Luspatercept-aamt (Monograph)

Brand name: Reblozyl
Drug class: Hematopoietic Agents

Medically reviewed by Drugs.com on May 10, 2024. Written by ASHP.

Introduction

Erythroid maturation agent; recombinant fusion protein.

Uses for Luspatercept-aamt

Beta Thalassemia

Treatment of anemia in adults with beta thalassemia who require regular RBC transfusions; designated an orphan drug by FDA for this indication.

Not indicated for use as a substitute for RBC transfusions in patients who need immediate anemia correction.

Thalassemia International Federation guideline states that luspatercept can be considered for adults who require regular RBC transfusions; however, data on its long-term use, real life application, and use in the pediatric population are lacking.

Myelodysplastic Syndromes Associated Anemia

Treatment of anemia in adults without previous erythropoiesis stimulating agent (ESA) use with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular RBC tranfusions. Designated an orphan drug by FDA for treatment of MDS.

Not indicated for use as a substitute for RBC transfusions in patients who need immediate anemia correction.

Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia

Treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adults with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis; designated an orphan drug by FDA for treatment of MDS.

Not indicated for use as a substitute for RBC transfusions in patients who need immediate anemia correction.

Luspatercept-aamt Dosage and Administration

General

Pretreatment Screening

Assess and review hemoglobin and transfusion history prior to each dose. If a RBC transfusion occurred prior to the dose, use pretransfusion hemoglobin to evaluate dose.
Verify pregnancy status for females of reproductive potential before starting luspatercept-aamt.
Monitor BP prior to each administration.

Patient Monitoring

Monitor BP during treatment.
Monitor for signs and symptoms of thromboembolism.
Monitor patients with beta thalassemia for signs and symptoms of extramedullary hematopoietic (EMH) masses at therapy initiation and during treatment.

Premedication and Prophylaxis

Consider thromboprophylaxis in patients with beta thalassemia at increased risk of thromboembolic events.

Administration

Administer via sub-Q injection into upper arm, thigh, and/or abdomen by a healthcare professional.

Available as a lyophilized powder that must be reconstituted prior to use.

Calculate exact total dosing volume of 50 mg/mL solution required for patient. Divide doses requiring larger reconstituted volumes (i.e., >1.2 mL) into separate similar volume injections and inject into separate sites. If multiple injections required, use new syringe and needle for each sub-Q injection.

Discard any unused portion. Do not pool unused portions from vials. Do not administer more than 1 dose from a vial. Do not mix with other medications.

If a dose is delayed or missed, administer as soon as possible and continue therapy as prescribed, with at least 3 weeks between doses.

Reconstitution

Reconstitute the number of luspatercept-aamt vials necessary to achieve appropriate dose based on patient weight.

Use a syringe with suitable graduations for reconstitution to ensure dosage accuracy.

Reconstitute with Sterile Water for Injection, USP, using volumes described in Table 1; direct fluid for reconstitution onto lyophilized powder. Discard needle and syringe used for reconstitution.

Allow to stand for 1 minute. Gently swirl vial in a circular motion for 30 seconds. Stop swirling and let vial sit in an upright position for 30 seconds. If undissolved powder is observed, repeat prior step until powder is completely dissolved.

Invert vial and gently swirl in an inverted position for 30 seconds. Bring vial back to upright position, and let it sit for 30 seconds. Repeat this step 7 more times to ensure complete reconstitution of material on sides of vial.

Table 1. Luspatercept-aamt Reconstitution Volumes.1
Vial Size	Required Sterile Water for Injection (mL) for Reconstitution	Final Concentration	Deliverable Volume (mL)
25 mg	0.68	25 mg/0.5 mL	0.5
75 mg	1.6	75 mg/1.5 mL	1.5

Dosage

Adults

Beta Thalassemia

Sub-Q

Recommended initial dosage: 1 mg/kg once every 3 weeks. Dosage may be titrated based on response as noted in Table 2. Discontinue therapy if a patient does not experience a reduction in transfusion burden after 9 weeks of treatment at the maximum dose level (1.25 mg/kg) or if unacceptable toxicity occurs.

Table 2. Luspatercept Dose Titration - Beta Thalassemia.1
	Dosing Recommendation
Dose Increases for Insufficient Response at Treatment Initiation
No reduction in RBC transfusion burder after at least 2 consecutive doses (6 weeks) at the initial starting dose	Increase dose to 1.25 mg/kg every 3 weeks
No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25 mg/kg	Discontinue therapy
Dose Modifications for Predose Hemoglobin Levels or Rapid Hemoglobin Rise
Predose hemoglobin ≥11.5 g/dL in the absence of transfusions	Interrupt therapy and restart when hemoglobin is no more than 11 g/dL
Increase in hemoglobin >2 g/dL within 3 weeks in the absence of tranfusions	Modify dose as recommended: If current dose is 1.25 mg/kg, reduce to 1 mg/kg If current dose is 1 mg/kg, reduce to 0.8 mg/kg If current dose is 0.8 mg/kg, reduce to 0.6 mg/kg If current dose is 0.6 mg/kg, discontinue therapy

Do not increase the dose if the patient is experiencing an adverse reaction as described in Table 4.

