Betibeglogene Autotemcel (Zynteglo)

Number: 1016

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses betibeglogene autotemcel (Zynteglo) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of betibeglogene autotemcel (Zynteglo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of betibeglogene autotemcel, contact National Medical Excellence (NME) at 877-212-8811.

Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes® Gene Based, Cellular and Other Innovative Therapy (GCIT®) Network. For betibeglogene autotemcel (Zynteglo), see Aetna Institutes® GCIT Designated Centers. 

  1. Prescriber Specialties

    This medication must be prescribed by or in consultation with a hematologist.

  2. Criteria for Initial Approval

    Aetna considers a one dose total of betibeglogene autotemcel (Zynteglo) as medically necessary for transfusion-dependent beta-thalassemia when all of the following criteria are met:

    1. Member is 4 years of age or older and meets both of the following criteria:

      1. Member weighs at least 6 kg; and
      2. Member is reasonably anticipated to provide at least the minimum number of cells required to initiate the manufacturing process; and
    2. Member has a diagnosis of transfusion-dependent beta-thalassemia with a non-β0/β0 or β0/β0 genotype confirmed via genetic testing (see Appendix for examples); and
    3. Member requires regular blood cell transfusions and meets one of the following criteria within the previous two years:

      1. Member has received at least 100 milliliter per kilogram of packed red blood cells (pRBCs) per year; or
      2. Member has received at least 8 transfusions events of packed red blood cells (pRBCs) per year; and
    4. Member is eligible for a hematopoietic stem cell transplant (HSCT) but is unable to find a matched related donor; and
    5. Member has not received a prior hematopoietic stem cell transplant (HSCT); and
    6. Member has not received Zynteglo or any other gene therapy previously.

    Aetna considers all other indications as experimental, investigational, or unproven.

  3. Related Policies

Dosage and Administration

Betibeglogene autotemcel is available as Zynteglo, which is a cell suspension for intravenous infusion indicated for the treatment of adult and pediatric persons with β-thalassemia who require regular red blood cell (RBC) transfusions. Zynteglo is supplied in up to four 20 mL infusion bags containing a frozen suspension of genetically modified autologous cells, enriched for CD34+ cells. A single dose of Zynteglo contains a minimum of 5.0 × 106 CD34+cells/kg of body weight.

For autologous use only.

  • Persons are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for Zynteglo manufacturing. 
  • Dosing of Zynteglo is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. 
  • The minimum recommended dose is 5.0 × 106 CD34+ cells/kg. 
  • Full myeloablative conditioning must be administered before infusion of Zynteglo.
  • Prophylaxis for hepatic veno-occlusive disease (VOD) is recommended. Prophylaxis for seizures should be considered. 
  • Verify that the person’s identity matches the unique patient identification information on the Zynteglo infusion bag(s) prior to infusion. 
  • Do not sample, alter, or irradiate Zynteglo. 
  • Do not use an in-line blood filter or an infusion pump. 
  • Each infusion bag of Zynteglo is administered via intravenous infusion over a period of less than 30 minutes.

Source Bluebird Bio, 2022c

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Other CPT codes related to the CPB:
36430 Transfusion, blood or blood components
36440 Push transfusion, blood, 2 years or younger
36450 Exchange transfusion, blood; newborn
36455      other than newborn
36456 Partial exchange transfusion, blood, plasma or crystalloid necessitating the skill of a physician or other qualified health care professional, newborn
38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic
38206     autologous
38207 Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage
38208     thawing of previously frozen harvest, without washing, per donor
38209     thawing of previously frozen harvest, with washing, per donor
38215     cell concentration in plasma, mononuclear, or buffy coat layer
38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241     autologous transplantation
96365 - 96368 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96413 - 96415 Chemotherapy administration, intravenous infusion technique

HCPCS codes covered if selection criteria are met:
J3393 Injection, betibeglogene autotemcel, per treatment

ICD-10 codes covered if selection criteria are met:
D56.1 Beta thalassemia

Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

  • Zynteglo is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular blood cell (RBC) transfusions.

Betibeglogene autotemcel, also known as beti-cel, is branded as Zynteglo (Bluebird Bio, Inc.). Zynteglo is an autologous hematopoietic stem cell-based gene therapy (HSCT) indicated for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions. Zynteglo works by adding functional copies of a modified form of the beta-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic stem cells to allow them to make normal to near normal levels of total hemoglobin without regular RBC transfusions. The functional beta-globin gene is added into a patient’s cells outside of the body (ex-vivo), and then infused into the patient. Though Zynteglo is designed to be administered to the patient once, the treatment process is comprised of several steps that may take place over the course of several months.

Labeled warnings and precautions include delayed platelet engraftment, risk of neutrophil engraftment failure, risk of insertional oncogenesis, and hypersensitivity reactions.

The most common adverse reactions associated with Zynteglo included reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia, alopecia, epistaxis, abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder and pruritus. 

There is a potential risk of blood cancer associated with this treatment; however, no cases have been seen in studies of Zynteglo. Patients who receive Zynteglo should have their blood monitored for at least 15 years for any evidence of cancer. Patients should also be monitored for hypersensitivity reactions during Zynteglo administration and should be monitored for thrombocytopenia and bleeding (FDA, 2022). 

Beta-Thalassemia

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

On August 17, 2022, the U.S. Food and Drug Administration (FDA) announced the approval of Zynteglo (betibeglogene autotemcel), the first cell-based gene therapy for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions. Zynteglo is a one-time gene therapy product administered as a single dose. Each dose of Zynteglo is a customized treatment created using the patient’s own cells (bone marrow stem cells) that are genetically modified to produce functional beta-globin (a hemoglobin component). 

