Luspatercept is a recombinant fusion protein that combines the extracellular domain of the human activin receptor with the Fc fragment of immunoglobulin G and acts by interfering with transforming growth factor beta signaling and is used to treat severe forms of anemia due to beta thalassemia or myelodysplastic syndromes. Luspatercept has been linked to a low rate of serum enzyme elevations during therapy, but has not been linked to cases of clinically apparent liver injury with jaundice.


Luspatercept (lus pat’ er sept) is a recombinant fusion protein that combines the extracellular domain of human activin receptor type IIB with the Fc fragment of immunoglobulin G. Luspatercept stimulates the production of erythrocytes via inhibition of ligands, which activate intracellular pathways (by reducing SMAD2, SMAD3 signaling) that mediate intracellular apoptosis of erythrocytes. Inhibition of this pathway causes an increase in erythrocyte maturation and proliferation. In clinical trials in patients with refractory and severe anemia due to beta thalassemia, myelofibrosis and myelodysplastic syndromes, luspatercept therapy decreased transfusion requirements and increased hemoglobulin levels in 60% to 70% of patients. Luspatercept was approved as therapy of beta thalassemia in the United States in 2019, and a year later its indications were expanded to include patients with myelodysplastic syndromes who were transfusion dependent or not responding to growth factor therapy. Luspatercept is available under the brand name Reblozyl as a lyophilized power for subcutaneous administration in single use vials of 25 and 75 mg. Luspatercept is given subcutaneously every 3 weeks in doses based upon body weight, the initial dosage being 1.0 mg/kg with potential for dose increase (1.25, 1.33 or 1.75 mg/kg) or decrease (to 0.8 or 0.6 mg/kg) depending upon efficacy and tolerance. Common side effects include injection site reactions, hypertension and nonspecific symptoms of fatigue, headache, dizziness, body pain and rash. Acute hypersensitivity reactions occur in <1% of patients. Less common, but potentially severe side effects include an increased risk of thrombosis and thromboembolism, severe hypertension, and embryo-fetal toxicity.


In prelicensure controlled trials, serum ALT elevations occurred in 9% to 12% with luspatercept and a similar proportion of subjects treated with placebo (7% to 12%). The elevations were usually mild-to-moderate in severity, asymptomatic and self-limited in course. ALT elevations above 5 times the ULN occurred in 1% to 2% of recipients and rarely led to discontinuation of therapy. Luspatercept therapy was also associated with serum bilirubin elevations (11% vs 5% in placebo recipients), which occurred in some patients with concurrent serum aminotransferase elevations. However, no patient developed clinically apparent, symptomatic acute liver injury, and some of the bilirubin elevations were likely due to red blood cell hemolysis and enhanced production and turnover, particularly in patients with thalassemia. In preregistration clinical trials and subsequently with its more widespread use, luspatercept has not been linked to instances of clinically apparent liver injury.

Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

Mechanism of Injury

Luspatercept is a recombinant human protein and as such is unlikely to be intrinsically hepatotoxic. Blocking essential intracellular pathways of TGFβ ligands in the liver may lead to some degree of hepatic dysfunction and injury. Hypersensitivity reactions can occur with administration of luspatercept, which may be associated with mild liver enzyme elevations.

Outcome and Management

Luspatercept has been linked to mild-to-moderate serum enzyme elevations during therapy. Discontinuation for serum enzyme elevations is rarely necessary, but should be done if the elevations are accompanied by symptoms or jaundice or for persistent ALT elevations of more than 5 times the upper limit of normal (ULN). There is no information on cross sensitivity to liver injury between luspatercept and other growth factors or therapies for anemia.

Drug Class: Hematologic Agents

Other drugs for myelodysplastic syndromes: Azacitidine, Decitabine, Decitabine/Cedazuridine



Luspatercept – Reblozyl®


Hematologic Agents




References updated: 27 July 2023

Abbreviations used: MDS, myelodysplastic syndrome; sc, subcutaneously; TGFβ, transforming growth factor beta.

  • FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2020/761136Orig2s000MedR.pdf
    (FDA website including product label and multidiscipline review of data submitted in support of luspatercept approval includes discussion of hepatotoxicity, therapy being associated with increase in ALT elevations [9% vs 4% with placebo] and bilirubin [11% vs 3%], with several patients having concurrent elevations in both).
  • Platzbecker U, Germing U, Götze KS, Kiewe P, Mayer K, Chromik J, Radsak M, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017;18(10):1338-1347. [PubMed: 28870615]
    (Among 58 adults with myelodysplastic syndromes [MDS] treated with varying doses of luspatercept, doses of 0.75-1.75 mg/kg were associated with better responses in hemoglobin levels but also increases in adverse events of fatigue, bone pain and diarrhea; no mention of ALT elevations or hepatotoxicity).
  • Fenaux P, Kiladjian JJ, Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood. 2019;133:790-794. [PubMed: 30602619]
    (Review of the mechanism of action and rationale for use of luspatercept and other activin inhibitors in MDS where it blocks TGFβ signaling, which normally inhibits terminal erythroid differentiation; no mention of hepatotoxicity or effect on aminotransferase levels).
  • Markham A. Luspatercept: first approval. Drugs. 2020;80:85-90. [PubMed: 31939073]
    (Review of the mechanism of action, history of development, pharmacokinetics, clinical efficacy and safety of luspatercept shortly after its approval for use in beta thalassemia mentions side effects of bone pain [20% vs 8% in placebo controls], arthralgia [19% vs 12%], headaches [26% vs 24%], dizziness [11% vs 5%], nausea [9% vs 6%], and hypertension [8% vs 3%], with serious adverse events in 3.6% including cerebral vascular accidents and deep vein thrombosis; no mention of ALT elevations or hepatotoxicity).
  • Fenaux P, Platzbecker U, Mufti GJ, Garcia-Manero G, Buckstein R, Santini V, Díez-Campelo M, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382:140-151. [PubMed: 31914241]
    (Among 229 adults with MDS on transfusion therapy who were treated with luspatercept [1.0 to 1.75 mg/kg] vs placebo injections every 3 weeks for 48 weeks, transfusion independence for at least 8 weeks between weeks 1-24 was achieved by 38% vs 13%, while common adverse events included fatigue [27% vs 13%] diarrhea [22% vs 9%], asthenia [20% vs 12%], nausea [20% vs 9%], dizziness [20% vs 5%] and ALT elevations [5.9% vs 3.9%], which were above 5 times the ULN in 2% vs none, one leading to drug discontinuation).
  • Cappellini MD, Viprakasit V, Taher AT, Georgiev P, Kuo KHM, Coates T, Voskaridou E, et al.; BELIEVE Investigators. A phase 3 trial of luspatercept in patients with transfusion-dependent β-thalassemia. N Engl J Med. 2020;382:1219-1231. [PubMed: 32212518]
    (Among 336 adults with transfusion dependent beta thalassemia treated with luspatercept [1.0-1.25 mg/kg] or placebo injections every 3 weeks, transfusion burdens decreased by one-third in 21% of luspatercept- vs 4.5% of placebo-treated subjects, while adverse events included bone pain [20% vs 8%], arthralgia [19% vs 12%], dizziness [11% vs 5%], hypertension [8.1% vs 2.8%], uric acid elevations [7.2% vs none], and thromboembolic events [3.6% vs 0.9%]; no mention of ALT elevations or hepatotoxicity).
  • Taher AT, Musallam KM, Cappellini MD. β-Thalassemias. N Engl J Med. 2021;384:727-743. [PubMed: 33626255]
    (Review of the pathogenesis, clinical features, complications, management and therapy of beta thalassemia including the role of luspatercept, mentions the hepatic complications of transfusion therapy but not hepatotoxicity of luspatercept or other medical treatments).
  • Delgado J, Voltz C, Stain M, Balkowiec-Iskra E, Mueller B, Wernsperger J, Malinowska I, et al. The European Medicines Agency review of luspatercept for the treatment of adult patients with transfusion-dependent anemia caused by low-risk myelodysplastic syndromes with ring sideroblasts or beta-thalassemia. Hemasphere. 2021;5:e616. [PMC free article: PMC8288896] [PubMed: 34291195]
    (Summary of the review of luspatercept efficacy and safety supporting the European Medicines Agency’s approval of luspatercept for beta-thalassemia and MDS, mentions that total adverse event rates were similar among the 571 patients on luspatercept and the 193 on placebo [95% vs 91%], but that serious adverse events were more frequent [24% vs 15%] with luspatercept as were discontinuations [8.8% vs 3.6%]; no mention of ALT elevations or hepatotoxicity).
  • Santini V. Advances in myelodysplastic syndrome. Curr Opin Oncol. 2021;33:681-686. [PubMed: 34474438]
    (Review of the pathogenesis, clinical features, complications, diagnosis, cytogenetics, and therapy of MDS mentions the use of luspatercept as well as telomerase inhibitors and hypomethylating agents).
  • Schulz F, Nachtkamp K, Kasprzak A, Gattermann N, Haas R, Germing U. Luspatercept as a therapy for myelodysplastic syndromes with ring sideroblasts. Expert Rev Hematol. 2021;14:509-516. [PubMed: 34161752]
