Earn CME/CE in your profession:

Continuing Education Activity

Luspatercept is a medication used to manage and treat anemia in myelodysplastic syndromes, primary myelofibrosis, and beta-thalassemia. It is a recombinant fusion protein that binds transforming growth factor-beta ligands to reduce SMAD2 and SMAD3 signaling. This activity describes the indications, actions, and contraindications for luspatercept as a valuable agent in the management when applicable for interprofessional team members.


  • Summarize the indications for luspatercept in the management of anemia due to myelodysplastic syndromes, primary myelofibrosis, and beta-thalassemia.
  • Review the importance of luspatercept in reducing requirements for blood transfusions and iron overload and the risk factors for using blood transfusions and iron overload.
  • Outline the typical presentation of a patient with anemia due to lower-risk myelodysplastic syndrome, beta-thalassemia, and primary myelofibrosis with blood transfusions.
  • Identify the importance of improving care coordination amongst the interprofessional team to enhance care delivery for patients with anemia due to myelodysplastic syndrome, primary myelofibrosis, and beta-thalassemia patients who are undergoing blood transfusions.


Luspatercept is an FDA-approved drug indicated to be used to treat anemia in patients who need regular red blood cell transfusions in beta-thalassemia.[1] It is also indicated for use in patients who fail erythropoietin stimulating agents (ESA) and have lower risk myelodysplastic syndrome with ring sideroblasts.

The ringed sideroblastic phenotype subgroup of patients has higher response rates.[2] Refractory anemia with ring sideroblasts (RARS) and iron overload are complications and are managed similarly to lower-risk myelodysplastic syndrome and myeloproliferative neoplasm. Luspatercept, an erythroid maturation agent, will tremendously increase the ability to manage anemia. Patients with myelodysplastic syndrome (MDS) with the SF3B1 mutation show a homogeneous disease phenotype in which they have an erythroid dysplasia in granulocytic or megakaryocytic lineages signifying that SF3B1 mutation specifies the distinct portion of MDS.[3][4][5]

The recommendation for luspatercept administration is 1mg/kg subcutaneously once every three weeks for patients with beta-thalassemia.[6][7] FDA approved subcutaneous luspatercept in the USA to treat anemia associated with beta-thalassemia, based on the results of the phase III BELIEVE trial.[8] This medication promotes late-stage erythropoiesis even in patients who have failed treatments with erythropoiesis-stimulating agents in beta-thalassemia.

Luspatercept is not meant for use as a substitute for red blood cell transfusions in patients who need rapid correction of anemia.

Mechanism of Action

Luspatercept is a fusion protein consisting of the extracellular domain of activin receptor type IIB fusion protein and the Fc-part of human immunoglobulin G1 (IgG1). Luspatercept blocks the transforming growth factor-beta (TGF-beta) superfamily inhibitors to reduce SMAD2 and SMAD3 signaling. This activity prevents the activation of a variety of TGF-beta superfamily members involved, leading to ineffective erythropoiesis in the late stage.[9][10][7]  

Another example of a similar drug is sotatercept. These medications fall under erythropoietin modulating agents that help increase effective erythropoietin, which is lacking in conditions like lower-risk MDS, beta-thalassemia, and primary myelofibrosis. 


Before administrating luspatercept, assess and review hemoglobin results before each administration. Luspatercept is recommended at 1 mg/kg once every three weeks by subcutaneous injection into the upper arm, thigh, or abdomen for patients with beta-thalassemia. 

If the patient's RBC transfusion reduction burden is not met with the two consecutive doses of luspatercept injection at the 1 mg/kg starting dose, increasing the dose to 1.25 mg/kg may be more therapeutic. However, luspatercept dosing should remain below the dose of 1.25 mg/kg in beta-thalassemia treatment and below 1.75 mg/kg in lower-risk MDS treatment. A patient who is not receiving transfusion therapy and demonstrates more than 2 g/dl of hemoglobin levels within three weeks should reduce the dose of luspatercept.[11]

