New changes in the classification of acute myeloid leukemia proposed by WHO 2022

 Actualităţi în clasificarea OMS 2022 privind încadrarea leucemiilor acute mieloide

First published: 18 decembrie 2023

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.65.4.2023.8957


The new revision of WHO (World Health Organization) 2022 classification of acute myeloid leukemia (AML) aims to highlight the new data obtained mainly in the recent years regarding the pathogenesis of this disease. It stands out the removal of the 20% blast cutoff for the diagnosis of AML subtypes with defined genetic ab­nor­ma­li­ties, ex­cept for AML with BCR::ABL1 fusion and AML with CEBPA mu­ta­tion. Also, we mention the eli­mi­na­tion of the AML, NOS (not otherwise specified) ca­te­go­ry, a slightly confusing ter­mi­no­lo­gy because this sub­type was characterized ac­cor­ding to morphological dif­fe­ren­tia­tion, therefore the in­tro­duc­tion of the new category called AML defined by dif­fe­ren­tia­tion seems more suitable. Another category, called AML with other defined genetic alterations, is in­tro­duced, an entity that will include new subtypes of AML that have the potential to become defined subtypes in the fu­ture. Regarding AML, myelodysplasia-related (AML-MR), it excludes mor­pho­logy as the single diagnostic criterion, re­vi­sing the defining cytogenetic abnormalities, and in­tro­du­cing eight defining mutations for the diagnosis of AML-MR. Also, it is observed the reclassification of the ca­te­go­ry of therapy-related myeloid neoplasms into the en­ti­ty of secondary myeloid neoplasms, along with the ca­te­go­ry of myeloid proliferations associated with Down syn­drome, a separate entity defined earlier by the 2016 WHO cla­ssification.

acute myeloid leukemia (AML), AML with de­fined genetic abnormalities, AML defined by dif­fe­ren­tia­tion, AML myelodysplasia-related (AML-MR), World Health Or­ga­nization 2022 (WHO 2022), AML with other defined genetic alterations, secondary myeloid neoplasms, myeloid neoplasms post-cytotoxic therapies (MN-pCT)


Noua revizuire a clasificării OMS (Organizaţia Mondială a Sănătăţii) din 2022 a leucemiilor acute mieloide (LAM) are ca scop evidenţierea noilor date obţinute în ultimii ani cu privire la patogeneza bolii. Se remarcă eliminarea cut­off-ului de 20% blaşti pentru diagnosticul subtipurilor de LAM cu anomalii genetice definite, cu excepţia LAM cu fu­ziu­ne BCR::ABL1 şi LAM cu mutaţia CEBPA. De asemenea, se observă eliminarea categoriei LAM, NOS (not otherwise spe­ci­fied), terminologie uşor derutantă, deoarece sub­ti­­pu­rile erau caracterizate în funcţie de diferenţierea mor­fo­lo­gi­că, şi introducerea categoriei denumite LAM de­fi­ni­tă prin diferenţiere. Se introduce o nouă categorie, nu­mi­tă LAM cu alte alterări genetice definite, categorie care va cu­prin­de noile subtipuri de LAM care au potenţial să devină sub­ti­puri definite în viitor. În ceea ce priveşte LAM aso­ci­ată mielodisplaziei (LAM-MR), se exclude morfologia drept criteriu unic de diagnostic, se revizuiesc anomaliile ci­to­ge­ne­ti­ce definitorii şi se introduce un set de opt mutaţii so­ma­ti­ce definitorii pentru diagnosticul de LAM-MR. Se ob­servă translarea categoriei de neoplasme mieloide aso­ciate te­ra­pi­ei în categoria de neoplasme mieloide se­cundare, la care se adaugă şi categoria de proliferări mieloide asociate cu sin­dro­mul Down, entitate separată în clasificarea OMS 2016.


The 2022 World Health Organization (WHO) classification of acute myeloid leukemia (AML) continues to integrate the morphology, immunophenotyping, cytogenetics and molecular biology to establish the positive diagnosis. However, the emphasis on defining it in more details through genetic changes involved in AML pathology is noteworthy, this being a step that will allow the development of personalized therapy in the future.

