CurrentCignaPolicy IP0486

Hematology - Gene Therapy - Zynteglo (betibeglogene autotemcel) Coverage Policy

Defines Cigna's coverage, prior authorization, and medical necessity criteria for one-time administration of Zynteglo in patients with transfusion-dependent beta-thalassemia, including clinical, laboratory, and documentation requirements for providers and plan determinations.

Policy Summary

PayerCigna

PolicyHematology - Gene Therapy - Zynteglo (betibeglogene autotemcel) Coverage Policy

Policy CodePolicy IP0486

Change TypeRevisions & clarifications (2024–2026)

Effective DateThe policy effective date is in force until updated or retired.

Next Review Date

Key ActionObtain prior authorization; approvals are one-time (per lifetime) with 1-year duration to allow preparation and administration.

SourceLink

POLICY UPDATE CHANGES

The upper age threshold (< 51 years of age) was removed; lower age threshold remains ≥ 4 years of age.

The liver iron concentration threshold was changed from ≥ 15.5 mg/g to ≥ 15 mg/g to align with labeling.

Patient screening requirement for certain viruses was reworded to 'Patient screening is negative for ALL of the following...' removing prior phrasing referencing collection/manufacturing.

Conditions Not Covered updated to specify 'Concomitant Use with Aqvesme (mitapivat tablets) or Reblozyl (luspatercept-aamt subcutaneous injection)'.

one-timedosing/approval frequency

≥5.0 x10^6 CD34+/kgrequired cell dose

Age ≥4

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minimum eligible age

86–91%efficacy (NORTHSTAR)

1 yearapproval duration

Coverage Criteria for Zynteglo (Initial Therapy)

Initial Therapy (FDA-Approved Indication)

Approve a one-time (per lifetime) single dose if the patient meets ALL of the following (A through P):

Main FDA-Approved Criteria: A) Patient is ≥ 4 years of age;

B) Patient has not received a gene therapy for beta-thalassemia in the past (verify claims history or physician attestation);

C) Prescribing physician deems hematopoietic stem cell transplantation appropriate for the patient;

D) Patient meets ONE of the following:

ONE of: i. No HLA-matched donor
OR: ii. Has an HLA-matched donor who is unable or unwilling to donate

E) Patient has ONE of the following genotypes as confirmed by genetic testing (documentation required):

ONE of: i. Nonβ0/β0 genotype (examples include β0/β+, βE/β0, β+/β+)
OR: ii. β0/β0 genotype (examples include β0/β+(IVS-I-110) and β+(IVS-I-110)/β+(IVS-I-110))

F) Patient is transfusion-dependent, defined by ONE of the following (documentation required):

ONE of: i. Receipt of ≥ 100 mL packed red cells/kg/year in the previous 2 years
OR: ii. Receipt of ≥ 8 transfusions per year in the previous 2 years

G) Patient meets BOTH of the following (documentation required):

i: Patient has been evaluated for the presence of severe iron overload
ii: Patient does not have evidence of severe iron overload (examples: myocardial T2* < 10 ms, liver iron concentration ≥ 15 mg/g, abnormal liver biopsy, or clinical organ damage)

H) Patient does not have an active bacterial, viral, fungal, or parasitic infection;

I) Patient does not have any of the following:

i: Prior or current malignancy, myeloproliferative disorder, or significant immunodeficiency (excludes adequately treated carcinoma in situ of the cervix and non-melanoma skin cancers)
ii: Advanced liver disease (examples include ALT or AST > 3× ULN, direct bilirubin > 3× ULN, active hepatitis, extensive bridging fibrosis, or cirrhosis) [documentation required]

J) Patient will discontinue iron chelation therapy for at least 7 days prior to myeloablative conditioning;

K) Patient meets ALL of the following related to mobilization and conditioning:

i: Planned mobilization, apheresis, and myeloablative conditioning
ii: Use of a granulocyte-colony stimulating factor and a hematopoietic stem cell mobilizer (e.g., filgrastim and plerixafor)
iii: Use of busulfan for myeloablative conditioning
iv: Total hemoglobin ≥ 11.0 g/dL at BOTH timepoints: prior to mobilization and prior to myeloablative conditioning

