Luspatercept-aamt (Reblozyl)

Number: 0963

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses luspatercept-aamt (Reblozyl) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of luspatercept-aamt (Reblozyl) is required of all Aetna participating providers and members in applicable plan designs. For precertification of luspatercept–aamt, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Aetna considers luspatercept–aamt (Reblozyl) medically necessary for the following indications:
   
   
   1. Anemia with beta thalassemia - for treatment of anemia with beta thalassemia in members 18 years of age or older when all of the following criteria are met:
      
      
      1. The member has symptomatic anemia evidenced by a pretreatment or pretransfusion Hgb level less than or equal to 11 g/dL (grams per deciliter); and
      2. The member has a diagnosis of beta thalassemia (β-thalassemia) or hemoglobin E/β-thalassemia (β-thalassemia with mutation and/or multiplication of alpha globin is allowed) confirmed by one of the following:
         
         
         1. Hemoglobin electrophoresis or high-performance liquid chromatography (HPLC); or
         2. Molecular genetic testing; and

      3. The member required at least 6 red blood cell (RBC) units transfused in the previous 24 weeks.

         Note: If a red blood cell (RBC) transfusion occurred prior to dosing, the pretransfusion hemoglobin (Hgb) level must be considered for dosing purposes.

   2. Anemia of myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm - for treatment of anemia of myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm in members 18 years of age or older when all of the following criteria are met:

      1. The member has one of the following:

         1. Very low- to intermediate-risk myelodysplastic syndrome; or
         2. Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T); and
      2. The member has symptomatic anemia evidenced by a pretreatment or pretransfusion Hgb level less than or equal to 11 g/dL; and
      3. The member has been receiving regular red blood cell (RBC) transfusions as defined by greater than or equal to 2 units per 8 weeks.

   3. Myelofibrosis-associated anemia treatment.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of luspatercept–aamt (Reblozyl) therapy medically necessary for members requesting authorization for an indication listed in Section I when both of the following criteria are met:

   1. Member has achieved or maintained a reduction in red blood cell transfusion burden; and
   2. Member has not experienced an unacceptable toxicity from Reblozyl.

Dosage and Administration

Reblozyl is supplied for injection as 25 mg and 75 mg lyophilized powder in single-dose vials for reconstitution. Reblozyl should be reconstituted and administered by a healthcare professional. 

The recommended starting dose is 1 mg/kg once every 3 weeks by subcutaneous injection. Review hemoglobin (Hgb) results prior to each administration.

See full prescribing information for dosing titration and dosing modification information, Full Prescribing Information for Reblozyl.

Source: Bristol-Myers Squibb, 2023

Experimental, Investigational, or Unproven

Aetna considers luspatercept–aamt (Reblozyl) therapy experimental, investigational, or unproven for the treatment of hemoglobin S/β-thalassemia or alpha-thalassemia because the safety and efficacy has not been established in the peer-reviewed published literature.  

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
81361 - 81364	HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
J0896	Injection, luspatercept-aamt, 0.25 mg
ICD-10 codes covered if selection criteria are met:
C94.6	Myelodysplastic disease, not elsewhere classified
D46.0 - D46.Z	Myelodysplastic syndromes
D56.1	Beta thalassemia
D56.5	Hemoglobin E-beta thalassemia
D75.81	Myelofibrosis
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
D56.0	Alpha thalassemia
D56.3	Thalassemia minor
D56.8	Other thalassemias

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Treatment of anemia in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions
• Treatment of anemia without previous erythropoiesis stimulating agent use (ESA-naïve) in adult patients with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require regular red blood cell (RBC) transfusions
• Treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell 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)
  
  Limitations of Use: Reblozyl is not indicated for use as a substitute for red blood cell (RBC) transfusions in patients who require immediate correction of anemia.

