ModifiedPremera BluecrossPolicy 5.01.42

Gene Therapies for Thalassemia

Criteria and coverage stance for two autologous gene therapies (Casgevy and Zynteglo) for individuals with transfusion‑dependent β‑thalassemia, including eligibility, exclusions, dosing, monitoring, and coding; intended for providers and payers managing medical benefit requests.

Policy Summary

PayerPremera Bluecross

PolicyGene Therapies for Thalassemia

Policy CodePolicy 5.01.42

Change TypeMaterial revisions to eligibility, lab thresholds, and added product (Casgevy)

Effective DateJun 1, 2025

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of transfusion history, globin gene testing, donor availability, and baseline labs per product thresholds.

SourceLink

POLICY UPDATE CHANGES

Updated Casgevy coverage criteria to require absence of an available 10/10 HLA‑matched related donor and to change multiple laboratory and renal function thresholds.

Updated Zynteglo criteria to add exclusions for uncorrected bleeding disorder, prior or current malignancy, advanced liver disease, and age/weight limits.

Added coverage criteria for Casgevy (exagamglogene autotemcel).

Added HCPCS codes J3393 and J3392 for listed products.

2products covered

89%transfusion‑independence rate

5.0M CD34+/kgminimum dose

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injections per lifetime

2025-06-01policy effective

Coverage Criteria for Gene Therapies

Casgevy (exagamglogene autotemcel) — Medical Necessity

Covered when ALL of the following are met

Casgevy eligibility: Patient aged 12 to 35 years; documented diagnosis of β-thalassemia by globin gene testing; requires regular peripheral blood transfusions to maintain target hemoglobin; documented transfusion history of at least 100 mL/kg/year of packed red cells OR disease managed with ≥8 transfusions/year in the prior 2 years; Karnofsky (adults ≥16) or Lansky (adolescents <16) performance status ≥80; negative HIV serologic test; does not have an available 10/10 HLA-matched related donor; no T2*-weighted MRI measurement of myocardial iron <10 msec or other evidence of severe iron overload per treating physician; no advanced liver disease as defined in policy (persistent AST, ALT, or direct bilirubin >2× ULN; baseline PT >1.5× ULN; MRI evidence of cirrhosis or biopsy showing cirrhosis/bridging fibrosis/active hepatitis); and meets any additional product-specific exclusions listed in policy.all criteria required

Uses FDA label considerations for HIV testing and manufacturing

Zynteglo (betibeglogene autotemcel) — Medical Necessity

Covered when ALL of the following are met

Zynteglo eligibility: Patient aged 50 years or younger; documented diagnosis of β-thalassemia by globin gene testing; requires regular peripheral blood transfusions to maintain target hemoglobin; documented transfusion history of at least 100 mL/kg/year of packed red cells OR disease managed with ≥8 transfusions/year in the prior 2 years; Karnofsky (adults ≥16) or Lansky (adolescents <16) performance status ≥80; negative HIV serologic test; clinically stable and eligible to undergo hematopoietic stem cell transplant; no T2*-weighted MRI myocardial iron <10 msec or other evidence of severe iron overload per treating physician; no advanced liver disease as defined in policy (see product section); baseline eGFR not less than product-specified threshold; no prior gene therapy or allogeneic HSCT; no prior or current malignancy (exceptions specified) or familial cancer syndrome in immediate family; no active uncontrolled HCV or HBV; no contraindication to required mobilization/conditioning agents; WBC ≥3 ×10^9/L and platelets ≥100 ×10^9/L unless related to hypersplenism; and no uncorrected bleeding disorder.all criteria required

Includes product-specific contraindications and laboratory thresholds per prescribing information

Zynteglo (betibeglogene autotemcel) - Initial Therapy

Covered when ALL of the following are met

Zynteglo initial coverage criteria summary: Individual has transfusion-dependent β-thalassemia and meets trial-analogous inclusion criteria (including genotype considerations used in pivotal trials); is clinically stable and eligible to undergo hematopoietic stem cell transplant; meets product age and weight limits (≤50 years; if <5 years must weigh ≥6 kg); does not have an uncorrected bleeding disorder, any prior or current malignancy, or history of advanced liver disease; meets product prescribing information laboratory and safety requirements; and satisfies other product-specific exclusions and contraindications.see product label

Derived from prescribing information updates and 2023 policy updates.

