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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Drugs
Policy Number:196
Effective Date: 07/13/2020
Original Policy Date:12/17/2019
Last Review Date:06/09/2020
Date Published to Web: 12/18/2019
Subject:
Luspatercept-aamt (Reblozyl)

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.

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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 people with beta thalassemia, low levels of hemoglobin lead to a lack of oxygen in many parts of the body and anemia, which can cause pale skin, weakness, fatigue and more serious complications. 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. People with beta thalassemia are also at an increased risk of developing abnormal blood clots.

On November 8, 2019, the U.S. Food & Drug Administration (FDA) approved Reblozyl (luspatercept-aamt) by Celgene and Acceleron Pharma. The FDA granted Fast Track designation and Orphan Drug designation to Reblozyl (luspatercept-aamt). This is the first therapy to treat anemia in adult patients with beta thalassemia in the US. Reblozyl (luspatercept-aamt) is an erythroid maturation agent indicated 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 (luspatercept-aamt) is a recombinant fusion protein that binds several endogenous TGF-B superfamily ligands, thereby diminishing Smad2/3 signaling. Reblozyl (luspatercept-aamt) promoted erythroid maturation through differentiation of late-stage erythroid precursors (normoblasts) in mice. In a model of B-thalassemia, Rebloyzl (luspatercept-aamt) decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis in mice.

The FDA approval of Reblozyl (luspatercept-aamt) was based on the safety and efficacy of phase 3 BELIEVE (NCT0260443) trial. The multicenter, randomized, double-blind, placebo-controlled trial enrolled 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 who were randomized 2:1 to Reblozyl (luspatercept-aamt) (n=224) or placebo (n=112). Reblozyl (luspatercept-aamt) 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 red blood cell (RBC) transfusions; iron-chelating agents; use of antibiotic, antiviral, and antifungal therapy; and/or nutritional support, as needed. The BELIEVE trial showed a highly statistically significant improvement in the primary endpoint of erythroid response, defined as at least a 33% cut from baseline in RBC transfusion burden with a reduction of at least two units during a defined period of 12 consecutive weeks, from weeks 13 to 24, compared to placebo. 21% of patients who received Reblozyl (luspatercept-aamt) achieved at least a 33% reduction in transfusions compared to 4.5% of patients who received placebo. Reblozyl (luspatercept-aamt) also met all key secondary endpoints of statistically significant improvements in RBC transfusion burden from baseline of at least 33 percent decrease during the weeks 37 to 48 period, and at least a 50 percent reduction from week 13 to week 24, at least a 50 percent decrease from weeks 37 to 48, and a mean change in transfusion burden from weeks 13 to 24.

The median duration of treatment was similar between Reblozyl (luspatercept-aamt) and placebo arms (63.3 weeks vs. 62.1 weeks, respectively). Per protocol, patients in the Reblozyl (luspatercept-aamt) and placebo arms were to remain on therapy for at least 48 weeks in the double-blind phase of the trial. Among patients receiving Reblozyl (luspatercept-aamt), 94% were exposed for 6 months or longer and 72% were exposed for greater than one year. The median age of patients who received Reblozyl (luspatercept-aamt) was 30 years (range 18-66); 59% female; 54% white, and 36% Asian.

The most common adverse reactions (>10%) in patients with beta thalassemia were headache, bone pain, arthralgia, fatigue, cough, abdominal pain, diarrhea, and dizziness. There is an increased risk in patients with beta thalassemia to develop thrombosis, thromboembolism, or hypertension. This medication may cause fetal harm and all females should use effective contraception.

Reblozyl (luspatercept-aamt) is administered by subcutaneous injection by a healthcare professional. The recommended starting dose is 1 mg/kg once every 3 weeks. Review hemoglobin (Hgb) results prior to each administration. Do not increase the dose beyond the maximum dose of 1.25 mg/kg.

On April 3, 2020, the Food and Drug Administration approved luspatercept-aamt (REBLOZYL) 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). The recommended starting dose of luspatercept-aamt is 1 mg/kg once every 3 weeks by subcutaneous injection. Review hemoglobin results prior to each administration.

Efficacy was demonstrated in the MEDALIST trial (NCT02631070), a randomized, multi-center, double-blind, placebo-controlled trial in 229 patients with IPSS-R very low, low, or intermediate-risk myelodysplastic syndromes who had ring sideroblasts and required RBC transfusions (2 or more RBC units over 8 weeks). Patients were randomized 2:1 to luspatercept-aamt or placebo. All patients received best supportive care, which included RBC transfusions. The main efficacy endpoint in MDS-RS and MDS-RS-T was the proportion of patients who were RBC-transfusion independent (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period between Weeks 1 and 24. Of the 153 patients who received luspatercept-aamt, 58 (37.9%, 95% CI: 30.2, 46.1) were RBC-TI for at least 8 weeks, compared to 10 patients (13.2%, 95% CI: 6.5, 22.9) who received placebo (treatment difference 24.6% (95% CI: 14.5, 34.6; p<0.0001.)


Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)


    I. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., hematologist, oncologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis
      II. Reblozyl (luspatercept-aamt) is considered medically necessary for the following diagnoses:
            • Anemia in adult patients (ages ≥ 18 years) with beta thalassemia who require regular red blood cell (RBC) transfusions (defined as 6-20 RBC units in the 24 weeks prior and no transfusion-free period for ≥ 35 days during that period) when ALL of the following criteria are met:
              • Diagnosis is confirmed by lab testing and/or chart notes (documentation required) AND member does not have hemoglobin (sickle) S/B-thalassemia or (alpha) a-thalassemia
              · Member is not currently pregnant
              · If member has a concurrent cancer diagnosis, member has an ECOG score of 0 or 1
              · Platelet count ≤ 1000 x 109/L
              · Member does not have deep vein thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to beginning treatment
              · Member does not have poorly controlled diabetes
              · Member must not have major organ damage (including liver, heart, lung and kidney disease)
              · Member must not have uncontrolled hypertension
              · Member must not have recent (≤ 24 weeks prior to beginning treatment) use of ESA (erythropoietin-stimulating agents such as procrit, epogen, etc.)
              · Member must not concurrently be on immunosuppressant therapy, hydroxyurea, or chronic anticoagulant therapy
              · Member must not have any of the following conditions:
                  o Active hepatitis C (HCV) infection
                  o Active infectious hepatitis B (HBV)
                  o Known human immunodeficiency virus (HIV) that is not controlled by ART (antiretroviral) therapy.
          • Anemia in adult patients (ages ≥ 18 years) 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), who have failed an erythropoiesis stimulating agent and require 2 or more RBC units over 8 weeks, when ALL of the following criteria are met:
            • Diagnosis is confirmed by documentation of MDS that meets classification of very low, low, or intermediate risk disease
            • There is <5% bone marrow blasts
            • There is presence of ring sideroblasts
            • Member is not currently pregnant
            • Member has an ECOG score of 0-2
            • Peripheral blood WBC count < 13,000/µL
            • Member requires red blood cell RBC transfusions (2 or more RBC units over 8 weeks)
            • Member must be refractory/intolerant/ineligible to prior ESA treatment
            • Member does not have secondary MDS (i.e. MDS that is known to have arisen as a result of chemical injury or treatment with chemotherapy and/or radiation for other diseases)
            • Member has not had a prior allogenic or autologous stem cell transplant
            • Member has not had prior use of a disease modifying agent for the treatment of MDS
          [INFORMATIONAL NOTE: As per the FDA labeled package insert: Limitations of use: Rebloyzl (luspatercept-aamt) is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia. Additionally the BELIEVE trial excluded patients with a diagnosis of hemoglobin (sickle) S/B-thalassemia or (alpha) a-thalassemia (eg, Hemoglobin H).]

      III. When Reblozyl (luspatercept-aamt) is medically necessary for the indications mentioned above, it is covered initially at the following doses and durations:
            • 1 mg/kg once every 3 weeks by subcutaneous injection administered by a healthcare professional
                • For beta thalasemia indication: If a patient does not achieve a reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose, increase the Reblozyl dose to 1.25 mg/kg. Do not increase the dose beyond the maximum dose of 1.25 mg/kg.
                  • Initial approval for 15 weeks (see table 1)
                • For MDS indication: If a patient is not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting dose, increase the Rebloyzl dose to 1.33 mg/kg. If a patient is not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1.33 mg/kg starting dose, increase the Rebloyzl dose to 1.75 mg/kg. Do not increase the dose more frequently than every 6 weeks or beyond the maximum dose of 1.75 mg/kg.
                  • Initial approval for 21 weeks (see table 2)
                  Table 1: Beta Thalassemia - Rebloyzl Dose Titration for Response

                  Rebloyzl Dosing Recommendation
                  Starting Dose1 mg/kg every 3 weeks
                  Dose Increases for Insufficient Response at Initiation of Treatment
                  No reduction in RBC transfusion burden after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting doseIncrease the dose to 1.25 mg/kg every 3 weeks
                  No reduction in RBC transfusion burden after at 3 consecutive doses (9 weeks) at the 1.25 mg/kg Discontinue treatment
            Table 2: MDS-RS and MDS/MPN-RS-T Associated Anemia - Rebloyzl Dose Titration for Response

            Rebloyzl Dosing Recommendation
            Starting Dose1 mg/kg every 3 weeks
            Dose Increases for Insufficient Response at Initiation of Treatment
            Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1 mg/kg starting doseIncrease the dose to 1.33 mg/kg every 3 weeks
            Not RBC transfusion-free after at least 2 consecutive doses (6 weeks) at the 1.33 mg/kg Increase the dose to 1.75 mg/kg every 3 weeks
            No reduction in RBC transfusion burden after at least 3 consecutive doses (9 weeks) at the 1.75 mg/kgDiscontinue treatment

            [INFORMATIONAL NOTE: As per the FDA labeled package insert dosing and administration section: Discontinue Reblozyl (luspatercept-aamt) if a patient does not experience a decrease in transfusion burden after 9 weeks of treatment (administration of 3 doses) at the maximum dose level or if unacceptable toxicity occurs at any time.

