Luspatercept–aamt (Reblozyl«) was approved by the US Food and Drug Administration (FDA) on November 8, 2019 for the treatment of anemia in adult individuals with beta thalassemia who require regular red blood cell (RBC) transfusions. Luspatercept–aamt (Reblozyl«) is not indicated for use as a substitute for RBC transfusions in individuals who require immediate correction of anemia. A supplemental approval was granted on 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 adults 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–aamt (Reblozyl«) is a recombinant fusion protein that causes erythroid maturation. Luspatercept–aamt (Reblozyl«) binds to and inhibits several endogenous transforming growth factor (TGF)-β superfamily ligands involved in late stage erythropoiesis, thereby diminishing abnormally elevated Smad2/3 signaling and enhancing RBC production and preventing anemia.
Beta thalassemia is a relatively rare inherited blood disorder in the United States, but its incidence of symptomatic cases is estimated to be approximately 1 in 100,000 individuals in the general population. Many states in the United States diagnose infants with a hemoglobin disorder through newborn screenings, although most states do not routinely test for thalassemia. Beta thalassemia is caused by variations in the HBB gene (usually in an autosomal recessive pattern) that provides instructions for making the beta-globin protein, a component (subunit) of hemoglobin. A lack of beta-globin leads to a shortage of functional hemoglobin, the iron-containing protein in red blood cells (RBC) that carries oxygen to cells throughout the body, creating a shortage of mature RBC. This shortage of mature red blood cells leads to anemia and other associated health problems, such as organ damage or abnormal blood clots, in those with beta thalassemia.
Beta thalassemia has three main forms, minor, intermedia, and major, which indicate the severity of the disease. Individuals with beta thalassemia minor (trait) are usually asymptomatic and individuals often are unaware that they have the condition. Individuals with thalassemia intermedia are typically diagnosed later in life, exhibit a wide variability in symptoms and severity (less severe phenotype than thalassemia major), and may only require periodic blood transfusions (non-transfusion-dependent thalassesmia). The most severe form of beta thalassemia is thalassemia major (also known as Cooley's anemia), diagnosed within the first two years of life, and require life-long, regular blood transfusions to replenish their red blood cell supply. In beta thalassemia major, there is minimal to no beta globin chain production and consequently little to no adult hemoglobin (HbA). Beta thalassemia major 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 (ie, HbE/beta thalassemia); HbE is a beta+ type of mutation. Worldwide, individuals with HbE/beta-thalassaemia represent approximately 50% of those affected with severe beta thalassaemia.
Over time, an influx of iron-containing hemoglobin from chronic blood transfusions can lead to a buildup of iron in the body, resulting in liver, heart, and hormone problems. Individuals are required to undergo chelation therapy to remove the excess iron from the body. The only available curative option is a hematopoietic stem cell transplant.
The safety and efficacy of luspatercept–aamt (Reblozyl«) was evaluated in a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial (BELIEVE) in adults (n=336) with a documented diagnosis of β-thalassemia (77% of participants), hemoglobin E/β-thalassemia, or β-thalassemia combined with alpha-thalassemia who required regular red blood cell transfusions (6-20 red blood cell [RBC] units in the 24 weeks prior to randomization and no transfusion-free period for ≥ 35 days during that period. Participants were randomized 2:1 to luspatercept–aamt (Reblozyl«) 1 mg/kg subcutaneously every 21 days plus best supportive care (BSC) (n=224) or placebo plus BSC (n=112) administered subcutaneously once every 21 days, as long as a reduction in transfusion requirement was observed or until unacceptable toxicity resulted. All participants were eligible to receive best supportive care, which included RBC transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and/or nutritional support, as needed. The BELIEVE trial excluded those with hemoglobin S/β-thalassemia or alpha-thalassemia or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency). Those with recent deep vein thrombosis or stroke or recent use of ESA, immunosuppressant, or hydroxyurea therapy were also excluded.
The baseline transfusion burden 12 weeks prior to randomization was approximately a median of 6.12 transfusion (minimum 3, maximum 14). The primary outcome of this trial was the proportion of participants achieving RBC transfusion burden reduction (≥33% reduction from baseline) with a reduction of at least 2 units from Week 13 to Week 24. Twenty-one percent of those who were in the luspatercept–aamt (Reblozyl«) group achieved at least a 33% reduction in transfusions compared to 4.5% of the individuals who received a placebo (p<0.0001). Thromboembolic events were reported more frequently in those treated with luspatercept–aamt (Reblozyl«) (3.6%), compared to placebo (0.9%).