L) Patient screening is negative for ALL of the following (documentation required):

i: HIV-1 and -2
ii: Hepatitis B virus
iii: Hepatitis C virus
iv: Human T-lymphotropic virus-1 and -2

M) Reproductive potential requirements (per prescribing physician):

i Female of reproductive potential: Female: negative serum pregnancy test prior to mobilization and prior to conditioning AND effective contraception from mobilization through at least 6 months after Zynteglo
ii Male of reproductive potential: Male: use effective contraception from mobilization through at least 6 months after Zynteglo

N) Medication is prescribed by a hematologist or stem cell transplant specialist;

O) Current patient body weight obtained within 30 days (documentation required);

P) If criteria A–O are met, approve one IV dose of Zynteglo providing a minimum of 5.0 x 10^6 CD34+ cells/kg (verification required).

Zynteglo (betibeglogene autotemcel) is covered only for the FDA‑approved indication and dosing described elsewhere in this policy. Use of Zynteglo for any other indication, regimen, or clinical situation is not medically necessary. This includes, but is not limited to, use outside the specified patient selection criteria, dosing frequency, or clinical workflows required for infusion and follow‑up.

Zynteglo is not medically necessary for patients who have previously undergone hematopoietic stem cell transplantation (allogeneic or autologous) or who have received prior gene therapy. The prescribing clinician must confirm and document that the patient has not received a prior hematopoietic stem cell transplant or prior gene therapy before approval will be considered. Additionally, concomitant use with Aqvesme (mitapivat) or Reblozyl (luspatercept‑aamt) is specifically listed as a condition not covered.

Coding, Clinical Thresholds, and Key Clinical Values

Considered Medically Necessary when criteria metHCPCSCovered

J3393

Injection, betibeglogene autotemcel, per treatment

Transfusion dependence — thresholds

Transfusion dependenceReceipt of ≥ 100 mL packed red cells/kg/year in the previous 2 years OR receipt of ≥ 8 transfusions per year in the previous 2 years

DocumentationTransfusion history for the prior 2 years required

Timing windowAssessment based on transfusions received during the previous 2 years

Hemoglobin — requirement

Hemoglobin requirementTotal hemoglobin ≥ 11.0 g/dL at both timepoints: prior to mobilization and prior to myeloablative conditioning

Timepoints specifiedMeasure hemoglobin immediately prior to mobilization and again prior to conditioning

Prior Authorization, Documentation, and Pre-treatment Requirements

Prior Authorization

Prior Authorization Required

Prior Authorization is required for benefit coverage of Zynteglo. Approvals are one-time (per lifetime) as a single dose and are issued for an approval duration of 1 year to allow preparation and administration. Zynteglo must be prescribed by a physician who specializes in the condition being treated. Claims submitted without covered codes related to this therapy will be denied.

All approvals are one-time (per lifetime) as a single dose; approval duration = 1 year.
Prescriber requirement: hematologist or stem cell transplant specialist (see criteria).
Claims without covered codes will be denied; prior authorization is required for benefit coverage.

Note

Pre-treatment Evaluation

Before authorization, a comprehensive pre-treatment evaluation must be completed to confirm transplant appropriateness and readiness for Zynteglo. This evaluation is not a step-therapy sequence — it is required assessment prior to approval. The prescribing physician must confirm suitability for hematopoietic stem cell transplantation, planned mobilization/apheresis/myeloablative conditioning, and contraception/pregnancy testing as applicable.

