Reblozyl and Its Role in Treating Anemia in MDS and Beta Thalassemia

1. Reblozyl and Its Role in Treating Anemia in MDS and Beta Thalassemia Introduction: The challenge of anemia in MDS and beta thalassemia Anemia is a hallmark of both myelodysplastic syndromes (MDS) and β-thalassemia, often resulting from ineffective erythropoiesis. MDS are a heterogeneous group of clonal hematopoietic disorders managed according to risk stratification. Lower-risk patients may receive ESAs or lenalidomide (for del(5q)), while higher-risk cases often require hypomethylating agents, intensive chemotherapy, or allogeneic stem cell transplantation.1 Supportive care with regular red blood cell (RBC) transfusions remains common in both lower- and higher-risk MDS, but carries risks of iron overload, reduced quality of life, and increased healthcare costs, with iron chelation used to mitigate complications. Despite advances in supportive care and disease-specific therapies, substantial unmet needs remain, particularly for patients who are transfusion-dependent or refractory to standard treatments.1 In β-thalassemia, defective hemoglobin synthesis and excess unpaired alpha chains cause ineffective erythropoiesis, leading to severe anemia and compensatory bone marrow expansion with extramedullary hematopoiesis. Lifelong RBC transfusions are often required, increasing the risk of iron overload, organ damage, and morbidity. Suppressed hepcidin levels further enhance iron absorption, while complications such as hepatosplenomegaly, facial deformities, and liver dysfunction can arise.2 Although hematopoietic stem cell transplantation offers a curative option for select patients, but most rely on lifelong transfusions and iron chelation, facing complications, treatment burden, and psychosocial challenges.1 What is Reblozyl (Luspatercept)? Reblozyl, is an innovative recombinant fusion protein designed to address the underlying pathology of anemia in these conditions. It is classified as an erythroid maturation agent, An EMA helps immature RBCs (called erythroid cells) develop and become mature, working RBCs. This may result in more healthy RBCs and improve anemia.3 Approved Indications

2. Reblozyl is approved for the treatment of: •Beta-thalassemia–related anemia in adults who require regular RBC transfusions. •Anemia in MDS or in myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) in adults who fail erythropoiesis-stimulating agents (ESAs) and need ≥2 RBC units over 8 weeks.4,5 Limitations of use: Reblozyl is not indicated as a substitute for RBC transfusions in patients requiring immediate correction of anemia. It is intended for longer-term management rather than emergency intervention.4 Mechanism of Action: Enhancing late-stage erythropoiesis Luspatercept exerts its therapeutic effect by modulating the transforming growth factor-beta (TGF-β) superfamily signaling pathway. It functions as a ligand trap for select TGF-β superfamily members, including growth differentiation factor 11 (GDF11), activins, and certain bone morphogenetic proteins (BMPs). Inhibition of GDF11 has been demonstrated to restore terminal erythroid maturation and late-stage erythropoiesis through suppression of SMAD2/3 signaling. While GDF11 appears to play a central role, the full spectrum of luspatercept’s molecular targets has not yet been fully delineated, suggesting additional ligands may contribute to its erythropoiesis-enhancing activity.1 Clinical Evidence Supporting Use In the MEDALIST trial, 37.9% of patients with lower-risk MDS treated with luspatercept achieved RBC-transfusion independence for 8 weeks, compared with 13.2% on placebo (p<0.0001). The results highlight luspatercept’s ability to reduce transfusion burden and improve outcomes and quality of life in this patient population.6 In the phase 3 COMMANDS trial, 59% of ESA-naive lower-risk MDS patients treated with luspatercept achieved transfusion independence versus 31% with epoetin alfa (p<0.0001). Treatment was well tolerated, with manageable adverse events, positioning luspatercept as a promising alternative to standard ESA therapy.7 In the phase 3 BELIEVE trial, luspatercept significantly reduced RBC transfusions in adults with transfusion-dependent β-thalassemia. 21.4% achieved ≥33% reduction versus 4.5% with

