Luspatercept-aamt – Uses, Dosage, Side Effects, Interaction

Luspatercept is an erythroid maturation agent used to treat anemia secondary to beta-thalassemia in patients requiring regular red blood cell transfusions. Luspatercept is a recombinant fusion protein comprised of a modified extracellular domain of activin receptor type IIB fused to the FC domain of human IgG1.[rx,rx] It was first approved for use in the United States in November 2019 under the brand name Reblozyl® for the treatment of anemia in patients with beta-thalassemia who require regular blood transfusions.[rx] Luspatercept is novel in that it ameliorates anemia via action on late-stage erythropoiesis, in contrast to typical erythropoiesis-stimulating agents (ESAs), such as darbepoetin alfa and epoetin alfa, which act only on early-stage erythropoiesis.[rx] Luspatercept’s novel mechanism of action, then, is uniquely suited for the treatment of conditions in which late-stage erythropoiesis is defective, such as beta-thalassemia and other myelodysplastic diseases.[rx,rx]

Mechanism of action

Beta thalassemia is a genetic red blood cell disorder caused by mutations in the β-globin gene – these mutations cause oxidative stress and premature apoptosis of erythroblasts, thereby leading to ineffective erythropoiesis.[rx] The transforming growth factor beta (TGF-β) superfamily of endogenous ligands (including activins, growth differentiation factors, and bone morphogenetic proteins) are involved in the inhibition of erythroid differentiation via activation of the Smad2/3 subfamily of intracellular effectors.[rx,rx,rx]

Luspatercept is a fusion protein comprising a modified extracellular domain of activin receptor type IIB (a target for many TGF-β ligands) fused to the FC domain of human IgG1. Luspatercept ameliorates ineffective erythropoiesis in patients with beta-thalassemia by acting as a “ligand trap” for various members of the TGF-β superfamily, preventing their downstream signaling and subsequent inhibition of late-stage erythroid maturation. The specific members of the TGF-β superfamily targeted by luspatercept are currently unknown, though growth differentiation factor 11 (GDF11) has been experimentally excluded as a potential target.[rx]

Luspatercept binds to, and inhibits, several ligands that act as negative regulators of late-stage erythropoiesis, thereby alleviating the ineffective erythropoiesis observed in patients with beta-thalassemia.[rx,rx] Thromboembolic events (e.g. deep vein thrombosis, pulmonary embolism, ischemic stroke) have been reported in patients with beta-thalassemia receiving luspatercept – patients with a greater baseline risk of thromboembolism may benefit from concomitant thromboprophylaxis while undergoing therapy with luspatercept.[rx] Luspatercept may carry some degree of embryo-fetal toxicity and should therefore be avoided in pregnancy. Women of childbearing age should use an effective form of contraception during therapy and for 3 months after completion of therapy.[rx] Luspatercept may also lead to the development of extramedullary hematopoietic (EMH) masses in adult patients with transfusion-dependent beta-thalassemia.[rx]

Indications

  • Luspatercept is indicated for the treatment of anemia in adults with beta-thalassemia who require regular red blood cell transfusions.[rx]
  • Anemia
  • Luspatercept is indicated for the treatment of adults with transfusion-dependent anemia due to very low, low, and intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts, who had an unsatisfactory response to or are ineligible for erythropoietin-based therapy.[rx]
  • Luspatercept is indicated for the treatment of adults with transfusion-dependent anemia associated with beta-thalassemia.[rx]
  • Treatment of anemia in beta-thalassemia patients who require regular red blood cell 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. 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. 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.
  • The recommendation for luspatercept administration is 1mg/kg subcutaneously once every three weeks for patients with beta-thalassemia. FDA approved subcutaneous luspatercept in the USA to treat anemia associated with beta-thalassemia, based on the results of the phase III BELIEVE trial. 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.
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Use in Cancer

Luspatercept-aamt is approved to treat:

Luspatercept-aamt is also being studied in the treatment of other conditions.