Compendial Use

• Myelofibrosis-associated anemia

Luspatercept-aamt is available as Reblozyl (Celgene Corporation, a Bristol-Myers Squibb Company). Luspatercept-aamt, an erythroid maturation agent, is a recombinant fusion protein that binds several endogenous TGF-β superfamily ligands, thereby diminishing Smad2/3 signaling. In models of β-thalassemia and MDS, luspatercept-aamt decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis in mice. Luspatercept-aamt promoted erythroid maturation through differentiation and increasing the percentage of late-stage erythroid precursors (normoblasts) in the bone marrow of mice and increased erythroid precursors in humans, thereby increasing erythropoiesis (BMS, 2023).

Labeled warnings and precautions include thrombosis/thromboembolism and extramedullary hematopoietic masses in patients with beta thalassemia, and hypertension. Reblozyl may cause embryo-fetal toxicity. Patients are advised not to breastfeed while on Reblozyl therapy.

The prescribing information includes the following warnings and precautions for Reblozyl: thrombosis/thromboembolism in patients with beta thalassemia, hypertension, and embryo-fetal toxicity. The most common adverse reactions (10% or more) include fatigue, headache, musculoskeletal pain, arthralgia, dizziness/vertigo, nausea, diarrhea, cough, abdominal pain, dyspnea, COVID-19, edema peripheral, hypertension, and hypersensitivity. 

Beta Thalassemia 

Beta thalassemia, also called "Cooley’s anemia," is an inherited blood disorder that reduces the production of hemoglobin, an iron-containing protein in red blood cells that carries oxygen to cells throughout the body. In beta thalassemia, low levels of hemoglobin lead to a lack of oxygen in many parts of the body and anemia, causing pale skin, weakness, fatigue and more serious complications. People with beta thalassemia are also at an increased risk of developing abnormal blood clots. Supportive treatment for people with beta thalassemia often consists of lifelong regimens of chronic blood transfusions for survival and treatment for iron overload due to the transfusions.

On November 08, 2019, the FDA approved Reblozyl (luspatercept–aamt) for the treatment of anemia (lack of red blood cells) in adult patients with beta thalassemia who require regular red blood cell (RBC) transfusions. Reblozyl was approved by the FDA with both a fast track and orphan drug designations. Reblozyl was approved based on the results of a multicenter, randomized, double-blind, placebo-controlled trial in which (n = 336) patients with beta thalassemia requiring regular red blood cell transfusions (6 to 20 RBC units per 24 weeks) with no transfusion-free period greater than 35 days during that period were randomized 2:1 to Reblozyl (n = 224) or placebo (n = 112) (BELIEVE Trial; NCT02604433). Reblozyl was administered subcutaneously once every 3 weeks as long as a reduction in transfusion requirement was observed or until unacceptable toxicity. All patients 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 trial excluded patients with hemoglobin S/β-thalassemia or alpha-thalassemia, had major organ damage (liver disease, heart disease, lung disease, renal insufficiency), and patients with recent deep vein thrombosis or stroke and platelet counts greater than 1,000 x 10⁹/L, or recent use of ESA, immunosuppressant, or hydroxyurea therapy. The median age was 30 years (range of 18 to 66). The trial was comprised of patients who were 42 % male, 54.2 % white, 34.8 % Asian, and 0.3 % Black or African American. The percent of patients reporting their race as "other" was 7.7 %, and race was not collected or reported for 3 % of patients (Reblozyl prescribing information, 2019).

The primary efficacy endpoint of Reblozyl in adult patients with beta thalassemia was the proportion of patients achieving RBC transfusion burden reduction (greater than or equal to 33 % reduction from baseline) with a reduction of at least 2 units from Week 13 to Week 24. Twenty-one percent of the patients who received Reblozyl achieved at least a 33 % reduction in transfusions compared to 4.5 % of the patients who received a placebo (risk difference: 17; 95 % CI: 10.4 to 23.6); P < 0.0001) from Week 13 to Week 24. From Week 37 to Week 48, 19.6 % of patients who received Reblozyl achieved at least a 33 % reduction in transfusions compared to 3.6 % of patients who received placebo (risk difference: 16.1; 95 % CI: 9.8 to 22.4); P < 0.0001). The proportion of patients achieving RBC transfusion burden reduction (greater than or equal to 50 % reduction from baseline) with a reduction of at least 2 units for 12 consecutive weeks was also greater with Reblozyl (7.6 %) compared to placebo (1.8 %) from Week 13 to Week 24 (risk difference: 5.8; 95 % CI: 1.6 to 10.1; P = 0.0303) and from Week 37 to Week 48 (10.3 % with Reblozyl compared with 0.9 %  with placebo; risk difference: 9.4; 95 % CI: 5 to 13,7; P = 0.0017). The transfusion reduction meant that the patient needed fewer transfusions over 12 consecutive weeks while taking Reblozyl (Reblozyl prescribing information, 2019).

