Notification



Notification Issue Date:



Medicare Advantage Policy

Title:Luspatercept–aamt (Reblozyl®)
Policy #:MA08.110

This policy is applicable to the Company’s Medicare Advantage products only. Policies that are applicable to the Company’s commercial products are accessible via a separate commercial policy database.


The Company makes decisions on coverage based on the Centers for Medicare and Medicaid Services (CMS) regulations and guidance, benefit plan documents and contracts, and the member’s medical history and condition. If CMS does not have a position addressing a service, the Company makes decisions based on Company Policy Bulletins. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable. Although the Medicare Advantage Policy Bulletin is consistent with Medicare’s regulations and guidance, the Company’s payment methodology may differ from Medicare.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.


This Policy Bulletin document describes the status of CMS coverage, medical terminology, and/or benefit plan documents and contracts at the time the document was developed. This Policy Bulletin will be reviewed regularly and be updated as Medicare changes their regulations and guidance, scientific and medical literature becomes available, and/or the benefit plan documents and/or contracts are changed.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's Evidence of Coverage.

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

INITIAL THERAPY
Luspatercept–aamt (Reblozyl®) is considered medically necessary and, therefore, covered for the treatment of anemia in adult individuals with beta thalassemia who require regular red blood cell (RBC) transfusions, when all of the following criteria, including dosing and frequency, are met:
  • Documented diagnosis of β-thalassemia, hemoglobin E/β-thalassemia, or β-thalassemia combined with alpha-thalassemia confirmed by one of the following tests:
    • Molecular genetic testing that reveals pathogenic variation(s) in the HBB gene causing β-thalassemia
    • Hemoglobin electrophoresis
  • There is documentation the individual is transfusion-dependent, requiring regular RBC transfusions (i.e., at least six units of red blood cell [RBC] in the previous 24 weeks and no transfusion-free period for ≥ 35 days during that period).
  • Treatment will not be combined with a gene therapy used to treat β-thalassemia
  • Dosing and Frequency: 1 mg/kg as a subcutaneous injection every three weeks. If a reduction in RBC transfusion burden is not achieved after at least 2 consecutive doses (6 weeks), luspatercept–aamt (Reblozyl®) will be covered up to a maximum dose of 1.25 mg/kg every three weeks.

CONTINUATION THERAPY
Continuation of luspatercept–aamt (Reblozyl®) is considered medically necessary and, therefore, covered for individuals who have demonstrated a documented reduction in the number of transfusions compared to baseline.

NOT MEDICALLY NECESSARY

Continuation therapy with luspatercept–aamt (Reblozyl®) is considered not medically necessary and, therefore, not covered for individuals who do not experience a decrease in transfusion burden after 5 doses (two doses at 1 mg/kg and three doses at 1.25 mg/kg). The available published peer-reviewed literature does not support its use in the treatment of this disease.

When molecular genetic testing reveals established benign variation(s) or wild-type genotype in the HBB gene, luspatercept–aamt (Reblozyl®) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support its use in the treatment of this disease.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for luspatercept–aamt (Reblozyl®), including those listed below, are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.
  • Individuals with hemoglobin S/β-thalassemia or alpha-thalassemia
  • Individuals with non-transfusion-dependent beta-thalassemia
  • As a substitute for RBC transfusions in those who require immediate correction of anemia

When molecular genetic testing reveals likely pathogenic or variations of unknown significance (VUS) in the HBB gene, the use of luspatercept–aamt (Reblozyl®) is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

DOSING AND FREQUENCY REQUIREMENTS

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this policy to ensure consistency with the most recently published recommendations for the use of luspatercept–aamt (Reblozyl®). Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to: the US Food and Drug Administration (FDA); Company-recognized authoritative pharmacology compendia; or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of luspatercept–aamt (Reblozyl®) outside of the Dosing and Frequency Requirements listed in this policy. For a list of Company-recognized pharmacology compendia, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the utilization management activities. The Company reserves the right to conduct post-payment review and audit procedures for any claims submitted for luspatercept–aamt (Reblozyl®).

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

When coverage of luspatercept–aamt (Reblozyl®) is requested outside of the Dosing and Frequency Requirements listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.
Policy Guidelines

There is no Medicare coverage determination addressing luspatercept–aamt (Reblozyl®); therefore, the Company policy is applicable.

DRUG INFORMATION

Luspatercept–aamt (Reblozyl®) is administered as a subcutaneous injection every three weeks. Per prescribing information: Assess hemoglobin (Hb) prior to each dose. If a RBC transfusion occurred prior to the dose, consider pretransfusion Hb for dosing purposes. If the pre-dose Hb is ≥11.5 g/dL (and Hb is not influenced by recent transfusion), delay luspatercept–aamt (Reblozyl®) until Hb is ≤11 g/dL.

