CurrentBlue Cross Blue Shield - MassachusettsPolicy 050

Gene therapies for sickle cell disease (Casgevy, Lyfgenia) — Coverage Criteria

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Coverage criteria, coding, and authorization requirements for exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) for treatment of sickle cell disease for Blue Cross Blue Shield - Massachusetts members.

Policy Summary

PayerBlue Cross Blue Shield - Massachusetts

PolicyGene therapies for sickle cell disease (Casgevy, Lyfgenia) — Coverage Criteria

Policy CodePolicy 050

Change TypeAnnual review — no material changes noted

Effective DateN/A

Next Review DateN/A

Key ActionSubmit initial authorization requests using Authorization Manager and include facility and servicing provider NPIs; complete the applicable prior authorization request form.

SourceLink

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CurrentBlue Cross Blue Shield - MassachusettsPolicy 050

Gene therapies for sickle cell disease (Casgevy, Lyfgenia) — Coverage Criteria

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Policy Summary

PayerBlue Cross Blue Shield - Massachusetts

PolicyGene therapies for sickle cell disease (Casgevy, Lyfgenia) — Coverage Criteria

Policy CodePolicy 050

Change TypeAnnual review — no material changes noted

Effective DateN/A

Next Review DateN/A

Key ActionSubmit initial authorization requests using Authorization Manager and include facility and servicing provider NPIs; complete the applicable prior authorization request form.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

≥12 yrsmin age for coverage

1 lifetimedosing limit

≥4 / 24 moCasgevy VOC history

Requiredprior auth

15 yrsLyfgenia monitoring

94%Lyfgenia VOE elimination

Coverage Criteria for Gene Therapies

Initial therapy - Casgevy

Casgevy (exagamglogene autotemcel) is covered when ALL of the following are met:

Casgevy eligibility: 1) At least 12 years of age; AND 2) Documented genetic test confirming diagnosis of sickle cell disease with genotype of βS/βS, βS/β0, or βS/β+ (additional genotypes may be considered on an Individual Consideration basis based on disease severity); AND 3) History of at least 4 severe vaso-occlusive crises in the past 24 months; AND 4) Does not have a known 10/10 HLA-matched related donor willing to participate in an allogeneic HSCT; AND 5) No history of receiving allogeneic hematopoietic stem cell transplant; AND 6) No advanced liver disease; AND 7) Negative serologic test for HIV infection; AND 8) No active bacterial, fungal, parasitic, or viral infection, including active/uncontrolled HBV or HCV; AND 9) No prior gene therapy or current consideration for another gene therapy for sickle cell disease

Repeat treatment is considered investigational.

Initial therapy - Lyfgenia

Lyfgenia (lovotibeglogene autotemcel) is covered when ALL of the following are met:

Lyfgenia eligibility: 1) At least 12 years of age; AND 2) Diagnosis of sickle cell disease confirmed by genetic testing: either homozygous sickle cell disease (e.g., Hb SS) or heterozygous genotypes (e.g., Hb SC, Hb Sβ+, Hb Sβ0, Hb SD, Hb SOArab, Hb SE); AND 3) Documented history within the last 12 months of one qualifying clinical sign or symptom despite appropriate supportive care: a) acute pain event requiring medical visit with administration of pain medications, hydration, or transfusion; b) acute chest syndrome; c) acute hepatic sequestration; d) acute splenic sequestration; or e) priapism lasting >2 hours requiring medical visit; AND 4) Meets institutional stem cell transplant requirements for individuals expected to receive gene therapy (adequate performance status [Karnofsky or Lansky], absence of advanced liver disease, adequate eGFR, adequate DLCO, adequate LVEF, absence of clinically significant active infection); AND 5) No prior allogeneic hematopoietic stem cell transplant; AND 6) No prior gene therapy and not under consideration for another gene therapy for sickle cell disease

Repeat treatment is considered investigational.