The safety and effectiveness of Zynteglo were established in 2 ongoing Phase 3 open-label, single-arm, 24-month, multicenter clinical studies (Northstar-2, NCT02906202 and Northstar-3, NCT03207009) that included adult and pediatric patients (aged 4 to 34 years) with beta-thalassemia requiring regular transfusions. All patients (n = 41) were administered Zynteglo with a median (min, max) dose of 9.4 (5.0, 42.1) × 106 CD34+ cells/kg as an intravenous infusion. The primary endpoint for both studies was the proportion of patients who achieved transfusion independence, defined as a weighted average total hemoglobin (Hb) of at least 9 g/dL without any packed RBC (pRBC) transfusions for at least 12 months. Of 41 patients receiving Zynteglo, 89% achieved transfusion independence. Following completion of the 24-month parent studies, patients were invited to enroll in an ongoing long-term safety and efficacy follow-up study for an additional 13 years (Study 3). Patients were considered to be eligible for the Phase 3 studies if they had a history of transfusions of at least 100 mL/kg/year of pRBCs or with 8 or more transfusions of pRBCs per year in the 2 years preceding enrollment. Patients who had 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 were not accepted into the studies. MRI of the liver was performed on all patients. Patients older than 18 years with MRI results demonstrating liver iron content greater than or equal to 15 mg/g underwent liver biopsy for further evaluation. Patients younger than 18 years with MRI results demonstrating liver iron content greater than or equal to 15 mg/g were excluded from the studies unless a liver biopsy could provide additional data to confirm eligibility. Patients with a liver biopsy demonstrating bridging fibrosis, cirrhosis, or active hepatitis, were also excluded (Bluebird Bio, 2022; FDA, 2022).

Study 1 (Northstar-2; NCT02906202) conducted by Locatelli et al (2022), evaluated the efficacy and safety of betibeglogene autotemcel (beti-cel) in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β0/β0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of greater than or equal to 9 g per deciliter without red-cell transfusions for 12 months or more). A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months. Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter. Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. The authors concluded that treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-β0/β0 genotype, including those younger than 12 years of age.  

Among 14 evaluable patients in Study 2 (Northstar-3; NCT03207009), 12 (86%) achieved transfusion independence (TI) with a median (min, max) weighted average Hb during TI of 10.20 g/dL. All patients who achieved TI were able to maintain TI with a min, max duration of ongoing TI of 12.5+, 32.8+ months. The median (min, max) time to last pRBC transfusion prior to TI was 0.8 (0.0, 1.9) months following Zynteglo infusion (Park, 2022).

Inclusion criteria for Study 1 and Study 2 required (not an all-inclusive list): weight of a minimum of 6 kilograms (kg) and are reasonably anticipated to be able to provide at least the minimum number of cells required to initiate the manufacturing process; a diagnosis of transfusion-dependent β-thalassemia (TDT) with a history of at least 100 milliliter per kilogram per year (mL/kg/year) of pRBCs in the 2 years preceding enrollment (all participants), or be managed under standard thalassemia guidelines with greater than or equal to 8 transfusions of pRBCs per year in the 2 years preceding enrollment (participants 12 years or older).

Exclusion criteria for Study 1 and Study 2 (not an all-inclusive list) were: presence of a mutation characterized as β0 mutation at both alleles of the β-globin gene (HBB) gene (Study 1); presence of a mutation characterized as other then β0 (e.g., β+, βE, βC) on at least one β-globin gene (HBB) allele (Study 2); positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 and HIV-2), hepatitis B virus (HBV), or hepatitis C (HCV); any prior or current malignancy; prior hematopoietic stem cell transplantation (HSCT); advanced liver disease; a cardiac T2* less than 10 ms by MRI; prior receipt of gene therapy; and a known and available human leukocyte antigen (HLA) matched family donor.

Appendix

Examples of non-β0/β0 OR β0/β0 genotypes:

  • β0/β0
  • β0/β+
  • βE/β0
  • β0/IVS-I-110
  • IVS-I-110/IVS-1-110.

References

The above policy is based on the following references:

  1. Bluebird Bio. A study evaluating the efficacy and safety of the LentiGlobin® BB305 drug product in participants with transfusion-dependent β-thalassemia. ClinicalTrials.gov Identifier: NCT03207009. Bethesda, MD: National Library of Medicine; February 21, 2022a.
  2. Bluebird Bio. A study evaluating the efficacy and safety of the LentiGlobin® BB305 drug product in participants with transfusion-dependent β-thalassemia, who do not have a β0/β0 genotype. ClinicalTrials.gov Identifier: NCT02906202. Bethesda, MD: National Library of Medicine; April 27, 2022b.
  3. Bluebird Bio, Inc. Zynteglo (betibeglogene autotemcel) suspension for intravenous infusion. Prescriber Information. Somerville, MA: Bluebird Bio; revised August 2022c.
  4. Cappellini MD, Farmakis D, Porter J, et al. 2021 guidelines for the management of transfusion dependent thalassaemia (TDT). Nicosia, Cyprus: Thalassaemia International Federation, 2021.
  5. Lal A, Locatelli F, Kwiatowski JL, et al. Northstar-3: Interim results from a phase 3 study evaluating lentiglobin gene therapy in patients with transfusion-dependent β-thalassemia and either a β0 or IVS-I-110 mutation at both alleles of the HBB gene. Blood 2019;134 (Supplement 1): 815.
  6. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene autotemcel gene therapy for non-β0/β0 genotype β-thalassemia. N Engl J Med. 2022;386(5):415-427.
  7. Park B. Zynteglo approved as first gene therapy for beta-thalassemia. MPR. August 18, 2022.
  8. U.S. Food and Drug Administration (FDA). FDA approves first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular blood transfusions. FDA News Release. Silver Spring, MD: FDA; August 17, 2022.