Lovotibeglogene Autotemcel (Lyfgenia)

Number: 1053

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses lovotibeglogene autotemcel (Lyfgenia) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of lovotibeglogene autotemcel (Lyfgenia) is required of all Aetna participating providers and members in applicable plan designs. For precertification of lovotibeglogene autotemcel (Lyfgenia), contact National Medical Excellence (NME) at 877-212-8811.

Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes^® Gene Based, Cellular and Other Innovative Therapy (GCIT^®) Network. For lovotibeglogene autotemcel (Lyfgenia), see Aetna Institutes® GCIT Designated Centers. 

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a hematologist.

2. Criteria for Initial Approval

   Aetna considers a one dose total of lovotibeglogene autotemcel (Lyfgenia) medically necessary for treatment of sickle cell disease when all of the following criteria are met:

   1. Member is 12 years of age or older; and
   2. Member has a diagnosis of sickle cell disease with one of the following genotypes confirmed by molecular or genetic testing:
      
      
      1. βs/βs
      2. βs/β0
      3. βs/β+; and
   3. Member has a documented history of at least 2 severe vaso-occlusive episodes per year during the previous two years (see Appendix for examples); and
   4. Member is eligible for a hematopoietic stem cell transplant (HSCT) but is unable to find a human leukocyte antigen (HLA)-matched related donor; and
   5. Member has not received a prior hematopoietic stem cell transplant (HSCT); and
   6. Member has not received Lyfgenia or any other gene therapy previously; and
   7. Member does not have more than two α-globin gene deletions; and
   8. Member meets one of the following:
      
      1. Has experienced, at any time in the past, an inadequate response or intolerance to a trial of hydroxyurea; or
      2. Has a contraindication to hydroxyurea.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Related Policies 

   1. CPB 0626 - Hematopoietic Cell Transplantation for Thalassemia Major and Sickle Cell Anemia
   2. CPB 0964 - Crizanlizumab-tmca (Adakveo)
   3. CPB 1052 - Exagamglogene Autotemcel (Casgevy)

Dosage and Administration

Lovotibeglogene autotemcel is available as Lyfgenia, a cell suspension for autologous use and administered as a single dose intravenous infusion. A single dose of Lyfgenia contains a minimum of 3 × 10⁶ CD34+ cells per kg of body weight, in one to four infusion bags.

• Individuals are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for Lyfgenia manufacturing. 
• Dosing of Lyfgenia is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. 
• The minimum recommended dose is 3 × 10⁶ CD34+ cells/kg. 
• Myeloablative conditioning must be administered before infusion of Lyfgenia. 
• A minimum of 48 hours of washout before Lyfgenia infusion is to be allowed following myeloablative conditioning.
• For additional information, refer to the Full Prescribing Information for Lyfgenia.

Source: bluebird bio, 2023b

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96365 – 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug)
96413 - 96415	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J3394	Injection, lovotibeglogene autotemcel, per treatment
Other HCPCS codes related to the CPB:
S0176	Hydroxyurea, oral, 500 mg
ICD-10 codes covered if selection criteria are met:
D57.00 – D57.09, D57.1	Sickle-cell disorders

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Lyfgenia is indicated for the treatment of patients 12 years of age or older with sickle cell disease and a history of vaso-occlusive events.

Limitations of Use:

Following treatment with Lyfgenia, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions. Lyfgenia has not been studied in patients with more than two α-globin gene deletions.

Lovotibeglogene autotemcel, also known as lovo-cell, is branded as Lyfgenia (bluebird bio, Inc.). Lyfgenia is a cell-based gene therapy that contains human blood stem cells that are genetically modified with a replication-incompetent, self-inactivating lentiviral vector (LVV), a gene delivery vehicle. Lyfgenia works by adding functional copies of a modified β-globin gene into the patient's hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After a one-time, single-dose intravenous Lyfgenia infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce red blood cells (RBCs) containing biologically active β^A-T87Q-globin that will combine with α-globin to produce functional hemoglobin (Hb) containing β^A-T87Q-globin (HbA^T87Q). HbA^T87Q has similar oxygen-binding affinity to hemoglobin A (HbA). Thus, RBCs containing HbA^T87Q have a lower risk of sickling and occluding blood flow, thereby, reducing vaso-occlusive events (VOEs). 

This cell-based gene therapy process requires the patient to undergo CD34+ HSC mobilization (where stem cells are stimulated out of the bone marrow space) followed by apheresis (the procedure used to collect stem cells from the blood) to isolate the CD34+ cells needed for Lyfgenia manufacturing. The cells are, then, genetically modified ex vivo (outside the body) with BB305 LVV to introduce the HbA^T87Q gene. Prior to the Lyfgenia infusion, the patient will undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the genetically-modified autologous cells in Lyfgenia, as part of a hematopoietic (blood) stem cell transplant (HSCT) procedure.

