Drug and Biologic Coverage Policy

Effective Date ...... 5/1/2021 Next Review Date… ...... 5/1/2022 Coverage Policy Number ...... IP0115

Luspatercept

Table of Contents Related Coverage Resources

Overview ...... 1 Medical Necessity Criteria ...... 1 Reauthorization Criteria ...... 2 Authorization Duration ...... 2 Conditions Not Covered...... 2 Coding / Billing Information ...... 2 Background ...... 3 References ...... 4

INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations.

Overview

This policy supports medical necessity review for luspatercept (Reblozyl®).

Medical Necessity Criteria

Luspatercept (Reblozyl) is considered medically necessary when ONE of the following is met (1 or 2):

1. Beta-Thalassemia. Individual meets ALL of the following criteria: A. 18 years of age or older B. Treatment of with a documented diagnosis of Beta-Thalassemia C. Individual requires regular red cell transfusions D. The is being prescribed by or in consultation with a hematologist.

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2. or Myelodysplastic/Myeloproliferative Neoplasm. Individual meets ALL of the following criteria: A. 18 years of age or older B. Treatment of anemia with a documented diagnosis of EITHER of the following: i. Myelodysplastic syndromes with ring sideroblasts (MDS-RS) ii. Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis associated anemia (MDS/MPN-RS-T) C. Individual has very low- to intermediate-risk myelodysplastic syndrome (determined by the Revised International Prognostic Scoring System [IPSS-R score less than or equal to 5.0; see Appendix]) D. Individual does not have a confirmed mutation with deletion 5q (del 5q) E. Individual currently requires blood transfusions, defined as at least two red blood cell units over the previous 8 weeks F. Individual meets ONE of the following: i. Individual has tried an erythropoiesis stimulating agent (ESA) for at least 3 months, unless intolerant ii. Serum level is greater than 500 mU/L G. Pretreatment hemoglobin level is < 10.0 g/dL H. Luspatercept (Reblozyl) will not be used in combination with an erythropoiesis stimulating agent (ESA) I. The medication is being prescribed by or in consultation with a hematologist or oncologist.

When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to therapy.

Note: Receipt of sample product does not satisfy any criteria requirements for coverage.

Reauthorization Criteria

Luspatercept (Reblozyl) is considered medically necessary for continued use when initial criteria are met AND there is documentation of beneficial response including the following: 1. According to the prescriber, the individual has experienced a clinically meaningful decrease in transfusion burden

Authorization Duration

Initial approval duration: • Beta-Thalassemia: up to 4 months • MDS-RS or MDS/MPN-RS-T: up to 6 months

Reauthorization approval duration: • Beta-Thalassemia: up to 12 months • MDS-RS or MDS/MPN-RS-T: up to 12 months

Conditions Not Covered

Luspatercept (Reblozyl) is considered experimental, investigational or unproven for ANY other use.

Coding / Billing Information

Note: 1) This list of codes may not be all-inclusive. 2) Deleted codes and codes which are not effective at the time the service is rendered may not be eligible for reimbursement.

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Covered when medically necessary when used to report Luspatercept (Reblozyl):

HCPCS Description Codes J0896 Injection, luspatercept-aamt, 0.25 mg

Background

OVERVIEW Reblozyl is an erythroid maturation agent indicated for the following conditions:1 • Beta-thalassemia, for treatment of adults with anemia who require regular red blood cell (RBC) transfusions. • Myelodysplastic syndromes with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) associated anemia, for those failing an erythropoiesis stimulating agent and requiring two or more RBC units over 8 weeks in adult patients with very low- to intermediate-risk disease.

Safety and efficacy have not been established in patients < 18 years of age.

Dosing Information For all indications, the starting dose is 1 mg/kg given subcutaneously once every 3 weeks.1 Assess and review hemoglobin levels and transfusion record prior to each dose. Discontinue if a patient does not experience a decrease in transfusion burden after 9 weeks of treatment (administration of three doses) at the maximum dose level. For beta thalassemia, the maximum recommended dose is 1.25 mg/kg given once every 3 weeks. For MDS and MDS/MPN, the maximum dose is 1.75 mg/kg given once every 3 weeks.

Disease Overview Beta-thalassemia, an inherited blood disorder, is characterized by reduced levels of functional hemoglobin.2 Patients with a severe form (beta-thalassemia major) become symptomatic due to low hemoglobin level (e.g., increased cardiac effort, tachycardia, poor growth) or ineffective erythropoiesis (e.g., bone changes, massive splenomegaly). Even with treatment, severe complications may arise due to iron overload secondary to increased intestinal absorption and frequent blood transfusions. The frequency of symptomatic patients with beta-thalassemia is estimated at approximately 1 in 100,000 individuals in the general population but is less common in the US.