Casgevy (exagamglogene autotemcel) - Initial Therapy

Covered when ALL of the following are met

Casgevy initial coverage criteria summary: Individual has transfusion-dependent β-thalassemia; does not have an available 10/10 HLA-matched related donor; baseline PT is not greater than 1.5× ULN; persistent AST, ALT, or direct bilirubin values are not greater than 2× ULN; baseline eGFR is ≥60 mL/min/1.73 m^2; individual is clinically stable and eligible to undergo hematopoietic stem cell transplant; and meets other product FDA prescribing information requirements and exclusions.specific numeric lab thresholds listed

Reflects 2025 clarifications to Casgevy criteria and NICE guidance context.

Initial therapy and product-specific eligibility

Covered when ALL of the following are met (per policy history and updates):

General eligibility: Individual has transfusion-dependent β-thalassemia and meets product-specific FDA labeling and policy clinical criteria.

Supported by inclusion of Casgevy and Zynteglo criteria in policy history.

Donor availability: Individual does not have an available 10/10 HLA-matched related donor.

Revised language in 06/01/25 interim review.

Laboratory thresholds: Baseline PT not greater than 1.5× ULN; no persistent AST, ALT, or direct bilirubin >2× ULN; baseline eGFR ≥60 mL/min/1.73 m^2.PT ≤1.5× ULN; AST/ALT/direct bilirubin ≤2× ULN; eGFR ≥60

Updated thresholds recorded 06/01/25.

Exclusions applicable to both products and detailed in the policy include advanced liver disease defined by any of the following: persistent AST, ALT, or direct bilirubin values above policy-specified cutoffs, prolonged coagulation times or imaging/biopsy evidence of cirrhosis. The policy also excludes individuals with prior gene therapy or prior allogeneic hematopoietic stem cell transplant and those with active, uncontrolled hepatitis B or C infection or significant immunodeficiency per product labeling. Documentation of these exclusions is required as part of prior authorization review.

Specific exclusions called out include an uncorrected bleeding disorder, any prior or current malignancy (with the limited exceptions noted in the product prescribing information), and a history of advanced liver disease. For Zynteglo the policy previously specified baseline renal cutoff and other labs; the 2023–2025 updates reinforced these product‑specific exclusions and age/weight constraints that must be confirmed in the clinical record prior to authorization.

Per the 2025 interim update, Casgevy coverage requires that the individual does not have an available 10/10 HLA‑matched related donor. If such a donor is available, the individual is excluded from Casgevy coverage under this policy.

All uses of Casgevy and Zynteglo not specifically described as medically necessary in this policy are considered investigational. Additionally, repeat treatment with either product is considered investigational and is not authorized under the policy. Prior authorization reviews should reference FDA dosing and administration information when evaluating requests.

When a suitable HLA‑matched related donor exists and hematopoietic stem cell transplant (HSCT) is clinically appropriate, HSCT should be considered prior to gene therapy. The policy and referenced guidance (NICE) advise offering exagamglogene autotemcel only when HSCT is suitable but a matched related donor is not available.

Requests are considered not medically necessary when baseline laboratory values exceed the policy thresholds specified for eligibility. For Casgevy these updated cutoffs include baseline PT greater than 1.5 times ULN, any persistent AST, ALT, or direct bilirubin value > 2 times ULN, or baseline eGFR less than 60 mL/min/1.73 m2. Authorization should be denied when these lab criteria are not met.

Coding and Product Dose Information

Covered HCPCS codes (gene therapy products)HCPCSCovered

J3392	Injection, exagamglogene autotemcel, per treatment (Casgevy)
J3393	Injection, betibeglogene autotemcel, per treatment (Zynteglo)

Reported HCPCS codesHCPCS

J3590

Added HCPC code J3590 to report Zynteglo

Policy coding updates and product reporting codesHCPCS

J3590	Unclassified biologics (added to report Zynteglo)
J3393	HCPCS code added July 01, 2024 (policy update)
J3392	HCPCS code added Jan 01, 2025 (policy update)

Product dose and lifetime limit — minimum dose and single-injection lifetime limit

Minimum product dose5.0 x 10^6 CD34+ cells/kg

Lifetime dosing limitSingle injection per lifetime

Dose referencePer policy recommended dose section

Serum ferritin — chelation threshold

Chelation initiation thresholdInitiate iron chelation when serum ferritin > 1000 mcg/L

ContextThreshold cited from 2023 prescribing information review and clinical studies defining transfusion dependence

Prior Authorization, Documentation, and Denial Risk

Prior Authorization

Prior authorization and benefit application — Prior authorization required

Prior authorization is required for Casgevy (exagamglogene autotemcel) and Zynteglo (betibeglogene autotemcel). These products are managed through the medical benefit; non-formulary exception reviews may be approved up to 12 months. Verify product-specific prior authorization rules and updated HCPCS coding prior to submission.