Myelodysplastic Syndrome (MDS) Associated Anemia

Sub-Q

Recommended initial dosage: 1 mg/kg once every 3 weeks. Dosage may be titrated based on response as noted in Table 3.

Discontinue therapy if a patient does not experience a reduction in transfusion burden, including no increase from baseline hemoglobin, after 9 weeks of treatment at the maximum dose level (1.75 mg/kg) or if unacceptable toxicity occurs.

If upon dose reduction (see Table 3), the patient loses response or hemoglobin concentration drops by ≥1 g/dL in 3 weeks in the absence of transfusion, increase dose by one dose level. Wait a minimum of 6 weeks between dose increases.

Table 3. Luspatercept Dose Titration - MDS Associated Anemia.1
	Dosing Recommendation
Dose Increases for Insufficient Response at Treatment Initiation
Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose	Increase dose to 1.33 mg/kg every 3 weeks
Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1.33 mg/kg dose	Increase dose to 1.75 mg/kg every 3 weeks
No reduction in RBC transfusion burden including no increase from baseline hemoglobin after at least 3 consecutive doses (9 weeks) at 1.75 mg/kg	Discontinue therapy
Dose Modifications for Predose Hemoglobin Levels or Rapid Hemoglobin Rise
Predose hemoglobin ≥11.5 g/dL in the absence of transfusions	Interrupt therapy and restart when hemoglobin is no more than 11 g/dL
Increase in hemoglobin >2 g/dL within 3 weeks in the absence of tranfusions	Modify dose as recommended: If current dose is 1.75 mg/kg, reduce to 1.33 mg/kg If current dose is 1.33 mg/kg, reduce to 1 mg/kg If current dose is 1 mg/kg, reduce to 0.8 mg/kg If current dose is 0.8 mg/kg. reduce to 0.6 mg/kg If current dose is 0.6 mg/kg, discontinue therapy

Do not increase the dose if the patient is experiencing an adverse reaction as described in Table 5.

Dosage Modifications for Toxicity

Interrupt treatment for adverse reactions as described in Table 4 (beta thalassemia) and Table 5 (MDS associated anemia).

Table 4. Dosing Modification for Adverse Reactions - Beta Thalassemia.1
Adverse Reaction	Dosing Recommendation
Grade 3 or 4 hypersensitivity reactions	Discontinue therapy
Other grade 3 or 4 adverse reactions	Interrrupt therapy and restart when adverse reaction resolves to no more than grade 1
EMH masses causing serious complications	Discontinue therapy

Table 5. Dosing Modification for Adverse Reactions - MDS Associated Anemia.1
Adverse Reaction	Dosing Recommendation
Grade 3 or 4 hypersensitivity reactions	Discontinue therapy
Other grade 3 or 4 adverse reactions	Interrupt therapy and restart treatment at next lower dose level (see Table 3) when the adverse reaction resolves to no more than grade 1 If dose delay is >12 consecutive weeks, discontinue therapy

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Luspatercept-aamt

Contraindications

None.

Warnings/Precautions

Thrombosis/Thromboembolism

In adults with beta thalassemia, thromboembolic events (TEEs) reported including DVT, PE, portal vein thrombosis, and ischemic strokes.

Patients with known risk factors for thromboembolism (e.g., splenectomy or concomitant use of hormone replacement therapy) may be at increased risk of thromboembolic conditions.

Consider thromboprophylaxis in patients with beta thalassemia at increased risk of TEEs.

Monitor for signs and symptoms of TEEs and institute treatment promptly.

Hypertension

Hypertension reported.

Monitor BP prior to each dose administration. Treat new-onset hypertension or exacerbations of preexisting hypertension with anti-hypertensive therapy.

Extramedullary Hematopoietic Mass

Extramedullary hematopoietic (EMH) masses with spinal cord compression symptoms reported. Possible risk factors for EMH mass development in patients with beta thalassemia include history of EMH masses, splenectomy, splenomegaly, hepatomegaly, or low baseline hemoglobin (<8.5 g/dL).

Monitor patients with beta thalassemia for signs, symptoms, or complications related to EMH masses at therapy initiation and during treatment. Treat according to clinical guidelines and discontinue luspatercept-aamt if serious complications due to EMH masses arise.

Avoid use in patients requiring treatment to control EMH mass growth.