    (Review of the mechanism of action, clinical efficacy, side effects, and role of luspatercept in management of myelodysplastic syndromes with ring sideroblasts; does not discuss ALT elevations or hepatotoxicity).
  • Piga A, Longo F, Gamberini MR, Voskaridou E, Ricchi P, Caruso V, Pietrangelo A, et al. Long-term safety and erythroid response with luspatercept treatment in patients with β-thalassemia. Ther Adv Hematol. 2022;13:20406207221134404. [PMC free article: PMC9726852] [PubMed: 36505885]
    (Among 63 patients with beta thalassemia treated in a long term, open-label extension study of luspatercept [0.6-1.25 mg/kg sc every 3 weeks], increases in hemoglobin were sustained as were reductions in transfusion requirements, while safety was “acceptable”, 88% had an adverse event, 12.5% a severe adverse event, most commonly bone pain [42%], headache [31%], myalgia [22%], 1 case of biliary colic and 1 death [cardiac arrest], no mention of ALT elevations or hepatotoxicity).
  • Taher AT, Cappellini MD, Kattamis A, Voskaridou E, Perrotta S, Piga AG, Filosa A, et al.; BEYOND Investigators. Luspatercept for the treatment of anaemia in non-transfusion-dependent β-thalassaemia (BEYOND): a phase 2, randomised, double-blind, multicentre, placebo-controlled trial. Lancet Haematol. 2022;9:e733-e744. [PubMed: 36007538]
    (Among 145 patients with non-transfusion dependent beta-thalassemia treated with luspatercept [1.0 to 1.25 mg/kg sc every 3 weeks] vs placebo for at least one year, hemoglobin levels rose by 1.0 mg/dL or greater in a greater proportion of luspatercept vs placebo recipients [77% vs none], while serious adverse events were less frequent [11% vs 25%]; common adverse events of luspatercept include bone pain [37% vs 6%], headache [30% vs 20%] and arthralgia [29% vs 14%], while changes in ALT levels and hepatotoxicity were not mentioned ).
  • Sekeres MA, Taylor J. Diagnosis and treatment of myelodysplastic syndromes: a review. JAMA. 2022;328:872-880. [PubMed: 36066514]
    (Concise review of clinical features, natural history, diagnosis, and management of MDS; adverse events are listed in tables but without mention or discussion of ALT elevations or hepatotoxicity).
  • Platzbecker U, Götze KS, Kiewe P, Germing U, Mayer K, Radsak M, Wolff T, et al. Long-term efficacy and safety of luspatercept for anemia treatment in patients with lower-risk myelodysplastic syndromes: the phase II PACE-MDS Study. J Clin Oncol. 2022;40:3800-3807. [PMC free article: PMC9671752] [PubMed: 35998303]
    (Among 108 patients with lower-risk MDS treated with luspatercept for up to 5 years [median=1 year], 54% had a hematologic improvement while adverse events arose in 45% including fatigue, hypertension, diarrhea, headache and bone pain; no mention of ALT elevations or hepatotoxicity).
  • Platzbecker U, Della Porta MG, Santini V, Zeidan AM, Komrokji RS, Shortt J, Valcarcel D, 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. Lancet. 2023;402:373-385. [PubMed: 37311468]
    (Among 356 adults with low or intermediate risk MDS with transfusion dependence treated with either luspatercept [1-1.75 mg/kg] sc every 3 weeks or epoetin [450-1050 IU/kg] sc every week for at least 24 weeks, transfusion independence was achieved in 59% vs 31% and adverse events were frequent [92% vs 85%], often serious [38% vs 35%] and for luspatercept included fatigue, weakness, nausea, dyspnea, hypertension and headache; liver toxicity arose in 2% vs 3% but only one [on epoetin] was serious).
  • Lanino L, Restuccia F, Perego A, Ubezio M, Fattizzo B, Riva M, Consagra A, et al; Fondazione Italiana Sindromi Mielodisplastiche (FISiM) Clinical network. Real-world efficacy and safety of luspatercept and predictive factors of response in patients with lower risk myelodysplastic syndromes with ring sideroblasts. Am J Hematol. 2023;98:E204-E208. [PubMed: 37222267]
    (Among 201 adults with low or intermediate risk MDS with ring sideroblasts and transfusion dependence treated in an Italian observational, compassionate use protocol of luspatercept [1.0-1.75 mg/kg] for up to one year, transfusion independence was achieved in 39% of patients, while serious adverse events arose in 17% which were largely cardiac, infectious, and accidents; no mention of ALT elevations or hepatotoxicity).
  • Garcia-Manero G. Myelodysplastic syndromes: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98:1307-1325. [PubMed: 37288607]
    (Review of the classification of MDS and risk categorization with an update on management including discussion of hypomethylation agents and luspatercept; no mention of ALT elevations or hepatotoxicity).
  • Randall MP, DeZern AE. The management of low-risk myelodysplastic syndromes-current standards and recent advances. Cancer J. 2023;29:152-159. [PubMed: 37195771]
    (Review of treatment of low-risk MDS including erythropoietin, iron chelation, lenalidomide, luspatercept and low dose hypomethylating agents; no discussion of hepatotoxicity).