The right diagnosis can lead to the right treatment: Recent advances in the identification of unique biomarkers associated with some myeloid neoplasms and acute leukemia have prompted the World Health Organization (WHO) to update its 2008 Classification of Tumors of Hematopoietic Tissues (1). These revised guidelines were recently published in Blood.
This new 2016 classification does not include major changes to the disease categories. Rather, it incorporates new knowledge of these disorders published since 2008, such as the discovery of the diagnostic and prognostic CALR mutation marker, in addition to JAK2 and MPL mutations, prompting the need for a revised classification (2). Novel molecular findings with diagnostic and/or prognostic importance have been incorporated into the 2016 revision, and represent the efforts of pathologists and hematologists working closely with clinicians and geneticists (3).
To develop these new guidelines, the WHO convened a clinical advisory committee in early 2014 comprising nearly 100 pathologists, hematologists, oncologists and geneticists to propose revisions to the 2008 classification. The categories of myeloproliferative neoplasms (MPNs) have not significantly changed since the 2008 edition, but discoveries of new mutations and biomarkers, as well as improved understanding of the morphologic features of some disease entities, have impacted the diagnostic criteria. Figure 1 schematically represents how mutational analysis and biomarker testing can support MPN diagnosis.
Figure 1.Diagnosis of myoproliferative neoplasms using WHO criteria and biomarker analysis of JAK2 V617F, CALR and MPL.
Here are some highlights of the major and proposed changes for myeloproliferative neoplasms:
Chronic myeloid leukemia (CML), BCR-ABL1–positive: Most cases of CML can be diagnosed from findings from peripheral blood, combined with detection of t(9;22)(q34.1;q11.2) or BCR-ABL1. Newly diagnosed patients may lead a nearly normal life expectancy when treated with tyrosine kinase inhibitors (TKIs), but regular monitoring for BCR-ABL1 load and for development of TKI resistance is crucial to detect disease progression.
BCR-ABL1–negative MPNs: Under the new WHO disease classification, a major WHO criterion for essential thrombocythemia (ET) is the presence of a JAK2, CALR or MPL mutation. Similarly, one of the major WHO criteria for both overt primary myelofibrosis (PMF) and prefibrotic/early primary myelofibrosis (prePMF) is the presence of JAK2, CALR or MPL mutation, or in the absence of these mutations, presence of another clonal marker. The presence of JAK2 V617F or JAK2 exon 12 mutation remains a WHO major criterion for polycythemia vera (PV).
Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T): Diagnosis of MDS/MPN-RS-T is strongly supported by the presence of SF3B1 mutations, together with JAK2 V617F, or mutations in the CALR or MPL genes.
Below are some highlights of the major and proposed changes for acute myeloid leukemia (AML):
Acute Myeloid Leukemia with recurrent genetic abnormalities: To stress the significance of the PML-RARA fusion, instances of acute promyelocytic leukemia (APL) with this fusion are now called APL with PML-RARA. AML with mutated NPM1 and AML with biallelic mutations of CEBPA continue to be confirmed disease entities. It is worthy of mention that the value of NPM1 mutations as minimal residual disease (MRD) biomarkers for AML has recently been shown elsewhere (6). A new provisional entity of AML with BCR-ABL1 has been established to recognize these rare, de novo, AML cases that may benefit from treatment with tyrosine kinase inhibitors. Though the diagnostic distinction between de novo AML with BCR-ABL1 and blast transformation of CML may be difficult to distinguish, the significance of detecting this fusion is important when considering options for targeted therapy. AML with mutated RUNX1 is another provisional entity added to the classification of de novo AML, and are not associated with MDS-related cytogenetic abnormalities.
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1. Arber, D.A. et al. (2016) Blood 127(20):2391–2405; doi:10.1182/blood-2016-03-643544
2. ASH Clinical News June 2016, Volume 2, Issue 6. What To Call What We Treat, Part II: WHO Releases Updated Classification of Myeloid Neoplasms and Acute Leukemia. http://ashclinicalnews.org/what-to-call-what-we-treat-part-ii-who-releases-updated-classification-of-myeloid-neoplasms-and-acute-leukemia/
3. Cazzola, M. (2016) Blood 127:2361-2364; doi:10.1182/blood-2016-03-657379
4. Barbui et al. (2011) J Clin Oncol 29:761-770. DOI: 10.1200/JCO.2010.31.8436
5. Vannucchi, A. M. et al. (2015) Ann. Oncol. 26 (suppl 5): v85–v99.
6. Grimwade, D. and Freeman, S.D. (2014) Blood 124(23):3345–3355; doi:10.1182/blood-2014-05-577593