New Tefferi paper text (1)

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cheng_ho
Posts: 202
Joined: Sun Apr 03, 2016 11:27 pm

New Tefferi paper text (1)

Post by cheng_ho » Mon Apr 19, 2021 5:03 pm

he World Health Organization classification system recognizes the presence of ring sideroblasts (RS), in excess of 15% (or 5% in the presence of SF3B1 mutation) of bone marrow erythroid precursors, as a distinguishing feature to classify myelodysplastic syndromes with RS (MDS-RS) and myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T).1 In addition to RS, these two clinicopathologic entities share SF3B1 mutation, which is detected in the majority of patients, and morphologically (erythroid dysplasia) and physiologically (anemia) apparent ineffective erythropoiesis.1 In the current edition of AJH, Montalban-Bravo et al retrospectively compared patients with MDS/MPN-RS-T (n=52) vs those with MDS-RS (n=88).2 The authors found the two groups to be similar in terms of hemoglobin level, bone marrow RS and blast percentages, SF3B1 mutation incidence (92% vs 82%, respectively) and allele burden, serum ferritin and Epo levels and overall survival (median >5 years in both instances);2 differences included higher frequency of JAK2V617F (58% vs 0%) and associated kinase signalling genes (e.g. CALR, MPL, CBL) in MDS/MPN-RS-T and distinct transcriptomic profiles between the two entities.2 Putative pathogenetic mechanisms for ineffective erythropoiesis in myeloid neoplasms with RS include alterations in both early (increased proliferation and apoptosis of erythoid precursors) and late (abnormal differentiation and maturation of erythroid progenitors) stage erythropoiesis resulting from intrinsic clonal defects3 compunded by abnormalities in specific signalling pathways, expression of inflammatory cytokines and systemic iron homeostasis.4 Such information has led to the recent development of targetted therapy for ineffective erythropoiesis, including luspatercept (TGF-ligand trap),5,6 whereas the therapeutic value for imetelestat was recognized within the context of a broader anti-clonal activity.7,8 Luspatercept is a recombinant activin receptor type IIB fusion protein that was designed to trap TGF- superfamily ligands (including activin), thus derailing their engagement with their cognate receptors, which otherwise results in activation of SMAD2/3 signaling, which is believed to inhibit terminal erythroid differentiation.9 The drug is now FDA/EMA approved for use in adult patients with transfusion-requiring beta thalassemia and low/intermediate-risk MDS-RS and MDS/MPN-RS-T (approval dates 2019/2020). Luspatercept is administered by subcutaneous injection (initial dose 1 mg/kg with possibility to increase to 1.75 mg/kg) every three weeks.

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