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The 5th edition of the World Health Organization classification of haematolymphoid tumors: key updates to ALL classification

Apr 27, 2023
Learning objective: After reading this article, learners will be able to recall key updates to the WHO classifications for ALL.

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Now set to be published later this year, the upcoming 5th edition of the World Health Organization (WHO) classification of hematolymphoid tumors (WHO-HAEM5) updates the conceptual framework and reflects major developments that have occurred in the field since 2017. This revised edition has systematically developed upon prior classifications and includes a restructuring of entities into a hierarchical system, updates to nomenclature, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities. By family, clinical entities are usually arranged in order of more indolent and progressing to increasingly aggressive subtypes.1

Below, we present key updates in the acute lymphoblastic leukemia (ALL) classification of  WHO-HAEM5, published on behalf of the WHO by Alaggio et al.1 in Leukemia. The Lymphoma Hub has previously reported on the changes and new additions to B-cell lymphoid proliferations and lymphomas.

Updates to B-cell ALL classification in WHO-HAEM51

An overview of the changes and new additions to the B-cell ALL (B-ALL) classification relative to the previously revised 4th edition (WHO-HAEM 4R) are summarized in Figure 1 and Figure 2, respectively.

Figure 1. Changes to B-ALL classification*

B-ALL, B-cell acute lymphoblastic leukemia; NOS, not otherwise specified.
*Adapted from Alaggio, et al.1


Figure 2. New additions to B-ALL classification* 

B-ALL, B-cell acute lymphoblastic leukemia.
*Adapted from Alaggio, et al.1

 B-ALL can be solely identified based on immunophenotypic and morphological-based features; most of its clinical entities are diagnosed based on cytogenetic testing, although some require molecular genetic subtyping.

In WHO-HAEM5, B-ALL is predominantly classified according to ploidy changes and underlying chromosomal rearrangements or genetic biomarkers, such as AMP21, BCR::ABL1 fusion, KMT2A rearrangements, ETV6::RUNX1 fusion, TCF3::PBX1 fusion, or IGH::IL3 fusion. These groups are mostly unchanged relative to WHO-HAEM4R, with minor nomenclature updates to focus on molecular events instead of cytogenetic alterations, enabling a wider application of detection techniques as well as the addition of genetic findings based on overlap in gene expression. B-ALL not otherwise specified (NOS) should be exclusively used for cases that cannot be classified after comprehensive testing.

B-ALL with TCF3::HLF fusion is a rare subtype clinically characterized by aggressive manifestations. B-lymphoblastic leukemia/lymphoma with BCR: ABL1-like features was previously a provisional entity and is now a confirmed subtype within the WHO-HAEM5 classification; it has shared gene expression and phenotypic features with the BCR::ABL1 fusion and is prevalent across all ages. A new entity, B-ALL with ETV6::RUNX1-like features is also a new addition.

The B-ALL with other defined genetic abnormalities subtype describes an entity that includes the following genetic markers: UX4, MEF2D, ZNF384 or NUTM1 rearrangements with IG::MYC fusion and with PAX5alt or PAX5.

Updates to T-cell ALL classification in WHO-HAEM51

Updates to the classification of T-cell ALL (T-ALL) are highlighted in Figure 3.

Figure 3. Changes to T-ALL classification* 

T-ALL, T-cell acute lymphoblastic leukemia; NK, natural killer; NOS, not otherwise specified.
*Adapted from Alaggio, et al.1

Relative to WHO-HAEM4R, the entities of T-ALL are broadly unchanged in WHO-HEAM5 with only minor updates to the nomenclature. Compared to T-ALL NOS, early T-precursor ALL displays gene expression signatures corresponding to an earlier stage of normal precursor T-cells and has a unique immunophenotypic profile that includes expression of stem cell and/or myeloid markers. Despite advancements in the understanding of the T-ALL molecular landscape, there is still not enough evidence to establish genetic subtypes of clinical relevance.

Although provisionally listed in WHO-HAEM4R, natural killer-lymphoblastic leukemia has not been listed in WHO-HEAM5 due to a lack of published information on the expression of its associated markers (e.g CD94, CD161), overlap in morphology and immunophenotypes with other entities such as CD56+ T-ALL and acute myeloid leukemia, and the lack of a clear and reliable diagnostic criteria.


WHO-HAEM5 represents a significant overhaul of the WHO system of classification of hematolymphoid tumors, including key changes to classification of ALL. Updates to the family of B-ALL reflect the large increase in information regarding lymphoid tumors, their molecular complexity, and advances in diagnostic techniques. This disease classification lays the foundation for future elucidations of disease biology, which will be fundamental for guiding patient care and treatment.

  1. Alaggio R, Amador C, Anagnostopoulos, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms. Leukemia. 2022;36(7):1720-1748. DOI: 1038/s41375-022-01620-2


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