ModifiedPremera BluecrossPolicy 5.01.640

Pharmacologic Treatment of Sickle Cell Disease

Defines medical and pharmacy benefit coverage, site-of-service criteria, and clinical coverage criteria for specific pharmacologic treatments for sickle cell disease for Premera Blue Cross members.

Policy Summary

PayerPremera Bluecross

PolicyPharmacologic Treatment of Sickle Cell Disease

Policy CodePolicy 5.01.640

Change TypeModified — material changes include addition of gene therapies and removal of withdrawn agent

Effective DateOct 3, 2025

Next Review DateN/A

Key ActionObtain prior authorization for listed medical-benefit agents and document hydroxyurea use or intolerance as required.

SourceLink

POLICY UPDATE CHANGES

Added coverage for Casgevy (exagamglogene autotemcel) and Lyfgenia (lovotibeglogene autotemcel) for the treatment of sickle cell disease.

Removed Oxbryta (voxelotor) from the policy as it has been withdrawn from the market.

Added HCPCS codes J0791 and J3590; later added J3394 and J3392 and removed unlisted J3590 for Casgevy.

Added coverage criteria for Xromi (hydroxyurea).

Clarified that the medications listed are subject to the product's FDA dosage and administration prescribing information.

Clarified that Site of Service Medical Necessity criteria can apply to injection drugs and an exception for Alaska fully-insured members.

6+named therapies

Up to 12 moinitial auth length

One-time

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gene therapy approval

J0791, J3392, J3394HCPCS codes

45%VOC reduction (crizanlizumab)

Coverage Criteria for Sickle Cell Disease Therapies

Adakveo (crizanlizumab-tmca) — Coverage Criteria

Adakveo (crizanlizumab-tmca) — medical benefit site-of-service and coverage criteria. Covered when ALL of the following are met:

ALL of the following

Individual is aged 16 years or older.
Has had an occurrence of at least 1 vaso-occlusive crisis (VOC), acute chest syndrome, hepatic sequestration, or similar sickle-related complication in the past 12 months.
Concurrent use of or treatment failure with hydroxyurea, unless hydroxyurea is contraindicated or not tolerated.
Is not on a planned chronic blood transfusion program.
Adakveo is prescribed by or in consultation with a hematologist.
Site-of-service criteria: IV infusion or injectable administration is provided in the most appropriate, safe and cost-effective site (physician office, infusion center, home infusion where available and safe, or hospital outpatient infusion department) and meets medical necessity for the selected site as defined in this policy. Medical necessity for hospital-based outpatient or inpatient administration is limited to situations such as lack of a qualified outpatient/home infusion option within 50 miles, clinical conditions that increase infusion risk (eg, unstable cardiac or pulmonary disease, unstable renal function, difficult vascular access, acute mental status changes, history of severe infusion reactions), or cytokine release syndrome meeting policy criteria.
Prescriber documents baseline and ongoing monitoring and follow-up to assess clinical response; authorization may be granted up to 12 months for initial and reauthorization reviews.
Evidence summary: SUSTAIN trial showed a reduction in median annual VOC rate with crizanlizumab; the STAND phase 3 trial did not show a reduction in VOCs leading to a healthcare visit. Safety profile includes infrequent infusion-related reactions and other adverse events; clinicians should weigh benefit and risk when considering therapy.

Endari (L‑glutamine) — Coverage Criteria

Endari (L-glutamine) — pharmacy benefit coverage criteria. Covered when ALL of the following are met:

ALL of the following

Individual has a diagnosis of sickle cell disease (eg, sickle cell anemia or sickle beta‑0 thalassemia).
Individual is prescribed L‑glutamine at FDA‑approved dosing (0.3 g/kg body weight) consistent with product labeling.
Prescribed by or in consultation with a hematologist when clinically appropriate.
Documentation of concomitant hydroxyurea use when applicable is acceptable; Endari may be used with or without hydroxyurea.
All other uses not outlined in this policy are considered investigational.

Xromi (hydroxyurea) — Coverage Criteria

Xromi (hydroxyurea) — pharmacy benefit coverage criteria. Covered when ALL of the following are met:

ALL of the following

Individual is aged 6 months or older.
Indication: to reduce frequency of painful crises and reduce need for blood transfusions in individuals with sickle cell anemia with recurrent moderate to severe painful crises.
Documentation of inadequate response or intolerance to generic hydroxyurea, OR documentation that an oral liquid formulation is clinically necessary (eg, trouble swallowing), justifying use of Xromi specifically.
Prescribed and monitored per standard clinical practice; laboratory monitoring and dose adjustments documented in chart notes.
Length of approval: initial and reauthorization reviews may be approved for up to 12 months when drug‑specific criteria are met and chart notes demonstrate continued clinical benefit (eg, no increase in number of VOCs over 12 months compared to baseline).