Myelodysplastic syndromes are cancers in which cells in the bone marrow do not mature and become healthy blood cells.5 Patients with MDS with refractory anemia and ring sideroblasts have too few RBCs in the blood with too much iron inside the cell. However, the number of white blood cells and platelets are normal. Supportive therapy may include transfusions and use of erythropoiesis-stimulating agents (ESAs). ESAs may be given to increase the number of mature RBCs made by the body and to lessen the effects of anemia. Myelodysplastic/myeloproliferative neoplasms are diseases of the blood and bone marrow with features of myelodysplastic syndromes as well as myeloproliferative neoplasms (e.g., a greater than normal number of blood stem cells become one or more types of blood cells and the total number of blood cells slowly increases). In the pivotal study evaluating Reblozyl for MDS/MPN, patients with deletion 5q were excluded from enrollment. All patients were required to have disease refractory to ESAs (unless endogenous erythropoietin level was elevated), and the median pretransfusion hemoglobin level was 7.6 g/dL (range, 5 to 10 g/dL).

Guidelines Guidelines do not address Reblozyl for treatment of beta-thalassemia. Standards of Care Guidelines for Thalassemia (2012) are published by the Children’s Hospital and Research Center of Oakland.3 Life-long blood transfusions and iron chelation are the main treatments for beta-thalassemia. Transfusions are usually needed every 3 to 4 weeks and are recommended to maintain the pre-transfusion Hb level above 9 to 10 g/dL and post- transfusion Hb level should not exceed 14 g/dL. Blood transfusions are given to improve anemia as well as suppress ineffective erythropoiesis. Most serious growth, bone, and neurologic complications are prevented with

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regular transfusions. Once transfusions are started, transfusion-related complications become a major source of morbidity. Hydroxyurea is described as an experimental agent for beta-thalassemia. The Thalassaemia International Federation (2014) also recommends transfusions and iron chelation for treatment of beta- thalassemia.4 These guidelines state that transfusions are usually administered every 2 to 5 weeks and are recommended to maintain the pre-transfusion Hb level above 9 to 10.5 g/dL and post-transfusion Hb level below 14 to 15 g/dL. The primary goal of chelation therapy is to maintain safe levels of body iron by balancing iron from blood transfusion with iron excretion by chelation. Despite literature suggesting hydroxyurea may be beneficial in certain patients with beta-thalassemia, use is not recommended outside of a clinical trial.

The National Comprehensive Cancer Network (NCCN) guidelines for MDS (version 1.2021 – September 11, 2020) recommend Reblozyl in patients symptomatic anemia due to MDS, in patients without del(5q), who have no response to ESAs (defined by rise in hemoglobin level or decrease in transfusion burden) following 3 to 4 months of treatment.6 Reblozyl is also a treatment option for patients who have serum erythropoietin levels > 500 mU/mL. Reblozyl is also a treatment option for MDS/MPN with ring sideroblasts and thrombocytosis.

Appendix The revised International Prognostic Scoring System (IPPS-R) shows the same disease factors as IPSS, but in a more detailed way. The following five disease factors are: Blasts, Cytogenetics, Hemoglobin, Absolute neutrophil count, Platelet count.6

Factors Prognostic Factors Scored Risk Groups Based on Total IPPS-R Risk Score Blast cells in bone • Less than or equal to 2 = 0 marrow (percent) • Greater than 2 to less than 5 = 1 • 5 to 10 = 2 • Greater than 10 = 3 Cytogenics • -Y,del(11q) = 0 • Normal, del(5q), del(12p), del(20q), double including del(5q) = 1 • Del(7q), +8, +19, i(17q), any other Very Low = 1.5 or lower single or double including -7/del(7q), complex: 3 abnormalities = 3 Low = 2 to 3 • Greater than 3 abnormalities = 4 Cytopenias Hemoglobin level (g/dL) Intermediate = 3.5 to 4.5 • Equal to or greater than 10 = 0 High = 5 to 6 • 8 to less than 10 = 1

• Less than 8 = 1.5 Very High = 6.5 or greater Platelet count (x 109/L of blood) • Equal to or greater than 100 = 0 • 50 to less than 100 = 0.5 • Less than 50 = 1 Neutrophil count [(ANC) x 109/L of blood] • Equal to or greater than 0.8 = 0 • Less than 0.8 = 0.5

References

1. Reblozyl® for subcutaneous injection [prescribing information]. Summit; NJ and Cambridge, MA: Celgene/Acceleron Pharma; April 2020. 2. National Organization for Rare Disorders (NORD). Beta thalassemia. Available at: https://rarediseases.org/rare-diseases/thalassemia-major//. Accessed on November 17, 2020.

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2. Standards of Care Guidelines for Thalassemia – 2012. Children’s Hospital and Research Center Oakland. Available at: https://thalassemia.com/documents/SOCGuidelines2012.pdf. Accessed November 17, 2020. 3. Cappellini MD, Cohen A, Porter J, et al. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 3rd edition. Nicosia (CY): Thalassaemia International Federation; 2014. Available at: https://www.ncbi.nlm.nih.gov/books/NBK269382/. Accessed on November 17, 2020. 4. National Cancer Institute, National Institutes of Health. Myelodysplastic syndromes treatment. Updated September 10, 2020. Accessed on November 17, 2020. Available at: https://www.cancer.gov/types/myeloproliferative/patient/myelodysplastic-treatment-pdq. 5. The NCCN® Myelodysplastic Syndromes Clinical Practice Guidelines in Oncology (Version 1.2021 – September 11, 2020). 2020 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org/clinical.asp. Accessed on November 17, 2020. 6. Greenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring System for myelodysplastic syndromes. Blood 2012; 120: 2454-65.

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