Although there are no known contraindications, Lyfgenia carries a boxed warning for hematologic malignancy. At the time of initial product approval, two patients treated with an earlier version of Lyfgenia using a different manufacturing process and transplant procedure developed acute myeloid leukemia (AML). One patient with α-thalassemia trait was diagnosed with myelodysplastic syndrome (MDS). The additional hematopoietic stress associated with mobilization, conditioning, and infusion of Lyfgenia, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Additional labeled warnings and precautions include delayed platelet engraftment, neutrophil engraftment failure (defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 10⁹ cells/L obtained on different days by Day 43 after Lyfgenia infusion), potential risk of lentiviral vector-mediated insertional oncogenesis, and hypersensitivity reactions (including anaphylaxis due to the dimethyl sulfoxide (DMSO) or dextran 40 in Lyfgenia).

The most common adverse reactions of Grade 3 or more (incidence of 20% or more) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia. 

Per the label, patients should not take prophylactic human immunodeficiency virus (HIV) anti-retroviral medications for at least one month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. 

Patients who have received Lyfgenia are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, patients who have received Lyfgenia should not be screened for HIV infection using a PCR-based assay.

Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning. 

Patients are not to receive myelosuppressive iron chelators for 6 months post-treatment with Lyfgenia. 

The safety and efficacy of Lyfgenia in children less than 12 years of age have not been established. Lyfgenia has not been studied in patients 65 years of age and older. In addition, Lyfgenia has not been studied in patients with HIV-1 or HIV-2.

Sickle Cell Disease

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by the presence of hemoglobin S (HbS), which causes RBCs to become rigid, sticky and sickle shaped. The hallmarks of SCD are vaso-occlusive crisis (VOC) and hemolytic anemia. VOC (previously called sickle cell crisis) occurs when sickled RBCs obstructs blood flow in the blood vessels causing tissue hypoxia resulting in severe, debilitating pain. In hemolytic anemia, sickled RBCs break down prematurely, leading to anemia. Other vaso-occlusive events (VOEs), or complications associated with SCD, include acute chest syndrome (ACS), avascular necrosis, infection, organ damage, and stroke (not an all-inclusive list).

The exact number of people living with SCD in the United States is unknown. It is estimated that SCD affects approximately 100,000 Americans, predominantly among African Americans, and that about 1 in 13 babies is born with the sickle cell trait. In addition, SCD can occur among Hispanic Americans, which is estimated to occur in 1 out of every 16,300 births (CDC, 2023).

SCD is a disease that worsens over time. Management has included prevention and treatment of pain episodes and other complications (e.g., hydration, temperature regulation, blood transfusions, and pharmacotherapy options such as hydroxyurea, L-glutamine, voxelotor, crizanlizumab, analgesics). Hematopoietic stem cell transplantation (HSCT) is a cure for SCD; however, patients require a relative who is a close genetic match to be a donor to have the best chance for a successful transplant. Autologous hematopoietic stem cell-based gene therapy has been studied for a potential treatment of SCD.

On December 8, 2023, the FDA approved Lyfgenia (lovotibeglogene autotemcel), for the treatment of SCD in patients ages 12 and older who have a history of VOEs. Lyfgenia is a one-time gene therapy that offers the potential to resolve VOEs and is custom-designed to treat the underlying cause of SCD. Lyfgenia will be available at bluebird bio’s established network of Qualified Treatment Centers (QTCs), which receive specialized training to administer complex gene therapies like Lyfgenia. bluebird plans to make the therapy available in early 2024.

The safety and effectiveness of Lyfgenia is based on the data from a single-arm, 24-month, open-label, multicenter Phase 1/2 study in patients (12 to 50 years) with SCD and history of VOEs (defined as episodes of acute pain with no medically determined cause other than a vaso-occlusion, lasting more than two hours and severe enough to require care at a medical facility). Thirty-six patients received the intravenous infusion of Lyfgenia with a median (min, max) dose of 6.4 (3,14) × 10⁶ CD34+ cells/kg (48 hours after the last myeloablative busulfan conditioning dose). As Lyfgenia is an autologous therapy, prophylactic long-term immunosuppressive agents were not required. No patients experienced graft failure or graft rejection. Thirty-two patients were evaluable for the endpoints of complete resolution of VOEs (VOE-CR) and severe VOEs in the 6-18 months post Lyfgenia infusion including 8 adolescent patients. Severe VOEs were resolved in 30 out of 32 patients (94%), and 28 out of 32 patients (88%) achieved VOE-CR during this time period. 

Patients treated with Lyfgenia in bluebird bio-sponsored clinical studies will be monitored for a total of 15 years through a long-term safety and efficacy follow-up study.

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Appendix

Examples of Severe Vaso-Occlusive Events

1. Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous [IV] non-steroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions
2. Acute chest syndrome
3. Priapism lasting > 2 hours and requiring a visit to a medical facility
4. Splenic sequestration  
5. Hepatic sequestration

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References