Adverse Effects

The most common adverse effects of luspatercept are fatigue, headache, myalgia, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, hypertension, hyperuricemia, and hypersensitivity. Luspatercept is not a substitute for blood transfusions in the medically necessary. The bone pain, hyperuricemia, and hypertension side effects tend to be the grade 3 or 4 reactions and can lead to a generalized decline of physical health.[1]

Luspatercept doping is also a concern that may occur as the medication increases erythropoiesis and the formation of red blood cells. However, due to the long half-life of luspatercept, the ELISA screening and western blotting can be used to detect drugs in the human serum in the future. In a more recent study, the use of ammonium sulfate precipitate, immunoaffinity purification, tryptic digestion, and liquid chromatography-tandem mass spectrometry (LC-MS) developed an assay for the combination of sotatercept and luspatercept testing in doping control human serum samples. This assay is optimal and is a better application to use for sports drug testing.[10][12] 


No contraindications are directly associated with luspatercept at this time; it an efficient drug with a good safety profile. However, it is not recommended as a replacement for an immediate necessity of blood transfusion.[2] 

Although the medication itself has limited contraindications, stimulating erythropoiesis can lead to hyperviscosity of the blood leading to thromboembolic events and hypertension. Therefore, pregnant women, hypertensive patients, women on oral contraceptive pills, and patients with underlying blood conditions that can cause increased red blood cell count should be consulted with and given other options to achieve treatment success.


Before administration of luspatercept, hemoglobin levels, liver function tests include alanine transferase, and aspartate transferase levels should have monitoring to ensure proper dosing and metabolism of the medication. 

Luspatercept can be detected in the human serum through screening with ELISA and Western blotting. Initially, the serum needed to perform the testing was an increased sample of antibodies requiring 10 μg per sample. However, now ELISA can be used as a fast screening tool with 100 μL of serum; the limit of detection (LOD) is 15.6 ng/mL.

More recent guidelines overcame this obstacle by creating a solution in which the antigen-antibody complex can assist in procuring the complex by undergoing purification and separation of the complex using the anti-antibody-coated magnetic beads. Western blotting uses covalently stable antibodies on agarose beads, leading to immunoprecipitation of ACVR2B-antibody, followed by Sarcosyl-PAGE and western blotting. Western blotting can be used for initial investigation and confirmatory testing of luspatercept use in human serum.[10][12]


Due to the long half-life of luspatercept, toxicity is not of significant concern. Dosing should be monitored according to hemoglobin levels and should not exceed 1.25 mg/kg in the treatment of beta-thalassemia and 1.75mg/kg in treating lower-risk MDS to avoid toxicity. The main concerns are adverse events, including bone pain, fatigue, diarrhea, asthenia, nausea, and dizziness, as well as general physical health deterioration.[9]

Enhancing Healthcare Team Outcomes

Managing the administration of luspatercept to patients with anemia from lower-risk myelodysplastic syndrome with ring sideroblasts and beta-thalassemia requires an interprofessional team of healthcare professionals that includes nurses, laboratory technicians, pharmacists, researchers, and several clinicians trained in different specialties. After diagnosis, prompt admission into medical and adherence/retention in that care is fundamental to the administration of effective erythropoietin stimulating agent therapy, like luspatercept. Improvement of anemia and less blood transfusion requirement is the top factor of favorable treatment outcomes. Common obstacles to successful results are limited clinical trials in treating anemia resulting from other conditions.

The emphasis on monitoring hemoglobin and transfusion requirements is important. Clinicians such as primary care doctors, hematologists, nursing staff, and clinical pharmacists must all engage in open communication, educate the patient, and monitor labs and treatment outcomes. For instance, if a patient undergoing treatment of beta-thalassemia has not achieved a reduction in transfusion burden by two doses of luspatercept, the clinicians should increase the dose to no more than 1.25mg/kg. Just like in the treatment of lower-risk MDS, the dose should not exceed 1.75mg/kg. The patient should also be monitored for another two consecutive doses to ensure the transfusion burden has decreased. The clinical pharmacist is also a valuable professional needed for medication consultation and verifying dosing parameters and administration. On follow-up visits, the nurse team must verify hemoglobin levels and do so by asking about signs and symptoms of anemia and lab results. Failure to comply with all aspects of administration and monitoring can lead to detrimental effects on patient's health.