BENEFIT APPLICATION

Subject to the applicable Evidence of Coverage, luspatercept–aamt (Reblozyl®) is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

For Medicare Advantage members, certain drugs are available through either the member's medical benefit (Part B benefit) or pharmacy benefit (Part D benefit), depending on how the drug is prescribed, dispensed, or administered. This medical policy only addresses instances when luspatercept–aamt (Reblozyl®) is covered under a member's medical benefit (Part B benefit). It does not address instances when luspatercept–aamt (Reblozyl®) is covered under a member’s pharmacy benefit (Part D benefit).

However, services that are identified in this policy as experimental/investigational or not medically necessary are not eligible for coverage or reimbursement by the Company.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Luspatercept–aamt (Reblozyl®) was approved by the FDA on November 8, 2019 for the treatment of anemia in adult individuals with beta thalassemia who require regular red blood cell (RBC) transfusions. (Limitations of use: Luspatercept–aamt (Reblozyl®) is not indicated for use as a substitute for RBC transfusions in individuals who require immediate correction of anemia.) The safety and effectiveness in pediatric individuals have not been established, and based on findings in juvenile animals, is not recommended for use in the pediatric population.

Description

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.

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.

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.

PEER-REVIEWED LITERATURE
Summary

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. 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 patients 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%).

OFF-LABEL INDICATION

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.
References

Angelucci E, Matthes-Martin S, Baronciani D, et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014 May;99(5):811-20.

Benz EJ. Clinical manifestation and diagnosis of the thalassemias. [UpToDate Web Site]. Updated 08/19/2019. Available at: http://www.uptodate.com/home [via subscription only]. Accessed December 16, 2019.

Elsevier’s Clinical Pharmacology Compendium. luspatercept. 11/10/2019. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed December 9, 2019.

Langhi D, Ubiali, EMA, Marques JFC, et al. Guidelines on Beta-thalassemia major – regular blood transfusion therapy: Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular: project guidelines: Associação Médica Brasileira – 2016. Rev Bras Hematol Hemoter. 2016 Oct-Dec; 38(4): 341–345.

Lexi-Drugs Compendium. luspatercept. 11/26/2019. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed December 9, 2019.

Olivieri NF, Pakbaz Z, Vichinsky E. Hb E/beta-thalassaemia: a common & clinically diverse disorder. Indian J Med Res. 2011;134(4):522–531.

National Cancer Institute at the National Institutes of Health (NIH). NCI Drug Dictionary. Luspatercept. [Cancer.gov Web Site]. Available at: https://www.cancer.gov/publications/dictionaries/cancer-drug/def/luspatercept . Accessed November 13, 2019.

National Institutes of Health. Clinical trials: An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Adults Who Require Regular Red Blood Cell Transfusions Due to Beta (β) Thalassemia (BELIEVE). (NCT02604433). [ClinicalTrials Web site]. last updated 06/05/2019. Available at: https://clinicaltrials.gov/ct2/show/NCT02604433 . Accessed November 13, 2019.

National Institutes of Health (NIH). Genetics Home Reference. HBB gene. Reviewed 07/2015. Available at: https://ghr.nlm.nih.gov/gene/HBB . Accessed November 13, 2019.

National Institutes of Health (NIH). Genetics Home Reference. Beta thalassemia. Reviewed 09/2015. Available at: https://ghr.nlm.nih.gov/condition/beta-thalassemia . Accessed November 13, 2019.

National Organization of Rare Diseases (NORD). Beta thalassemia.Updated 2018. Available at: https://rarediseases.org/rare-diseases/thalassemia-major/ . Accessed December 16, 2019.
Piga A, Perrotta S, Gamberini MR, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. 2019. Mar 21; 133 (12): 1279-1289.

Reblozyl® (luspatercept–aamt). [prescribing information]. Cambridge, MA: Celgene Corp.; 11/2019. Available at: https://www.reblozylpro.com/ . Accessed December 9, 2019.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Luspatercept–aamt (Reblozyl®). 12/10/2019. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed December 9, 2019.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Luspatercept–aamt (Reblozyl®) prescribing information and approval letter [FDA Web site]. 11/2019. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/ . Accessed November 8, 2019.


Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

MEDICALLY NECESSARY

D56.1 Beta thalassemia

D56.5 Hemoglobin E-beta thalassemia



HCPCS Level II Code Number(s)



THE FOLLOWING CODE(S) ARE USED TO REPRESENT LUSPATERCEPT--AAMT (REBLOZYL®)

C9399 Unclassified drugs or biologicals

J3590 Unclassified biologics


Revenue Code Number(s)

N/A

Coding and Billing Requirements

BILLING REQUIREMENTS

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).
Cross References




Policy History

MA08.110
03/09/2020The following new policy has been developed to communicate the Company's coverage criteria for luspatercept–aamt (Reblozyl®).




Version Effective Date: 03/09/2020
Version Issued Date: 03/09/2020
Version Reissued Date: N/A