Myelodysplastic syndromes (MDS) are a group of cancers caused by variation(s) in gene(s) and are characterized by ineffective hematopoiesis and progressive cytopenias. The hematopoietic stem cells become abnormal and either stop replicating, or they create defective (dysplasia, die early, etc.) new blood cells. The defective cells overcrowd the bone marrow causing even fewer healthy blood cells to be created or survive and enter the bloodstream. MDS affects all three lines of blood cells, causing symptomatic anemia (dyspnea, fatigue, weakness), infection, and bleeding . MDS predominating affects the elderly male population and has the risk of progression to an aggressive cancer, acute myeloid leukemia. There are many types of MDS classified by the following features: percent of blast cells in bone marrow, chromosome changes, number of low blood counts, hemoglobin levels, platelets and neutrophil counts, and presence of severe anemia.
The only curative option for MDS are an allogeneic hematopoietic cell transplantation (HCT). Other treatment options for MDS, depending on genetic and other hematologic factors, may include erythropoiesis-stimulating agent (ESA) therapy, red-cell transfusions with iron chelation therapy, lenalidomide, or hypomethylating agents (e.g., azacitidine, decitabine). Individuals with anemia and lower-risk MDS in whom ESA therapy is not effective (serum erythropoietin levels above 200 U/L) generally become dependent on red-cell transfusions. Treatment goals for those with lower-risk MDS include transfusion independence, improvement in hemoglobin levels, and maintenance of or improvement in quality of life.
The safety and efficacy of luspatercept–aamt (Reblozyl«) to decrease the severity of anemia was evaluated in a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial (MEDALIST) by Fenaux et al 2020, in adults (n=229) with a documented diagnosis of myelodysplastic syndrome (MDS) with ring sideroblasts according to World Health Organization criteria (i.e., with either ≥15% ring sideroblasts or ≥5% ring sideroblasts if an SF3B1 variation was present, and with <5% bone marrow blasts). About 87% of participants had MDS with ring sideroblasts (MDS-RS), while the remainder were categorized as Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). Participants had disease defined according to the IPSS-R as being of very low (10% of participants), low (72% of participants), or intermediate risk (17% of participants) MDS. Participants required regular red blood cell transfusions (≥2 units per 8 weeks during the 16 weeks before randomization), and had an inadequate response to prior treatment with an erythropoiesis-stimulating agent (ESA), be intolerant of ESAs, or have a serum erythropoietin > 200 U/L. The study excluded individuals with MDS with deletion 5q (del 5q), white blood cell count > 13 Gi/L, neutrophils < 0.5 Gi/L, platelets < 50 Gi/L, or with prior use of a disease modifying agent for treatment of MDS. The median age was 71 years (range 26-95). Ninety-one percent of individuals had a variation in the SF3B1 gene.
In the double-blind Primary Phase of the trial, participants were randomized (2:1) to receive luspatercept or placebo, administered subcutaneously every 3 weeks for 24 weeks with no crossover allowed. The starting dose of luspatercept was 1 mg/kg. If a new transfusion was necessary after the individuals were considered to have transfusion independence, they could continue receiving luspatercept, with adjustment to a dose of 1.33 mg/kg, and then to 1.75 mg/kg. At Week 25, disease was assessed and those without clinical benefit discontinued luspatercept or placebo and entered follow-up. Those who had clinical benefit without disease progression could enter the double-blind Extension Phase (n=126) and continue receiving luspatercept or placebo until they had unacceptable toxic effects or disease progression, withdrew consent, or met discontinuation criteria. Follow-up will continue for ≥3 years following the last dose.
The primary end point of RBC transfusion independence for 8 weeks or longer during weeks 1 through 24, was seen in 58 individuals (38%) who received luspatercept versus 10 individuals (13%) who received placebo (P<0.001). The results showed that there was a greater reduction in the severity of anemia in transfusion dependent individuals with lower-risk myelodysplastic syndromes with ring sideroblasts who received luspatercept. The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
D46.1 Refractory anemia with ring sideroblasts
D46.9 Myelodysplastic syndrome, unspecified
D56.1 Beta thalassemia
D56.5 Hemoglobin E-beta thalassemia
Policy: MA08.012c:Off-label Coverage for Prescription Drugs and/or Biologics