3. placebo, and 70.5% achieved this reduction over any 12-week period. Luspatercept was well tolerated, highlighting its role as a first-in-class erythroid maturation therapy.8 Common Side Effects and Safety Profile Reblozyl is generally well-tolerated, with most side effects being mild to moderate in nature. The most commonly reported adverse events include: •Fatigue, cephalalgia, vertigo, musculoskeletal pain, nausea, diarrhea, abdominal pain, cough, trouble breathing, swelling of hands, legs or feet, high blood pressure, and allergic reactions. •Thromboembolic events; chest pain, dyspnea, limb pain/swelling, sudden weakness/numbness, severe headache, or vision/speech/balance problems. •Extramedullary hematopoietic masses; severe back pain, limb weakness/numbness, or loss of bowel/bladder control.9 •Pregnancy: May cause fetal harm; advise against use in pregnant women. •Lactation: Detected in animal milk; avoid breastfeeding during treatment and 3 months after. •Reproductive Potential: Use effective contraception; pregnancy testing recommended; may impair female fertility. •Pediatric Use: Safety and efficacy not established; not recommended. •General Advice: Monitor and counsel patients in these populations due to potential serious risks. •Drug Abuse Potential: Misuse may lead to polycythemia and life-threatening cardiovascular complications.10 Conclusion Reblozyl offers a transformative approach to managing anemia in MDS and beta thalassemia by addressing limitations of prior therapies and providing a novel mechanism to stimulate effective RBC production. Its ability to reduce transfusion needs and improve patient outcomes is supported by high-quality evidence. However, as with all medical therapies, the decision to use Reblozyl should be made by a healthcare professional considering individual patient needs. Note:

4. This blog is for educational purposes only and does not replace professional medical advice. Individuals seeking treatment should consult a licensed healthcare provider regarding appropriate therapy choices. Disclaimer: Rx4U procures prescribed medicines directly from manufacturers or authorized distributors. It does not claim ownership of any trademarks and complies with the provisions of the Trademark Act, 1999, particularly Sections 30 and 30(1) concerning ‘Fair Use’. It solely facilitates access to new launches through named patient import. References 1.Cappellini MD, Taher AT, Verma A, Shah F, Hermine O. Erythropoiesis in lower-risk myelodysplastic syndromes and beta-thalassemia. Blood Reviews. 2022 Dec;59:101039. 2.Needs T, Gonzalez-Mosquera LF, Lynch DT. Beta Thalassemia [Internet]. PubMed. Treasure Island (FL): StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK531481/ 3.Vinchi F, Uwe Platzbecker. Luspatercept: A peaceful revolution in the standard of care for myelodysplastic neoplasms. HemaSphere. 2024 Mar 1;8(3):1–3. 4.Food and drug Administration. HIGHLIGHTS OF PRESCRIBING INFORMATION [Internet]. 2019. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761136lbl.pdf 5.Center for Drug Evaluation and Research. FDA approves luspatercept-aamt for anemia in adults with MDS. FDA [Internet]. 2020 Apr 6; Available from: https://www.fda.gov/drugs/resources- information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds 6.Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, et al. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. New England Journal of Medicine. 2020 Jan 9;382(2):140–51. 7.Platzbecker U, Della G, Santini V, Zeidan AM, Komrokji RS, Shortt J, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion- dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. The Lancet. 2023 Jul 1;402(10399):373–85. 8.Cappellini MD, Viprakasit V, Taher A, Georgiev P, Kuo KHM, Coates TD, et al. The Believe Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell (RBC) Transfusions. Blood. 2018 Nov 29;132(Supplement 1):163–3.

5. 9.Benefits & Side Effects of REBLOZYL® (luspatercept-aamt) for Anemia in Beta Thalassemia [Internet]. REBLOZYL® (luspatercept-aamt) Patient Site. Available from: https://www.reblozyl.com/beta-thalassemia/about-reblozyl/benefits-and-side-effects 10.REBLOZYL® (luspatercept-aamt) First Line Safety - LR-MDS | For HCPs [Internet]. Reblozylpro.com. 2024 [cited 2025 Sep 25]. Available from: https://www.reblozylpro.com/mds-first-line/safety