Casgevy and Lyfgenia — Gene/Cell Therapy Coverage Criteria

Casgevy (exagamglogene autotemcel) and Lyfgenia (lovotibeglogene autotemcel) — gene therapies medical benefit coverage criteria. Covered when ALL of the following are met:

ALL of the following

Patient age: Casgevy — aged 12 years or older; Lyfgenia — aged 12 to 50 years as specified in FDA labeling and product guidance.
Confirmed diagnosis of sickle cell disease (SCD).
History of at least 4 sickle‑cell related events (eg, VOCs requiring supportive care) in the prior 24 months.
Karnofsky performance status ≥60 for adults (≥16 years) or Lansky performance status ≥60 for adolescents (<16 years) for Lyfgenia as applicable.
Failed or intolerant to hydroxyurea therapy, unless contraindicated or not tolerated; prior therapy and response documented.

Coding and Billing (HCPCS)

HCPCS CodesHCPCS

J0791	Injection, crizanlizumab-tmca, (Adakveo) 5 mg.
J3392	Injection, exagamglogene autotemcel, per treatment (Casgevy) (new code effective 01/01/25)
J3394	Injection, lovotibeglogene autotemcel, per treatment (Lyfgenia)

Policy-related HCPCS updatesHCPCS

J0791	HCPCS code added to policy history
J3590	Unlisted biologics code previously listed then removed for Casgevy
J3394	HCPCS code added effective 7/1/2024
J3392	HCPCS code added 01/01/25

inv-13: Re-authorization clinical response — No increase in VOCs in 12 months compared to baseline

Re-authorization requirementNo increase in number of vaso-occlusive events (VOCs) in 12 months compared to baseline documented in chart notes

Approval durationNon-formulary exception reviews and routine approvals for Adakveo, Endari, and Xromi may be approved for up to 12 months when response documented

Evidence documentationChart notes must demonstrate continued positive clinical response (no increase in VOCs vs baseline)

Applies to agentsAdakveo (crizanlizumab-tmca), Endari (L-glutamine), Xromi (hydroxyurea)

inv-14: Age eligibility (Casgevy trial) — 12 to 35 years

Provider Requirements and Authorization Actions

Prior Authorization

Prior Authorization Required

Prior authorization is required for medical-benefit agents listed in this policy. Approvals and length of authorization vary by product: up to 12 months for Adakveo (crizanlizumab-tmca), Endari (L‑glutamine), and Xromi (hydroxyurea) when criteria are met; Casgevy (exagamglogene autotemcel) and Lyfgenia (lovotibeglogene autotemcel) are authorized as one-time infusions when criteria are met. Follow product-specific coverage criteria and document ongoing clinical response for any reauthorization requests.

Adakveo (crizanlizumab-tmca): medical benefit; prior authorization may be approved up to 12 months when criteria met
Casgevy (exagamglogene autotemcel): medical benefit; one-time infusion authorization when criteria met
Lyfgenia (lovotibeglogene autotemcel): medical benefit; one-time infusion authorization when criteria met
Endari (L‑glutamine): pharmacy benefit; prior authorization may be approved up to 12 months when criteria met
Xromi (hydroxyurea): pharmacy benefit; prior authorization may be approved up to 12 months when criteria met

Background and Rationale

Sickle cell disease (SCD) is an inherited hemoglobin disorder in which red blood cells assume a rigid, sickle shape, impairing their ability to flow through the microvasculature. This leads to vaso-occlusion, recurrent acute painful episodes (vaso-occlusive crises), chronic hemolytic anemia, increased infection risk, and progressive organ damage. Clinical management focuses on prevention and reduction of acute VOCs, lowering transfusion dependence, and minimizing long-term organ complications to improve quality of life.

Definitions

inv-24: Vaso-occlusive crisis (VOC) — acute painful episode definition and clinical relevance

DefinitionAn acute painful episode caused by blockage of blood vessels from sickled red blood cells (vaso-occlusion) leading to tissue ischemia and often requiring supportive care

Clinical manifestationsPresents as severe pain crises, can include acute chest syndrome and organ ischemia

Clinical relevanceVOCs are a key endpoint for disease-modifying therapies and are used to document treatment response and coverage eligibility

inv-25: Myeloablative conditioning — definition and example (e.g., busulfan) with associated risks

DefinitionHigh-intensity (myeloablative) chemotherapy given prior to autologous HSC infusion to allow engraftment (example agent: busulfan)

Typical use

Policy Summary

PayerPremera Bluecross

PolicyPharmacologic Treatment of Sickle Cell Disease

Policy CodePolicy 5.01.640

Change TypeModified — material changes include addition of gene therapies and removal of withdrawn agent

Effective DateOct 3, 2025

Next Review DateN/A

Key ActionObtain prior authorization for listed medical-benefit agents and document hydroxyurea use or intolerance as required.

SourceLink

On This Page

Length of approval: initial and reauthorization reviews may be approved for up to 12 months when drug‑specific criteria are met and chart notes document clinical response (eg, reduction in vaso‑occlusive events or hospitalizations).

Trial evidence (phase 3) demonstrated fewer pain crises and fewer hospitalizations over 48 weeks versus placebo; long‑term safety beyond one year is less well characterized.

All other uses not outlined in this policy are considered investigational.

Candidate evaluation and treatment plan prescribed by or in consultation with a hematologist and a transplant specialist experienced in gene/cell therapy and myeloablative conditioning.

