| Populations | Interventions | Comparators | Outcomes |
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Sickle cell disease is a genetic hemoglobinopathy that results from a genetic variant in the HBB gene resulting in the production of dysfunctional hemoglobin which forms polymers in the red blood cells of individuals. The sickled red blood cells have a shorter life span and do not move as freely as normal, round, red blood cells resulting in anemia and vascular obstruction. Recurrent acute pain crises, or vaso-occlusive crises are the most prevalent manifestation of sickle cell disease. It is estimated that there are 100,000 individuals living with sickle cell disease in the United States. Two gene therapies have been approved by the U.S. Food and Drug Administration. Lovotibeglogene autotemcel adds functional copies of a modified βA-globin gene (βA-T87Q-globin) into an individual's hematopoietic stem cell through transduction of autologous CD34+ cells with BB305 lentiviral vector. After infusion, the transduced CD34+ hematopoietic stem cells engraft in the bone marrow and differentiate to produce red blood cells containing βA-T87Q gene that will produce HbAT87Q protein (functional gene therapy-derived hemoglobin). Exagamglogene autotemcel is a cellular gene therapy consisting of autologous CD34+ hematopoietic stem cells edited by CRISPR/Cas9-technology at the erythroid specific enhancer region of the BCL11A gene to reduce BCL11A expression in erythroid lineage cells. After infusion, the edited CD34+ cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression. Reduced BCL11A expression results in an increase in γ-globin expression and fetal hemoglobin protein production in erythroid cells.
For individuals who are 12 years and older with sickle cell disease who receive lovotibeglogene autotemcel, the evidence includes one single-arm prospective study. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related mortality and treatment-related morbidity. In the pivotal HGB-206 (Group-C) trial, a total of 36 participants received a single intravenous infusion of lovotibeglogene autotemcel. Of the 36 total participants, 32 were evaluable for the endpoints of complete resolution of vaso-occlusive events (VOEs) and severe VOEs (sVOEs) in the 6 to 18 months post-infusion. Severe VOEs were eliminated for 94% (30/32) and all VOEs were eliminated for 88% (28/32) of evaluable study participants between 6- and 18- months post-infusion. Safety data included 54 study participants who initiated stem cell collection. Three cases of hematologic malignancy (2 cases of acute myeloid leukemia and 1 case of myelodysplastic syndrome) were reported in the pivotal trial. As per the prescribing label, individuals treated with lovotibeglogene autotemcel should have lifelong monitoring for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment, and integration site analysis at months 6, 12, and as warranted. Other adverse reactions were related to myeloablative conditioning or underlying disease. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time period. After the primary evaluation period to last follow-up, 4 of the 28 trial participants who achieved complete resolution of VOE (VOE-CR) experienced VOEs. After the primary evaluation period up to 24 months, 17 of 35 (49%) trial participants were prescribed opioids for sickle cell and non-sickle cell-related pain. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as adverse effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty still remains about the degree of risk of insertional oncogenesis with lovotibeglogene autotemcel in real-world practice. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that lovotibeglogene autotemcel will frequently be successful in treating sickle cell disease in at least the short-term. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
For individuals who are 12 years and older with sickle cell disease who receive exagamglogene autotemcel, the evidence includes one single-arm prospective study. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related mortality, and treatment-related morbidity. In the pivotal single-arm study CLIMB-121, a total of 44 study participants received a single intravenous infusion of exagamglogene autotemcel. Of the 44 total participants, 31 were evaluable for the primary endpoint. The primary endpoint of proportion of study participants who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel infusion was achieved by 29 of 31 or 93.5% study participants. The key secondary endpoint of proportion of study participants who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period was achieved by 100% or 30 of the 30 evaluable study participants. Safety data includes 44 study participants. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. Serious adverse reactions after myeloablative conditioning and exagamglogene autotemcel infusion were observed in 45% of study participants. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time. After the primary evaluation period to last follow-up, one of the 29 study participants who achieved primary endpoint experienced an acute pain episode meeting the definition of a severe VOC at month 22.8 requiring a 5-day hospitalization. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as adverse effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty remains about the degree of risk of unintended, off-target editing in CD34+cells due to uncommon genetic variants. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that exagamglogene autotemcel will frequently be successful in treating sickle cell disease in at least short-term. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
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Exagamglogene autotemcel and lovotibeglogene autotemcel are considered medically necessary for individuals if they meet criteria 1 through 6:
Are at least 12 years of age.
