or co-occurring NPM1 mutations. NPM1 mutations remain to identify favourable risk AML, however, in cases of co-occurring adverse risk cytogenetics, patients should be classified to have adverse ELN 2022 risk. In addition to mutations in ASXL1, RUNX1, or TP53, which define adverse risk AML since the ELN 2017 classifications, the MR gene mutations (affecting the genes BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2) now additionally define adverse ELN 2022 risk. Congruent to the ICC, only mutated TP53 with a VAF >10% is considered to define adverse ELN 2022 risk.
Prognostic relevance

Several studies analyzed changes in the risk distribution and prognosis of the ELN 2022 compared to the ELN 2017 classification. Overall, approximately 85% of analysed patients remained in their respective risk group, while 5% were reclassified to have more favorable, and 10 % to have more adverse risk.14,18,29,30 Reclassification of ELN from 2017 to 2022 occurred most often in patients with low FLT3-ITD AR from favourable to intermediate risk and in patients with MR gene mutations from intermediate to adverse risk.29 Several authors independently showed the prognostic relevance of the ELN 2022 classification regarding the achievement of complete remission, OS, RFS, and relapse incidence, especially in patients treated with intensive chemotherapy and consolidated by HSCT.10,14,18,29–31

However, in most studies, the ELN 2022 classification did not allow for a more precise risk prediction than the ELN 2017. Some analyses also suggested that older age as an independent prognostic factor might allow for a better risk classification than the ELN 2022.29,31 In addition, especially for patients treated with the non-intensive combination hypomethylating agents and venetoclax, the ELN 2022 seems to have limited prognostic potential.32 In this context, a molecular prognostic signature including mutated FLT3-ITD, NRAS, KRAS, and TP53, was suggested as a useful alternative.33


With the advent of new technologies and our growing understanding of AML biology, the assessment of molecular data has become increasingly relevant for precisely diagnosing and stratifying the risk of AML patients. While this reflects the complexity of AML, these analyses are not universally available in all countries and clinics due to their significant cost, the requirement for high technical expertise, and the current lack of adequate standardization. Consequently, a substantial proportion of AML patients face hindrances in achieving proper risk stratification.

Despite existing discrepancies, there is a considerable degree of agreement between the WHO 2022 and ICC, with congruent allocation in more than 80% of AML patients in real-life cohorts.14,25 The variations primarily revolve around bone marrow blast cut-offs, biological aspects, or slight differences in the inclusion criteria for corresponding subgroups. Notably, these differences between both classifications highlight areas that may require further discussion and adjustment in the near future.

Nevertheless, the coexistence of two parallel classification systems poses challenges for treating physicians and health authorities, creates confusion among patients, and may complicate the inclusion criteria for future clinical trials. Consequently, we believe it is crucial to once again strive towards a unified cancer classification system, fostering a common language that can be shared by the international scientific community.


The authors declare no conflict of interest.




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