Gene therapy evidence summaries

Evidence summaries and safety considerations for gene therapies:

Casgevy (exagamglogene autotemcel) evidence: CLIMB-THAL III (treated participants 12–35 years) used pharmacokinetic‑adjusted busulfan myeloablation followed by Casgevy infusion. Primary endpoint: maintained weighted average hemoglobin ≥9 g/dL without RBC transfusion for ≥12 months (starting 60 days after last transfusion). Results: 42/44 participants stopped RBC transfusions; median time since last transfusion 9 months; mean total Hb >11 g/dL maintained after 3 months. For participants with ≥12 months follow-up, 16/17 were free of severe VOCs. Mean edited BCL11A allele proportions at Month 6: marrow CD34+ 74.3% and peripheral blood 63.4% (remained stable).as reported

Safety considerations: AEs/SAEs comparable to busulfan myeloablation/autologous transplant; neutrophil engraftment achieved in trial; risk of unintended off‑target editing cannot be ruled out. Guidance to discontinue hydroxyurea/voxelotor/crizanlizumab ≥8 weeks before mobilization/conditioning and manage iron chelators around conditioning (stop ≥7 days prior; avoid some chelators for months after infusion).

Lovotibeglogene autotemcel (Lyfgenia) evidence: Pivotal HGB‑206 (Group C): 36 participants infused, 32 evaluable for VOE endpoints; between 6–18 months post‑infusion severe VOEs were eliminated in 94% (30/32) and all VOEs eliminated in 88% (28/32). Safety: across studies 54 participants initiated stem cell collection and 3 cases of hematologic malignancy were reported (2 AML, 1 MDS). Uncertainty remains about long‑term durability and oncogenic risk. Label requires lifelong monitoring for hematologic malignancies (CBC with differential at least every 6 months for at least 15 years) and integration site analysis at months 6 and 12 and as warranted.

When the policy’s required coverage criteria for exagamglogene autotemcel (Casgevy) or lovotibeglogene autotemcel (Lyfgenia) are not fully met, use of these gene therapies is considered investigational and therefore not medically necessary. The policy explicitly states that each product is investigational if the listed eligibility criteria are not satisfied and that either product is investigational for all other indications outside those criteria. Repeat treatment with either agent is also considered investigational.

Policy history documents prior coverage decisions for Lyfgenia: the policy originally listed Lyfgenia as non‑covered effective 1/1/2024, then was revised such that lovotibeglogene autotemcel (Lyfgenia) was considered medically necessary for individuals meeting criteria effective 4/1/2024. The policy’s history is maintained in the Policy History section and includes subsequent annual reviews and clarifications through 3/15/2026.

Use of lovotibeglogene autotemcel (Lyfgenia) or exagamglogene autotemcel (Casgevy) for indications not specified in the coverage criteria — including repeat administration — is expressly considered investigational. The document notes repeat treatment with either product is investigational, and both products are investigational for any indications beyond those enumerated in the eligibility criteria.

This section is a placeholder where the policy does not provide additional not‑medically‑necessary wording beyond the investigational statements. For administrative and denial‑risk purposes, requests that do not meet the stated medical necessity criteria or that lack required prior authorization may be denied; see the Authorization and Denial Triggers sections for operational details.

Supportive and Disease-Modifying Regimens for SCD

Treatment	Role / Indication	Supporting details
Hydroxyurea	Disease-modifying therapy; first-line to reduce frequency of acute pain crises	Used to reduce number of acute pain crises and in those with history of acute chest syndrome or severe anemia; improves blood flow by decreasing sickling and altering RBC adhesion; increases RBC survival and decreases WBC, reticulocyte, and platelet counts.
Chronic transfusion (packed red blood cells)	Supportive therapy for stroke prevention and management of severe anemia	Generally used for primary or secondary stroke prevention; may be part of acute care alongside hydration, transfusion, and supplemental oxygen for pain crises.
Stem cell transplant (allogeneic hematopoietic stem cell transplant)	Potentially curative option	Curative potential limited by degree of myeloablation required and availability of matched donors.
L-glutamine	Disease-modifying therapy to decrease frequency of acute pain crises	Approved by FDA July 7, 2017 for reducing acute complications of sickle cell disease in adults and pediatric individuals 5 years and older.
Crizanlizumab	Disease-modifying therapy to reduce vaso-occlusive crises frequency	Humanized monoclonal antibody against P‑selectin; FDA-approved November 15, 2019 for individuals ≥16 years; dosing: 2 loading doses 2 weeks apart then every 4 weeks.
Voxelotor	Disease-modifying therapy targeting HbS polymerization	Reversibly binds hemoglobin to stabilize oxygenated state; FDA-approved November 25, 2019 for treatment of sickle cell disease in individuals ≥12 years.