In their open-label, nonrandomized, uncontrolled study, Piga et al (2019; NCT01749540 and NCT02268409) aimed to determine whether luspatercept could improve anemia and disease complications in patients with β-thalassemia. This study consisted of a 24-week dose-finding and expansion stage (initial stage) and a 5-year extension stage, currently ongoing. Sixty-four patients were enrolled; 33 were non-transfusion dependent (mean hemoglobin, less than 10.0 g/dL; less than 4 RBC units transfused per 8 weeks), and 31 were transfusion dependent (greater than or equal to 4 RBC units per 8 weeks). Patients received 0.2 to 1.25 mg/kg luspatercept subcutaneously every 21 days for greater than or equal to 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 greater than or equal to 1.5 g/dL from baseline for greater than or equal to 14 consecutive days (without RBC transfusions) for non-transfusion-dependent patients or RBC transfusion burden reduction greater than or equal to  20 % over a 12-week period versus the 12 weeks before treatment for transfusion-dependent patients. Eighteen non-transfusion-dependent patients (58 %) receiving higher dose levels of luspatercept (0.6 to 1.25 mg/kg) achieved mean hemoglobin increase greate than or equal to 1.5 g/dL over greater than or equal to 14 days versus baseline. Twenty-six (81 %) transfusion-dependent patients achieved greater than or equal to 20 % reduction in RBC transfusion burden. The most common grade 1 to 2 adverse events were bone pain, headache, and myalgia. As of the cut-off, 33 patients remain on study. In this study, a high percentage of β-thalassemia patients receiving luspatercept had hemoglobin or transfusion burden improvements. The authors concluded that these findings support a randomized clinical trial to assess efficacy and safety.

Myelodysplastic Syndromes 

On April 3, 2020, the FDA approved Reblozyl (luspatercept-aamt) for the treatment of 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). Efficacy was demonstrated in the MEDALIST trial by Fenaux et al (NCT02631070). Fenaux et al (2020; NCT02631070;) stated patients with anemia and lower-risk myelodysplastic syndromes in whom erythropoiesis-stimulating agent therapy is not effective generally become dependent on red-cell transfusions. Luspatercept, a recombinant fusion protein that binds transforming growth factor β superfamily ligands to reduce SMAD2 and SMAD3 signaling, showed promising results in a phase 2 study. This double-blind, placebo-controlled, phase 3 trial randomly assigned 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. 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 % versus 8 % for weeks 1 through 24, and 33 % versus 12 % for weeks 1 through 48; P < 0.001 for both comparisons). The most common luspatercept-associated adverse events (of any grade) included fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of adverse events decreased over time. The authors concluded that 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.

Platzbecker et al (2023) stated that ESAs are the standard-of-care (SOC) treatment for anemia in most patients with lower-risk MDS; however, responses are limited and transient.  Luspatercept promotes late-stage erythroid maturation and has shown durable effectiveness in patients with lower-risk MDS.  In an open-label, randomized-controlled, phase-III clinical trial (the COMMANDS trial), these investigators reported the findings of a pre-specified interim analysis of luspatercept versus epoetin alfa for the treatment of anemia due to lower-risk MDS; this study is being carried out at 142 sites in 26 countries.  Eligible patients were aged 18 years or older, had a diagnosis of MDS of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System [IPSS-R]), were ESA-naive, and required RBC transfusions (2 to 6 packed RBC units per 8 weeks for 8 weeks or more immediately before randomization).  Integrated response technology was employed to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline RBC transfusion burden (less than 4 units per 8 weeks versus 4 units or more per 8 weeks), endogenous serum erythropoietin concentration (200 or more U/L versus greater than 200 to less than 500 U/L), and ring sideroblast status (positive versus negative).  Luspatercept was administered subcutaneously once every 3 weeks starting at 1.0 mg/kg body weight with possible titration up to 1.75 mg/kg.  Epoetin alfa was administered subcutaneously once-weekly starting at 450 IU/kg body weight with possible titration up to 1,050 IU/kg (maximum permitted total dose of 80,000 IU).  The primary endpoint was RBC transfusion independence for at least 12 weeks with a concurrent mean hemoglobin (Hb) increase of at least 1.5 g/dL (weeks 1 to 24), evaluated in the intention-to-treat (ITT) population.  Safety was examined in patients who received at least 1 dose of study treatment. 

