Description
Betibeglogene autotemcel (Zynteglo^®) is an autologous gene therapy which includes hematopoietic stem cells (HSCs) that have been genetically modified ex vivo. Betibeglogene autotemcel adds functional copies of a modified β-globin gene into patients’ hematopoietic (blood) stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 lentiviral vector (LVV). After Betibeglogene autotemcel infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce RBCs containing biologically active βA-T87Q-globin (a modified β-globin protein) that will combine with α-globin to produce functional adult Hb containing βA-T87Q-globin (HbAT87Q). βA-T87Q-globin expression is designed to correct the β/α-globin imbalance in erythroid cells of patients with β-thalassemia and has the potential to increase functional adult HbA and total Hb to normal levels and eliminate dependence on regular packed red blood cells (pRBC) transfusions.

Policy
Zynteglo is considered MEDICALLY NECESSARY when the following criteria is met:

1. Diagnosis of transfusion-dependent beta-thalassemia as confirmed by the presence of a mutation at both alleles of the β-globin gene (i.e., β0/β0, β0/β+, β+/β+, β0/βE) 
2. One of the following: 
   • Patient has a history of transfusions of at least 100 mL/kg/year of packed red blood cells (pRBCs) 
   • Patient requires 8 or more red blood cell (RBC) transfusions per year 
3. Patient is 4 years of age or older [A] 
4. Provider attests that patient is clinically stable and eligible to undergo hematopoietic stem cell transplant (HSCT) 
5. Patient has obtained a negative test result for all of the following prior to cell collection: 
   • Hepatitis B virus (HBV) 
   • Hepatitis C virus (HCV) 
   • Human T-lymphotrophic virus 1 & 2 (HTLV-1/HTLV-2) 
   • Human immunodeficiency virus (HIV) 
6. Patient is able to provide an adequate number of cells to meet the minimum recommended dose of 5 x 10^6 CD34+ cells/kg 
7. Patient does not have any of the following [1 – 4]: 
   • Severely elevated iron in the heart (e.g., patients with cardiac T2* less than 10 msec by MRI) 
   • Advanced liver disease 
   • MRI results of the liver demonstrating liver iron content greater than or equal to 15 mg/g (unless biopsy confirms absence of advanced disease) 
8. Both of the following: 
   • Iron chelation therapy (e.g., deferoxamine, deferasirox) will be discontinued for at least 7 days prior to initiating myeloablative conditioning therapy 
   • Prophylactic HIV anti-retroviral medications (e.g., Truvada, Descovy) or hydroxyurea will be discontinued for at least one month prior to mobilization (or for the expected duration for elimination of those medications) 
9. Prescribed by a stem cell transplant specialist or hematologist 
10. Patient has never received Zynteglo treatment in their lifetime

Zynteglo is considered NOT MEDICALLY NECESSARY for all other indications.

Rationale
β-Thalassemia
It is an inherited blood disorder that occurs as a result of a genetic variant in the HBB gene that codes for the production of β-globin chains. As a result, there is reduced synthesis or absence of β-globin chains leading to impaired production of hemoglobin. The clinical presentation is that of anemia which requires iron supplementation and multiple downstream sequelae from the disease. These sequelae include growth retardation, skeletal changes (particularly in the face and long bones of the legs), osteoporosis, leg ulcers, and development of extramedullary masses. High output heart failure from anemia is also common without treatment. Without transfusion therapy, such patients die within the first few years of life, primarily from heart failure or infection.

Life expectancy of individuals with transfusion-dependent β-thalassemia is much lower than population norms. From 2011 to 2021 the median age of death for a person in the US with transfusion-dependent β-thalassemia was 37.² Additionally, individuals with transfusion-dependent β-thalassemia report decreased quality of life due to the impact on physical and mental health.

