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Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022 International Consensus Classification (ICC), MDS/MPN consists of clonal monocytosis of undetermined significance (CMUS), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with SF3B1 mutation (MDS/MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocytosis not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. These disorders exhibit a diverse range of genetic alterations involving various transcription factors (e.g., RUNX1), signaling molecules (e.g., NRAS, JAK2), splicing factors (e.g., SF3B, SRSF2), and epigenetic regulators (e.g., TET2, ASXL1, DNMT3A), as well as specific cytogenetic abnormalities (e.g., 8 trisomies, 7 deletions/monosomies). Clinical studies exploring therapeutic options for higher-risk MDS/MPN overlap syndromes mostly involve hypomethylating agents, but other treatments such as lenalidomide and targeted agents such as JAK inhibitors and inhibitors targeting PARP, histone deacetylases, and the Ras pathway are under investigation. While these treatment modalities can provide partial disease control, allogeneic bone marrow transplantation (allo-BMT) is the only potentially curative option for patients. Important prognostic factors correlating with outcomes after allo-BMT include comorbidities, splenomegaly, karyotype alterations, and the bone marrow blasts percentage at the time of transplantation. Future research is imperative to optimizing therapeutic strategies and enhancing patient outcomes in MDS/MPN neoplasms. In this review, we summarize MDS/MPN diagnostic criteria, biology, and current and future treatment options, including bone marrow transplantation.

Abstract Objectives Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are a group of rare and heterogeneous hematopoietic disorders that frequently present a diagnostic challenge. Here we present our institutional experience with next-generation sequencing (NGS), together with morphologic, flow cytometric, and cytogenetic evaluation, in the diagnosis of MDS/MPN, with particular emphasis on MDS/MPN unclassifiable (MPN-U). Methods We evaluated the morphologic, flow cytometric, cytogenetic, and molecular characteristics of all MDS/MPN cases that underwent NGS at our institution between April 2016 and February 2019. Results Thirty-seven cases of MDS/MPN were identified, including 14 cases of MDS/MPN-U. Ninety-seven percent harbored mutations and immunophenotypic aberrancies (36/37), while only 38% had cytogenetic abnormalities (12/32). The MDS/MPN-U group had the highest rate of myeloblast phenotypic abnormalities and had a high mutation rate of approximately 2.7 mutated genes per case, most commonly in JAK2, SRSF2, and ASXL1. Conclusions No single ancillary study was abnormal in every case, but all cases had at least one abnormal finding, demonstrating the usefulness of a multiparameter approach to the diagnosis of MDS/MPN. Although a few specific mutations were found exclusively in MDS/MPN-U and JAK2 mutations were most prevalent, larger studies are needed to determine whether MDS/MPN-U has a mutational “fingerprint,” which may aid in diagnosis and targeted therapy.

Myelofibrosis (MF), Myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes have a broad range of clinical presentations and molecular abnormalities, making their diagnosis and classification complex. This paper reviews molecular aberration, epigenetic modifications, chromosomal anomalies, and their interactions with cellular and other immune mechanisms in the manifestations of these disease spectra, clinical features, classification, and treatment modalities. The advent of new-generation sequencing has broadened the understanding of the genetic factors involved. However, while great strides have been made in the pharmacological treatment of these diseases, treatment of advanced disease remains hematopoietic stem cell transplant.

Background Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO ( A B asket study of N ove l therapy for untreated M DS/MPN a nd R elapsed/ R efractory O verlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. Methods ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. Discussion Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. Trial registration This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).

