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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

Juvenile myelomonocytic leukemia; moving forward

Leukemia volume 37, pages 720–722 (2023)Cite this article

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We read with interest the letter of Niemeyer et al. [1] providing some comments and observations regarding the recently-published summary of the new 5th edition of WHO Classification of Hematolymphoid Tumors (WHO 2022) [2] for juvenile myelomonocytic leukemia (JMML). Several authors of the letters have contributed to the recently-published International Consensus Classification (ICC) [3] and also the recently-published WHO Classification of Pediatric Tumors [4], which has been completed prior to WHO 2022. It is to be noted that WHO 2022 diagnostic criteria for JMML emphasize clinicopathologic correlation with an eye on worldwide applicability. We would like to respond to some of these points and also provide our own observations regarding the proposed ICC:

  1. 1.

    The WHO 2022 classifies and defines JMML as a myeloproliferative neoplasm largely due to its proliferative genetic mechanism related to constitutive activation of the RAS/MAPK signaling pathway and also high tumor burden causing organ infiltration, particularly affecting the spleen and liver. Likewise, the ICC has removed JMML from the myelodysplastic/myeloproliferative {MDS/MPN} group, as shown by their statement that “JMML was previously considered a myelodysplastic/myeloproliferative neoplasm”, and chose to place it together with JMML-like neoplasms, Noonan syndrome-associated myeloproliferative disorder, and refractory cytopenia of childhood in a new group of disorders entitled “Paediatric and/or germline-associated disorders”. The rationale for the authors’ critical position on this issue is unclear, as they themselves define JMML in the letter as a clonal malignant myeloproliferative disorder, which is in general agreement with WHO 2022. Regarding clonality, the WHO 2022 Classification has eliminated the term “clonal” from JMML defining statement, which matches the other myeloproliferative neoplasms. The ICC definition of JMML seems to be based on clonality, which may be difficult to prove in practical clinical setting, particularly when the driver gene is germline. Furthermore, clonality has proven insufficient to define JMML as highlighted by somatic RAS mutations associated with RAS-associated lymphoproliferative disorder (RALD) and also the various clonal immunohematological disorders related to CBL loss of heterozygosity [5].

  2. 2.

    Niemeyer et al. take issue with the fact that dysplastic features are not considered by WHO 2022 as an integral defining component of JMML. Although some degree of dysplastic features may be seen in JMML, particularly in cases associated with monosomy 7, these features are not prominent in most cases and are not a requirement for the diagnosis. The proposed ICC description and criteria for JMML (including Table 22 in ref. [3]) do not mention dysplastic features anywhere. In the WHO 2001 Classification [6], the following statement on page 56 “Dyspoiesis, including….., may be noted in some cases but most often dysplasia is minimal”. In the 4th edition of the WHO Classification (WHO 2009) [7], page 83, the following statement is included “Most often dysplasia is minimal…..marked megakaryocytic dysplasia is unusual”. The very same statement is repeated in the revised 4th edition of the WHO Classification (WHO 2017) [8], pages 90–91. It is clear that for many years there has been a general agreement that the dysplastic features in JMML are minimal, particularly in the absence of monosomy 7, and are not required for the diagnosis. Moreover, dysplastic features, by themselves do not disqualify a tumor from being included under myeloproliferative neoplasms. Dysplastic features may be seen in some myeloproliferative neoplasms, particularly in advanced stages of the disease. Also, the WHO 2017 considers dysplastic features as a supportive diagnostic criterion for chronic eosinophilic leukemia, NOS (CEL), which is classified as a myeloproliferative neoplasm. Similarly the ICC describes dysplastic megakaryocytes as one of the morphologic criteria for the diagnosis of CEL.

  3. 3.

    For the clinical, hematologic, and laboratory criteria (ICC, Table 22.I), the ICC focuses on absence of features, including absence of BCR::ABL1 and absence of 20% or more blasts while in the mean time acknowledges that the criteria that need to be present may also be absent (monocytosis absent in 7% and splenomegaly absent in 3%). The WHO 2022 requires PB monocytosis ≥ 1×109/L and evidence of organ infiltration in a broader term, which encompasses splenomegaly, hepatomegaly, and other organs. In addition, the WHO 2022 now mandates the exclusion of KMT2A gene rearrangements, since pediatric KMT2A-rearranged acute leukemias can manifest with features that may be indistinguishable from JMML, including low percentage of peripheral blood blasts [9] and are much more common in children than chronic myeloid leukemia, particularly in patients presenting with monocytosis. While the ICC criteria do not include the exclusion of that possibility, the letter acknowledges the need to exclude KMT2A-rearranged neoplasms without including any related test in the diagnostic workup. We chose to place it in the initial diagnostic approach as mentioned above.

  4. 4.