Medical benefit management: Casgevy and Zynteglo
Non-formulary exception reviews may be approved up to 12 months
Confirm HCPCS updates (e.g., J3392, J3393, J3590)

Prior Authorization

Prior authorization required for gene therapy — product-specific prior authorization requirement

Product-specific prior authorization is required; ensure the individual meets the applicable age and clinical eligibility for the specific gene therapy requested (e.g., Casgevy: ages 12–35; Zynteglo: ≤50 years and weight requirements for <5 years). Requests that do not meet the updated product-specific eligibility criteria will be denied.

Background

β‑thalassemia is an inherited disorder of the HBB gene resulting in reduced or absent β‑globin production and chronic anemia. In its transfusion‑dependent form, patients require regular red blood cell transfusions and are at risk for complications from iron overload. Standard management includes chronic transfusions, iron chelation, and consideration of allogeneic hematopoietic stem cell transplant; autologous gene therapies aim to restore functional β‑globin expression using modified CD34+ hematopoietic stem cells to reduce or eliminate transfusion dependence.

Definitions and Key Terms

Transfusion-dependent β-thalassemia — definition used in policy and trials (≥100 mL/kg/yr or ≥8 transfusions/yr)

Operational definitionTransfusion-dependent β-thalassemia: history of ≥100 mL/kg/year of packed red blood cells or ≥8 transfusions per year for the prior 2 years

Clinical correspondenceGenerally corresponds to β-thalassemia major but may include some intermedia cases

Use in policyApplied as an enrollment/eligibility threshold in trials and coverage criteria

Betibeglogene autotemcel — product definition

Product descriptionBetibeglogene autotemcel: autologous CD34+ hematopoietic stem cell product with a modified βA-T87Q globin gene to produce HbA T87Q protein

MechanismReengineered CD34+ cells engraft and produce red blood cells expressing functional gene therapy-derived hemoglobin

Policy Summary

PayerPremera Bluecross

PolicyGene Therapies for Thalassemia

Policy CodePolicy 5.01.42

Change TypeMaterial revisions to eligibility, lab thresholds, and added product (Casgevy)

Effective DateJun 1, 2025

Next Review DateN/A

Key ActionSubmit prior authorization with documentation of transfusion history, globin gene testing, donor availability, and baseline labs per product thresholds.

SourceLink

On This Page

Age/weight constraints: For Zynteglo, historic criteria require age ≤50 years and if <5 years must weigh ≥6 kg; these product-specific constraints were added in 12/01/23 review.

Specific product age/weight constraints captured in policy history.

Transplant candidacy: Individual must be clinically stable and eligible to undergo hematopoietic stem cell transplant per prior policy history statements and NICE guidance when applicable.

Captured in policy history and NICE TA1003 reference.

Clinical noteUsed to assess iron overload status prior to gene therapy eligibility

eGFR — baseline renal function requirement

Baseline eGFR requirementBaseline eGFR must be >= 60 mL/min/1.73m2

Policy change noteUpdated from >=70 to >=60 mL/min/1.73m2 in 2025 review

RelevanceRequired for Casgevy eligibility per 2025 updates

PT — baseline prothrombin time threshold

Baseline PT thresholdBaseline prothrombin time (PT) must not be greater than 1.5 times the ULN

ClarificationPolicy changed from PT or PTT to PT only in 2025 update

Coverage implicationExceeding this threshold is a coverage exclusion for Casgevy

AST/ALT/direct bilirubin — hepatic laboratory thresholds

Hepatic laboratory thresholdsNo persistent AST, ALT, or direct bilirubin value greater than 2 times the ULN

Policy changeThreshold lowered from >3x ULN to >2x ULN for Casgevy in 2025 update

Coverage implicationPersistent values above this cutoff constitute an exclusion to coverage

Casgevy age criteria: 12–35 years

Zynteglo age criteria: ≤50 years; <5 years must meet minimum weight

Documentation Required

Prior authorization and documentation — prior authorization required and documentation expectations

Prior authorization must include clinical and diagnostic documentation supporting the diagnosis, transfusion dependence, genotype/subtype, and lab thresholds. Missing or incomplete documentation that fails to demonstrate the required clinical criteria or the presence of exclusions may result in denial.

Documented β-thalassemia diagnosis by globin gene testing
Documentation of transfusion dependence (see transfusion-supporting items)
Performance status (Karnofsky ≥80 for ≥16 y or Lansky ≥80 if <16 y)
Negative HIV serology per FDA label

Documentation Required

Documentation supporting transfusion-dependent diagnosis and genotype/subtype details

Provide documentation demonstrating transfusion-dependent status and transfusion history: include quantity-based and frequency-based evidence as applicable. This should support that the individual required regular peripheral blood transfusions to maintain target hemoglobin and meets the policy thresholds for transfusion volume or frequency.

