Evidence-Based Minireview: Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes: a focused review

Abstract

Myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes are unique myeloid neoplasms, with overlapping features of MDS and MPN. They consist of four adult onset entities including chronic myelomonocytic leukemia (CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), BCR-ABL1 negative atypical chronic myeloid leukemia (aCML) and MDS/MPN-unclassifiable (MDS/MPN-U); with juvenile myelomonocytic leukemia (JMML) being the only pediatric onset entity. Among these overlap neoplasms, CMML is the most frequent and is hallmarked by the presence of sustained peripheral blood monocytosis with recurrent mutations involving TET2 (60%), SRSF2 (50%) and ASXL1 (40%); with RAS pathway mutations and JAK2V617F being relatively enriched in proliferative CMML subtypes (WBC ≥13 × 109/L). CMML usually presents in the 7th decade of life, with a male preponderance and is associated with a median overall survival of <36 months. Adverse prognosticators in CMML include increasing age, high WBC, presence of circulating immature myeloid cells, anemia, thrombocytopenia and truncating ASXL1 mutations. While allogeneic stem cell transplantation remains the only curative option, given the late onset of this neoplasm and high frequency of comorbidities, most patients remain ineligible. Hypomethylating agents such as azacitidine, decitabine and oral decitabine/cedazuridine have been US FDA approved for the management of CMML, with overall response rates of 40-50% and complete remission rates of <20%. While these agents epigenetically restore hematopoiesis in a subset of responding patients, they do not impact mutational allele burdens and eventual disease progression to AML remains inevitable. Newer treatment modalities exploiting epigenetic, signaling and splicing abnormalities commonly seen in CMML are much needed.

Myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T): Mayo-Moffitt collaborative study of 158 patients

“…MDS/MPN-RS-T is distinguished from myelodysplastic syndrome with ring sideroblasts (MDS-RS) by the presence of thrombocytosis (platelet count ≥450 × 10 9 /L) and bone marrow (BM) megakaryocyte morphology similar to that seen in MPN. MDS/MPN-RS-T is in addition characterized by presence of SF3B1 mutations in 60–90% of patients and JAK2 V617F in a smaller percentage [ 1 , 5 – 10 ]. In order to be classified under the MDS/MPN-RS-T category, patients should also meet certain exclusionary criteria such as BM blast% ≥5, peripheral blood (PB) blast% ≥1, and cytogenetic abnormalities such as t(3; 3)(q21.3; q26.2), inv(3)(q21.3; q26.2) or isolated del(5q), or the BCR/ABL1 fusion oncogene [ 1 , 11 ].…”

Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes

“…10% of white blood count differential) in the absence of known reactive causes of monocytosis or WHO-defined molecular entities associated with monocytosis (BCR-ABL1, PDGFRA, PDGFRB, FGFR1, and PCM1-JAK2 rearrangements), with or without bone marrow dysplasia, and with a characteristic molecular signature enriched in ASXL1, TET2, SRSF2, and SETBP1 mutations. 107,108 CMML is a disease of aging, with a median age at diagnosis of 73 years, and has a male preponderance. 107,108 CMML can be more specifically classified into CMML-0, -1, and -2 according to the percentage of peripheral blood and bone marrow blast equivalents (which include blasts and promonocytes) and the presence or absence of Auer rods.…”

“…107,108 CMML is a disease of aging, with a median age at diagnosis of 73 years, and has a male preponderance. 107,108 CMML can be more specifically classified into CMML-0, -1, and -2 according to the percentage of peripheral blood and bone marrow blast equivalents (which include blasts and promonocytes) and the presence or absence of Auer rods. CMML also can be classified into proliferative CMML and dysplastic CMML subtypes; a white blood cell count of more than 13 Â 10 9 /L defines the former.…”

“…2 The median age of onset is 73, with outcomes being favorable in comparison with other overlap neoplasms (median OS, 76 months), including very low rates of leukemic transformation (1%-2%). 107,133,134 MDS/MPN with ring sideroblasts and thrombocytosis is characterized by the presence of bone marrow ring sideroblasts: erythroid precursors in which, after Prussian blue staining, a minimum of five siderotic granules cover at least a third of the nuclear circumference. 135 In most instances, MDS/MPN with ring sideroblasts and thrombocytosis develops on the background of SF3B1-(90%) or DNMT3A-(10%) mutated age-related clonal cytopenias, with additional mutations like TET2, DNMT3A, ASXL1, and SETBP1 resulting in evolution to MDS-RS, followed by acquisition of signaling mutations such as JAK2V617F (50%), MPL, and SH2B3 (5% each) giving rise to defining proliferative features, including thrombocytosis.…”

Chronic Myelomonocytic Leukemia: Hematopathology Perspective

“…A number of novel therapeutic options are becoming available. These agents and their mechanisms of action are discussed in detail in two recent reviews by Patnaik et al [60,61] Targeted therapies exploiting specific genetic lesions and biologic pathways are attractive options that need to be further investigated in the setting of CMML.…”