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Luspatercept is a recombinant fusion protein that binds several endogenous TGF‐Beta superfamily ligands and promotes erythroid maturation. Luspatercept is administered by subcutaneous injection. Due to the need for assessment of hemoglobin prior to each administration, luspatercept must be administered by a healthcare professional.  

The U.S. Food and Drug Administration (FDA) has approved luspatercept (Reblozyl®) for the following indications:

• Anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions.
• Anemia failing an erythropoiesis stimulating agent and requiring 2 or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

Luspatercept is not indicated for use as a substitute for RBC transfusion in patients who require immediate correction of anemia. Serious adverse reactions have occurred in patients treated with luspatercept. Patients with beta thalassemia are at increased risk for thromboembolism and should be monitored for signs and symptoms of thromboembolic events, with appropriate treatment initiated promptly.  Blood pressure should be monitored during treatment with initiation of anti-hypertensive treatment if necessary. Luspatercept may cause fetal harm. Females of reproductive potential should be advised of the potential risk of the fetus and use of effective contraception. 

Beta thalassemia 

Beta thalassemia is an inherited blood disorder caused by mutations in the HBB gene, which reduces the production of hemoglobin leading to a lack of oxygen in many parts of the body. The HBB gene provides instructions for making beta-globin. Hemoglobin consists of four protein subunits, typically two subunits of beta-globin and two subunits of alpha-globin. Beta thalassemia is classified into types depending on the severity of symptoms: beta thalassemia major (also known as Cooley's anemia), beta thalassemia intermedia, and beta thalassemia minor (also known as beta thalassemia trait). Genotypes of beta thalassemia include the following: 

• Beta-zero (B⁰) thalassemia: Mutations in the HBB gene prevent the production of any beta-globin.
• Beta-plus (B⁺) thalassemia: HBB gene mutations allow some beta-globin to be produced in reduced amounts.
• Hemoglobin E – beta thalassemia: Co-inheritance of a beta thalassemia mutation in one copy of the HBB gene with inheritance of the structural variant hemoglobin E.  Patients may be asymptomatic, or have clinical presentation ranging from mild to severe.
• Sickle beta thalassemia: Mutations are present in each copy of the HBB gene: one that RBCs to form a "sickle" or crescent shape and a second that is associated with beta thalassemia. 

Myelodysplastic syndromes

The term myelodysplastic syndromes (MDS) refers to a heterogeneous group of clonal hematopoietic disorders characterized by impaired maturation of hematopoietic cells and a tendency to transform into acute myelocytic leukemia (AML). MDS can occur as a primary (idiopathic) disease, or be secondary to cytotoxic therapy, ionizing radiation, or other environmental insult. Signs and symptoms of anemia, often complicated by infections or bleeding, are common in MDS. The vast majority of MDS diagnoses occur in individuals over the age of 55–60 years. A subset of patients with MDS have red blood cells that contain rings of iron deposits around the nucleus (ring sideroblasts). Another subset of patients with MDS have an increased number of ring sideroblasts and thrombocytes (platelets). This form of MDS is considered a rare disorder.

I.    Initial Review for Luspatercept (Reblozyl®) for Beta Thalassemia

Luspatercept may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Age 18 years or older; AND
• Absence of sickle beta thalassemia or alpha thalassemia; AND
• Diagnosis of beta thalassemia (including beta+ thalassemia, beta0 thalassemia, and hemoglobin E beta thalassemia); AND
• Required transfusion of 6-20 RBC units in the 24 weeks prior; AND
• No transfusion-free period for ≥35 days in the 24 weeks prior; AND
• Prescribed by or in consultation with a hematologist or other specialist with expertise in the diagnosis and management of beta thalassemia; AND
• No FDA labeled contraindications to luspatercept (see table 1 below); AND
• Dose is within the FDA labeled dose for the indication (see table 2 below). 
  

II.    Renewal Review for Luspatercept (Reblozyl®) for Beta Thalassemia

Luspatercept may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Previously approved for luspatercept through the initial review process; AND
• Demonstrated a minimum one-third reduction in RBC transfusions in response to luspatercept; AND
• Prescribed by or in consultation with a hematologist or other specialist with expertise in the diagnosis and management of beta thalassemia; AND
• No FDA labeled contraindications to luspatercept (see table 1 below); AND
• Dose is within the FDA labeled dose for the indication (see table 2 below). 