Diagnosis of sickle cell disease confirmed by genetic testing demonstrating the following:
Homozygous sickle cell disease (e.g., HbSS) OR
Heterozygous sickle cell disease (e.g., HbSC, HbSβ+, HbSβ0, HbSD, HbSOArab, HbSE)
Documented history of one of the following clinical signs or symptoms in the last 12 months in the setting of appropriate supportive care measures for sickle cell disease (e.g., pain management plan):
Acute pain event requiring a visit to a medical facility and administration of pain medications (e.g., oral or intravenous opioids or intravenous non-steroidal anti-inflammatory drugs), hydration therapy, or red blood cell transfusions
Acute chest syndrome
Acute splenic sequestration
Priapism lasting > 2 hours and requiring a visit to a medical facility.
Meet the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy (see Policy Guidelines). These requirements may include:
Adequate Karnofsky performance status or Lansky performance status;
Absence of advanced liver disease;
Adequate estimate glomerular filtration rate (eGFR);
Adequate diffusing capacity of the lungs for carbon monoxide (DLCO);
Adequate left ventricular ejection fraction (LVEF);
Absence of clinically significant active infection(s).
Have not received a previous allogenic hematopoietic stem cell transplant.
Have not received any gene therapy or are under consideration for treatment for another gene therapy for sickle cell disease.
Exagamglogene autotemcel and lovotibeglogene autotemcel are considered investigational when the above criteria are not met.
Lovotibeglogene autotemcel is considered investigational for all other indications.
Repeat treatment with exagamglogene autotemcel or lovotibeglogene autotemcel is considered investigational.
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CPT |
96372 |
Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular |
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96413 |
Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug |
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96415 |
Chemotherapy administration, intravenous infusion technique; each additional hour |
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38206 |
Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous |
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ICD10 PCS |
3E033GC |
Introduction of Other Therapeutic Substance into Peripheral Vein, Percutaneous Approach |
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3E043GC |
Introduction of Other Therapeutic Substance into Central Vein, Percutaneous Approach |
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3E03305 |
Introduction of Other Antineoplastic into Peripheral Vein, Percutaneous Approach |
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3E04005 |
Introduction of Other Antineoplastic into Central Vein, Open Approach |
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6A550ZV |
Pheresis of Hematopoietic Stem Cells, Single |
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6A551ZV |
Pheresis of Hematopoietic Stem Cells, Multiple |
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XW133H9 |
Transfusion of Lovotibeglogene Autotemcel into Peripheral Vein, Percutaneous Approach, New Technology Group 9 |
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XW133J8 |
Transfusion of Exagamglogene Autotemcel into Peripheral Vein, Percutaneous Approach, New Technology Group 8 |
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XW143H9 |
Transfusion of Lovotibeglogene Autotemcel into Central Vein, Percutaneous Approach, New Technology Group 9 |
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XW143J8 |
Transfusion of Exagamglogene Autotemcel into Central Vein, Percutaneous Approach, New Technology Group 8 |
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HCPCS |
C9399 |
Unclassified drugs or biologicals |
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J3394 |
Injection, lovotibeglogene autotemcel, per treatment (eff 07/01/2024) |
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J3490 |
Unclassified drugs |
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J3590 |
Unclassified drugs |
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J3392 |
Injection, exagamglogene autotemcel, per treatment |
| ICD10 CM | D57.00- D57.819 | Sickle Cell Disease code range |
Minimum dose is 3 × 106 CD34+ cells/kg.
1 injection per lifetime.
