New drugs for myeloid neoplasms with ring sideroblasts: Luspatercept vs imetelstat
Authors: Ayalew Tefferi
Journal: American Journal of Hematology (2021)

The 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 signaling 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 signaling 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-β 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-β 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 3 weeks. In a phase-3, placebo-controlled MEDALIST trial (n = 229) of transfusion-dependent patients with low/intermediate risk MDS-RS and who failed treatment with erythropoiesis stimulating agents (ESAs) or serum erythropoietin (Epo) level of >200 U/L, 28% of patients in the luspatercept treated group vs 8% in the placebo group achieved transfusion-independence for a consecutive 12 weeks period during weeks 1 through 24; median duration of transfusion independence was 31 vs 14 weeks, respectively; SF3B1 mutant allele burden was not affected by treatment and did not influence treatment response.9 Luspatercept-treated patients also experienced higher rates of erythroid-lineage hematologic improvement (53% vs 12%) and platelet response (63% vs 33%) while the rate of leukemic progression was similar between the two treatment arms. Relatively frequent adverse events included headaches, dizziness, fatigue, nausea, diarrhea, bone pain and abdominal pain. The activity of luspatercept has also been examined in MDS/MPN-RS-T10 and myelofibrosis.11 In the former, study patients (n = 23) were retrospectively identified from the aforementioned MEDALIST trial of whom 14 received luspatercept and nine placebo; nine (64%) vs two (22.2%) patients, respectively, were reported to have achieved 8-week duration of transfusion independence in the first 24 weeks. In a separate phase-2 study of 79 patients with myelofibrosis-associated anemia, 43 were identified as being transfusion dependent; achievement of transfusion-independence for 12 consecutive weeks, during the first 24 weeks of treatment, was observed in only two (10%) patients receiving luspatercept alone and in six (27%) patients receiving luspatercept in combination with ruxolitinib.11 Telomerase is a holoenzyme made up of human telomerase reverse transcriptase, an RNA template and specialized proteins, and participates in the synthesis and maintenance of telomere length in rapidly dividing cells. Imetelstat is a lipid-conjugated oligonucleotide that targets the RNA template of human telomerase. In 2015, Mayo Clinic investigators reported on 33 patients with high/intermediate-2-risk myelofibrosis who were treated with imetelstat (2-h intravenous infusion; starting dose, 9.4 mg/kg every 1 to 3 weeks) and observed a complete (n = 4; 12%) or partial remission in seven patients (21%).7 All four patients with complete remission (CR) experienced reversal of bone marrow fibrosis while three of the four achieved molecular response as well. Interestingly, the CR rate was 38% among patients with spliceosome mutations (SF3B1 or U2AF1) vs 4% among those without such mutations. The particular observation suggested potential activity in myeloid neoplasms with similar mutations, including MDS-RS and MDS/MPN-RS-T.8 In a separate study of nine such patients by the same investigators, including five with MDS/MPN-RS-T, and three with MDS-RS, three (38%) of eight transfusion-dependent patients became transfusion-independent at a median time of 11 weeks, and their response lasted for a median of 28 weeks (range, 9–37); one of the three patients also had resolution of leukocytosis and thrombocytosis. From mutation standpoint, three patients were mutated for JAK2, seven for SF3B1 and one for U2AF1. All three anemia responders and the fourth patient with spleen response were SF3B1 mutated. Treatment-emergent side effects included severe myelosuppression and liver function test abnormalities. In a more recent study of imetelestat therapy in 57 patients with transfusion-dependent lower-risk MDS that was refractory to ESAs,12 the 8-week and 24-week transfusion independence rates were 37% and 23%, respectively, with a median response duration of 65 weeks. Furthermore, CR was reported in five (9%) patients and marrow CR (mCR) in six (11%); five of the 11 mCR/CR patients had complete resolution of dysplasia; eight of the 11 CR/mCR patients demonstrated RS on screening BM aspirate and four had complete disappearance of BM RS, Among 13 patients with pre-treatment and post-treatment mutation analysis, 11 patients had baseline SF3B1 mutations, and 10 had a reduction (range, 10% to 93%) in SF3B1 variant allele frequency from baseline. Imetelestat has also shown activity in essential thrombocythemia13 and its potential disease-modifying activity in myelofibrosis was further suggested in an ongoing study.14 Taken together, the aforementioned data suggested a broader disease-modifying activity for imetelestat in myeloid neoplasms, with or without RS, and possibly influenced by the presence or absence of specific mutations. Accordingly, imetelestat might be preferable to luspatercept if the goal of therapy were to prolong survival or effect suppression of the malignant clone. However, such a prospect requires validation in a controlled study, whose likelihood of success might depend on selection of study patients based on specific molecular markers.7, 8, 12 Such an approach might also identify those patients who are unlikely to respond to treatment, and thus spare them from being uneccesarily exposed to drug side effects. In contrast to what might be the case with imetelestat, the therapeutic activity of luspatercept appears to be limited to partial amelioration of anemia, in a subset of patients with RS; furthermore, despite its interesting (assumed) mechanism of action, the overall impact of luspatercept on producing robust and durable anemia responses currently remains less than impressive. Previously published work have documented the value of both ESAs (≈50% response rate)15 and lenalidomide (≈30% response rate),16-20 for the treatment of anemia associated with MDS/MPN-RS-T; similar response rates to both ESAs and lenalidomide have also been reported in MDS-RS.21 By contrast, as was underlined in the current edition of AJH by Montalban-Bravo et al.,2 as well as noted in previous publications,15 therapeutic success with hypomethylating agents in MDS/MPN-RS-T has been less than stellar and not much better in MDS-RS.21 Regardless, current data argues for the value of ESAs as front-line treatment of choice for anemia associated with MDS/MPN-RS-T or MDS-RS and identify lenalidomide as a reasonable second-line treatment of choice, before resorting to luspatercept.22 Whether or not newer drugs, in-class or otherwise, that target specific regulators of erythropoiesis, including those that modulate hepcidin expression, would perform better remains to be seen. The authors declare no conflict of interest.