III.  Initial Review of Luspatercept (Reblozyl®) for Myelodysplastic Syndromes or Myelodysplastic/ Myeloproliferative Neoplasm

Luspatercept may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Age 18 years or older; AND
• Diagnosis of ONE of the following:
  • Myelodysplastic syndromes; or
  • Myelodysplastic/myeloproliferative neoplasm;
• AND
• Documented lower risk disease defined by one of the following:
  • Revised International Prognostic Scoring System (IPSS-R): very low, low, intermediate (Score 0 to ≤ 4.5); or
  • IPSS: low/intermediate-1 (Score 0 to 1); or
  • World Health Organization-Based Prognostic Scoring System (WPSS): very low, low, Intermediate (Score 0 to 2)
• AND
• ONE of the following:
  • Ring sideroblasts ≥ 15%; or
  • Ring sideroblasts ≥ 5% with an SF3B1 mutation; 
• AND
• BOTH of the following:
  • Hemoglobin <10 g/dL; and
  • Required transfusion of at least 2 units of packed red blood cells (pRBCs) in the prior 8 weeks;
• AND
• ONE of the following:
  • Patient is ineligible for erythropoiesis stimulating agent (ESA) therapy (e.g. serum erythropoietin >200 U/L); OR
  • Disease not responsive to prior treatment with (ESA) therapy; OR
  • Prior ESA therapy discontinued due to adverse event;
• AND
• Other causes of anemia (e.g., gastrointestinal bleeding, hemolysis, renal disease, nutritional deficiency, etc.) have been ruled out and/or addressed; AND
• Prescribed by or in consultation with a hematologist, oncologist, or other specialist with expertise in the diagnosis and management of myelodysplastic syndromes; AND
• No FDA labeled contraindications to luspatercept (see table 1 below); AND 
• Dose is within the FDA labeled dose for the indication (see table 2 below).

IV.   Renewal Review of Luspatercept (Reblozyl®) for Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasm

Luspatercept may be considered MEDICALLY NECESSARY AND APPROPRIATE when ALL of the following criteria are met:

• Previously approved for luspatercept through the initial review process; AND
• Demonstrated transfusion independence for a minimum of 8 weeks since starting treatment with luspatercept; AND
• Prescribed by or in consultation with a hematologist, oncologist, or other specialist with expertise in the diagnosis and management of myelodysplastic syndromes; AND
• No FDA labeled contraindications to luspatercept (see table 1 below); AND
• Dose is within the FDA labeled dose for the indication (see table 2 below).

V.     Experimental/Investigative Uses

All other uses of luspatercept, including but not limited to non-transfusion-dependent beta-thalassemia, and treatment of patients not meeting the criteria above, are considered EXPERIMENTAL/INVESTIGATIVE due to the lack of clinical evidence demonstrating an impact on improved health outcomes. 

Table 1.  FDA Labeled Contraindications

Table 2. Dosing

NOTE:  See documentation submission requirements below if the requested dose is higher or more frequent than the dosing criteria provided in this table.

Documentation Submission:

Documentation supporting the medical necessity criteria described in the policy must be included in the prior authorization, when prior authorization is required. In addition, the following documentation must also be submitted:

Initial Review

• Clinical notes describing the diagnosis and clinical features of the diagnosis, including the frequency of RBC transfusions.
• The dose being requested. If the requested dose is higher or more frequent than the dosing guidelines provided in the table above, a clear explanation for the medical necessity of the requested dose must be submitted, including prior dosing (strength and frequency) associated with inadequate response.

Renewal Review

• Documentation of prior approval for luspatercept through the initial review process.
• Documentation demonstrating positive clinical response:
  • For anemia in patients with beta thalassemia: ≥ 33% reduction from baseline in RBC transfusion frequency or 
  • For anemia in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms: transfusion independence for a minimum of 8 weeks since starting treatment with luspatercept;
• The dose being requested. If the requested dose is higher or more frequent than the dosing guidelines provided in the table above, a clear explanation for the medical necessity of the requested dose must be submitted, including prior dosing (strength and frequency) associated with inadequate response.