This new classification of acute myeloid leukemias includes the following categories: acute myeloid leukemia with defined genetic abnormalities, acute myeloid leukemia defined by differentiation, and myeloid sarcoma (Table 1), a classification to which secondary myeloid neoplasms are added(1).

Table 1. WHO 2022 classification of acute myeloid leukemias(1)
Table 1. WHO 2022 classification of acute myeloid leukemias(1)
Table 2. Cytogenetic and molecular abnormalities defining AML-MR (WHO 2022)
Table 2. Cytogenetic and molecular abnormalities defining AML-MR (WHO 2022)

Acute myeloid leukemia with defined genetic abnormalities

The most important change that WHO 2022 makes in this category of AML is the elimination of the blast cutoff for establishing the diagnosis.

In WHO 2016, the diagnosis of AML was determined by the presence of ≥20% blasts in the bone marrow or peripheral blood, the only subtypes that did not require this criterion being acute promyelocytic leukemia (APL) with the PML::RARA fusion and AML with the fusion RUNX1-RUNX1T1 or CBFB-MYH11(2).

At this time, the cutoff of 20% blasts in the bone marrow and/or peripheral blood is the removed for all disease subtypes except for AML with BCR::ABL1 fusion and AML with CEBPA mutation, entities that still require ≥20% blasts to establish the positive diagnosis. The cutoff ≥20% blasts for AML with the BCR::ABL1 fusion is maintained because of the difficulty to differentiate it from the blast phase of chronic myeloid leukemia; in the case of AML with CEBPA mutation, there is not yet enough information to support the removal of this cutoff(1).

Regarding APL with the PML::RARA fusion and AML with the RUNX1-RUNX1T1 or CBFB-MYH11 fusion, the diagnostic criteria have not been changed, but the importance of the improvement in the evaluation techniques of minimal residual disease (MRD) is emphasized, as well as the importance of additional molecular abnormalities that becomes necessary for the patient management and appropriate treatment selection. Likewise, even in the case of AML with the DEK::NUP214 or RBM15::MRTFA fusion, the diagnostic criteria do not change(1).

Within the three subtypes of AML with gene rearrangements involving KMT2A, MECOM and NUP98, a blast count below 20% is accepted for the diagnosis, because multiple studies have shown that the clinical manifestations are similar to those of the patients with high blast counts. The identification of the fusion partner is not necessary, but its identification could provide additional information regarding the prognosis and management of the disease(1).

AML with NPM1 and CEBPA mutation also do not require a blast count criterion for the diagnosis. Multiple studies showed that MDN or MDN/MPN with NPM1 transform into AML very quickly, information which sustains the removal of the blast cutoff for diagnosis. In the case of AML with CEBPA mutation, biallelic mutations (biCEBPA) are accepted, as well as a single mutation located at the level of the basic leucine zipper (bZIP) region of the gene (smbZIP-CEBPA); the latter is  associated with a favorable prognosis(1,3).

Another change in the new classification is the elimination of the provisional entity AML with RUNX1 mutation, due to the lack of data to support its strength as a single entity(4).

In the context of acute myeloid leukemia, myelodysplasia-related (AML-MR), previously named AML with myelodysplastic changes, WHO introduces multiple changes. The diagnosis requires the presence of ≥20% blasts expressing myeloid immunophenotyping and the presence of one or more specific cytogenetic or molecular abnormalities associated with myelodysplastic neoplasms (MDN), defining AML which is de novo or post-MDN or post-MDN/MPN (myelodysplastic neoplasm/myeloproliferative neoplasm). Thus, the morphology is excluded as the unique criterion for diagnosis, the defining cytogenetic abnormalities are revised, and eight defining mutations are introduced for the diagnosis of AML-MR(1). The defining cytogenetic abnormalities for this category of AML remain the same as in the 2016 WHO classification, except for the balanced cytogenetic abnormalities which have been subsequently removed. The defining somatic mutations for AML-MR are as follows: ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2. These mutations show >95% specificity for AML post-MDN or post-MDN/MPN(1,2).