    The main difference between the two classifications is that the ICC gives a major weight to genetics over any other criteria. This approach may warrant further discussion. Indeed, it is becoming increasingly clear that JMML-associated genetic alterations are also common in pediatric MDS [10]. Given the presence of RAS/MAPK pathway mutations in more than 40% of primary pediatric MDS, the ICC-recommended presence/absence criteria accompanied by the presence of a specific genetic abnormality may not be sufficient to differentiate some cases of pediatric MDS from JMML. Additionally, creating two separate neoplasms: JMML and JMML-like, solely on the basis of genetic background should also be subjected to further scrutiny. We have chosen to subclassify the rare and still poorly documented cases with JMML phenotype and RAS pathway activation due to upstream gene fusion under the heading ‘JMML with non-canonical genetic abnormality’ as we had no a priori justification or evidence to question the diagnosis of JMML under which these cases were reported. Yet, we also acknowledge that future studies may help shed more light on this particular group and give justification for the creation of a separate entity, if needed. It should also be noted that most hematologic neoplasms in the current and previous WHO editions are classified on numerous grounds, such as morphologic, clinical features, infectious etiology, and clinical course among others. In most hematologic neoplasms, genetic and molecular findings identify separate groups or subcategories of the same neoplasm aiming at a tailored therapeutic intervention without creating new neoplasms. Examples are B-acute lymphoblastic leukemia, acute myeloid leukemia, mantle cell lymphoma among others. We believe that genetic background helps with subcategorization of the same neoplasm rather than form a basis for creating new disease types, particularly the main disease is quite rare to start with. Finally, the genetic alterations included in the ICC are rather restrictive since only germline NF1 and CBL mutations are considered. There is increasing evidence that bi-allelic somatic events affecting CBL or NF1 drive some JMML cases and the genetic criteria should include these mutations as the WHO 2022 did [11]. We have included a Table to help summarize the differences between WHO 2022 and ICC for JMML (see Table 1).

    Table 1 Comparison between the WHO 5th edition and ICC criteria for JMML.
    Full size table

The WHO 2022 classifies and defines JMML as a myeloproliferative neoplasm largely due to its proliferative genetic mechanism related to constitutive activation of the RAS/MAPK signaling pathway and also high tumor burden causing organ infiltration, particularly affecting the spleen and liver. Likewise, the ICC has removed JMML from the myelodysplastic/myeloproliferative {MDS/MPN} group, as shown by their statement that “JMML was previously considered a myelodysplastic/myeloproliferative neoplasm”, and chose to place it together with JMML-like neoplasms, Noonan syndrome-associated myeloproliferative disorder, and refractory cytopenia of childhood in a new group of disorders entitled “Paediatric and/or germline-associated disorders”. The rationale for the authors’ critical position on this issue is unclear, as they themselves define JMML in the letter as a clonal malignant myeloproliferative disorder, which is in general agreement with WHO 2022. Regarding clonality, the WHO 2022 Classification has eliminated the term “clonal” from JMML defining statement, which matches the other myeloproliferative neoplasms. The ICC definition of JMML seems to be based on clonality, which may be difficult to prove in practical clinical setting, particularly when the driver gene is germline. Furthermore, clonality has proven insufficient to define JMML as highlighted by somatic RAS mutations associated with RAS-associated lymphoproliferative disorder (RALD) and also the various clonal immunohematological disorders related to CBL loss of heterozygosity [5].

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Data sharing not applicable to this article as no datasets were generated or analyzed in this study. This is a correspondence letter.

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Authors and Affiliations

  1. Department of Pathology & Immunology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

    M. Tarek Elghetany

  2. Université Paris Cité, Institut de recherche Saint-Louis and the Department of Genetics, Robert Debré Hospital, Paris, France

    Hélène Cavé

  3. Pathology Unit, Department of Laboratories, Bambino Gesù Children’s Hospital, Rome, Italy

    Rita De Vito

  4. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA

    Mrinal M. Patnaik

  5. Department of Hematology, Gustave Roussy Cancer Center, Université Paris-Saclay, Villejuif, France

    Eric Solary

  6. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    Joseph D. Khoury

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MTE wrote the first draft, HC, RDV, MMP, ES, and JDK reviewed the manuscript and provided critical edits and modifications. All authors read and approved the manuscript.

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Correspondence to M. Tarek Elghetany.

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MMP has received research funding from Kura Oncology and StemLine Pharmaceuticals and has served on the advisory board for CTI Pharmaceuticals. The other authors declare no competing interests.

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Elghetany, M.T., Cavé, H., De Vito, R. et al. Juvenile myelomonocytic leukemia; moving forward. Leukemia 37, 720–722 (2023). https://doi.org/10.1038/s41375-023-01818-y

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