[Clinical significance of clonal hematopoiesis and disease boundaries in bone marrow failure diseases].

Aplastic anemia (AA) is a non-neoplastic bone marrow failure syndrome caused by the destruction of hematopoietic stem and progenitor cells by the immune system. However, in some cases of AA, a small number of specific clones with gene mutations are observed without clinical manifestations. Cases with mutated PIG-A, BCOR/BCORL1, or HLA class I allele clones respond better to immunosuppressive therapies (ISTs). Cases with MDS-related clones, such as DNMT3A or ASXL1 mutations, are at a higher risk for secondary MDS. In this review, I will focus on the clonal hematopoiesis (CH) in AA and discuss its clinical significance, including its impact on disease boundaries and transition. I will also discuss the pathophysiology and diagnosis of hypoplastic MDS, a type of MDS that responds to ISTs.

Biology and clinical management of hypoplastic MDS: MDS as a bone marrow failure syndrome.

Hypoplastic MDS is a subset of MDS characterized by marrow hypocellularity diagnosed in 10-15% of MDS patients. The pathogenesis of this disease shares features of aplastic anemia with activation of the effector T cells against hematopoietic stem and progenitor cells and high-risk MDS with acquisition of somatic mutations that provide survival and growth advantage of these cells in the inflammatory bone marrow microenvironment. Clonal evolution in hypoplastic MDS may be associated with accumulation of DNA damage and progression to AML while clonal hematopoiesis in aplastic anemia is strongly related to immune escape of the hematopoietic cells. Distinction of hypoplastic MDS from other acquired and inherited bone marrow failure syndromes is frequently challenging but it is critical for the appropriate clinical management of the patients. Treatment with immunosuppression is an important component of the clinical approach to patients with hypoplastic MDS while hypomethylating agents and early allogeneic bone marrow transplantation are also considerations in some patients. In this review, we summarize the current literature on the biology of hypoplastic MDS, the differences between this disease and other bone marrow failure syndromes, and the treatment algorithm for patients with this subtype of MDS.

Myelodysplastic syndromes and overlap syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological neoplasms characterized by ineffective hematopoiesis, morphologic dysplasia, and cytopenia. MDS overlap syndromes include various disorders, such as myelodysplastic/myeloproliferative neoplasms and hypoplastic MDS with aplastic anemia characteristics. MDS overlap syndromes share the characteristics of other diseases, which make differential diagnoses challenging. Advances in genomic studies have led to the discovery of frequent mutations in MDS and overlap syndromes; however, most of the mutations are not specific for the diagnosis of these diseases. The molecular characteristics of the overlap syndromes usually do not show a just "in-between" form but rather heterogeneous features. Established diagnostic criteria for these diseases based on clinical, morphologic, and laboratory features are still useful when combined with genomic data. It is expected that further studies for MDS and overlap syndromes will place emphasis on the roles of mutations as therapeutic targets and prognostic indicators.

An association between hypoplastic myelodysplastic syndrome and T-prolymphocytic leukaemia.

Myelodysplastic syndrome (MDS) represents one of the most challenging health-related problems in the elderly, characterized by dysplastic morphology in the bone marrow in association with ineffective hematopoiesis. Hypoplastic MDS (h-MDS) accounts for 12-17% of all patients with MDS and has yet to be shown to alter the disease course or prognosis. The concept that T-cell-mediated autoimmunity contributes to bone marrow failure in MDS has been widely accepted due to hematologic improvement after immunosuppressive therapy. T-cell expansion is known to occur in these patients, but development of chronic T-cell disorders, especially T-prolymphocytic leukemia (PLL) in a hypocellular MDS is extremely rare, which has an aggressive course. The possible explanation for the association between the two disorders is that T-PLL might arise from a clonally arranged MDS stem cell. We report a unique case of h-MDS with non-progressive pancytopenia and severe hypocellular marrow for 2 years, followed by T-PLL within few months.