Definitions and Product Description

Transfusion-dependent beta-thalassemia — definition

DefinitionTransfusion-dependent beta-thalassemia: beta-thalassemia with severity requiring regular red blood cell transfusions

Clinical featuresChronic anemia from reduced or absent β-globin leading to symptoms such as fatigue, poor growth, and potential organ damage

Management implicationsOften requires lifelong RBC transfusions and iron chelation to prevent iron overload

Zynteglo — product description and mechanism

Product nameZynteglo (betibeglogene autotemcel)

Therapy typeAutologous hematopoietic stem cell-based gene therapy using BB305 lentiviral vector encoding βA-T87Q globin

Background

Beta‑thalassemia is an inherited disorder of β‑globin production that in severe forms causes lifelong transfusion dependence and iron overload. Zynteglo is an autologous, CD34+ cell‑based lentiviral gene therapy developed to introduce a functional β‑globin gene and has been studied to achieve durable transfusion independence in patients with transfusion‑dependent beta‑thalassemia; however, its use is limited to patients meeting specified clinical, laboratory, and documentation criteria.

Policy Summary

PayerCigna

PolicyHematology - Gene Therapy - Zynteglo (betibeglogene autotemcel) Coverage Policy

Policy CodePolicy IP0486

Change TypeRevisions & clarifications (2024–2026)

Effective DateThe policy effective date is in force until updated or retired.

Next Review Date

Key ActionObtain prior authorization; approvals are one-time (per lifetime) with 1-year duration to allow preparation and administration.

SourceLink

On This Page

DocumentationLab results required in the medical record for both timepoints

Cell dose — minimum

Minimum cell doseMinimum 5.0 x 10^6 CD34+ cells/kg (one-time per lifetime dose must contain at least this amount)

Dose compositionA single dose may be composed of one or more infusion bag(s)

VerificationVerification of CD34+ cell dose required prior to approval/administration

Liver iron concentration — threshold

High LIC thresholdHigh liver iron concentration defined as ≥ 15 mg/g

ContextLIC used as an example of severe iron overload when assessing eligibility

DocumentationEvaluation for severe iron overload (including LIC) is required

Verify the patient is ≥ 4 years of age and has not previously received gene therapy for beta-thalassemia.
Confirm transplant appropriateness and whether an HLA-matched donor is available or able/willing to donate.
Confirm planned mobilization (G-CSF and mobilizer), apheresis, myeloablative conditioning with busulfan, and hemoglobin ≥ 11.0 g/dL at required timepoints.

Documentation Required

Required Documentation

Documentary evidence must be provided as part of the prior authorization request. Required documentation supports genetic, infectious disease, treatment history, dosing, and reproductive safety criteria.

Genetic testing confirming genotype (nonβ0/β0 or β0/β0) [documentation required].
Verification of no prior gene therapy or prior hematopoietic stem cell transplantation (claims history or prescriber attestation) [verification in claims history required].
Transfusion history and transfusion dependence documentation as applicable.
Iron overload management: confirmation patient discontinued iron chelation ≥ 7 days prior to myeloablative conditioning [documentation required].
Viral screening: negative results for HIV-1/2, Hepatitis B, Hepatitis C, and HTLV-1/2 [documentation required].
Reproductive safety: negative serum pregnancy test (females of reproductive potential) prior to mobilization and prior to conditioning, and documentation of effective contraception use for required duration; males of reproductive potential documentation of contraception use.
Current patient body weight obtained within 30 days [documentation required] and verification of weight-based dosing to achieve ≥ 5.0 x 10^6 CD34+ cells/kg [verification required].

Billing Rule

Prior Authorization and Coding

Claims for Zynteglo must include covered procedure and diagnosis codes consistent with the coverage criteria. Prior authorization must be obtained before billing; claims submitted without the required covered codes or without an approved prior authorization will be denied as not covered.

Obtain prior authorization prior to service for benefit coverage.
Ensure claims include appropriate covered diagnosis/procedure codes and supporting documentation.
Denials: submissions without covered codes or lacking prior authorization will be denied.

Manufacturing/sourcePrepared from the patient’s own CD34+ hematopoietic stem cells obtained via apheresis

Administration and dosingOne-time (per lifetime) IV infusion containing a minimum of 5.0 x 10^6 CD34+ cells/kg