Record of transfusions: ≥100 mL/kg packed red cells per year OR at least 8 transfusions/year in the previous 2 years
Dates and volumes of transfusion episodes and indication for each transfusion
Labs and clinical notes showing ongoing need for transfusion to maintain hemoglobin targets

Documentation Required

Required documentation — verify member eligibility per clinical criteria including donor availability and labs

Required documentation must confirm eligibility and absence of exclusions. Include age, globin gene testing results, transfusion history, performance status, HIV testing, and relevant laboratory values (liver tests, PT, eGFR). Also document transplant candidacy and donor availability.

Age and weight (if applicable)
Globin gene testing results and genotype/subtype
Transfusion history (volumes, counts, dates)
Karnofsky or Lansky performance status
HIV serology
Baseline AST, ALT, direct bilirubin values with reference ranges
Baseline prothrombin time (PT)
Baseline estimated glomerular filtration rate (eGFR)

Note

HSCT consideration — recommend HSCT when suitable HLA-matched related donor is available (NICE recommendation context)

Hematopoietic stem cell transplantation (HSCT) should be considered when clinically suitable. For individuals who are suitable for HSCT, gene therapy eligibility generally requires that a 10/10 HLA-matched related donor is not available.

Evaluate HSCT suitability and candidacy prior to gene therapy
Gene therapy indications often require no available 10/10 HLA-matched related donor
Document HSCT evaluation notes and donor search results

Denial Risk

Failure to meet product-specific eligibility or presence of exclusions — likely denial when key criteria missing

Coverage will be denied if product-specific eligibility criteria or exclusions are present or undocumented. Common exclusion triggers include prior gene therapy or allogeneic HSCT, uncontrolled active infections, prior or current malignancy (with specified exceptions), uncorrected bleeding disorders, contraindications to conditioning agents, and certain family history of hereditary cancer syndromes.

Prior gene therapy or prior allogeneic HSCT — exclusion
Any prior or current malignancy (exceptions noted in policy) — exclusion
Uncorrected bleeding disorder — exclusion
Contraindication to conditioning agents (e.g., busulfan, plerixafor, G-CSF) — exclusion
Active uncontrolled HBV or HCV infection — exclusion
Family history of familial cancer syndromes may be exclusionary

Denial Risk

Coverage exclusion triggers — denial risk if laboratory thresholds exceeded

Specific laboratory thresholds trigger coverage exclusions; verify and document labs relative to policy thresholds. Exceeding these thresholds or failing to provide baseline labs increases denial risk.

Persistent AST, ALT, or direct bilirubin greater than 2× ULN (Casgevy) or greater than 3× ULN (policy prior language reflected) — exclusion trigger
Baseline PT greater than 1.5× ULN — exclusion trigger (Casgevy specifies PT >1.5× ULN)
Baseline eGFR less than 60 mL/min/1.73 m2 (Casgevy current threshold) — exclusion trigger
T2*-weighted MRI myocardial iron <10 msec or other evidence of severe iron overload — exclusion trigger

Indication contextDeveloped to reduce or eliminate transfusion dependence in transfusion-dependent β-thalassemia

Transfusion independence — outcome definition from trials (e.g., 89% pooled rate)

Trial outcome definitionTransfusion independence: no transfusions for a continuous period of at least 12 months with weighted average hemoglobin ≥9 g/dL

Pivotal trial resultPooled betibeglogene autotemcel studies reported transfusion-independence achieved in 89% (95% CI, 74% to 97%) of evaluable participants

Evidence noteDefined and reported in HGB-207 and HGB-212 single-arm studies contributing to coverage decisions

GVHD — definition and relevance to HSCT

DefinitionGraft-versus-host disease (GVHD): immune complication of allogeneic hematopoietic stem cell transplant, classified as acute (grade 2–4) or chronic

RelevanceIncidence and severity of GVHD vary by donor match and inform consideration of HSCT versus autologous gene therapy

Reported outcomesRetrospective HSCT cohorts report grade 2–4 acute GVHD rates and chronic GVHD rates used in comparative context

Transfusion-dependent beta-thalassemia — additional term definition

Term definitionTransfusion-dependent beta-thalassemia: severe genotype requiring regular red blood cell transfusions

Clinical implicationUsed interchangeably with transfusion-dependent β-thalassemia in trials and policy to define eligibility

Policy useForms the baseline condition for consideration of gene therapy products in this policy