Luspatercept - Uses, Dosage, Side Effects, Drug Warnings, and Precautions

Overview:

The major cause of the clinical seriousness of beta-thalassemias has been ineffective erythropoiesis. Therefore for various years, the transfusion of red blood cells (RBCs) has been the standard form of management. The most common type of beta-thalassemia is related to faulty production of the beta-globin chains leading to an unbalanced ratio of alpha-globin to beta-globin. The free or unbound alpha-globin chains are precipitated in erythroid precursors that cause ineffective erythropoiesis (production of red blood cells), compensatory hemopoietic expansion, and chronic hemolytic anemia.

In 1980, the introduction of bone marrow transplantation helped to restore the capability of the cells to produce functional hemoglobin. Currently, gene therapy is being investigated where globin lentiviral vectors and genome editing can help to inhibit the BCL11A gene. However, these approaches have limitations as they require transplantation conditioning and can be used only in a small population of patients.

The United States Food and Drug Administration (FDA) approved Luspatercept in 2019 to treat anemia in adult patients with beta-thalassemia where regular red blood cells (RBC) transfusions are required. It is a recombinant fusion protein that helps in binding the transforming growth factor-beta ligands and reduces SMAD2 and SMAD3 signaling. Luspatercept belongs to the class of medications known as erythroid maturation agents. It acts by increasing the production and quality of red blood cells.

What Is Beta-Thalassemia?

Beta-thalassemia is a type of blood disorder that causes a decrease in the production of hemoglobin (an iron-containing protein present in the RBCs that carries oxygen to all the cells of the body).

Beta-thalassemia patients have low levels of hemoglobin and as a result, reduced oxygen supply throughout the body. Individuals with beta thalassemia are at high risk of developing abnormal blood clots. These patients have decreased blood cells that make the skin pale and cause weakness and fatigue.

Beta thalassemia can be classified, depending on the severity of symptoms, into the following two types:

• Thalassemia major (transfusion-dependent thalassemia or Cooley's anemia)

• Thalassemia intermedia (non-transfusion-dependent thalassemia).

Individuals with thalassemia major show signs and symptoms within the first two years of life and can become a life-threatening condition. The signs and symptoms include:

• Individuals do not grow at an expected rate.

• Jaundice (yellowing of skin and eyes).

• Enlarged spleen, heart, and liver.

• Distorted bone shape.

• Delayed puberty.

For Patients:

Why Is Luspatercept Prescribed?

Luspatercept is used in patients with beta-thalassemia that are receiving blood transfusions to manage anemia (a decreased red blood cell count).

Luspatercept can also be used to treat anemia to some types of myelodysplastic syndrome (a group of disorders due to poorly formed blood cells) in adults. It can also be used in those who are receiving blood transfusions and have not responded to treatment with an erythropoiesis-stimulating agent (ESA).

How Is Luspatercept Used?

Luspatercept is available in the form of a powder that is mixed with liquid to form an injectable solution. It is then injected subcutaneously. It is injected or administered by a doctor or nurse once in 3 weeks in a hospital or clinic.

The doctor might adjust the dosage of Luspatercept or delay or stop the treatment if the body does not respond well to the medication and if certain side effects are experienced. The patient must inform the doctor how they feel during the treatment with Luspatercept injection.

What Are the Warnings and Precautions For Luspatercept?

The following precautions must be taken before receiving Luspatercept:

1. Allergy: The patient must inform the doctor and pharmacist in case of any allergies to Luspatercept or any of the ingredients in Luspatercep injection. Ask the pharmacist for a list of the ingredients in the medication.

2. Drug History: Inform the doctor about the other prescription and nonprescription medications, nutritional supplements, vitamins, and herbal products they are taking or plan to take. The patient must inform the doctor of any of the following medications:

• Hormone replacement therapy (HRT).

• Oral contraceptives (birth control pills).

The doctor might need to change the dosage of the medications or monitor the patient carefully for side effects.

3. Medical History: Inform the doctor in case of the following conditions:

• Blood clots in the eyes, legs, or lungs; high blood pressure.

• Extramedullary hematopoietic masses (formation of blood cells outside of the bone marrow creating clumps of blood cells).

• An enlarged liver or spleen.

• If the spleen is removed.