            If a planned administration of Rebloyzl (luspatercept-aamt) is delayed or missed, administer Rebloyzl (luspatercept-aamt) as soon as possible and continue dosing as prescribed, with at least 3 weeks between doses. Assess and review hemoglobin (Hgb) results prior to each administration. If an RBC transfusion occurred prior to dosing, the pretransfusion Hgb must be considered for dosing purposes. If the pre-dose Hgb is greater than or equal to 11.5 g/dL and the Hgb level is not influenced by recent transfusion, delay dosing until the Hgb is less than or equal to 11 g/dL.]
        IV. Continued Reblozyl (luspatercept-aamt) is subject to medical necessity review and will be approved annually if the following continuation criteria are met:
              a. Member continues to meet the criteria in section I and II; AND
              b. For beta thalassemia indication: member has a positive response/hematological improvement, defined as ≥ 33% reduction from baseline in red blood cell count (RBC) transfusion burden; OR
              c. For MDS indication: member has a positive response, defined as RBC transfusion independence during any consecutive 8-week period, decrease in transfusion requirement, or increase in hemoglobin; AND
              d. No unacceptable toxicity, such as severe thrombosis/ thromboembolism, hypertension, etc.
        V. Reblozyl (luspatercept-aamt) is considered medically necessary for the following off-label indications:
              • Myelodysplastic Syndromes
                • Treatment of lower risk* disease associated with symptomatic anemia with ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation)
                    • with serum erythropoietin >500 mU/mL
                    • with serum erythropoietin ≤500 mU/mL following no response to the combination of an erythropoiesis-stimulating agent (ESA) and granulocyte-colony stimulating factor (G-CSF)
                      *Lower risk defined as IPSS-R (Very Low, Low, Intermediate), IPSS (Low/Intermediate-1), WPSS (Very Low, Low, Intermediate)
        V. Other uses of Reblozyl (luspatercept-aamt) are considered investigational, including but not limited to anemia in non-transfusion-dependent beta-thalassemia, and anemia in myelofibrosis.

      Medicare Coverage:
      There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL specifically for this drug. Per Local Coverage Article A53127 Self-Administered Drug Exclusion List, Medicare covers drugs that are furnished “incident to” a physician’s service provided that the drugs are medically reasonable and necessary, approved by the Food and Drug Administration (FDA) and are not usually administered by the patients who take them. Therefore, Medicare Advantage Products will cover Luspatercept-aamt (Reblozyl) when the Horizon BCBSNJ Medical Policy criteria is met AND the drug is furnished and administered by a licensed medical provider as part of a physician service.

      Novitas Solutions, Inc., Local Coverage Article: Billing and Coding: Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents (A53049). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00024370.

      Novitas Solutions, Inc., Local Coverage Article: Self-Administered Drug Exclusion List: (A53127). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00024370.

      Medicaid Coverage:
      For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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      Horizon BCBSNJ Medical Policy Development Process:

      This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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      Index:
      Luspatercept-aamt (Reblozyl)
      Reblozyl (luspatercept-aamt)

      References:
      1. Reblozyl Prescribing Information. Celegene Corporation. Summit, NJ. April 2020. https://media.celgene.com/content/uploads/reblozyl-pi.pdf

      2. An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Adults Who Require Regular Red Blood Cell Transfusions Due to Beta (â) Thalassemia (BELIEVE). November 2019. https://clinicaltrials.gov/ct2/show/NCT02604433

      3. Reblozyl. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2019 [2019 November 25]. Available from www.clinicalpharmacology.com.

      4. AMCP (Academy of Managed Care Pharmacy) Dossier for REBLOZYL (luspatercept-aamt). Version 1.0. November 22, 2019.

      5. ClinicalTrials.gov. A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MEDALIST). NCT02631070. Available at: https://clinicaltrials.gov/ct2/show/NCT02631070

      6. National Comprehensive Cancer Network. NCCN Drugs & Biologics Compendium. Rebloyzl. 2020. Available at: https://www.nccn.org/professionals/drug_compendium/content/

      Codes:
      (The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

      CPT*

      HCPCS
      J0896

      * CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association
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      Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

      The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy

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