CurrentCignaPolicy IP0486

Zynteglo

Cigna coverage policy governing prior authorization and medical necessity criteria for one-time administration of Zynteglo for patients with transfusion-dependent beta-thalassemia; applies to Cigna-administered health benefit plans.

Policy Summary

PayerCigna

PolicyZynteglo

Policy CodePolicy IP0486

Change TypeSelected revision (material clinical changes)

Effective DateMay 8, 2025

Next Review Date

Key ActionObtain prior authorization for a one-time, per-lifetime Zynteglo infusion and provide required documentation including transfusion history, genetic testing, infection screening, and verification of minimum CD34+ cell dose.

SourceLink

POLICY UPDATE CHANGES

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

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

Screening language for certain viruses was clarified/modified (removal of 'cellular' and change to 'Patient screening is negative for ALL of the following').

one-timedose per lifetime

≥4minimum patient age for approval

≥5.0 x10^6/kgrequired cell dose

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Coverage Criteria for Zynteglo (betibeglogene autotemcel)

FDA-Approved Indication

Approve one-time single dose when ALL of the following criteria A through P are met

A) Age: Patient is >= 4 years of age;

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B) No prior gene therapy: Patient has not received a gene therapy for beta-thalassemia in the past (verification in claims history required); if no claims history is available, the prescribing physician must confirm the patient has not previously received Zynteglo or Casgevy.;

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C) HSCT appropriate: According to the prescribing physician, a hematopoietic stem cell transplantation is appropriate for the patient;

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D) HLA donor status: Patient meets ONE: (i) does not have an HLA-matched donor OR (ii) has an HLA-matched donor but the individual is not able or not willing to donate;

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E) Genotype: Patient has ONE of the following genotypes confirmed by genetic testing: (i) non-beta0/beta0 genotype (examples: beta0/beta+, betaE/beta0, beta+/beta+) OR (ii) beta0/beta0 genotype;

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F) Transfusion dependence: Patient is transfusion-dependent as defined by ONE: (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 (documentation required);

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G) Iron overload evaluation: Patient meets BOTH: (i) has been evaluated for the presence of severe iron overload (documentation required) AND (ii) does not have evidence of severe iron overload (examples include myocardial T2* < 10 msec, liver iron concentration >= 15 mg/g, abnormal liver biopsy, or clinical evidence of organ damage);

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

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I) Malignancy and liver disease exclusions: Patient does not have prior or current malignancy, myeloproliferative disorder, or significant immunodeficiency disorder (excluding adequately treated in situ cervical carcinoma and non-melanoma skin cancers) AND does not have advanced liver disease (examples: ALT or AST >3x ULN, direct bilirubin >3x ULN, active hepatitis, extensive bridging fibrosis, or cirrhosis) (documentation required);

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J) Iron chelation: According to the prescribing physician, patient will have been discontinued from iron chelation therapy for at least 7 days prior to myeloablative conditioning;

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K) Treatment logistics and hemoglobin: According to the prescribing physician, patient meets ALL: (i) will undergo mobilization, apheresis, and myeloablative conditioning; (ii) a G-CSF product and a hematopoietic stem cell mobilizer will be used for mobilization; (iii) busulfan will be used for myeloablative conditioning; AND (iv) total hemoglobin >= 11.0 g/dL at BOTH timepoints: prior to mobilization and prior to myeloablative conditioning;>= 11.0 g/dL

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L) Infectious disease screening: Patient screening is negative for ALL: HIV-1 and -2, Hepatitis B virus, Hepatitis C virus, and HTLV-1 and -2 (documentation required);

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M) Reproductive potential: For patients of reproductive potential, meet ONE: (i) Female: negative serum pregnancy test prior to mobilization and reconfirmed prior to conditioning AND use effective contraception from mobilization through at least 6 months after administration; OR (ii) Male: use effective contraception from mobilization through at least 6 months after administration;

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N) Prescriber specialty: Medication is prescribed by a hematologist or a stem cell transplant specialist physician;

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O) Weight documentation: Current patient body weight has been obtained within 30 days (documentation required);

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P) Dose verification: If criteria A through O are met, approve one IV dose to provide a one-time (per lifetime) single dose containing a minimum of 5.0 x 10^6 CD34+ cells/kg of body weight (verification required);>= 5.0 x 10^6 CD34+ cells/kg

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Zynteglo (betibeglogene autotemcel) is not covered for uses outside the specified FDA‑approved indication for transfusion‑dependent beta‑thalassemia. The policy explicitly states that Zynteglo for any other use is considered not medically necessary and that the list of excluded uses may be updated as new data become available.