Contraindications

  • 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.
  • 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.
  • high blood pressure
  • obstruction of a blood vessel by a blood clot
  • a blood clot
  • past history of complete removal of the spleen
  • pregnancy
  • a patient who is producing milk and breastfeeding

Dosage

Strengths: aamt 25 mg; aamt 75 mg

Anemia

  • Initial dose: 1 mg/kg subcutaneously once every 3 weeks
  • If no reduction in red blood cell transfusions after 2 doses (6 weeks), increase to 1.25 mg/kg.
  • Maximum dose: 1.25 mg/kg
  • This drug is not a substitute for red blood cell transfusions in the immediate correction of anemia.
  • Assess and review hemoglobin (Hgb) prior to each administration; if a red blood cell transfusion occurred prior to dosing, use pretransfusion Hgb for dosing purposes.
  • If pre-dose Hgb is 11.5 g/dL or higher (not related to recent transfusion), delay dose until Hgb is 11 g/dL or less.
  • If treatment response is lost, search for causative factors (e.g. bleeding event); if typical causes are excluded, increase dose to 1.25 mg.
  • Discontinue therapy if no decrease in transfusions is seen after 9 weeks (3 doses) at the maximum dose or unacceptable toxicity occurs (at any time).

Thalassemia

  • Initial dose: 1 mg/kg subcutaneously once every 3 weeks
  • If no reduction in red blood cell transfusions after 2 doses (6 weeks), increase to 1.25 mg/kg.
  • Maximum dose: 1.25 mg/kg
  • This drug is not a substitute for red blood cell transfusions in the immediate correction of anemia.
  • Assess and review hemoglobin (Hgb) prior to each administration; if a red blood cell transfusion occurred prior to dosing, use pretransfusion Hgb for dosing purposes.
  • If pre-dose Hgb is 11.5 g/dL or higher (not related to recent transfusion), delay dose until Hgb is 11 g/dL or less.
  • If treatment response is lost, search for causative factors (e.g. bleeding event); if typical causes are excluded, increase dose to 1.25 mg.
  • Discontinue therapy if no decrease in transfusions is seen after 9 weeks (3 doses) at the maximum dose or unacceptable toxicity occurs (at any time).
  • Treatment of anemia in beta thalassemia patients who require regular red blood cell transfusions

Administration advice:

  • For subcutaneous administration only into the upper arm, thigh, and/or abdomen.
  • Missed/delayed doses: administer as soon as possible and continue dosing as prescribed, with at least 3 weeks between doses.
  • Assess and review hemoglobin (Hgb) prior to each administration; if a red blood cell transfusion occurred prior to dosing, use pretransfusion Hgb for dosing purposes.
  • If pre-dose Hgb is 11.5 g/dL or higher (not related to recent transfusion), delay dose until Hgb is 11 g/dL or less.
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Side Effects

The Most Common

  • muscle or joint pain
  • bone pain
  • headache
  • flu-like syndrome
  • cough
  • diarrhea
  • nausea
  • stomach pain
  • tiredness
  • pain, redness, or itching at the injection site
  • leg pain or feeling of warmth in the lower leg
  • swelling of the hands, feet, ankles, or lower legs
  • sudden chest pain
  • shortness of breath
  • trouble breathing
  • rash
  • hives
  • weakness or numbness of an arm or leg
  • difficulty walking
  • sudden, severe headache
  • confusion
  • dizziness or faintness
  • sudden changes in vision, such as loss of vision or blurred vision
  • trouble speaking
  • sudden, severe back pain; numbness, weakness or trouble moving feet, legs, hands or arms; or loss of bowel and bladder control

More common

  • Blurred vision
  • bone pain
  • dizziness
  • headache
  • nervousness
  • pounding in the ears
  • slow or fast heartbeat
  • Body aches or pain
  • chills
  • cough
  • diarrhea
  • difficulty in moving
  • ear congestion
  • general feeling of discomfort or illness
  • loss of appetite
  • loss of voice
  • lower back, side, or stomach pain
  • muscle pain or stiffness
  • nausea or vomiting
  • runny or stuffy nose
  • shivering
  • sneezing
  • sore throat
  • stomach pain
  • sweating
  • trouble sleeping
  • unusual tiredness or weakness