Embryo-fetal Toxicity

Based on animal findingss, may cause fetal harm.

Advise pregnant women of the potential fetal risk. Advise females of reproductive potential to use an effective method of contraception during treatment and for at least 3 months after the final dose.

Immunogenicity

Anti-luspatercept-aamt antibodies, including neutralizing antibodies, reported in patients with beta thalassemia and patients with MDS. Most antibodies were of low titers.

No severe acute hypersensitivity reactions reported and no association between hypersensitivity type or injection site reaction and presence of these antibodies.

No apparent effect of anti-drug antibodies on clinical response observed.

Specific Populations

Pregnancy

No available data on luspatercept-aamt use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. May cause fetal harm based on animal reproduction studies.

Lactation

No data on presence of luspatercept-aamt in human milk, the effects on the breastfed child, or the effects on milk production. Luspatercept-aamt was detected in milk of lactating rats. When a drug is present in animal milk, it is likely present in human milk.

Do not breastfeed during treatment and for 3 months after the last dose.

Females and Males of Reproductive Potential

Prior to initiating luspatercept-aamt, verify pregnancy status in females of reproductive potential. Administration during pregnancy may cause embryo-fetal harm.

Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months following the last dose.

Findings from animal studies reveal that luspatercept-aamt may impair female fertility, however, this effect was reversible.

Pediatric Use

Safety and efficacy not established; based on findings in juvenile animals, luspatercept-aamt not recommended for use in pediatric patients.

Geriatric Use

In clinical studies in beta thalassemia, insufficient number of patients ≥65 years of age to determine a difference in response from younger patients.

No differences in efficacy or safety were noted between patients ≥65 years of age and younger patients with MDS.

Hepatic Impairment

No clinically significant differences in pharmacokinetics in patients with mild to severe hepatic impairment (total bilirubin ≤ULN and AST or ALT > ULN, or total bilirubin >ULN and any AST or ALT). Effect of AST or ALT >3 times ULN on pharmacokinetics unknown.

Renal Impairment

No clinically significant differences in pharmacokinetics were found in patients with mild to moderate renal impairment (eGFR 30 to 89 mL/minute). Impact of severe renal impairment (eGFR <30 mL/minute) on pharmacokinetics is unknown.

Common Adverse Effects

Most common (>10%) adverse reactions: fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, COVID-19, peripheral edema, hypertension, hypersensitivity.

Drug Interactions

No clinically significant differences in luspatercept-aamt pharmacokinetics were observed when used concomitantly with iron-chelating agents.

Luspatercept-aamt Pharmacokinetics

Absorption

Absorbed with a median time to peak concentration of 5 (3 to 8) days post-dose in adults with beta thalassemia or 6 (3 to 7) days post-dose in patients with MDS.

Absorption not affected by sub-Q injection site (upper arm, thigh, or abdomen).

Elimination

Metabolism

Expected to be catabolized into small peptides and amino acids via catabolic degradation processes in multiple tissues.

Half-life

Geometric mean half-life was approximately 11 days in patients with beta thalassemia and 14 days in patients with MDS.

Stability

Storage

Parenteral

Injection, for sub-Q use

Store vials at 2-8°C in original carton; protect from light. Do not freeze.

If reconstituted solution is not used immediately, may store at 20-25°C in original vial for up to 8 hours. Discard if not used within 8 hours of reconstitution.

Alternatively, reconstituted solution may be stored under refrigeration (2-8°C) for up to 24 hours in the original vial. Remove from refrigerated condition 15-30 minutes prior to injection to allow solution to reach room temperature. Discard if not used within 24 hours of reconstitution.

Do not freeze reconstituted solution.

Actions

Recombinant fusion protein that binds endogenous TGF-β superfamily ligands and reduces Smad2/3 signaling.
Promotes erythroid maturation through differentiation and increased erythropoiesis in mice and humans.

Advice to Patients

Advise patients with beta thalassemia of the potential risk of thromboembolic events, review potential risk factors, and recommend reducing modifiable risk factors for developing thromboembolic events (e.g. smoking, use of oral contraceptives).
Caution patients about possible blood pressure increases during therapy.
Advise patients with beta thalassemia of the potential risk of developing extramedullary hematopoietic masses, review risk factors, and instruct patients to report signs and symptoms.
Advise females of reproductive potential to inform clinicians if they are or plan to become pregnant or plan to breastfeed. Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months following the last dose. Advise against breastfeeding during treatment and for 3 months after the last dose.
Advise patients to notify their clinician about current or planned therapies, including prescription and OTC drugs, dietary and herbal supplements, and illnesses.
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Luspatercept-aamt can be obtained through designated specialty pharmacies and distributors. Contact manufacturer for specific availability information.