Hypoplastic Myelodysplastic Syndromes: Just an Overlap Syndrome?

SIMPLE SUMMARY: Hypoplastic myelodysplastic syndromes (hMDS) represent a diagnostic conundrum. They share morphologic and clinical features of both MDS (dysplasia, genetic lesions and cytopenias) and aplastic anemia (AA; i.e., hypocellularity and autoimmunity) and are not comprised in the last WHO classification. In this review we recapitulate the main clinical, pathogenic and therapeutic aspects of hypo-MDS and discuss why they deserve to be distinguished from normo/hypercellular MDS and AA. We conclude that hMDS may present in two phenotypes: one more proinflammatory and autoimmune, more similar to AA, responding to immunosuppression; and one MDS-like dominated by genetic lesions, suppression of immune surveillance, and tumor escape, more prone to leukemic evolution. ABSTRACT: Myelodysplasias with hypocellular bone marrow (hMDS) represent about 10–15% of MDS and are defined by reduced bone marrow cellularity (i.e., <25% or an inappropriately reduced cellularity for their age in young patients). Their diagnosis is still an object of debate and has not been clearly established in the recent WHO classification. Clinical and morphological overlaps with both normo/hypercellular MDS and aplastic anemia include cytopenias, the presence of marrow hypocellularity and dysplasia, and cytogenetic and molecular alterations. Activation of the immune system against the hematopoietic precursors, typical of aplastic anemia, is reckoned even in hMDS and may account for the response to immunosuppressive treatment. Finally, the hMDS outcome seems more favorable than that of normo/hypercellular MDS patients. In this review, we analyze the available literature on hMDS, focusing on clinical, immunological, and molecular features. We show that hMDS pathogenesis and clinical presentation are peculiar, albeit in-between aplastic anemia (AA) and normo/hypercellular MDS. Two different hMDS phenotypes may be encountered: one featured by inflammation and immune activation, with increased cytotoxic T cells, increased T and B regulatory cells, and better response to immunosuppression; and the other, resembling MDS, where T and B regulatory/suppressor cells prevail, leading to genetic clonal selection and an increased risk of leukemic evolution. The identification of the prevailing hMDS phenotype might assist treatment choice, inform prognosis, and suggest personalized monitoring.