Luspatercept-aamt (Reblozyl)

Number: 0963

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of Reblozyl is required of all Aetna participating providers and members in applicable plan designs. For precertification of luspatercept–aamt, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Aetna considers luspatercept–aamt (Reblozyl) medically necessary for

1. The treatment of anemia with beta thalassemia 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 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 hemoglobin electrophoresis or high-performance liquid chromatography (HPLC); and
   3. The member required at least 6 red blood cell (RBC) units transfused in the previous 24 weeks.

2. The treatment of very low- to intermediate-risk myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm 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 grams per deciliter; and
   2. The member has been receiving regular RBC transfusions; and
   3. The member meets either of the following:
      
      
      1. Ring sideroblasts are greater than or equal to 15%; or
      2. Ring sideroblasts are greater than or equal to 5% and less than 15% and the patient has an SF3B1 mutation; and
   4. The member meets either of the following:
      
      
      1. Pretreatment serum erythropoietin levels greater than 500 mU/mL; or
      2. Pretreatment serum erythropoietin levels less than or equal to 500mU/mL following no response to the combination of an erythropoiesis-stimulating agent (ESA) and granulocyte-colony stimulating factor (G-CSF).

Aetna considers continued treatment with luspatercept–aamt (Reblozyl) medically necessary in members requesting authorization for anemia with beta thalassemia, myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm when the all of the following criteria are met:

1. Member must achieve or maintain red blood cell transfusion burden reduction; and
   

2. Member must not experience an unacceptable toxicity from Reblozyl; and
   

3. Member must have a pre-dose Hgb level less than or equal to 11 grams per deciliter; if the Hgb level is greater than 11 grams per deciliter, the prescriber agrees to hold the dose until the level falls to 11 grams per deciliter.

Note: For initial therapy and continuation of therapy, if a red blood cell (RBC) transfusion occurred prior to dosing, the pretransfusion hemoglobin (Hgb) level must be considered for dosing purposes.

Aetna considers luspatercept–aamt (Reblozyl) experimental and investigational for the following

1. Members with hemoglobin S/β-thalassemia or alpha-thalassemia;

2. Members with recent deep vein thrombosis or stroke (defined as less than or equal to 24 weeks prior to initiation of Reblozyl therapy);

3. Members with platelet count greater than 1000 x 10⁹ per liter (i.e., greater than 1 million per microliter). 

Dosing Recommendations

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

Source: Celgene 2020.

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 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)

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 U.S. Food and Drug Administration 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 (6-20 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 or recent use of ESA, immunosuppressant, or hydroxyurea therapy. The median age was 30 years (range: 18-66). 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 (≥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, 23.6); p < 0.0001) from Week 13 to Week 24. From Week 37 to Week 48, 19.6 percent 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, 22.4); p < 0.0001). The proportion of patients achieving RBC transfusion burden reduction (≥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, 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, 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, <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 cutoff, 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.

Common side effects for patients taking Reblozyl were headache, bone pain, arthralgia (joint pain), fatigue, cough, abdominal pain, diarrhea and dizziness. Patients may experience hypertension while using Reblozyl. Health care professionals are advised to monitor a patient’s blood pressure during treatment and to initiate anti-hypertensive treatment if necessary. Patients who receive Reblozyl should be monitored for thrombosis (blood clots). The FDA advises health care professionals to tell females of reproductive age to use effective contraception during treatment with Reblozyl. Women who are pregnant or breastfeeding should not take Reblozyl because it may cause harm to a developing fetus or newborn baby (Reblozyl prescribing information, 2019). 

Myelodysplastic Syndromes 

On April 3, 2020, the Food and Drug Administration approved luspatercept-aamt (Reblozyl, Celgene Corporation) for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell (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% 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 (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.

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:
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:
D46.0 - D46.Z	Myelodysplastic syndromes
D56.1	Beta thalassemia
D56.5	Hemoglobin E-beta thalassemia
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
D56.0	Alpha thalassemia
D56.3	Thalassemia minor
D56.8	D56.8
I82.401 - I82.91	Deep vein thromboses (DVT)
I63.00 - I63.9	Cerebral infarction (Stroke)

The above policy is based on the following references: