Last Review Date: 04/04/2024

Date of Origin: 09/01/2022

Dates Reviewed: 09/2022, 04/2023, 04/2024

1. Length of Authorization ¹

Coverage will be provided for one treatment course (1 dose of Zynteglo) and may not be renewed.

2. Dosing Limits

A. Quantity Limit (max daily dose) [NDC Unit]:

• A single dose of Zynteglo containing a minimum of 5.0 × 10⁶ CD34+ cells/kg of body weight, in one or more infusion bags

B. Max Units (per dose and over time) [HCPCS Unit]:

• A single dose of Zynteglo containing a minimum of 5.0 × 10⁶ CD34+ cells/kg of body weight, in one or more infusion bags

3. Initial Approval Criteria ¹

Coverage is provided in the following conditions:

• Patient is at least 4 years of age; AND

• Provider has considered use of prophylaxis therapy for seizures prior to initiating myeloablative conditioning; AND
• Patient has been screened for hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotrophic virus 1 & 2 (HTLV-1/HTLV-2), and human immunodeficiency virus (HIV) in accordance with clinical guidelines prior to collection of cells (leukapheresis); AND
• Patient does not have a history of hypersensitivity to dimethyl sulfoxide (DMSO); AND
• Patient has not used prophylactic HIV anti-retroviral medication or hydroxyurea within 30 days prior to mobilization (or for the expected duration for elimination of those medications) and until all cycles of apheresis are completed (Note: if a patient requires anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis); AND
• Iron chelation therapy has been discontinued for at least 7 days prior to initiating myeloablative conditioning therapy and myelosuppressive iron chelators will be avoided for 6 months post-treatment; AND
• Patient has not received other gene therapies [e.g.,Casgevy™ (exagamglogene autotemcel), etc.]**; AND
• Patient will receive periodic life-long monitoring for hematological malignancies; AND
• Patient is eligible to undergo hematopoietic stem cell transplant (HSCT) and has not had prior HSCT; AND
• Patient does not have a known and available human leukocyte antigen (HLA) matched family donor willing to participate in an allogeneic HSCT; AND

Beta Thalassemia † Ф ^1,4-7

• Patient has a documented diagnosis of beta thalassemia (excludes alpha-thalassemia and hemoglobin S/ß-thalassemia variants) as outlined by the following:
  • Patient diagnosis is confirmed by HBB sequence gene analysis showing biallelic pathogenic variants; OR
  • Patient has severe microcytic hypochromic anemia, absence of iron deficiency, anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and hemoglobin analysis that reveals decreased amounts or complete absence of hemoglobin A (HbA) and increased HbA₂ with or without increased amounts of hemoglobin F (HbF); AND
• Patient has transfusion-dependent disease defined as a history of transfusions of at least 100 mL/kg/year of packed red blood cells (pRBCs) or with 8 or more transfusions of pRBCs per year in the 2 years preceding therapy; AND
• Patient will be maintained at a Hb ≥ 11 g/dL for 30 days prior to mobilization and 30 days prior to myeloablative conditioning; AND
• Patient does not have any of the following:
  • Severely elevated iron in the heart (i.e., patients with cardiac T2* less than 10 msec by magnetic resonance imaging [MRI]); OR
  • Advanced liver disease (i.e., persistent AST, ALT, or direct bilirubin value > 3 times the upper limit of normal (ULN), baseline prothrombin time or partial thromboplastin time > 1.5 times the ULN, MRI of the liver demonstrated cirrhosis, or liver biopsy demonstrated bridging fibrosis, active hepatitis, or cirrhosis); OR
  • Patients with an MRI of the liver with results demonstrating liver iron content ≥ 15 mg/g (unless biopsy confirms absence of advanced disease)

** Requests for subsequent use of betibeglogene after receipt of other gene therapies (e.g., exagamglogene, etc.) will be evaluated on a case-by-case basis      

† FDA Approved Indications; ‡ Compendia Recommended Indication(s); Ф Orphan Drug

4. Renewal Criteria ¹

Coverage cannot be renewed.

5. Dosage/Administration ¹

6. Billing Code/Availability Information

HCPCS Code(s):

• J3590 – Unclassified biologics
• C9399 – Unclassified drugs or biologicals (for hospital outpatient use ONLY)

NDC:

• Zynteglo up to 4 infusion bags, 20 mL/infusion bag, overwrap, and metal cassette: 73554-3111-xx

7. References

1. Zynteglo [package insert]. Somerville, MA; Bluebird bio, Inc: August 2022. Accessed March 2024.
2. Lai, X., Liu, L., Zhang, Z. et al. Hepatic veno-occlusive disease/sinusoidal obstruction syndrome after hematopoietic stem cell transplantation for thalassemia major: incidence, management, and outcome. Bone Marrow Transplant 56, 1635–1641 (2021)
3. Galanello R and Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010 May 21;5:11. Available at: https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-5-11. Accessed March 2024.
4. Origa R. Beta-Thalassemia. 2000 Sep 28 [Updated 2024 Feb 8]. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1426/. Accessed March 2024.
5. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene Autotemcel Gene Therapy for Non-β(0)/β(0) Genotype β-Thalassemia. N Engl J Med. 2022 Feb 3;386(5):415-427. doi: 10.1056/NEJMoa2113206. Epub 2021 Dec 11.
6. Schneiderman, J, Thompson AA, Walters MC, et al. Interim Results from the Phase 3 Hgb-207 (Northstar-2) and Hgb-212 (Northstar-3) Studies of Betibeglogene Autotemcel Gene Therapy (LentiGlobin) for the Treatment of Transfusion-Dependent β-Thalassemia. Bio Blood Marrow Trnsplt. Volume 26, Issue 3, Supplement, March 2020, Pages S87-S88. https://doi.org/10.1016/j.bbmt.2019.12.588
7. Magrin E, Semeraro M, Hebert N, et al. Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial. Nat Med. 2022 Jan;28(1):81-88. doi: 10.1038/s41591-021-01650-w. Epub 2022 Jan 24.
8. Beaudoin FL, Richardson M, Synnott PG, et al. Betibeglogene Autotemcel for Beta Thalassemia: Effectiveness and Value; Final Evidence Report. Institute for Clinical and Economic Review, July 19, 2022. https://icer.org/beta-thalassemia-2022/#timeline

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

The preceding information is intended for non-Medicare coverage determinations. Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determinations (NCDs) and/or Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. Local Coverage Articles (LCAs) may also exist for claims payment purposes or to clarify benefit eligibility under Part B for drugs which may be self-administered. The following link may be used to search for NCD, LCD, or LCA documents: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications, including any preceding information, may be applied at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCD/LCA): N/A