Coding and Related Parameters

HCPCS CodesHCPCS

C9399	Unclassified drugs or biologicals
J3392	Injection, exagamglogene autotemcel, per treatment
J3394	Injection, lovotibeglogene autotemcel, per treatment
J3490	Unclassified drugs
J3590	Unclassified biologics

ICD-10-PCS Procedure CodesICD-10

XW133J8	Transfusion of Exagamglogene Autotemcel into Peripheral Vein, Percutaneous Approach, New Technology Group 8
XW133H9	Transfusion of Lovotibeglogene Autotemcel into Peripheral Vein, Percutaneous Approach, New Technology Group 9
XW143H9	Transfusion of Lovotibeglogene Autotemcel into Central Vein, Percutaneous Approach, New Technology Group 9
XW143J8	Transfusion of Exagamglogene Autotemcel into Central Vein, Percutaneous Approach, New Technology Group 8

No explicit CPT/HCPCS/ICD codes in this segmentmixed

No codes listed

inv-11: Minimum CD34+ cell dose

Minimum CD34+ cell dose3 × 10^6 CD34+ cells/kg

Dosing limit1 injection per lifetime

ContextRecommended minimum dose listed under policy guidelines for gene therapy product dosing

inv-12: Primary endpoint hemoglobin threshold (CLIMB-THAL III)

Primary hemoglobin endpointMaintained weighted average hemoglobin ≥9 g/dL without RBC transfusion for ≥12 months (assessment begins 60 days after last RBC transfusion)

PopulationIndividuals receiving Casgevy in CLIMB-THAL III

Provider Action Requirements & Authorization

Prior Authorization

Prior Authorization Required

Prior authorization is required for the services described in this policy for both inpatient and outpatient settings. For any inpatient procedure described in this policy, precertification/preauthorization is required for all products. For outpatient procedures, prior authorization is required for Commercial Managed Care (HMO and POS), Commercial PPO and Indemnity, Medicare HMO Blue, and Medicare PPO Blue.

Inpatient: precertification/preauthorization IS REQUIRED for all products when performed inpatient.
Outpatient: Prior authorization IS REQUIRED for Commercial Managed Care (HMO and POS), Commercial PPO and Indemnity, Medicare HMO Blue, and Medicare PPO Blue.

Note

Prior Authorization / Policy Determinations

Policy determinations and prior authorizations are based on the medical necessity criteria in this policy (including age, genotype, clinical history, institutional requirements, and prior transplant/gene therapy status). Providers should confirm that the member meets the listed medical necessity criteria before requesting authorization. Policy history and prior determinations that affect authorization decisions are documented in the policy history and may change coverage or coding guidance over time.

Background on Sickle Cell Disease and Therapies

Sickle cell disease (SCD) is an inherited hemoglobinopathy in which production of abnormal hemoglobin S leads to red blood cell sickling, hemolysis, and recurrent vaso‑occlusion. These pathophysiologic processes cause acute complications such as vaso‑occlusive crises (VOC), acute chest syndrome, splenic or hepatic sequestration, stroke, and priapism, as well as chronic organ injury (renal, pulmonary, hepatic). The condition affects an estimated ~100,000 individuals in the U.S. and has both acute and long‑term morbidity that gene‑modifying therapies aim to reduce by restoring durable hemoglobin function and reducing or eliminating severe VOEs.

Definitions and Trial Endpoints

inv-23: Definition — Sickle cell disease genotypes (βS/βS, βS/β0, βS/β+)

Common genotypesβS/βS (homozygous sickle) — accounts for ~60–70% of SCD in the U.S.

Compound heterozygous genotypesβS/β0 and βS/β+ (sickle–beta thalassemia)

Definition contextGenotypes defined by presence of hemoglobin S from homozygosity or compound heterozygosity

inv-24: Definition — Sickle cell disease overview (hemoglobin S, clinical consequences)

Underlying defectPresence of hemoglobin S (HbS) due to sickle variant of beta globin causing RBC sickling

PathophysiologySickled RBCs polymerize, become rigid, cause vascular obstruction, ischemia, and shortened RBC lifespan leading to hemolysis

Policy Revision History

2026-03-15annual_reviewLatest

Annual review with literature update through January 13, 2025; references added and policy state clarified.

2024-04-01coverage_update

Lyfgenia (lovotibeglogene autotemcel) changed to medically necessary / covered effective 04/01/2024.

