Reblozyl (luspatercept-aamt)

P1, N=24, Not yet recruiting, Groupe Francophone des Myelodysplasies

Epoetin alfa was used simultaneously in 31 patients (60.7%). The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.

P=N/A, N=200, Recruiting, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico | Trial completion date: Jun 2030 --> Jun 2035 | Trial primary completion date: Sep 2026 --> Sep 2030

P=N/A, N=0, Withdrawn, Bristol-Myers Squibb | Not yet recruiting --> Withdrawn | N=86 --> 0

Despite some promising results, many therapies remain in early development or have faced setbacks, emphasizing the need for a more comprehensive understanding of the disease's pathobiology. Continued research into targeted therapies, homogenous clinical trial designs, as well as increased incorporation of molecular prognostic tools and artificial intelligence into trial design are essential for developing effective treatments for MDS and improving patient outcomes.

This year, luspatercept, an anti-anemic agent targeting the TGFβ pathway, became available for clinical use in Japan. Various research initiatives are currently underway to develop new medicines targeting specific molecules within innate immune and inflammasome-signaling pathways, including IL-1β, CD33, TLR, IRAK4, and p38MAPK.

P2, N=40, Recruiting, M.D. Anderson Cancer Center | Phase classification: P1 --> P2

P=N/A, N=90, Recruiting, Bristol-Myers Squibb

P=N/A, N=16, Recruiting, The First Affiliated Hospital of Anhui Medical University; The First Affiliated Hospital of Anhui Medical University

P2, N=40, Recruiting, The First Affiliated Hospital with Nanjing Medical University; The First Affiliated Hospital with Nanjing

P2, N=90, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P=N/A, N=86, Not yet recruiting, Bristol-Myers Squibb

P=N/A, N=104, Recruiting, Bristol-Myers Squibb | Trial completion date: Sep 2029 --> Dec 2027 | Initiation date: Nov 2023 --> Mar 2024 | Trial primary completion date: Dec 2028 --> Dec 2027

P3, N=309, Active, not recruiting, Celgene | Recruiting --> Active, not recruiting

P2, N=56, Not yet recruiting, GlaxoSmithKline

The treatment landscape of LR-MDS with anemia is also rapidly evolving; we review the role of supportive care, erythropoietin stimulating agents, lenalidomide, luspatercept, hypomethylating agents (HMAs), and immunosuppressive therapy (IST) in the management of LR-MDS with anemia. For those without previous luspatercept exposure it can be considered particularly if there is an SF3B1 mutation or the presence of ring sideroblasts. Other options include HMAs or IST; the Phase III IMERGE trial supports the efficacy of the telomerase inhibitor imetelstat in this setting and this may become a standard option in the future as well.

P2, N=70, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2024 --> May 2025

P4, N=58, Not yet recruiting, Peking Union Medical College Hospital

In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment...There were 29 (74.4%) patients with ≥15% RS, 6 (15.4%) with 5 to 14% RS, one (2.6%) with 1% RS, and 3 (7.7%) with no RS. Our study suggests that a quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15% and supports the revised 2022 definitions of the World Health Organization (WHO) and International Consensus Classification (ICC), which shift toward molecularly defined subtypes of MDS and appropriate testing.

Lower-risk MDS (LR-MDS) treatment ranges from observation to supportive measures and erythropoiesis-stimulating agents (ESAs), with emerging therapies like luspatercept showing promise...Emerging treatments, including oral HMAs and novel agents targeting FLT3, and IDH 1/2 mutations, show promise. Future research should refine treatment strategies for this elderly population focusing on quality-of-life improvement.

P=N/A, N=104, Recruiting, Bristol-Myers Squibb | Not yet recruiting --> Recruiting

P2, N=36, Recruiting, Institute of Hematology & Blood Diseases Hospital, China | Not yet recruiting --> Recruiting

P=N/A, N=200, Recruiting, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico | Trial completion date: Jun 2026 --> Jun 2030 | Trial primary completion date: Sep 2023 --> Sep 2026

P1, N=40, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P2, N=99, Recruiting, Celgene | Trial completion date: Oct 2028 --> Nov 2026 | Trial primary completion date: Apr 2028 --> Jun 2026

P2, N=249, Recruiting, Bristol-Myers Squibb | N=177 --> 249

P2, N=3, Terminated, Mayo Clinic | Trial completion date: May 2025 --> Jun 2023 | Active, not recruiting --> Terminated | Trial primary completion date: May 2024 --> Apr 2023; Slow accrual

P3, N=665, Recruiting, Celgene | Trial completion date: Mar 2030 --> May 2028 | Trial primary completion date: Mar 2030 --> May 2028

P2, N=99, Recruiting, Celgene | Phase classification: P2a --> P2 | N=54 --> 99 | Trial completion date: Nov 2026 --> Oct 2028 | Trial primary completion date: Jun 2026 --> Apr 2028

P2, N=3, Active, not recruiting, Mayo Clinic | Recruiting --> Active, not recruiting | N=33 --> 3

Luspatercept is a novel erythropoietic maturation agent approved for adult β-thalassemia and Myelodysplastic syndromes with ring sideroblasts (MDS-RS) associated with ineffective erythropoiesis. Here we report 2 patients with CSA due to mutations in ALAS2 and SLC25A38 genes who became unresponsive after a period of treatment with vitamin B6 and iron chelators but achieved transfusion independence and a markedly reduced spleen after combination with luspatercept.