Chronic myeloid malignancies are categorized to the three main categories myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs) and MDS/MPN overlap. So far, no specific genetic alteration profiles have been identified in the MDS/MPN overlap category. Recent studies identified mutations in SET-binding protein 1 ( SETBP1 ) as novel marker in myeloid malignancies, especially in atypical chronic myeloid leukemia (aCML) and related diseases. We analyzed SETBP1 in 1 130 patients with MPN and MDS/MPN overlap and found mutation frequencies of 3.8% and 9.4%, respectively. In particular, there was a high frequency of SETBP1 mutation in aCML (19/60; 31.7%) and MDS/MPN unclassifiable (MDS/MPN, U; 20/240; 9.3%). SETBP1 mutated ( SETBP1 mut) patients showed significantly higher white blood cell counts and lower platelet counts and hemoglobin levels than SETBP1 wild-type patients. Cytomorphologic evaluation revealed a more dysplastic phenotype in SETBP1 mut cases as compared with wild-type cases. We confirm a significant association of SETBP1 mut with −7 and isochromosome i(17)(q10). Moreover, SETBP1 mut were strongly associated with ASXL1 and CBL mutations ( P <0.001 for both) and were mutually exclusive of JAK2 and TET2 mutations. In conclusion, SETBP1 mut add an important new diagnostic marker for MDS/MPN and in particular for aCML.

The myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) category comprises a varied group of myeloid neoplastic diseases characterized by clinical and pathologic overlapping features of both myelodysplastic and myeloproliferative neoplasms. For these reasons, these tumors are challenging in terms of diagnosis. The recent World Health Organization (WHO) 2022 classification and the International Consensus Classification (ICC) made changes in the classification of MDS/MPN compared to the previous 2016 WHO classification and improved the diagnostic criteria of these entities. The aim of this review is to describe the main entities reported in the more recent classifications, focusing on chronic myelomonocytic leukemia (CMML), MDS/MPN with neutrophilia (or atypical CML [aCML]), and MDS/MPN with SF3B1 mutation and thrombocytosis/MDS/MPN with ring sideroblasts and thrombocytosis. A particular emphasis is given to the differential diagnosis and analysis of subtle divergences and semantic differences between the WHO classification and the ICC for these entities.

The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51–88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0–91) months. A JAK2 V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries.

Diagnosis of myeloid neoplasm is currently performed according to the presence of a predetermined set of clinical, morphological, and molecular diagnostic criteria agreed upon by a consensus of experts. Even strictly adhering to these criteria, it is possible to encounter patients who present features that are not easily ascribable to a single disease category. This is the case, e.g., of patients with de novo myeloid neoplasms with features intermediate between primary myelofibrosis (PMF) and chronic myelomonocytic leukemia (CMML). In this study, we retrospectively searched the pathological database of IRCCS Humanitas Research Hospital to identify cases of chronic myeloid neoplasm with monocytosis with a driver mutation of classic myeloproliferative neoplasms (MPN) and showing morphological MPN features. For each case, we assessed all epidemiological, clinical, histopathological, and molecular data. Then, we carried out a literature review, searching for cases with features similar to those of our patients. We retrieved a total of 13 cases presenting such criteria (9 from the literature review and 4 from our institution); in all of them, there was a coexistence of clinical, histopathological, and molecular myelodysplastic and myeloproliferative features. To date, according to current classifications (World Health Organization and International Consensus Classification), given the presence/absence of essential features for PMF or CMML, these patients should be formally diagnosed as myelodysplastic/myeloproliferative neoplasm unclassified/not otherwise specified (U/NOS). This review aims to summarize the features of these difficult cases and discuss their differential diagnosis and their classification according to the novel classifications and the existing literature on overlapping myeloid neoplasms.

The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone marrow. Ring sideroblasts are abnormal erythroblasts with iron-loaded mitochondria that are visualized by Prussian blue staining as a perinuclear ring of green-blue granules. The mechanisms that lead to the ring sideroblast formation are heterogeneous, but in all of them, there is an abnormal deposition of iron in the mitochondria of erythroblasts. Congenital sideroblastic anemias include nonsyndromic and syndromic disorders. Acquired sideroblastic anemias include conditions that range from clonal disorders (myeloid neoplasms as myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with ring sideroblasts) to toxic or metabolic reversible sideroblastic anemia. In the last 30 years, due to the advances in genomic techniques, a deep knowledge of the pathophysiological mechanisms has been accomplished and the bases for possible targeted treatments have been established. The distinction between the different forms of sideroblastic anemia is based on the study of the characteristics of the anemia, age of diagnosis, clinical manifestations, and the performance of laboratory analysis involving genetic testing in many cases. This review focuses on the differential diagnosis of acquired disorders associated with ring sideroblasts.