Coverage Policy Manual
Policy #: 2020006
Category: Pharmacy
Initiated: March 2020
Last Review: June 2023
  Luspatercept-aamt (e.g., Reblozyl)
Description:
Luspatercept-aamt, (previously called ACE 536) is a novel recombinant fusion protein containing a modified activin receptor type IIB (ActRIIB, ACVR2B) that acts as a ligand trap to block inhibitors of late-stage erythropoiesis.  In this manner, luspatercept functions as an erythroid maturation agent to restore RBC production and meliorate anemia.  It is indicated for the treatment of anemia in adult individuals with beta thalassemia who require regular blood transfusions.  
 
Beta thalassemia is an inherited hemoglobinopathy in which one or both beta globin chains is impaired.  The clinical manifestations of beta thalassemia include hemolytic anemia and impaired iron handling, the severity of which depends on the degree of impairment of in the beta globin production.
 
Beta thalassemia major, (also called Cooley’s anemia, Mediterranean anemia, transfusion-dependent thalassemia) is the most severe form of beta thalassemia where there is no beta globin chain production and little to no HbA.   This is caused by homozygosity or compound heterozygosity for beta0 thalassemia mutations, or in rare cases, beta+ thalassemia mutations with extremely low production of beta globin chains.   The other major cause is compound heterozygosity for hemoglobin E (i.e., HbE/beta thalassemia), a beta+ thalassemia mutation.
 
Beta thalassemia intermedia (Non-transfusion–dependent beta thalassemia) is a less severe phenotype than beta thalassemia major.  Individuals tend to have anemia, but are not transfusion dependent during early childhood.  The typical age of presentation is 2 to 4 years of age.  The phenotype for this thalassemia may be caused by homozygosity or compound heterozygosity for a beta+ thalassemia mutation or by heterozygosity for beta0 thalassemia mutation.  Individuals may have a range of presentations, from chronic hemolytic anemia who are not transfusion dependent during early childhood but may become transfusion dependent to those with mild to moderate anemia who rarely or never require transfusions.  
 
Myelodysplastic Syndromes
Myelodysplastic syndromes (MDS) are bone marrow disorders that are predominately seen in the elderly and characterized by ineffective hematopoiesis, progressive cytopenias and risk of progression to acute myeloid leukemia.  Lower-risk MDS most commonly manifests with symptomatic anemia.  A higher proportion of individuals with lower-risk MDS may eventually become dependent on RBC transfusions.
 
Regulatory Status
 
Luspatercept-aamt (e.g., Reblozyl®) was approved by the FDA November 8, 2019 for adult individuals with beta thalassemia who require regular blood transfusions.
 
Luspatercept-aamt (e.g., Reblozyl®) was approved by the FDA April 3, 2020 for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell units over 8 weeks in adult individuals with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.
 
On June 3, 2022, Bristol Myers Squibb (BMS) announced that it has withdrawn its Supplemental Biologics License Application (sBLA), as the company could not address the FDA’s questions about the benefit-risk profile of Reblozyl (luspatercept-aamt) for the treatment of anemia in adults with non-transfusion dependent (NTD) beta thalassemia based on the current dataset from the Phase 2 BEYOND trial, which evaluated Reblozyl plus best supportive care in 145 adults with the disease.
 
Coding
 
See CPT/HCPCS Code section below.
 
Policy/
Coverage:
Effective June 1,2020, Prior Approval is required for Luspatercept-aamt (e.g., Reblozyl®).
 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.  
 
Effective June 8, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of luspatercept-aamt for the treatment of anemia in individuals with beta thalassemia who require regular RBC transfusions (transfusion-dependent) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following are met:
 
    1. The individual is > 18 years of age AND 
    2. Has a diagnosis of beta thalassemia or hemoglobin E beta (E/β)-thalassemia; AND
    3. Required regular red blood cell transfusion, at initiation, defined as both of the following (Cappellini 2020):
a. Has received 6-20 RBC units in the last 24 weeks and
b. Had no transfusion –free period greater than 35 days in the last 24 weeks.
4. Has a baseline hemoglobin (Hgb) level less than or equal to 11 gm/dl.
5. Initial coverage is for 3 months. Concurrent review will require documentation of clinical improvement
 
The use of luspatercept-aamt for the treatment of Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia meets primary coverage criteria that there be scientific evidence of effectiveness in improving outcomes when ALL the following are met:
 