All humans have 2 copies of the HBB gene, and each copy produces the β-globin protein. Different types of β-thalassemia categorized by genotype are summarized in Table 1. When only 1 HBB gene is affected, the phenotype is less severe, and individuals are generally asymptomatic due to compensation from the other normal gene. These individuals are called β-thalassemia minor or carrier. However, if both copies of HBB gene are affected there is a quantitative reduction or absence of β-globin protein. Phenotypes that manifest as a reduction in β-globin chains are referred to as “β-thalassemia intermedia” and phenotypes that manifest as absence in β-globin chains are called “β-thalassemia major."

More recently, patients have been classified according to their transfusion status (i.e., transfusion-dependent β-thalassemia or non-transfusion-dependent β-thalassemia). For this evidence review, we will focus on transfusion-dependent β-thalassemia patients which generally includes “β-thalassemia major” but occasionally may include patients with “β-thalassemia intermedia." Clinical studies reviewed define “transfusion dependence” as history of at least 100 mL/kg/year of peripheral red blood cells or ≥ 8 transfusions of peripheral red blood cells per year for the prior 2 years. “Transfusion independence” was defined as a weighted average hemoglobin (Hb) of at least 9 g/dL without any transfusions for a continuous period of at least 12 months at any time during the study after infusion of betibeglogene autotemcel.

Table 1. Different Types of β-Thalassemia^5,6,7

β⁰ refers to no beta globin production; β+ refers to decreased beta globin production.

Epidemiology
β-thalassemia is one of the most common monogenic disorders, but its incidence varies geographically. Higher incidence and prevalence have been reported among individuals from Mediterranean, Africa, the Middle East, and Southeast Asia. While its occurrence is rare in United States, the pattern shows an increasing trend with migration and is expected to increase in the future. According to Bluebird Bio, approximately 1500 people in the United States currently live with transfusion-dependent β-thalassemia.⁸

Diagnosis
The diagnostic pathway for symptomatic thalassemia syndromes (thalassemia major and thalassemia intermedia) in a neonate, infant, or child begins with either recognition of symptoms (anemia, evidence of hemolysis and extramedullary hematopoiesis such as jaundice, skeletal abnormalities, and/or splenomegaly) or may be suspected based on a known family history. Initial laboratory testing includes a complete blood count, review of the blood smear, and iron studies. DNA-based genotyping of globin gene can be done relatively inexpensively, is required for precise diagnosis, and is especially important in carrier detection, prenatal testing, and genetic counseling.⁵

Treatment
The current standard of care for transfusion-dependent β-thalassemia includes blood transfusion, iron chelation therapies, and allogenic hematopoietic stem cell transplant.

As per the 2014 Thalassemia International Federation guidelines, transfusion is indicated when hemoglobin levels are less than 7 g/dL on 2 different occasions more than 2 weeks apart, or when hemoglobin levels are greater than 7 g/dL but there are co-occurring complications such as facial changes, poor growth, fractures, or clinically significant extramedullary hematopoiesis. The goal of treatment is to maintain a hemoglobin level of 9 to 10.5 g/dL, which has been shown to promote normal growth, suppress bone marrow activity, and minimize iron accumulation.^9,10 Transfusions are typically required every 2 to 5 weeks to reach this goal but can vary for patients such as those with heart failure who may require higher target hemoglobin levels.¹¹ Risks of repeated blood transfusions include transfusion reactions, allergic reactions, hemolytic anemia, transfusion-related acute lung injury, and transfusion-related graft versus host disease and alloimmunization.¹² In the event of alloimmunization, it becomes difficult to find a matched blood and also increases the likelihood of delayed transfusion reactions. However, the main complication from frequent blood transfusions is iron overload.