Rare

  • Chest pain or tightness
  • fever
  • hives, itching, or skin rash
  • hoarseness
  • inability to speak
  • irritation
  • joint pain, stiffness, or swelling
  • lightheadedness or fainting
  • loss of bowel or bladder control
  • numbness, weakness, or loss of voluntary movement in the feet, legs, hands, or arms
  • pain, redness, or swelling in the arm or leg
  • redness of the skin
  • seizures
  • severe back pain
  • severe or sudden headache
  • slurred speech
  • swelling of the eyelids, face, lips, hands, or feet
  • temporary blindness
  • trouble breathing or swallowing
  • weakness in the arm or leg on one side of the body, sudden and severe
  • Bleeding, blistering, burning, coldness, discoloration of skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
  • feeling of constant movement of self or surroundings
  • sensation of spinning

Drug Interaction

  • efgartigimod alfa
  • renal/liver
  • thromboembolism
  • Luspatercept – hypertension

Pregnancy and Lactation

US FDA pregnancy category: Not assigned

Pregnancy

Based on findings in animal reproduction studies, REBLOZYL may cause fetal harm when administered to a pregnant woman. There are no available data on REBLOZYL use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal
or fetal outcomes. In animal reproduction studies, administration of luspatercept-aamt to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, alterations to growth, and structural abnormalities at exposures (based on area under the curve [AUC]) above those occurring at the maximum recommended human dose (MRHD) (see Data). Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

Luspatercept-aamt was detected in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. There are no data on the presence of REBLOZYL in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with REBLOZYL, and for 3 months after the last dose.

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Why is this medication prescribed?

Luspatercept-aamt injection is used to treat anemia (a lower than normal number of red blood cells) in adults who are receiving blood transfusions to treat thalassemia (an inherited condition that causes a low number of red blood cells). Luspatercept-aamt injection is also used to treat anemia in adults with certain types of myelodysplastic syndrome (a group of conditions in which the bone marrow produces blood cells that are misshapen and does not produce enough healthy blood cells) and who are receiving blood transfusions, but have not responded to or cannot receive treatment with an erythropoiesis-stimulating agent (ESA). Luspatercept-aamt is in a class of medications called erythroid maturation agents. It works by increasing the number and quality of red blood cells.

How should this medicine be used?

Luspatercept-aamt injection comes as a powder to be mixed with liquid and injected subcutaneously (just under the skin). It is usually injected once every 3 weeks by a doctor or nurse in a medical office or clinic.

Your doctor may need to adjust your dose of luspatercept-aamt injection or delay or stop your treatment depending on how well your body responds to the medication and if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with luspatercept-aamt injection. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient.

What special precautions should I follow?

Before receiving luspatercept-aamt,

  • tell your doctor and pharmacist if you are allergic to luspatercept-aamt, any other medications, or any of the ingredients in luspatercep-aamt injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: hormone replacement therapy (HRT) or oral contraceptives (birth control pills). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you smoke or if you have or have ever had blood clots in your legs, lungs, or eyes; high blood pressure; extramedullary hematopoietic masses (formation of blood cells outside of the bone marrow that create clumps of developing blood cells in other areas of your body); an enlarged liver or spleen; or if you have had your spleen removed.
  • tell your doctor if you are pregnant or plan to become pregnant. You may need to have a pregnancy test before starting treatment. You should not become pregnant while you are taking luspatercept-aamt. You should use effective birth control to prevent pregnancy during your treatment with luspatercept-aamt and for at least 3 months after your final dose. Talk to your doctor about birth control methods that will work for you. If you become pregnant while using luspatercept-aamt injection, call your doctor immediately. Luspatercept-aamt may harm the fetus.
  • tell your doctor if you are breastfeeding. Do not breastfeed while you are using luspatercept-aamt injection and for 3 months after your final dose.
  • you should know that this medication may decrease fertility in women. Talk to your doctor about the risks of using luspatercept-aamt injection.

References