Among the approved JAK inhibitors (ruxolitinib, fedratinib, momelotinib, and pacritinib) for MF, momelotinib and pacritinib are preferably used in cytopenic patients; both agents are potent ACVR1 inhibitors that suppress hepcidin expression via the BMP6/ACVR1/SMAD pathway and restore iron homeostasis/erythropoiesis...Zilurgisertib (ACVR1 inhibitor) and DISC-0974 (anti-hemojuvelin monoclonal antibody) are evaluated in early phase clinical trials in patients with MF and anemia. Luspatercept (ACVR2B ligand trap) is assessed in transfusion-dependent MF patients in a registrational phase 3 trial. Approved ACVR1 inhibitors and novel agents in development are poised to improve the outcomes of anemic MF patients.

This review summarizes novel and promising treatments for anemia in myelofibrosis including transforming growth factor-β inhibitors luspatercept and KER-050, JAK inhibitors momelotinib, pacritinib, and jaktinib, BET inhibitors pelabresib and ABBV-744, antifibrotic PRM-151, BCL2/BCL-XL inhibitor navitoclax, and telomerase inhibitor imetelstat. Standard approaches to treat myelofibrosis-related anemia have limited efficacy and are associated with toxicity. New drugs have shown positive results in myelofibrosis-associated anemia when used alone or in combination.

Although options for reducing the transfusion burden have recently been improved, erythropoiesis-stimulating agents (ESAs), lenalidomide, hypomethylating agents, and, more recently, luspatercept have shown efficacy in rarely more than 50% of patients with a duration of response often far inferior to the patient's life expectancy. Targeting ligands of the transforming growth factor β pathway has led to the approval of luspatercept in LR-MDS with ring sideroblasts or SF3B1 mutation, potentially replacing first-line ESAs in this population. Here, we also discuss the evolving standard of care for the treatment of LR-MDS and explore some of the most promising next-generation agents under investigation.

According to our meta-analysis, luspatercept significantly improved transfusion independent rate and HIE response in patients with lower risk MDS and anaemia compared to control arm. Furthermore, there was no statistically significant difference in the treatment emergent SAEs, treatment discontinuation, treatment interruption or dose reduction and treatment related mortality between the two groups.

The basis of this combination followed a GFM trial showing that, in non-del 5q lower risk MDS failing an ESA, Lenalidomide + ESA gave better results than Lenalidomide alone (Toma A et al. We observed a significant number of adverse events attributed to LUSPA, some of which led to treatment discontinuation. The importance of RBC transfusion burden was the only prognostic factor of erythroid response.

Eligible patients were divided into 4 cohorts based on transfusion dependence (TD) and treatment with ruxolitinib (RUX). Our analysis identifies unique predictors of response to luspatercept treatment in patients with MF. While the data describe our findings across cohorts, cohort 3B (TD, receiving RUX), which had the highest response rate, also had higher levels of RANTES and TPO at baseline in responders. The ongoing phase 3 study, INDEPENDENCE (NCT04717414), would validate these observations in a larger cohort of patients

OBJECTIVESThis study aimed to conduct a systematic review and meta-analysis of clinical trials and RWD evidence to evaluate the efficacy of luspatercept among lower risk MDS patients. METHODSProspective randomized controlled trials (RCTs) and phase II trials, retrospective cohort studies and case series of patients with MDS treated with single agent luspatercept were retrieved from PubMed, EMBASE and conference proceedings.

Following the switch from Darbepoetin to Luspatercept, there was a significant improvement in Hb level and in quality of life in our 2 patients. This finding needs to be confirmed with larger studies.

Case 1 was hospitalized for 2 months, treated with 18 Gy radiation, dexamethasone for 2 months, hydroxyurea 2000 mg (24 mg/kg), hypertransfusion (goal Hb > 110 g/L) and luspatercept discontinuation. Paraspinal EMH is a rare complication in TDT patients, but its occurrence should be considered, especially with the increasing use of luspatercept. Screening guidelines for EMH should be established to detect and manage this potentially debilitating condition promptly. In the absence of guidelines, based on the high rate of EMH noted in our cohort, we propose screening MRI spine as a baseline prior to luspatercept, with consideration of regular surveillance MRI post therapy.

One of the small molecule TβRI inhibitors, Vactosertib, is currently undergoing a phase 1/2 clinical trial to evaluate its effect on osteosarcoma. For instance, Luspatercept, a TGF-β ligand trap, has been approved by the FDA for the treatment of anemia associated with myeloid dysplastic syndrome (MDS) with ring sideroblasts/mutated SF3B1 with acceptable safety. Clinical trials evaluating the long-term safety of Luspatercept are in process.