    1. The individual is > 18 years of age.
    2. Have diagnosis of myelodysplastic syndrome with ring sideroblasts (WHO, 2016; NCCN 2A), [i.e., with either ≥15% ring sideroblasts or ≥5% ring sideroblasts if an SF3B1 mutation was present and with <5 bone marrow blasts] AND
a. Had disease that was defined according to the IPSS-R as being of very low, low, or intermediate risk (NCCN 2A);
b. Had been receiving regular red cell transfusions (≥2 units per 8 weeks during the 16 weeks before randomization); and had disease that was refractory to or was unlikely to respond to erythropoiesis-stimulating agents (owing to an endogenous erythropoietin level of >200 U per liter in those who had not previously been treated with erythropoiesis-stimulating agents) or had discontinued such agents owing to an adverse event. (Fenaux, 2020)
c. With serum erythropoietin >500 mU/mL (NCCN 2A)
d. With serum erythropoietin <500 mU/mL following no response to the combination of an ESA and G-CSF.  (NCCN 2A)
3. Initial coverage will be for 3 months.  
4. Concurrent review will require documentation of clinical improvement
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
Beta Thalassemia
    • Starting dose is 1 mg/kg subcutaneously once every 3 weeks
   
 Increase for insufficient response at initiation of treatment
    • No reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at 1 mg/kg – increase dose to 1.25mg/kg every 3 weeks
    • No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25mg/kg – Discontinue treatment.
 
Predose Hgb levels or Rapid Hgb Rise
    • Predose hemoglobin is > 11.5 g/dL in the absence of transfusions- Interrupt treatment, restart when the hgb is no more than 11 g/dL
    • Increase in hgb is > 2 g/dL within 3 weeks in the absence of transfusions and
        • Current dose is 1.25 mg/kg – Reduce dose to 1 mg/kg
        • Current dose is 1 mg/kg – Reduce dose to 0.8 mg/kg
        • Current dose is 0.8 mg/kg – Reduce dose to 0.6 mg/kg
        • Current dose is 0.6 mg/kg – Discontinue treatment
 
MDS-RS and MDS/MPN-RS-T Associated Anemia
    • Starting dose is 1 mg/kg subcutaneously once every 3 weeks   
 
Increase for insufficient response at initiation of treatment
    • Not RBC transfusion free after at least 2 consecutive doses (6 weeks) at 1 mg/kg – increase dose to 1.33mg/kg every 3 weeks
    • Not RBC transfusion free after at least 2 consecutive doses (6 weeks) at 1.133mg/kg – Increase dose to 1.75 mg/kg every 3 weeks
    • No reduction in RBC transfusion burden after at least 3 consecutive doses (9 weeks) at 1.75 mg/kg – Discontinue treatment
  
Predose Hgb levels or Rapid Hgb Rise
    • Predose hemoglobin is > 11.5 g/dL in the absence of transfusions- Interrupt treatment, restart when the hgb is no more than 11 g/dL
    • Increase in hgb is > 2 g/dL within 3 weeks in the absence of transfusions and
        • Current dose is 1.75 mg/kg – Reduce dose to 1.33 mg/kg
        • Current dose is 1.33 mg/kg – Reduce dose to 1 mg/kg
        • Current dose is 1 mg/kg – Reduce dose to 0.8 mg/kg
        • Current dose is 0.8 mg/kg – Reduce dose to 0.6 mg/kg
        • Current dose is 0.6 mg/kg – Discontinue treatment
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of luspatercept-aamt does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of any indication other than those described above, including the following:
 
1. Individual has a diagnosis of alpha (α)-thalassemia: OR
2. Individual has a diagnosis of non-transfusion dependent beta-thalassemia, OR
3. Individual has a platelet count greater than 1000 X 109/L OR
4. If the individual has a history of deep vein thrombosis (DVT) or stroke within the last 24 weeks; OR
5. The use beyond 9 weeks of treatment (i.e., administration of 3 doses) in the absence of response (defined as decrease in transfusion burden from baseline) at maximum dose level (i.e.,1.25 mg/kg every 3 weeks.
6. Is used with any other treatment agents such as ESA’s, Hypomethylating agents (i.e., azacitidine, decitabine); Immunomodulary (i.e., Lenalidomide), or IDH Inhibitors.
 
