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 have 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) that have 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 for the treatment of 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.
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, which leads 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 one time 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. In a patient who is not receiving transfusion therapy and demonstrates more than 2 g/dl of hemoglobin levels within three weeks, should have a reduction of the dose of luspatercept.[11]
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 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, as well as 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 that will lead to immunoprecipitation of ACVR2B-antibody, followed by Sarcosyl-PAGE and western blotting. Western blotting can be used for initial investigation as well as 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 like bone pain, fatigue, diarrhea, asthenia, nausea, and dizziness as well as general physical health deterioration.[9]
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 physicians 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 are important. Clinicians such as primary care doctors, and hematologists, nursing staff, and clinical pharmacists must share in the effort to communicate, educate the patient, 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 also should be monitored for another two consecutive doses and 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 should do so by asking about signs and symptoms of anemia as well as 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.
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