4. Pregnancy: Inform the doctor if the patient is pregnant or plans to become pregnant. The patient might require a pregnancy test before initiating the treatment. The patient must not become pregnant while taking Luspatercept. The doctor advises effective birth control to prevent pregnancy during your treatment with Luspatercept and for three months after the final dose. Consult the doctor about birth control methods that are suitable for the patient. If the patient becomes pregnant while using Luspatercept injection, the doctor must be informed immediately because Luspatercept might be harmful to the fetus.

5. Breastfeeding: Inform the doctor if the patient is breastfeeding. It is not advised to breastfeed while using Luspatercept injection and for three months after the final dose.

6. Fertility: This medication might decrease fertility in women. The patient must consult the doctor about the risks of using Luspatercept injection.

What Special Dietary Instructions Should Be Followed?

The normal diet can be continued unless advised otherwise by the doctor.

What Should Be Done in Case of a Missed Dose?

If the appointment to receive an injection of Luspatercept is missed, the patient must call the healthcare provider immediately for rescheduling the appointment.

What Are the Side Effects of Luspatercept?

Luspatercept injection might lead to some side effects. Inform the doctor in case of the following side effects:

• Bone pain.

• Muscle or joint pain.

• Headache.

• Cough.

• Flu-like syndrome.

• Nausea.

• Diarrhea.

• Tiredness.

• Stomach pain.

• Pain, redness, or itching at the injection site.

Sometimes serious side effects might occur. The doctor must be informed immediately or get emergency medical treatment.

• Swelling of the hands, ankles, feet, or lower legs.

• Leg pain or feeling of warmth in the lower leg.

• Shortness of breath.

• Sudden chest pain.

• Trouble breathing.

• Hives.

• Rash.

• Difficulty walking.

• Confusion.

• Weakness or numbness of an arm or leg.

• Dizziness or faintness.

• Sudden, severe headache.

• Sudden changes in vision, like blurred vision or loss of vision.

• Trouble speaking.

• Sudden, severe back pain.

• Numbness of feet, legs, hands, or arms.

• Loss of bowel and bladder control.

Luspatercept injection may cause other side effects. Inform the doctor if there are any unusual problems while administration of this medication.

Other Important Information:

• All the appointments with the doctor and the laboratory must be maintained adequately.

• The doctor might suggest blood tests to evaluate the body's response to Luspatercept before every injection.

• The blood pressure of the patient should be monitored regularly.

• It is essential for the patient to keep a written list of all of the prescribed and nonprescribed (over-the-counter) medications that the patient is taking.

• The doctor must carry the list for every visit to the doctor or if admitted to a hospital in case of any emergencies.

For Doctors:

Indications

Luspatercept is approved by the Food and Drug Administration and indicated for the treatment of anemia in patients who require regular red blood cell transfusions in beta-thalassemia.

Other indications include:

• In patients who have no erythropoietin-stimulating agents (ESA).

• In patients with lower-risk myelodysplastic syndrome.

Luspatercept acts as an erythroid maturation agent that significantly increases the ability of the cells to manage anemia. Patients with myelodysplastic syndrome (MDS) who have SF3B1 mutation present a homogeneous disease phenotype. This leads to erythroid dysplasia in granulocytic or megakaryocytic lineages indicating that SF3B1 mutation specifies the distinct part of myelodysplastic syndrome (MDS).

The recommended dosage for Luspatercept administration is 1 milligram/kilogram subcutaneously once in three weeks for beta-thalassemia patients. Based on the results of the phase III BELIEVE trial, FDA approved subcutaneous administration of Luspatercept in the United States to treat anemia associated with beta-thalassemia. It helps to promote late-stage erythropoiesis in patients with failed treatments with erythropoiesis-stimulating agents in beta-thalassemia. Luspatercept is not indicated for use as a substitute for red blood cell transfusions in patients requiring rapid management of anemia.

Pharmacology:

The inhibitors of late-stage erythropoiesis include members of the TGF-beta superfamily ligands like

• TGF-beta.

• Activins.

• Growth differentiation factors (GDFs).

• Bone morphogenetic proteins.

Luspatercept was designed to compete with the extracellular sites of activin receptor type 2A or 2B, and act as ligand traps for TGF-β–like molecules. Further studies revealed that Luspatercept has the ability to reduce Smad-2/3 signaling; hence helps improve anemia in disorders characterized by ineffective erythropoiesis, like beta-thalassemiaand myelodysplastic syndromes (MDS). Luspatercept demonstrated an increase in red blood cell (RBC) count, hemoglobin levels, and hematocrit in a dose-dependent manner.