For members with contracts without primary coverage criteria, the use of luspatercept-aamt is considered investigational for the treatment of any indication or circumstance other than those described above, including the following:
 
1. Individual has a diagnosis of alpha (α)-thalassemia: OR
2. Individual has a platelet count greater than 1000 X 109/L OR
3. If the individual has a history of deep vein thrombosis (DVT) or stroke within the last 24 weeks; OR
4. The use beyond 9 weeks of treatment (i.e., administration of 3 doses) in the absence of response (defined as decrease in transfusion burden from baseline) at maximum dose level (i.e.,1.25 mg/kg every 3 weeks.
5. Is used with any other treatment agents such as ESA’s, Hypomethylating agents (i.e., azacitidine, decitabine); Immunomodulary (i.e., Lenalidomide), or IDH Inhibitors.
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective January 2022 to June 7, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of luspatercept-aamt (Reblozyl®) for the treatment of anemia in patients with beta thalassemia who require regular RBC transfusions meets primary coverage criteria when ALL the following are met:
 
  1. The individual is > 18 yrs of age and
  2. Has a diagnosis of beta thalassemia or hemoglobin E beta (E/β)-thalassemia; AND
  3. Required regular red blood cell transfusion, at initiation, defined as both of the following (Cappellini 2020):
    • Has received 6-20 RBC units in the last 24 weeks and
    • Had no transfusion –free period greater than 35 days in the last 24 weeks.
4. Has a baseline hemoglobin (Hgb) level less than or equal to 11 gm/dl.
5. Initial coverage is for 3 months. Concurrent review will require documentation of clinical improvement
 
The use of luspatercept-aamt (Reblozyl®) for the treatment of Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplatic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia meets primary coverage criteria when ALL the following are met:
 
  1. The individual is > 18 yrs of age.
  2. Have diagnosis of myelodysplastic syndrome with ring sideroblasts (WHO, 2016; NCCN 2A), [i.e., with either ≥15% ring sideroblasts or ≥5% ring sideroblasts if an SF3B1 mutation was present and with <5 bone marrow blasts] and
    • had disease that was defined according to the IPSS-R as being of very low, low, or intermediate risk (NCCN 2A);
    • had been receiving regular red cell transfusions (≥2 units per 8 weeks during the 16 weeks before randomization); and had disease that was refractory to or was unlikely to respond to erythropoiesis-stimulating agents (owing to an endogenous erythropoietin level of >200 U per liter in those who had not previously been treated with erythropoiesis-stimulating agents) or had discontinued such agents owing to an adverse event. (Fenaux, 2020)
    • with serum erythropoietin >500 mU/mL (NCCN 2A)
    • with serum erythropoietin <500 mU/mL following no response to the combination of an ESA and G-CSF.  (NCCN 2A)
3. Initial coverage will be for 3 months.  
4. Concurrent review will require documentation of clinical improvement
 
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
Beta Thalassemia
    • Starting dose is 1 mg/kg subcutaneously once every 3 weeks
   
  Increase for insufficient response at initiation of treatment
    • No reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at 1 mg/kg – increase dose to 1.25mg/kg every 3 weeks
    • No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25mg/kg – Discontinue treatment.
 
  Predose Hgb levels or Rapid Hgb Rise
    • Predose hemoglobin is > 11.5 g/dL in the absence of transfusions- Interrupt treatment, restart when the hgb is no more than 11 g/dL
    • Increase in hgb is > 2 g/dL within 3 weeks in the absence of transfusions and
        • Current dose is 1.25 mg/kg – Reduce dose to 1 mg/kg
        • Current dose is 1 mg/kg – Reduce dose to 0.8 mg/kg
        • Current dose is 0.8 mg/kg – Reduce dose to 0.6 mg/kg
        • Current dose is 0.6 mg/kg – Discontinue treatment
MDS-RS and MDS/MPN-RS-T Associated Anemia
    • Starting dose is 1 mg/kg subcutaneously once every 3 weeks   
 