2024-01-01policy_established

Policy Summary

PayerBlue Cross Blue Shield - Massachusetts

PolicyGene therapies for sickle cell disease (Casgevy, Lyfgenia) — Coverage Criteria

Policy CodePolicy 050

Change TypeAnnual review — no material changes noted

Effective DateN/A

Next Review DateN/A

Key ActionSubmit initial authorization requests using Authorization Manager and include facility and servicing provider NPIs; complete the applicable prior authorization request form.

SourceLink

On This Page

Additional observations: some participants experienced recurrent VOEs after primary evaluation; opioid use persisted in a portion of participants; limited sample size and follow‑up increase uncertainty around long‑term outcomes.

TimingMeasured starting 60 days after last RBC transfusion, sustained for at least 12 months

Authorization decisions are contingent on meeting the medical policy criteria for each gene therapy (e.g., Casgevy and Lyfgenia).
Refer to Policy History for previous determinations and effective dates that may affect prior authorization requirements and coding guidance.

Documentation Required

How to Request Authorization

Providers must submit initial authorization requests using Authorization Manager. For out-of-network providers, requests may be faxed to 888-973-0726. Use the Complete Prior Authorization Request Form for Gene Therapies within Authorization Manager when applicable (e.g., Casgevy #055, Lyfgenia #079).

Use Authorization Manager to submit authorizations, attach clinical documentation, check case status, and retrieve decision letters.
Enter the facility NPI/provider ID for service location and the servicing provider's NPI/provider ID (surgeon/performing clinician) — not the billing group.
Out-of-network submissions: fax 888-973-0726.

Note

Pre- and Post-Conditioning Medication Management (Casgevy)

Providers should be aware of pre- and post-conditioning medication management recommendations for exagamglogene autotemcel (Casgevy). Certain disease-modifying agents and iron chelators should be discontinued within defined windows prior to mobilization and conditioning, and restrictions apply after infusion.

Discontinue hydroxyurea, voxelotor, and/or crizanlizumab at least 8 weeks prior to the start of mobilization and conditioning.
Discontinue iron chelators at least 7 days prior to initiation of conditioning; consider phlebotomy as an alternative when appropriate.
After exagamglogene autotemcel infusion: avoid non-myelosuppressive iron chelators for at least 3 months and myelosuppressive iron chelators for at least 6 months.

Documentation Required

Post-Treatment Monitoring Requirements (Lovotibeglogene autotemcel)

Providers should ensure lifelong post-treatment monitoring for individuals treated with lovotibeglogene autotemcel (Lyfgenia) per the product labeling and study guidance. Monitoring focuses on detection of hematologic malignancies and scheduled laboratory assessments.

Lifelong monitoring for hematologic malignancies is recommended.
Obtain a complete blood count (with differential) at least every 6 months for at least 15 years after treatment.
Perform integration site analysis at months 6 and 12, and additionally as clinically warranted.

Note

Background on Prior/Concomitant Therapies

Background: Standard and disease-modifying therapies and how they relate to authorization and treatment planning are summarized here to inform pre-treatment evaluation and eligibility.

Current standard interventions for sickle cell disease include stem cell transplantation, chronic transfusion, and hydroxyurea.
Hydroxyurea, chronic transfusion, and other supportive treatments (e.g., pain management, hydration, transfusion, supplemental oxygen) are part of the treatment context considered when evaluating candidates for gene therapy.
Stem cell transplant can be curative but may be limited by donor availability and myeloablation requirements; prior allogeneic HSCT is an exclusion for gene therapy candidates per policy criteria.

Note

Provider Action — Not Specified in This Segment

Not specified: This document segment does not include an additional provider action beyond the prior authorization, submission instructions, medication management, monitoring, and background guidance above. Providers should consult the full policy and product labeling for any other required actions or site-specific institutional requirements.

Clinical consequencesRecurrent vaso-occlusive crises, acute chest syndrome, stroke, renal injury, priapism, infections, and multisystem chronic complications

inv-25: Primary endpoint (CLIMB-THAL III) — maintained weighted average Hb ≥9 g/dL without RBC transfusion for ≥12 months

Primary endpoint definition (CLIMB-THAL III)Maintained weighted average hemoglobin ≥9 g/dL without red blood cell (RBC) transfusion for ≥12 months after Casgevy infusion, starting 60 days after last RBC transfusion

Measurement windowAssessment begins 60 days after the last RBC transfusion and requires ≥12 months without transfusion

Clinical implicationEndpoint indicates sustained transfusion independence and hemoglobin maintenance post-infusion

Casgevy (exagamglogene autotemcel) policy established effective 01/01/2024.