Luspatercept

Mechanism of Action

Luspatercept is a recombinant fusion protein consisting of the extracellular domain of activin receptor type IIB fusion protein and the Fc portion of human immunoglobulin G1 (IgG1). Luspatercept blocks the transforming growth factor-β (TGF-β) superfamily inhibitors to reduce SMAD2 and SMAD3 signaling. This action prevents the activation of TGF-β superfamily members and improves various deficiencies associated with ineffective erythropoiesis. Luspatercept also promotes erythroid maturation via differentiation and increases the percentage of late-stage erythroid precursors (normoblasts) in the bone marrow and erythroid precursors, thereby increasing erythropoiesis.[3][11][9]

Pharmacokinetics

Absorption: The median time to reach maximum concentration (Tmax) is approximately 5 days (range: 3 to 8 days) in adults with β-thalassemia and around 6 days (range: 3 to 7 days) in adults with MDS. The absorption of luspatercept is not significantly affected by the chosen injection site (eg, abdomen, upper arm vs thigh).

Distribution: The geometric mean (%CV) volume of distribution (Vd) of luspatercept-aamt is 7.1 L (26.7%) in patients with β-thalassemia and 9.6 L (26.7%) in patients with MDS.

Metabolism: The geometric mean (%CV) half-life (t_1/2) of luspatercept is approximately 11 days (25.7%) in patients with β-thalassemia and 14 days (31.7%) in patients with MDS. Luspatercept is thought to be metabolized into smaller peptides and amino acids through general catabolic processes occurring in various tissues.

Elimination: The geometric mean (%CV) total clearance (CL) of luspatercept is 0.44 L/day (38.5%) in patients with β-thalassemia and 0.47 L/day (42.9%) in patients with MDS.

Administration

Available Dosage Forms and Strengths

Luspatercept is available as 25 mg and 75 mg lyophilized powder in single-dose vials for reconstitution and injection. This powder is white or off-white in color and can only be reconstituted using sterile water. If the reconstituted solution is not used immediately, it may be stored in the original vial at room temperature of 20 to 25 °C (68 to 77 °F)  for up to 8 hours. After this time, any remaining medication should be discarded.

• For the 25 mg vial of luspatercept powder for injection, 0.68 mL of sterile water is required for reconstitution, resulting in 25 mg/0.5 mL.
• For the 75 mg vial of luspatercept powder for injection, 1.6 mL of sterile water is required for reconstitution, resulting in 75 mg/1.5 mL.

The patient's hemoglobin level should be obtained before administering luspatercept. The total volume required is based on the indication. Any volume of reconstituted luspatercept exceeding 1.2 mL should be divided equally into separate doses and administered at different sites. If multiple injections are necessary, a new syringe and needle are required for each.

Adult Dosage

Beta-Thalassemia

For patients with β-thalassemia, 1 mg/kg of luspatercept should be injected subcutaneously into the upper arm, thigh, or abdomen once every 3 weeks. The dose should be titrated based on the patient responses listed below (see Table 1).

• Predose testing: Before each dose, clinicians should assess the patient's hemoglobin level and transfusion history.
• Adverse reactions: Clinicians should refer to the guidelines regarding treatment interruptions.
• Discontinuation criteria: Luspatercept therapy should be discontinued if transfusion requirements have not changed by week 9 (maximum 3 daily doses) or unacceptable toxicity occurs at any point in treatment.

Table 1: Dose Titration

Myelodysplastic Syndromes Associated Anemia

For patients with MDS anemia, the recommended initial dose is 1 mg/kg, given subcutaneously once every 3 weeks. The dose should be titrated based on patient responses listed below (see Table 2). Dosage adjustments should not occur more frequently than every 6 weeks (2 doses) or beyond the maximum dose of 1.75 mg/kg. If the therapeutic response becomes inadequate after a dose reduction (ie, a transfusion is needed) or the hemoglobin concentration is reduced by ≥1 g/dL in 3 weeks without transfusion, the dose should be increased to the next level.

• Predose testing: Before each dose, clinicians should assess the patient's hemoglobin level and review the patient's transfusion history.
• Adverse reactions: Clinicians should refer to guidelines for treatment interruptions.
• Discontinuation criteria: Discontinue therapy if the patient fails to demonstrate a reduction in transfusion requirements by week 9 of treatment (3 doses at maximum dose) at the maximum dose level (1.75 mg/kg) or for any unacceptable toxicity at any point in treatment.

Table 2: Dose Titration

Specific Patient Population

Hepatic impairment: No clinically significant differences have been observed in patients with mild-to-severe hepatic impairment. The effect of luspatercept administered to patients with aspartate aminotransaminase or alanine transaminase levels >3x the upper normal limit is unknown. 

Renal impairment: No clinically significant differences were observed in patients with mild-to-moderate (eGFR 30 to 89 mL/min/1.73 m²). The effect of luspatercept administered to patients with severe renal impairment (eGFR <30 mL/min/1.73 m²).