  Increase for insufficient response at initiation of treatment
    • Not RBC transfusion free after at least 2 consecutive doses (6 weeks) at 1 mg/kg – increase dose to 1.33mg/kg every 3 weeks
    • Not RBC transfusion free after at least 2 consecutive doses (6 weeks) at 1.133mg/kg – Increase dose to 1.75 mg/kg every 3 weeks
    • No reduction in RBC transfusion burden after at least 3 consecutive doses (9 weeks) at 1.75 mg/kg – Discontinue treatment
  Predose Hgb levels or Rapid Hgb Rise
    • Predose hemoglobin is > 11.5 g/dL in the absence of transfusions- Interrupt treatment, restart when the hgb is no more than 11 g/dL
    • Increase in hgb is > 2 g/dL within 3 weeks in the absence of transfusions and
        • Current dose is 1.75 mg/kg – Reduce dose to 1.33 mg/kg
        • Current dose is 1.33 mg/kg – Reduce dose to 1 mg/kg
        • Current dose is 1 mg/kg – Reduce dose to 0.8 mg/kg
        • Current dose is 0.8 mg/kg – Reduce dose to 0.6 mg/kg
        • Current dose is 0.6 mg/kg – Discontinue treatment
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of luspatercept-aamt (Reblozyl®) does not meet primary coverage criteria for the treatment of any indication other than those described above, including the following:
 
    • Individual has a diagnosis of alpha (α)-thalassemia: OR
    • Individual has a platelet count greater than 1000 X 109/L OR
    • If the individual has a history of deep vein thrombosis (DVT) or stroke within the last 24 weeks; OR
    • The use beyond 9 weeks of treatment (I.e. administration of 3 doses) in the absence of response (defined as decrease in transfusion burden from baseline) at maximum dose level (i.e.,1.25 mg/kg every 3 weeks.
    • Is used with any other treatment agents such as ESA’s, Hypomethylating agents (i.e. azaxitidine, decitabine); Immunomodulary (i.e. Lenalidomide), or IDH Inhibitors.
 
For members with contracts without primary coverage criteria, the use of luspatercept-aamt (Reblozyl®) is considered investigational for the treatment of any indication other than those described above, including the following:
 
    • Individual has a diagnosis of alpha (α)-thalassemia: OR
    • Individual has a platelet count greater than 1000 X 109/L OR
    • If the individual has a history of deep vein thrombosis (DVT) or stroke within the last 24 weeks; OR
    • The use beyond 9 weeks of treatment (I.e. administration of 3 doses) in the absence of response (defined as decrease in transfusion burden from baseline) at maximum dose level (i.e.,1.25 mg/kg every 3 weeks.
    • Is used with any other treatment agents such as ESA’s, Hypomethylating agents (i.e. azaxitidine, decitabine); Immunomodulary (i.e. Lenalidomide), or IDH Inhibitors.
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective June  1, 2020 through December 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of luspatercept-aamt (Reblozyl®) for the treatment of anemia in patients with beta thalassemia who require regular RBC transfusions meets primary coverage criteria when ALL of the following are met:
  1. The individual is > 18 yrs of age and
  2. Has a diagnosis of beta thalassemia or hemoglobin E beta (E/β)-thalassemia; AND
  3. Required regular red blood cell transfusion, at initiation, defined as both of the following:
      • Has received 6-20 RBC units in the last 24 weeks and
      • Had no transfusion –free period greater than 35 days in the last 24 weeks.
4. Has a baseline hemoglobin (Hgb) level less than or equal to 11 gm/dl.
5. Initial coverage is for 3 months. Concurrent review will require documentation of clinical improvement
 
 
The use of luspatercept-aamt (Reblozyl®) for the treatment of Myelodysplastic Syndromes with Ring Sideroblasts or Myelodysplatic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis Associated Anemia meets primary coverage criteria when ALL of the following are met:
 
  1. The individual is > 18 yrs of age.
  2. Have diagnosis of myelodysplastic syndrome with ring sideroblasts according to WHO criteria,    (i.e., with either ≥15% ring sideroblasts or ≥5% ring sideroblasts if an SF3B1 mutation was present and with <5 bone marrow blasts) and
    • had disease that was defined according to the IPSS-R as being of very low, low, or intermediate risk;
    • had been receiving regular red cell transfusions (≥2 units per 8 weeks during the 16 weeks before  randomization); and had disease that was refractory to or was unlikely to respond to erythropoiesis-stimulating agents (owing to an endogenous erythropoietin level of >200 U per liter in those who had not previously been treated with  erythropoiesis-stimulating agents) or had discontinued such agents owing to an adverse event.
3. Initial coverage will be for 3 months.  
4. Concurrent review will require documentation of clinical improvement
5. The use of luspatercept does not meet primary coverage criteria with any other treatment agents such as ESA’s, Hypomethylating agents (i.e. azaxitidine, decitabine); Immunomodulary (i.e. Lenalidomide), or IDH Inhibitors.
 