The interprofessional team must communicate, support, and monitor the patient to ensure the best chance for therapeutic success with the fewest adverse events. [Level5]

Article Details

Article Author

Bina Patel

Article Editor:

Leila Moosavi


7/12/2022 1:02:06 AM



Platzbecker U,Germing U,Götze KS,Kiewe P,Mayer K,Chromik J,Radsak M,Wolff T,Zhang X,Laadem A,Sherman ML,Attie KM,Giagounidis A, 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. The Lancet. Oncology. 2017 Oct;     [PubMed PMID: 28870615]


Kubasch AS,Platzbecker U, Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes. International journal of molecular sciences. 2019 Aug 7;     [PubMed PMID: 31394818]


Patnaik MM,Tefferi A, Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis:     [PubMed PMID: 30618061]


Arlet JB,Guillem F,Lamarque M,Dussiot M,Maciel T,Moura I,Hermine O,Courtois G, Protein-based therapeutic for anemia caused by dyserythropoiesis. Expert review of proteomics. 2016 Nov;     [PubMed PMID: 27661264]


Malcovati L,Cazzola M, Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts. British journal of haematology. 2016 Sep;     [PubMed PMID: 27391606]


Piga A,Perrotta S,Gamberini MR,Voskaridou E,Melpignano A,Filosa A,Caruso V,Pietrangelo A,Longo F,Tartaglione I,Borgna-Pignatti C,Zhang X,Laadem A,Sherman ML,Attie KM, Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. 2019 Mar 21;     [PubMed PMID: 30617198]


Komrokji RS, Luspatercept in Myelodysplastic Syndromes: Who and When? Hematology/oncology clinics of North America. 2020 Apr;     [PubMed PMID: 32089218]


Markham A, Luspatercept: First Approval. Drugs. 2020 Jan;     [PubMed PMID: 31939073]


Fenaux P,Platzbecker U,Mufti GJ,Garcia-Manero G,Buckstein R,Santini V,Díez-Campelo M,Finelli C,Cazzola M,Ilhan O,Sekeres MA,Falantes JF,Arrizabalaga B,Salvi F,Giai V,Vyas P,Bowen D,Selleslag D,DeZern AE,Jurcic JG,Germing U,Götze KS,Quesnel B,Beyne-Rauzy O,Cluzeau T,Voso MT,Mazure D,Vellenga E,Greenberg PL,Hellström-Lindberg E,Zeidan AM,Adès L,Verma A,Savona MR,Laadem A,Benzohra A,Zhang J,Rampersad A,Dunshee DR,Linde PG,Sherman ML,Komrokji RS,List AF, Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. The New England journal of medicine. 2020 Jan 9;     [PubMed PMID: 31914241]


Reichel C,Gmeiner G,Thevis M, Antibody-based strategies for the detection of Luspatercept (ACE-536) in human serum. Drug testing and analysis. 2017 Nov;     [PubMed PMID: 28929587]


Cappellini MD,Viprakasit V,Taher AT,Georgiev P,Kuo KHM,Coates T,Voskaridou E,Liew HK,Pazgal-Kobrowski I,Forni GL,Perrotta S,Khelif A,Lal A,Kattamis A,Vlachaki E,Origa R,Aydinok Y,Bejaoui M,Ho PJ,Chew LP,Bee PC,Lim SM,Lu MY,Tantiworawit A,Ganeva P,Gercheva L,Shah F,Neufeld EJ,Thompson A,Laadem A,Shetty JK,Zou J,Zhang J,Miteva D,Zinger T,Linde PG,Sherman ML,Hermine O,Porter J,Piga A, A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia. The New England journal of medicine. 2020 Mar 26;     [PubMed PMID: 32212518]


Walpurgis K,Thomas A,Lange T,Reichel C,Geyer H,Thevis M, Combined detection of the ActRII-Fc fusion proteins Sotatercept (ActRIIA-Fc) and Luspatercept (modified ActRIIB-Fc) in serum by means of immunoaffinity purification, tryptic digestion, and LC-MS/MS. Drug testing and analysis. 2018 Nov;     [PubMed PMID: 30285318]