AML with other defined genetic alterations is a new category that is characterized by the inclusion of new subtypes of AML or rare AML subtypes that may become defined subtypes in the future. Currently, the following AML with other defined genetic alterations have been described: AML with RUNX1T3(CBFA2T3)::GLIS2, AML with KAT6A::CREBBP, AML with FUS::ERG, AML with MNX1::ETV6, AML with NPM1::MLF(1,5).

Acute myeloid leukemia defined by differentiation

AML defined by differentiation, previously known as AML, NOS (not otherwise specified), is removed due to slightly confusing terminology, considering that AML subtypes were characterized according to morphological differentiation. This category is characterized by cases of AML that do not present defined genetic abnormalities. It is estimated that, with the progress of research in the field of genetic studies, the cases within this category of AML will gradually decrease(1).

The subtypes of AML defined by differentiation are as follows: AML with minimal differentiation, AML without maturation, AML with maturation, acute basophilic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroid leukemia, and acute megakaryoblastic leukemia.

This category still requires ≥20% blasts in bone marrow and/or blood (except for acute erythroid leukemia that requires ≥30% proerythroblasts). It does not meet the criteria for any AML type with defined genetic alterations or the criteria for mixed-phenotype acute leukemia, and it does not fulfill the diagnostic criteria for myeloid neoplasm post-cytotoxic therapy, or any prior history of myeloproliferative neoplasm.

Acute erythroid leukemia is characterized by ≥80% of bone marrow infiltration with erythroid predominance, of which ≥30% are proerythroblasts (or pronormoblasts) and a high presence of biallelic TP53 alterations. At this moment, the mutations within TP53 are underestimated. Also, in acute megakaryoblastic leukemia, there have been detected newly described gene fusions, namely CBFA2T3::GLIS2, a subtype of AML with other defined genetic alterations.

Myeloid sarcoma

Myeloid sarcoma is an isolated extramedullary tumor arising as a manifestation of AML or in the case of transformation of MDN, MDN/MPN or MPN. It is recommended that de novo myeloid sarcoma be further investigated, including both cytogenetic and molecular examination, for a better classification and an appropriate therapeutic plan. Molecular changes in myeloid sarcoma occurring concurrently with bone marrow involvement are concordant in 70% of cases, which is why myeloid sarcoma is considered to derive from a common hema­topoietic stem cell or its precursor(1).

Secondary myeloid neoplasms

This category defines diseases that appear in the context of known precipitating factors, being represented by myeloid neoplasms secondary to exposure to cytotoxic therapies (MN-pCT) such as chemotherapy or radiotherapy, and myeloid neoplasms associated with germline predisposition, this last subcategory also including myeloid proliferations associated with Down syndrome, a separate entity in the 2016 WHO classification. Thus, acute myeloid leukemia secondary to cytotoxic therapy and AML associated with germline predisposition are now part of this category. Also, the category of MN-pCT includes myeloid neoplasms arising in the context of the use of PRAP1 inhibitors. Likewise, AML secondary to transformation from MPN remains in the category of MPN – blast phase, and those transformed from MDN or MDN/MPN remain in the category of AML-MR(1).

It is recommended to add the annotation “post-cytotoxic therapy” or “associated with the germline variant (gene)” to the writing of the diagnosis, for example: APL with the fusion of PML::RARA post-cytotoxic therapy; AML with germline variants in the RUNX1 mutation(1)


The changes that have been recently introduced in the classification of AML emphasize a step forward to a better understanding of the pathogenesis, especially through the genetic studies. This can only stand as an improvement to our daily practice, that stimulates the future of personalized therapies.  


Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.


  1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. 

  2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. 

  3. The College of American Pathologists. What’s new in AML Classification (WHO 2022 vs International Consensus Classification). Accessed November 27, 2023. https://www.cap.org/member-resources/articles/whats-new-in-aml-classification-who-2022-vs-international-consensus-classification

  4. Classification of acute myeloid leukemia (AML). UpToDate. Accessed November 27, 2023. https://www.uptodate.com/contents/classification-of-acute-myeloid-leukemia-aml

  5. The New WHO Classification 2022. Accessed November 28, 2023. https://www.mll.com/en/the-new-who-classification-2022