Iron overload as a result of frequent transfusion results in iron accumulation in the heart, liver, and pituitary gland and can lead to heart failure, cirrhosis, hepatocellular carcinoma, hypothyroidism, hypoparathyroidism, hypogonadism, diabetes, and growth failure.¹³ Primary treatment for iron overload is chelation therapy (desferrioxamine, deferasirox, deferiprone) and is typically initiated after 10 to 20 transfusions or when the serum ferritin level rises above 1000 mcg/L.¹⁴ Chelation therapy is associated 
with side effects such as hearing problems, bone growth retardation and local reactions, gastrointestinal symptoms, arthralgia, and neutropenia. Another limitation of chelation therapy is lack of adherence when infused therapies are used as compared to higher adherence for patients taking oral therapy.¹⁵

Hematopoietic stem cell transplant is the only curative treatment with cure rates ranging from 80% to 90% in children who receive human leukocyte antigen-identical sibling transplant.¹⁶ Cure rates in adults are lower with a reported range of 65% to 70%.¹⁷ While the cure rates are high, the main limiting factor for hematopoietic stem cell transplant is lack of a compatible donor. Fewer than 25% of patients have compatible related or unrelated donors, and transplants with mismatched donors or unrelated umbilical cord blood have a lower success rate.¹⁸ Complications from hematopoietic stem cell transplant include mucositis, infection, graft failure, and graft versus host disease. If available, hematopoietic stem cell transplant should be offered to patients early in the disease course, prior to the onset of iron overload.¹⁴

There are no randomized trials comparing hematopoietic stem cell transplant with medical therapy for transfusion-dependent thalassemia.¹⁹ Only a 2017 retrospective case-control study has been published, showing no statistically different overall survival with transplantation versus conventional medical therapy (e.g., transfusions and iron chelation).¹⁷ The Center for International Blood and Marrow Transplant Research reported the results of a retrospective cohort of 1110 individuals with β-thalassemia who received a hematopoietic stem cell transplant between 2000 and 2016. The median age at transplantation was 6 years (range: 1 to 25 years), 61% received transplants with grafts from HLA-matched related donors, 7% from HLA-mismatched related donors, 23% from HLA-matched unrelated donors, and 9% from HLA-mismatched unrelated donors. The results are summarized in Table 2.

Table 2. Outcomes of Retrospective Cohort of Individuals Who Received Hematopoietic Stem Cell Transplant for β-Thalassemia

^a Matched relative representative of matched sibling in this study. 
GVHD: Graft-versus-host disease

Description
β-thalassemia is a genetic hemoglobinopathy that results from defects in β-globin synthesis leading to reduced synthesis or absence of β-globin chains causing impaired production of hemoglobin. The clinical presentation is that of anemia which requires transfusion and multiple downstream sequelae from iron overload. It is estimated that at least 1000 people in the United States have transfusion-dependent β-thalassemia. Betibeglogene autotemcel contains autologous CD34+ hematopoietic stem cells in which 
functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) have been added. Once the hematopoietic stem cells reengineered with βA-T87Q are infused, they engraft in the bone marrow and differentiate to produce red blood cells containing βA-T87Q gene that will produce HbAT87Q protein (functional gene therapy-derived hemoglobin) at levels that may eliminate or significantly reduce the need for transfusions.

Summary of Evidence
For individuals with transfusion-dependent β-thalassemia who receive betibeglogene autotemcel, the evidence includes 2 single-arm studies: HGB-207 (Northstar-2) and HGB-212 (Northstar-3). The Northstar-2 trial enrolled non- β0β0 genotype (less severe phenotype) while Northstar-3 trial enrolled β-thalassemia patients with either a β0or β+ IVS1 110 (G > A) variant (severe phenotype) at both alleles of the HBB gene. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related morbidity and treatment-related mortality. The 2 open-label, phase III, single-arm studies included a total of 41 individuals who received a single intravenous infusion of betibeglogene autotemcel. Of the 41 participants, 36 participants in whom transfusion independence was evaluable were included in the efficacy analysis. Transfusion independence was achieved in 89% (95% CI, 74% to 97%) of study participants. Limitations include a small sample size and limited duration of follow-up. There is uncertainty regarding the durability of effect over a longer time period. Long-term follow-up ( > 15 years) is required to establish precision around durability of the treatment effect. The small sample size creates uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and, as such, may not be observed in small trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty still remains about the degree of risk with betibeglogene autotemcel infusion in real-world practice. Insertional oncogenesis has been identified as a 
potential risk with transgene integration. There has been no evidence of insertional oncogenesis and no malignancies in the trials of betibeglogene autotemcel. However, cases of myelodysplastic syndrome and acute myeloid leukemia have been reported in gene therapy trials that use a lentiviral vector to treat other 
conditions. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

