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Table 1. Main clonal myeloid disorders in which a low platelet count may occasionally hide immune thrombocytopenia.§* Some lymphoid clonal disorders are also included as illustrative examples.
PRELEUKEMIC CLONAL MYELOID DISORDERS14,15
Clonal hematopoiesis of indeterminate potential (CHIP)
At least one somatic mutation otherwise found in myelodysplastic syndromes (MDS). Peripheral cytopenias absent but increased risk of developing MDS heralded by the development of persistent thrombocytopenia/other cytopenia(s). Increased overall mortality and increased risk of cardiovascular disease.
Idiopathic cytopenia of undetermined significance (ICUS)
Persistent thrombocytopenia or other cytopenia(s) for at least 6 months, which cannot be explained by any other etiology and do not fulfill the formal diagnostic
criteria for a myeloid disorder.
Myelodysplastic syndrome of lower risk (IPSS-R <3.5)2,3
Presence of single or multilineage dysplasia involving at least 10% of cells of each lineage at bone marrow examination and <10% and <5% of blast cells in bone
marrow and peripheral blood cells. Cytogenetic and/or somatic mutation associated with myeloid neoplasm invariably found and relevant for prognosis.
Chronic myelomonocytic leukemia (CMML) of lower risk2
CMML-0 (<2% peripheral blood blasts including promonocytes and <5% bone marrow blasts) and CMML-1 (2%-4% peripheral blood blasts including promonocytes and 5%-9% bone marrow blasts). Due to overlapping features of both MDS and myeloproliferative neoplasms, the two entities are currently included among myelodysplastic/myeloproliferative neoplasms (MDS/MPN). Splenomegaly may be a confounding factor for the diagnosis of immune thrombocytopenia. Cytogenetic and/or somatic mutations associated with myeloid neoplasms are invariably found and are relevant for prognosis.
CLONAL LYMPHOID DISORDERS
B-cell monoclonal lymphocytosis10
Monoclonal gammopathy of uncertain significance (MGUS)12
§Cytopenias defined as: hemoglobin <10 g/dL; platelet count <100x109/L; and absolute neutrophil count <1.8x109/L. *Only lower-risk myelodysplastic syndrome and chronic myelomono- cytic leukemia are mentioned, since in higher risk cases it would be difficult to make a bona fide diagnosis of immune thrombocytopenia in patients with thrombocytopenia due to the expected greater infiltration of bone marrow by blast cells and/or major dysplasia/hypoplasia of megakaryocytes that could by itself cause non-immune thrombocytopenia. IPSS-R: Revised International Prognostic Scoring System.
Clonal cytopenia of undetermined significance (CCUS)
One or more somatic mutations otherwise found in patients with myeloid neoplasms in bone marrow or peripheral blood with an allele burden of ≥2%. Persistent thrombocytopenia or other cytopenia(s) for at least 4 months that cannot be explained by any other etiology and do not fulfill the formal diagnostic criteria for a myeloid disorder.
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thrombocytopenia classifiable as ITP.7 Let’s now compare these figures with what could be expected by a casual association of ITP and MDS/CMML.
The annual incidence of new cases of ITP can be esti- mated to be around two per 100,000 individuals/year and that of MDS/CMML around five per 100,000 individu- als/year.8 Clearly any association being simply by chance can be immediately excluded, since, on the basis of chance alone, we would expect ten new cases of ITP associated with MDS/CMML every 1010 people, a rate several orders of magnitude below any clinical observable phenomenon, even accumulating cases occurring over two or three decades.
From these data it could be concluded that there is a definite causal association between ITP and low-grade MDS or CMML. Quite surprisingly, so far MDS and allied disorders are not generally mentioned among the possible causes of secondary ITP. It is noteworthy that not only ITP, but a variety of other autoimmune disorders, are con- sistently reported as being associated with myeloid pre- leukemic disorders, in up to 30% or more of cases.5,9 In these series, as in the one by Jachiet et al.,1 ITP could be found to occur prior to, in concomitance with, or after the diagnosis of these disorders, in keeping with current ter- minology. For these two latter instances, the term “sec- ondary”, instead of “associated” ITP seems more appro- priate and its use is recommended.
So what could be the pathogenic link between ITP and MDS/CMML or more in general with clonal myeloid dis- orders with a potential to evolve into leukemia? Jachiet et al.1 correctly point to a common background of deregulat- ed homeostasis of the immune system. This is a plausible
hypothesis further strengthened by the sparse reports of ITP observed in other disorders with subverted immuni- ty, such as monoclonal B-cell lymphocytosis preceding chronic lymphocytic leukemia or indolent lymphomas,10,11 monoclonal gammopathy of uncertain significance12 and in patients with congenital or acquired immunodeficien- cies such as common variable immunodeficiency.13
But, which comes first? Is the clonal expansion of an aberrant myeloid or lymphoid clone causing immune dys- regulation or vice versa does primary immune dysregula- tion promote a pre-malignant clonal expansion? So far this issue remains unsettled. As we have seen, the temporal succession of events is inconsistent and anyway not deter- minant to solve this conundrum, because of the complex interactions between hematopoiesisis, the immune sys- tem, genetic background, epigenetic features and environ- mental factors, as illustrated in some reviews.5,9
This study is an incentive to further investigate the path- ogenic mechanisms at the basis of the intriguing associa- tion between ITP (and other autoimmune disorders) and the various pre-leukemic myeloid or lymphoid disorders with a potential to evolve into overt malignancy.
From a practical standpoint, patients presenting with unexplained thrombocytopenia, associated or not with other cytopenias revealed by routine peripheral blood analysis, particularly in the elderly, should raise the suspi- cion of one of the various clonal myeloid or lymphoid disorders succinctly described in Table 1. In these disor- ders, disentangling secondary or associated ITP as the cause of thrombocytopenia may affect prognostication, management and follow-up. Indeed, thrombocytopenia may be inherent to the severity of the myeloid or lym-
haematologica | 2021; 106(5)