Pregnancy considerations: Based on the results of animal reproduction studies, luspatercept may cause fetal harm. Current data regarding luspatercept administration to pregnant patients is insufficient to determine the presence or absence of drug-associated risk of major congenital disabilities, miscarriage, or adverse maternal or fetal outcomes.

Breastfeeding considerations: Luspatercept has been detected in the milk of lactating animals. There is no data on its presence in human milk or its effects on milk production or the breastfed child. Since there is a potential for serious adverse reactions in breastfed children, breastfeeding is not recommended during luspatercept therapy and for 3 months after the last administered dose.

Adverse Effects

The most common adverse effects of luspatercept include fatigue, headache, myalgia, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, hypertension, hyperuricemia, and hypersensitivity. Luspatercept is not a substitute for blood transfusions.

For patients experiencing Grade 3 or higher adverse drug reactions, modify treatment as described below. Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is a life-threatening adverse drug reaction. Bone pain, hyperuricemia, and hypertension are typically classified as Grade 3 or 4 reactions and may cause a decline in general health.[1]

Patients with β-thalassemia: 

• Grade 3 or 4 hypersensitivity reactions: Discontinue treatment
• Other Grade 3 or 4 adverse reactions: Suspend treatment and restart when the adverse reaction resolves to Grade 1
• Extramedullary hematopoietic (EMH) masses: Discontinue treatment

Patients with MDS:

• Grade 3 or 4 hypersensitivity reactions: Discontinue treatment
• Other Grade 3 or 4 adverse reactions: Suspend treatment and restart at the next lower dose when the adverse reaction resolves to Grade 1. Discontinue treatment if this delay lasts longer than 12 consecutive weeks.

Contraindications

No contraindications are directly associated with luspatercept at this time; it is a drug with a good safety profile. However, it is not intended to substitute for blood transfusions, especially during emergent scenarios.[5]

Stimulating erythropoiesis can cause hyperviscosity of the blood, hypertension, and an elevated risk of thromboembolic events. Therefore, pregnant women, hypertensive patients, women on oral contraceptive pills, and patients with underlying conditions that cause increased red blood cell counts should be offered alternative therapy.

Warnings and Precautions

• Thrombosis/thromboembolism
• Hypertension: Clinicians should assess blood pressure before each dose. Anti-hypertensive agents may be administered to manage new-onset hypertension or exacerbations of preexisting hypertension.
• Extramedullary hematopoietic masses
• Embryo-fetal toxicity: Clinicians must advise women who are pregnant (or may become pregnant) of the potential risk to a fetus. These patients should also receive contraception when taking luspatercept and for at least 3 months after therapy is discontinued.[11]

Monitoring

Clinicians should obtain hemoglobin, alanine transferase, and aspartate transferase levels before and during therapy to ensure proper medication dosing and metabolism.

Luspatercept can be detected in the human serum through ELISA and Western blotting screening. Previously, 10 μg of antibodies per sample were required, which determined the amount of serum needed during collection. Today, ELISA can be used as a fast screening tool using only 100 μL of serum; the limit of detection (LOD) is 15.6 ng/mL. This solution is provided using anti-antibody-coated magnetic beads to purify the antigen-antibody complex.

Additionally, western blotting can be used for initial investigation and confirmatory testing of luspatercept use in human serum. This process involves covalently stable antibodies on agarose beads, leading to immunoprecipitation of ACVR2B-antibody, followed by Sarcosyl-PAGE and western blotting.[9][10]

Toxicity

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 for patients with β-thalassemia and 1.75 mg/kg for patients with lower-risk MDS. The adverse effects commonly associated with luspatercept therapy have been discussed above. Discontinue luspatercept administration based on the grade and severity of these reactions.[11]

Enhancing Healthcare Team Outcomes

Managing the administration of luspatercept to patients with anemia from lower-risk myelodysplastic syndrome with ring sideroblasts and β-thalassemia requires an interprofessional team of nurses, laboratory technicians, pharmacists, researchers, and clinicians trained in different specialties. After diagnosis, prompt admission and adherence to therapy are fundamental to the effectiveness of drugs such as luspatercept. Improvement of anemia and reduced blood transfusion requirements are critical factors for favorable treatment outcomes. Common obstacles to success include limited clinical trials for treating anemia resulting from other conditions.

The emphasis on monitoring hemoglobin and transfusion requirements is critical. Clinicians must communicate openly, educate the patient, and monitor labs and treatment outcomes. The clinical pharmacist plays a vital role in medication consultation, verifying dosing parameters, and overseeing administration. During follow-up visits, the nursing team must verify hemoglobin levels by reviewing symptoms of anemia and lab results. Failure to comply with all aspects of administration and monitoring may result in detrimental effects on the patient's health. The interprofessional team must communicate, support, and monitor the patient to ensure the best chance for therapeutic success with minimal adverse events.