Various studies conducted on mouse models of anemia associated with ineffective erythropoiesis documented that Smad-2/3 and GDF-11 inhibition helps to improve anemia and restore normal erythropoietic differentiation.

Therefore it was believed that GDF-11 could be the target of Luspatercept. But in 2019, Guerra and colleagues reported that GDF-11 is not the only target of Luspatercept. Further, Martinez et al published a study documenting that Luspatercept increases erythroid differentiation in murine beta-thalassemia by increasing GATA-1 availability. They also found a greater nuclear localization of pSmad-2/3 and Smad-4 with a reduced nuclear localization and expression of GATA-1 and TIF-1 by utilizing differentiating murine erythroleukemia cells and GDF-11–induced Smad-2/3 pathway overactivation. In addition, Luspatercept helped to increase the TIF1- gama nuclear localization and the GATA-1 expression.

Another consistent study has proved that Smad-2/3 signaling pathway overactivation negatively regulates terminal erythroid differentiation in mouse models of beta-thalassemia by reducing GATA-1 expression. Luspatercept-mediated inhibition of Smad-2/3 signaling increases erythroid maturation by enhancing the expression and functional availability of GATA-1. It is well established that GATA-1 is absolutely necessary for erythroid maturation.

Mechanism of Action:

Luspatercept is a type of fusion protein composed of the following:

• The extracellular domain of activin receptor (type IIB fusion protein).

• The Fc-part of human immunoglobulin G1 (IgG1).

Luspatercept acts by blocking the transforming growth factor-beta (TGF-beta) superfamily inhibitors and decreases SMAD2 and SMAD3 signaling. This activity is helpful in preventing the activation of a variety of TGF-beta superfamily members and causes ineffective erythropoiesis in the late stage.

What Are the Administration Guidelines for Luspatercept?

The recommended dose of Luspatercept is 1 milligram/kilogram once every three weeks. It is administered by subcutaneous injection into the upper arm, thigh, or abdomen in patients with beta-thalassemia. The hemoglobin results must be assessed and reviewed before every administration of Luspatercept.

The patient's red blood cell (RBC) transfusion reduction burden is not seen with the two consecutive dosages of Luspatercept injection at the 1 milligram/kilogram initial dose. The dose is increased to 1.25 milligrams/kilogram might be more therapeutic.

The dose of Luspatercept should remain below the dose of 1.25 milligrams/kilogram for the treatment of beta-thalassemia and below 1.75 milligrams/kilogram in lower-risk MDS treatment.

Adverse Effects:

The most common adverse effects of Luspatercept are:

• Fatigue.

• Headache.

• Myalgia.

• Arthralgia.

• Dizziness or vertigo.

• Nausea.

• Cough.

• Diarrhea.

• Abdominal pain.

• Dyspnea.

• Hypertension.

• Hyperuricemia.

• Hypersensitivity.

Luspatercept doping can also occur as the medicine leads to an increase in erythropoiesis and the formation of red blood cells. Luspatercept has a long half-life, therefore the drug can be detected in the human serum through enzyme-linked immunosorbent assay (ELISA) screening and western blotting in the future.

What Are the Contraindications of Luspatercept?

Luspatercept is an efficient and safe drug and no contraindications are associated with it. However, it cannot be used as a replacement for an immediate necessity of blood transfusion. The medication has limited contraindications, increased erythropoiesis can lead to hyperviscosity of the blood that can cause hypertension and thromboembolic events.

The following conditions that can lead to increased red blood cell count must be evaluated for other treatment options:

• Pregnant women.

• Hypertensive patients.

• Women on oral contraceptive pills.

Monitoring:

The following tests must be performed before administration of Luspatercept to ensure adequate dosing and metabolism of the medication.

• Hemoglobin levels.

• Liver function tests include alanine transferase and aspartate transferase levels.

Toxicity:

The toxicity of Luspatercept does not pose any serious concern due to the long half-life of Luspatercept. The dosage of the medicine must be monitored according to hemoglobin levels and must not be exceeded 1.25 milligrams/kilogram in beta-thalassemia treatment and 1.75 milligrams/kilogram in treating lower-risk MDS for avoiding toxicity. Toxicity to Luspatercep can lead to adverse events, including:

• General physical health deterioration.

• Bone pain.

• Fatigue.

• Diarrhea.

• Asthenia.

• Nausea.

• Dizziness.