Absence of disqualifying conditions, including but not limited to: Moyamoya disease; severe cerebral vasculopathy (eg, history of overt ischemic or hemorrhagic stroke, >50% stenosis/occlusion in circle of Willis); active or advanced liver disease (eg, cirrhosis, active hepatitis, significant fibrosis) or liver iron concentration ≥15 mg/g unless biopsy shows no cirrhosis/active hepatitis/significant fibrosis; uncontrolled HIV/HBV/HCV infection; current malignancy (except non‑melanoma skin cancer); significant cardiac or pulmonary disease that precludes myeloablation/transplant; absolute neutrophil count <1000/µL (or <500/µL for those on hydroxyurea) or platelet count <100,000/µL when specified; inability to receive RBC transfusions or evidence of severe iron overload as clinically relevant.

No prior gene therapy or allogeneic hematopoietic stem cell transplant, unless policy/expert guidance allows retreatment; repeat treatment with Casgevy or Lyfgenia is considered investigational and is not covered.

Pre‑treatment evaluations completed and documented (eg, organ function assessment, liver iron concentration, infectious disease screening, cardiac and pulmonary assessment, evaluation for contraindications to busulfan or plerixafor).

Treatment is delivered following appropriate myeloablative conditioning and in a center with capability for transplant and gene therapy administration and management of expected complications.

Length of approval: one‑time infusion/administration; reauthorization for repeat gene therapy is not applicable and repeat treatment is investigational.

Clinical evidence: Casgevy and Lyfgenia demonstrated resolution or substantial reduction of transfusion dependence or vaso‑occlusive events in single‑arm trials and phase 3 studies; selection and monitoring criteria reflect trial eligibility and safety considerations. Strict eligibility and comprehensive pre‑treatment evaluation are required to mitigate risks associated with conditioning and gene therapy.

12 to 35 years (Casgevy CLIMB-THAL III trial enrollment)

Indication contextAged 12–35 with transfusion-dependent beta-thalassemia in the cited Casgevy trial

Relevance to coveragePolicy reflects trial eligibility when considering Casgevy for appropriate candidates

Billing Rule

Drug Coding and Authorization

Certain HCPCS codes are used for billing these agents. Ensure correct coding on medical claims and include prior authorization when required.

HCPCS codes added: J0791, J3394 (effective 7/1/24), J3392 (effective 1/1/25)
Do not use unlisted code J3590 for covered products after coding updates
Include authorization number and supporting documentation with the claim to avoid processing delays

Step Therapy

Hydroxyurea Step Requirement

Many medical-benefit agents in this policy require prior use of, or concurrent treatment with, hydroxyurea (Xromi) or documentation of intolerance or inadequate response to hydroxyurea before approval of higher‑line therapies.

Documented concurrent use of or treatment failure with hydroxyurea required when listed in product-specific criteria
Provide chart notes showing trials, dosing, response, or intolerance to hydroxyurea

Prior Authorization

Non‑Formulary Exception Duration

Non-formulary exception review authorizations for drugs listed in this policy may be approved for up to 12 months when the criteria are met and documentation supports medical necessity.

Non-formulary exception approvals may be granted up to 12 months
Include clinical justification and relevant chart notes with requests

Documentation Required

Prescriber and Documentation Requirement

Prescriptions or infusion orders must be issued by, or in documented consultation with, a hematologist or hematology/transplant specialist as specified in the drug‑specific criteria. Maintain specialty consultation notes in the medical record.

Adakveo, Casgevy, and gene‑therapy products: prescribed by or in consultation with a hematologist or transplant specialist
Attach consultation notes to prior authorization requests to support medical necessity

Note

Member Benefit Verification

Verify member benefits and coverage before initiating therapy. Coverage depends on the member's specific plan; consult the member benefit booklet or contact Customer Service for benefit determination.

Check pharmacy vs medical benefit applicability (e.g., Endari and Xromi = pharmacy benefit; Adakveo, Casgevy, Lyfgenia = medical benefit)
Confirm any site‑of‑service medical necessity rules that may affect coverage (exceptions apply for Alaska fully‑insured members per policy)
Contact Customer Service or refer to the member benefit booklet for prior authorization submission instructions and benefit limits

Denial Risk

Site‑of‑Service Denial Risk

Site‑of‑service medical necessity criteria apply to medical‑benefit drug administration and may affect coverage. Failure to meet the SOS criteria for the administered setting can result in denial of payment. Note the Alaska exception for fully‑insured members.

SOS medical necessity applies to medical benefit reviews for administration locations (hospital outpatient, infusion center, physician office, home)
SOS criteria do NOT apply to Alaska fully‑insured members — only the infusion/injection drug medical necessity criteria apply per Alaska HB 226
Document clinical rationale if requesting administration in a higher‑acuity setting to justify medical necessity

Used as conditioning before infusion of modified CD34+ hematopoietic stem and progenitor cells for gene therapies (e.g., Casgevy, Lyfgenia)

Associated risksRisks include cytopenias, infections, and organ toxicity related to high-intensity chemotherapy

Operational notePharmacokinetic-adjusted busulfan myeloablation described in Casgevy and Lyfgenia trial protocols