Explicit exclusions include prior hematopoietic stem cell transplantation, prior receipt of gene therapy, and concurrent use with Reblozyl (luspatercept). These situations are considered not medically necessary and are therefore not eligible for coverage under this policy.

Use of Zynteglo is specifically considered not medically necessary for patients who have previously undergone a hematopoietic stem cell transplant; the prescribing physician must confirm the patient has not received a prior HSCT.

Prior receipt of any gene therapy for beta‑thalassemia is an exclusion, reflecting the fact that patients who received prior gene therapy were excluded from pivotal trials. Concurrent administration with Reblozyl (luspatercept) is also excluded because it was not studied in combination with Zynteglo in the pivotal trials.

Coding, Dosage, and Clinical Thresholds

Considered Medically Necessary when criteria are metHCPCSCovered

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Injection, betibeglogene autotemcel, per treatment

Transfusion dependence — quantitative thresholds for prior 2 years

Transfusion volume threshold (option 1)>= 100 mL packed red cells per kg per year in the previous 2 years

Transfusion frequency threshold (option 2)>= 8 transfusions per year in the previous 2 years

Documentation requirementDocumentation of transfusions in the prior 2 years is required (e.g., chart notes, transfusion records)

Minimum CD34+ cell dose — required cell dose threshold

Minimum CD34+ cell dose>= 5.0 x 10^6 CD34+ cells/kg of body weight (per one-time single dose)

Dose formOne intravenous infusion providing the minimum CD34+ cell dose

Provider Actions, Authorization, and Documentation Requirements

Prior Authorization

Prior Authorization and Approval Duration

Prior Authorization Recommended. Prior authorization is recommended for benefit coverage of Zynteglo. Approval is granted as a one-time (per lifetime) single dose. Approval duration is 1 year to allow adequate time to prepare for and administer the single dose. Zynteglo must be prescribed by a physician who specializes in the condition being treated. All approvals and denials will be forwarded to the Medical Director for evaluation.

Approval: one-time (per lifetime) single dose; duration = 1 year
Prescriber requirement: hematologist or stem cell transplant specialist (specialist in the condition)
All reviews (approvals and denials) forwarded to Medical Director

Documentation Required

Required Documentation and Verification

Documentation is required where noted in the criteria. Documentation may include, but is not limited to, chart notes, laboratory results, medical test results, claims records, prescription receipts, and/or other information. For certain criteria, verification in the claims history is required (e.g., prior receipt of gene therapy or prior claims for Zynteglo/Casgevy). For dosing criteria, verification of appropriate weight-based dosing may be required by the Medical Director.

Definitions

Definition of transfusion-dependent beta-thalassemia (clinical definition)

Clinical definitionTransfusion-dependent beta-thalassemia is defined by the need for regular RBC transfusions as specified by quantitative transfusion thresholds (see transfusion dependence criteria)

Quantitative criteria (volume)>= 100 mL packed red cells per kg per year in the previous 2 years

Quantitative criteria (frequency)>= 8 transfusions per year in the previous 2 years

DocumentationDocumentation of transfusion history in the prior 2 years is required to confirm transfusion dependence

Background

Beta‑thalassemia is an inherited disorder caused by reduced or absent production of the beta (β) globin chain, resulting in chronic anemia that commonly requires lifelong red blood cell transfusions and iron chelation. Zynteglo is an autologous CD34+ hematopoietic stem cell gene therapy designed to add functional β A‑T87Q globin and is administered as a one‑time intravenous infusion following mobilization, apheresis, and myeloablative conditioning.