NCCN 1 and 2A recommendations are covered in accordance with Coverage Policy #2000030
 
Dosage and Administration
 
Beta Thalassemia
  • Starting dose is 1 mg/kg subcutaneously once every 3 weeks
   
  Increase for insufficient response at initiation of treatment
  • No reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at 1 mg/kg – increase dose to 1.25mg/kg every 3 weeks
  • No reduction in RBC transfusion burden after 3 consecutive doses (9 weeks) at 1.25mg/kg – Discontinue treatment.
 
  Predose Hgb levels or Rapid Hgb Rise
  • Predose hemoglobin is > 11.5 g/dL in the absence of transfusions- Interrupt treatment, restart when the hgb is no more than 11 g/dL
  • Increase in hgb is > 2 g/dL within 3 weeks in the absence of transfusions and
    • Current dose is 1.25 mg/kg – Reduce dose to 1 mg/kg
    • Current dose is 1 mg/kg – Reduce dose to 0.8 mg/kg
    • Current dose is 0.8 mg/kg – Reduce dose to 0.6 mg/kg
    • Current dose is 0.6 mg/kg – Discontinue treatment
 
MDS-RS and MDS/MPN-RS-T Associated Anemia
  • Starting dose is 1 mg/kg subcutaneously once every 3 weeks  
 
  Increase for insufficient response at initiation of treatment
  • Not RBC transfusion free after at least 2 consecutive doses (6 weeks) at 1 mg/kg – increase dose to 1.33mg/kg every 3 weeks
  • Not RBC transfusion free after at least 2 consecutive doses (6 weeks) at 1.133mg/kg – Increase dose to 1.75 mg/kg every 3 weeks
  • No reduction in RBC transfusion burden after at least 3 consecutive doses (9 weeks) at 1.75 mg/kg – Discontinue treatment
 
  Predose Hgb levels or Rapid Hgb Rise
  • Predose hemoglobin is > 11.5 g/dL in the absence of transfusions- Interrupt treatment, restart when the hgb is no more than 11 g/dL
  • Increase in hgb is > 2 g/dL within 3 weeks in the absence of transfusions and
    • Current dose is 1.75 mg/kg – Reduce dose to 1.33 mg/kg
    • Current dose is 1.33 mg/kg – Reduce dose to 1 mg/kg
    • Current dose is 1 mg/kg – Reduce dose to 0.8 mg/kg
    • Current dose is 0.8 mg/kg – Reduce dose to 0.6 mg/kg
    • Current dose is 0.6 mg/kg – Discontinue treatment
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of luspatercept-aamt (Reblozyl®) for the treatment of anything other than the indications above including the following indications does not meet primary coverage criteria:
    • Individual has a diagnosis of alpha (α)-thalassemia: OR
    • Individual has a platelet count greater than 1000 X 109/L OR
    • History of deep vein thrombosis (DVT) or stroke within the last 24 weeks; OR
    • The use beyond 9 weeks of treatment (I.e. administration of 3 doses) in the absence of response (defined as decrease in transfusion burden from baseline) at maximum dose level (i.e.,1.25 mg/kg every 3 weeks
 
For members with contracts without primary coverage criteria, the use of luspatercept-aamt (Reblozyl®) is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Rationale:
Beta Thalassemia
The efficacy and safety of luspatercept was assessed in a randomized, multicenter, double-blind, placebo-controlled, multicenter trial (BELIEVE trial) of 336 adult patients with beta thalassemia (including Hemoglobin E/beta thalassemia and beta thalassemia with mutation and/or multiplication of alpha globin) requiring regular RBC transfusions (6-20 RBC units per 24 weeks) with no transfusion-free period greater than 35 days during the 24-week period (BELIEVE trial;
NCT02604433). Patients were randomized 2:1 to receive luspatercept (n=224) or placebo (n=112) subcutaneously once every 3 weeks as long as a reduction in transfusion requirement was observed or until unacceptable toxicity. All patients within the trial were permitted to receive best supportive care, including RBC transfusions; iron-chelating agents; antibiotic, antiviral, and antifungal therapy; and/or nutritional support, as needed. Patients with hemoglobin S/beta thalassemia or alpha thalassemia, or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency) were excluded from the trial. Other exclusion criteria included patients with recent deep vein thrombosis or stroke, or recent use of ESAs, immunosuppressants, or hydroxyurea therapy. The primary efficacy endpoint was based on the proportion of patients
achieving a reduction in RBC transfusion burden (≥33% reduction from baseline) with at least a 2-unit reduction from week 13 to week 24. Luspatercept compared with placebo significantly increased the proportion of patients with a 33% or greater reduction in RBC transfusion burden (with a reduction of at least 2 units) from weeks 13 to 24 (21.4% vs 4.5%; p<0.0001). However, the results of this trial have not been subjected to peer reviewed publication; therefore, the data are insufficient to determine if primary coverage criteria are met since identification of appropriate subsets of patients who might benefit and adequate data are unavailable (Reblozyl, package insert).
 
