Reblozyl (luspatercept-aamt)

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.

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

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.

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.

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.

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.

P3, N=100, Recruiting, Bristol-Myers Squibb | Phase classification: P3b --> P3

Three patients experienced a grade 2 adverse event (AE), including dizziness (2), and facial eczema (1), not related to dose-increase. These data show that, along with low transfusion burden at baseline, earlier access to luspatercept in the reimbursement phase led to increased rate of transfusion independence.

To better assess predictive factors of response to Luspatercept a larger number of patients need to be included. Table 1.

Iron chelation therapy : Exjade from 2019 to 2022, now suspended. Total number of MDS-RS patients treated with Luspatercept 15 Age years, median (range) 74 (52-83) Sex, n (%) Male 10 (67) Female 5 (33) Cytogenetic, n Normal 11 8 1 Y 1 del 11q 1 del 20q 1 IPSS-R Classification, n (%) Very Low Risk 1 (15) Low Risk 7 (47) Intermediate Risk 6 (38) Mutation status, detected by NGS SF3B1, n (%) 14 (92) Vaf , %, median (range) 39 (21,4-46,3) Patients with others concomitant mutations 11 (73%) IPSS M Classification, n (%) Very Low Risk 2 (13) Low Risk 8 (54) Moderatly Low Risk 4 (26) Intermediate Risk 1 (7) Duration of EPO traitment before Luspatercept Months, median, range 21, 6-104 Transfusion burden sec. IWG 2018 Low Trasfusion Burden, n (% ) 7 (46) High transfusion burden , n (%) 8 (54)

Preliminary data support this hypothesis, that is currently evaluated in a multicenter clinical trial. Figure 1.

Luspatercept showed statistically meaningful HI-E, durable RBC-TI, and favorable outcomes across subgroups and many MDS mutations vs ESAs. Luspatercept safety was comparable with previous MDS reports; luspatercept may represent a new standard of Tx in TD LR-MDS.

P3, N=665, Recruiting, Celgene | Phase classification: P3b --> P3

The IPSS-M also represents an important extension with regard to prognosis estimation for patients with therapy-related MDS.In 2020 Luspatercept has been approved for transfusion-dependent lower risk MDS patients harboring ring sideroblasts ± an SF3B1 mutation after failure of an erythropoiesis stimulating agent. In addition, data from the phase III trial with Imeltelstat give reason to hope that we will be able to offer a new second-line therapy to LR-MDS patients. For higher risk MDS patients azacitidine therapy remains the standard of care, results of phase III trials of combination therapies must be awaited.

Furthermore, in selected samples, addition of Luspatercept led to greater maturation of erythrocytes. Our current results support the preclinical in vitro efficacy of ALK5 inhibitors IOA-359 and IOA-360 alone and in combination with Luspartercept, highlighting their potential for further development and clinical testing in MDS/AML.

In pts in the COMMANDS trial, BL MB impacted response to ESAs but not to luspatercept. In both ITT and RS+ pts, luspatercept showed either superior or comparable clinical benefit in pts with LR-MDS with various BL MB. Interestingly, both luspatercept and ESAs had similar clinical benefit across various MB in the RS− subgroup.

The number of mutations did not correlate with ESA response, while IPSS-M score, which considers the prognostic weight of specific mutations, showed predictive significance. In the multivariate analysis IPSS-M score and TD were strong predictors of ESA response, irrespective of baseline sEPO, potentially defining at diagnosis LR-MDS for whom novel agents like luspatercept could be considered as first line therapeutic option.

Additionally, 33% and 56% were refractory to lenalidomide and luspatercept therapy, respectively. The combination of canakinumab and darbepoetin was safe and well tolerated and 300mg of canakinumab is the RP2D. Canakinumab inhibited inflammasome activation as evidenced by a reduction of ASC specks although this did not translate to clinical responses. Phase 2 of the study will focus on patients with lower transfusion burden and molecular subsets with highest IL-1β expression (e.g.

In conclusion, our results show that iron restriction by vamifeport enhances the erythroid maturation action of luspatercept, likely by improving iron utilization in erythroid cells and ameliorating their survival. Furthermore, vamifeport improves the myeloid skewing in the MDS model, suggesting disease-modifying activity as single agent as well as combined therapy with luspatercept. Together, these data prove that combo therapies aimed at restricting iron and boosting erythroid maturation may offer additive beneficial effects in MDS and provide pre-clinical evidence for combining iron restriction and TFG-β superfamily ligand-trap approaches as more effective therapeutic strategies for the treatment of MDS.

Eligible pts must be 18 years of age, with an Eastern Cooperative Oncology Group performance status ≤2, candidates for serial bone marrow assessments who are willing to undergo a bone marrow aspirate/biopsy during the trial, and meet one of the following: (a) IPSS-R–defined LR-MDS who failed to respond to or did not tolerate erythropoiesis-stimulating agents (ESAs) or luspatercept or hypomethylating agents (HMAs) and pts with del 5q who failed to respond to or did not tolerate lenalidomide; (b) CPSS–defined LR-CMML who failed to respond to or did not tolerate hydroxyurea or HMAs. The study is currently enrolling in Singapore, Hong Kong, and the USA with plans to treat approximately 80 pts. The first patient first visit was achieved on May 8, 2023.

Erythropoiesis-stimulating agents and other drugs, including lenalidomide, luspatercept and imetelstat (an investigational product), can lead to RBC transfusion independence and improve Hb levels in many patients; however, responses are generally transient and novel treatments are needed for this population...Additional exclusion criteria include prior treatment with azacitidine; decitabine; erythropoietin, other hematopoietic growth factor treatment or lenalidomide within 30 days of Day 1 or anticipated to be required during the study; and luspatercept within 30 days of Day 1 for NTD patients and within 16 weeks of Day 1 for TD patients...Summary: Etavopivat is a novel, investigational, once-daily, selective PKR activator with the potential to improve RBC health and lifespan. This phase 2 study will assess the safety of etavopivat and its impact on Hb levels and RBC transfusion burden in patients with LR-MDS and anemia.

This retrospective subgroup analysis of patients in the COMMANDS trial with the most frequent CHIP-related mutations (DNMT3A, TET2, ASXL1, and SF3B1) demonstrated novel effects of luspatercept in clonal hematopoiesis-related consequences including improvements in anemia, cytopenias, and reduced inflammation. Most importantly, NT-proBNP and elevated hepcidin levels were significantly downregulated in responders following luspatercept treatment. These results warrant evaluation of luspatercept in patients with high-risk CHIP mutations including clonal cytopenia of undetermined significance and patients with anemia of inflammation.

Prior treatment with ESA, G-CSF, and luspatercept was allowed with a 30-day washout period...One grade 4 event occurred (duodenal hemorrhage) in a patient with history of duodenal ulcers and concurrent aspirin use... Enasidenib at 200mg dose was safe and well tolerated in patients with lower-risk MDS. Thus far, one patient has seen trilineage improvement in blood counts and continues on study. The Phase 2 portion of the study is ongoing to further characterize safety and evaluate for efficacy to improve anemia and decrease transfusion needs.