Luspatercept use for lower risk myelodysplastic syndromes: Active but not enough

Ineffective erythropoiesis remains the principal source of diseaserelated symptoms and morbidity in myelodysplastic syndromes (MDS), resulting in symptomatic anemia, red blood cell transfusion dependence (RBC-TD), iron overload, and progressive physical debility. Potential mechanisms of ineffective erythropoiesis include alterations in both early and late-stage erythropoiesis secondary to clonal stem cell defects (e.g., SF3B1, TET2, and DNMT3A mutations), abnormalities in signaling pathways (e.g., JAK-STAT, SMAD2/3), overproduction of inflammatory cytokines (NLRP3 related ILIβ, IL6 and TNFα), unbalanced iron homeostasis, and free radical mediated damage. Several strategies have been employed to manage anemia in MDS including erythropoiesis stimulating agents (ESAs), lenalidomide, androgens such as danazol, DNA methyltransferase inhibitors (DNMTi), and combinatorial strategies with these agents. Two new drugs that have been added to this arsenal include luspatercept and imetelstat, with luspatercept being US FDA/EMA approved for use in adult patients with RBC-TD beta thalassemia and in patients with low-/intermediate-risk MDS-RS (ring sideroblasts) and MDS/MPNRS-T (MPN-myeloproliferative neoplasm, RS-T-ring sideroblasts with thrombocytosis). Luspatercept is a recombinant activin receptor type IIB fusion protein that is designed to trap TGF-β superfamily ligands (including activin), blocking their engagement with their cognate receptors, which otherwise would have resulted in activation of SMAD2/3 signaling (SMAD2/3 signaling is known to inhibit terminal erythroid differentiation). While luspatercept can alleviate anemia by enhancing late-stage erythropoiesis, it does not modify disease biology, with progression remaining inevitable. Luspatercept's US FDA/EMA approval was based on the Phase-3, randomized, placebo-controlled MEDALIST trial, where 229 patients with RBC-TD low-/intermediate-risk MDS-RS who failed treatment with ESAs or had an endogenous erythropoietin (EPO) level of >200 U/L, were randomized to receive luspatercept versus placebo (Table 1). Twenty-eight percent of patients in the luspatercept-treated group versus 8% in the placebo group achieved RBC-TI (transfusion independence) for a consecutive 12-week period during weeks 1 through 24 (p < .001); median duration of RBC-TI was 31 versus 14 weeks, respectively. This number increased to 33% for the luspatercept arm versus 12% for the placebo arm during weeks 1–48 (p < .001). However, only 14% of patients in the luspatercept arm had their 24-week response for RBC-TI maintained at 1 year. Luspatercept-treated patients experienced higher rates of erythroid-lineage hematologic improvement (HI—53% vs. 12%) and platelet responses (63% vs. 33%), while the rate of leukemic progression was similar between the two treatment arms. On longer term follow-up, the median duration of RBC-TI ≥ 8 weeks in the heavy RBC-TD patients was 26.9 weeks, whereas the median duration of the longest major erythroid response (mHI-E) was 11.86 weeks (similar to placebo arm), highlighting limitations with durability. The MEDALIST trial also led to the approval of luspatercept for MDS/MPN-RS-T, an MDS/MPN overlap syndrome with a high frequency of SF3B1 (80%–90%) and JAK2 (50%) mutations, without any clinical trial data supporting safety and efficacy. This was surprising given that 70% of luspatercept-treated patients versus 42% of placebo-treated patients in this study had a ≥30 10/L mean increment in their platelet counts, although these counts did remain within upper limits of normal. It was after approval that a post hoc analysis of the MEDALIST trial found that 23 (10%) patients actually met criteria for MDS/MPN-RS-T, with 14 receiving luspatercept and 9 receiving placebo. RBC-TI ≥ 8 weeks was seen in 64.3% of luspatercept-treated patients versus 22% of placebo-treated patients, with one patient developing a transient ischemic attack on the study drug. Given the higher thrombotic risk associated with MDS/MPN-RS-T, Mayo Clinic is now leading a prospective Phase 2 study to establish safety, efficacy, and an optimal dosing strategy for luspatercept, especially when concomitant cytoreduction with hydroxyurea is warranted (NCT05005182, www.clinicaltrials.gov). After luspatercept's approval, important real-world studies failed to replicate the initial enthusiasm for the agent, highlighting nuances with clinical trial selection criteria and the application of response crtieria. In a Mayo Clinic study, 39 (83% SF3B1 mutant) MDS-RS patients received luspatercept, with 31 patients having RBC-TD. Erythroid responses were documented in 18%, with 16% of RBC-TD patients responding. One reason for the suboptimal response might have been the fact that 95%, 38%, and 26% of these patients had prior exposures to ESA, DNMTi, and lenalidomide, respectively. In a second study assessing responses in 27 patients with chronic myeloid neoplasms without RS (Table 1; not including MPN), only 11% met the criteria for anemia response, including 8% of RBC-TD patients. Again, in this analysis, 70%, 44%, and 11% of luspatercept-treated patients did have prior exposures to ESA, DNMTi, and lenalidomide, respectively. In this issue of the journal, Lanino et al. present realworld data from an Italian luspatercept compassionate use trial for patients with lower risk MDS-RS (R-IPSS—very low, low, and intermediate risk; FISiM study), who were refractory to, or ineligible for ESA therapy and who were RBC-TD (≥2 units of red cells/8 weeks in the last 16 weeks prior to enrollment). Notably, these patients were not Received: 11 June 2023 Accepted: 12 June 2023