References

1. Zynteglo [package insert]. Somerville, MA; Bluebird bio, Inc: August 2022. Accessed August 2022.
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 August 2022.
4. Origa R. Beta-Thalassemia. 2000 Sep 28 [Updated 2021 Feb 4]. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1426/. Accessed August 2022.
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
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10. Chieco P and Butler C. 2021 CAF Information - The Cooleys Anemia Foundation. Published January 21st, 2022; Available at www.thalassemia.org/2021-caf-information/. Accessed Aug 3, 2022
11. Arian M, Mirmohammadkhani M, Ghorbani R, et al. Health-related quality of life (HRQoL) in beta-thalassemia major (-TM) patients assessed by 36-item short form health survey (SF-36): a meta-analysis. Qual Life Res. Feb 2019; 28(2): 321-334. PMID 30194626
12. Vitrano A, Calvaruso G, Lai E, et al. The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the major-intermedia dichotomy?. Br J Haematol. Jan 2017; 176(1): 124-130. PMID 27748513
13. Origa R. Beta-Thalassemia. 2000 Sep 28 [Updated 2021 Feb 4]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1426/
14. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. May 21 2010; 5: 11. PMID 20492708
15. Chonat S, Quinn CT. Current Standards of Care and Long Term Outcomes for Thalassemia and Sickle Cell Disease. Adv Exp Med Biol. 2017; 1013: 59-87. PMID 29127677
16. beta-thalassemia (beta-thal). Bluebird Bio. https://www.bluebirdbio.com/our-focus/transfusion-dependant-beta-thalassemia. Accessed July 15, 2022
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18. Cazzola M, Locatelli F, De Stefano P. Deferoxamine in thalassemia major. N Engl J Med. Jan 26 1995; 332(4): 271-2; author reply 272-3. PMID 7808503
19. Kremastinos DT, Farmakis D, Aessopos A, et al. Beta-thalassemia cardiomyopathy: history, present considerations, and future perspectives. Circ Heart Fail. May 2010; 3(3): 451-8. PMID 20484195
20. Thompson AA, Cunningham MJ, Singer ST, et al. Red cell alloimmunization in a diverse population of transfused patients with thalassaemia. Br J Haematol. Apr 2011; 153(1): 121-8. PMID 21323889
21. Olivieri NF, Liu PP, Sher GD, et al. Brief report: combined liver and heart transplantation for end-stage iron-induced organ failure in an adult with homozygous beta-thalassemia. N Engl J Med. Apr 21 1994; 330(16): 1125-7. PMID 8133854
22. Cappellini MD, Cohen A, Porter J, et al., editors. Guidelines for the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 3rd edition. Nicosia (CY): Thalassaemia International Federation; 2014. Available from: https://www.ncbi.nlm.nih.gov/books/NBK269382/
23. Trachtenberg F, Vichinsky E, Haines D, et al. Iron chelation adherence to deferoxamine and deferasirox in thalassemia. Am J Hematol. May 2011; 86(5): 433-6. PMID 21523808
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26. 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. May 2014; 99(5): 811-20. PMID 24790059
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31. Prescribing Label: ZYNTEGLO (betibeglogene autotemcel) suspension for intravenous infusion. Initial U.S. Approval: 2022. Available at https://www.fda.gov/media/160991/download. Accessed Aug 17, 2022
32. Institute for Clinical and Evidence Review. Betibeglogene Autotemcel for Beta Thalassemia: Effectiveness and Value (Final Evidence Report July 19, 2022). Available at https://icer.org/beta-thalassemia-2022/. Accessed August 4, 2022.
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