Between January 2, 2019 and August 31, 2022, a total of 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56 %) men and 158 (44 %) women (median age of 74 years [inter-quartile range (IQR) of 69 to 80]).  The interim effectiveness analysis was carried out for 301 patients (147 in the luspatercept group, and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier.  A total of 86 (59 %) of 147 patients in the luspatercept group, and 48 (31 %) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26.6; 95 % CI: 15.8 to 37.4; P < 0.0001).  Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR of 20 to 73]) versus epoetin alfa (27 weeks [19 to 55]).  The most frequently reported grade-3 or grade-4 treatment-emergent adverse events with luspatercept (3 % or more patients) were hypertension, anemia, dyspnea, neutropenia, thrombocytopenia, pneumonia, COVID-19, MDs, and syncope; and with epoetin alfa were anemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19, pneumonia, and MDS.  The most common suspected treatment-related adverse events (TRAEs) in the luspatercept group (3 % or more patients, with the most common event occurring in 5 % patients) were fatigue, asthenia, nausea, dyspnea, hypertension, and headache; and none (3 % or more patients) in the epoetin alfa group.  One death after diagnosis of acute myeloid leukemia (AML) was considered to be related to luspatercept treatment (44 days on treatment).  The authors concluded that in this interim analysis, luspatercept improved the rate at which RBC transfusion independence and increased Hb were achieved compared with epoetin alfa in ESA-naive patients with lower-risk MDS.  These researchers stated that long-term follow-up and additional data are needed to confirm these findings and further refine findings in other subgroups of patients with lower-risk MDS, including non-mutated SF3B1 or ring sideroblast (RS)-negative subgroups.

In August 2023, the FDA approved Reblozyl as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. Approval was based on the Phase 3 COMMANDS trial. The trial results showed 58.5% (n=86) of patients treated with Reblozyl, vs. 31.2% (n=48) of patients treated with epoetin alfa, achieved the primary endpoint of RBC transfusion independence of at least 12 weeks with a mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks (P < 0.0001). This study formed the basis for expanding the label indication to include ESA-naïve patients, regardless of ring sideroblast status.

Luspatercept Plus Recombinant Erythropoietin for the Treatment of Myelodysplastic Syndrome with Ring Sideroblasts

Fattizzo et al (2023) stated that patients with MDS RS are clinically characterized by severe anemia and transfusion need.  Erythropoiesis-stimulating agents, which stimulate Hb production and early maturation of erythroid precursors, are effective only in a portion of patients and for limited time.  Luspatercept is beneficial in unblocking late-stage erythropoiesis and has been approved for MDS RS patients failing or not-candidate to ESAs.  ESAs and/or luspatercept failure represents an unmet clinical need and most patients become life-long transfusion-dependent.  These researchers described the clinical combination of luspatercept with ESAs (subcutaneous epoetin alpha 40 to 80,000 IU/week) in 7 MDS RS patients.  Two patients had ESAs as pre-existing therapy, while 5 were re-challenged with ESAs as add-on treatment due to luspatercept failure.  Three patients achieved hematologic improvement, and 1 became transfusion-independent; no AEs were noted.  The authors reported for the 1st time the clinical combination of luspatercept and ESA in MDS RS patients and showed a benefit in about 50 % of cases, suggesting that stimulating both early and late-stage erythropoiesis may offer another option for treating this challenging patient population.

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References