Piga et al in an open-label, nonrandomized, uncontrolled study of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing (NCT01749540 and NCT02268409). Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, <10.0 g/dL; <4 red blood cell [RBC] units transfused per 8 weeks), and 31 were transfusion dependent (≥4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for ≥5 cycles (dose-finding stage) and 0.8 to 1.25 mg/kg (expansion cohort and 5-year extension). The primary end point was erythroid response, defined as hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction ≥20% over a 12-week period vs the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58%) receiving higher dose levels of luspatercept (0.6-1.25 mg/kg) achieved mean hemoglobin increase ≥1.5 g/dL over ≥14 days vs baseline. Twenty-six (81%) transfusion-dependent patients achieved ≥20% reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the interim analysis, only 33 patients remain in the study. The authors concluded that these findings support a randomized clinical trial to assess efficacy and safety.
 
MDS
In a double-blind, placebo-controlled, phase 3 trial, patients with very-low-risk, low-risk, or intermediate-risk myelodysplastic syndromes (defined according to the Revised International Prognostic Scoring System) with ring sideroblasts who had been receiving regular red-cell transfusions to receive either luspatercept (at a dose of 1.0 up to 1.75 mg per kilogram of body weight) or placebo, administered subcutaneously every 3 weeks were randomly assigned. The primary end point was transfusion independence for 8 weeks or longer during weeks 1 through 24, and the key secondary end point was transfusion independence for 12 weeks or longer, assessed during both weeks 1 through 24 and weeks 1 through 48.
Of the 229 patients enrolled, 153 were randomly assigned to receive luspatercept and 76 to receive placebo; the baseline characteristics of the patients were balanced. Transfusion independence for 8 weeks or longer was observed in 38% of the patients in the luspatercept group, as compared with 13% of those in the placebo group (P<0.001). A higher percentage of patients in the luspatercept group than in the placebo group met the key secondary end point (28% vs. 8% for weeks 1 through 24, and 33% vs. 12% for weeks 1 through 48; P<0.001 for both comparisons). The most common luspatercept-associated adverse events included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time.
Luspatercept reduced the severity of anemia in patients with lower-risk myelodysplastic syndromes with ring sideroblasts who had been receiving regular red-cell transfusions and who had disease that was refractory to or unlikely to respond to erythropoiesis-stimulating agents or who had discontinued such agents owing to an adverse event. (Fenaux P, Platzbecker U, Mufti G, et al., 2020)
 
In a randomized, double-blind, phase 3 trial, adults with transfusion-dependent β-thalassemia were assigned, in a 2:1 ratio, to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies.
A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo.
The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Cappellini M, Viprakasit V, Taher A, et al., 2020)
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
C9399Unclassified drugs or biologicals
J0896Injection, luspatercept aamt, 0.25 mg
J3490Unclassified drugs
J3590Unclassified biologics
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Cappellini M, Viprakasit V, Taher A, et al.(2020) A Phase 3 Trial of Luspatercept in Patients With Transfusion –Dependent B-Thalassemia, N Engl J Med. 2020 Mar 26;382(13):1219-1231. Doi: 10.1056/NEJMoa1910182

FDA approves first therapy to treat patients with rare blood disorder. Drugs@FDA:FDA approved Drugs Luspatercept-AAMT. Last accessed 02/19/2020

Fenaux P, Platzbecker U, Mufti G, et al.(2020) Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes, N Engl J Med 2020; 382:140-151. DOI: 10.1056/NEFMoal1908892

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Piga A, Perrotta S, Gamberini MR, et al.(2019) Luspatercept Improves Hemoglobin Levels and Blood Transfusion Requirements in a Study of Patients With ß-Thalassemia. Blood, 133 (12), 1279-1289. 2019 Mar 21. DOI: 10.1182/blood-2018-10-879247

Reblozyl® (luspatacept-aamt) [package insert]. Summit, NJ Celgene Coporation;
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