The requirement for eligibility for a stem cell transplant varied between the pivotal trial for exagamglogene autotemcel and lovotibeglogene autotemcel. These requirements are summarized below:
There is a boxed warning for hematologic malignancy for lovotibeglogene autotemcel. Hematologic malignancy has occurred in patients treated with lovotibeglogene autotemcel. It is recommended to monitor treated individuals closely for evidence of malignancy through complete blood counts at least every 6 months for at least 15 years after treatment and through integration site analysis at months 6, 12, and as warranted.
Drug-drug interactions between iron chelators and the myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of conditioning. Some iron chelators are myelosuppressive. It is recommended to avoid use of non-myelosuppressive iron chelators for at least 3 months and use of myelosuppressive iron chelators for at least 6 months after the infusion of exagamglogene autotemcel or lovotibeglogene autotemcel. Phlebotomy can be used in lieu of iron chelation, when appropriate.
Sickle cell disease is a genetic disorder characterized by the presence of hemoglobin S (HbS) that includes, either from homozygosity for the sickle variant in the beta globin chain of hemoglobin (βS/βS) or from compound heterozygosity of a sickle beta globin mutation with another beta globin mutation (eg, sickle-beta thalassemia such as βS/β0 or βS/β+ genotype). The homozygous from (βS/βS) accounts for 60% to 70% of sickle cell disease in the United States.1,
Production of hemoglobin with dysfunctional hemoglobin S forms polymers in the red blood cells of patients. Among healthy individuals, red blood cells are flexible and round allowing them to move easily through blood vessels. With sickle cell disease, those red blood cells are sickled or shaped like crescent moons causing them to slow down or cause blockage as blood flows through the blood vessels. This results in vascular obstruction and ischemia; a shortened lifespan of the red blood cells leading to both intravascular and extravascular hemolysis, and a sticky red blood cells surface increases adherence to the vascular endothelium which can result in vascular obstruction and can contribute to vascular proliferative lesions.2, Recurrent acute pain crises, or vaso-occlusive crises, are the most prevalent manifestations of sickle cell disease.3, Patients also experience acute complications including serious infections and non-infectious complications such as stroke, renal necrosis, and priapism.4, Acute chest syndrome is a potentially life-threatening complication that can involve chest pain and shortness of breath among other symptoms.5, Chronic complications can emerge across multiple organs and include delayed puberty, avascular necrosis, skin ulcers, chronic pain, neurocognitive impairment, chronic kidney injury, pulmonary hypertension, cardiovascular disease, and can result in early mortality.4,
Incidence and prevalence of sickle cell disease vary considerably by geography with the highest rates in equatorial Africa, Brazil, Saudi Arabia and central India populations.6, It is estimated that there are approximately 100,000 individuals living with sickle cell disease in the United States.7,
As of 2008, screening for sickle cell disease in newborns is mandated in all 50 states of the United States and the District of Columbia, regardless of birth setting.8, The diagnostic methods used after birth are those that separate hemoglobin species according to amino acid composition (hemoglobin electrophoresis or thin layer isoelectric focusing), solubility testing, and examination of the peripheral blood smear.1,
Specific interventions for sickle cell disease include stem cell transplantation, chronic transfusion with packed red blood cells, and hydroxyurea. While stem cell transplant can be curative, the degree of myeloablation required and lack of availability of matched donors limit its use. Chronic transfusion is generally used for primary or secondary stroke prevention. Hydroxyurea is used to reduce the number of acute pain crises in those with frequent or severe crises, and in those with a history of acute chest syndrome or severe anemia.3, Hydroxyurea improves blood flow by decreasing sickling of red blood cells and altering the adhesion of red blood cells to endothelium. Also, it increases red blood cells survival and decreases white blood cell, reticulocyte and platelet counts.1, Acute pain crisis may be managed with pain medications including opioids, and may require additional inpatient or outpatient treatments including hydration, transfusion, supplemental oxygen, and a variety of other treatments.3,
In recent years, multiple specific disease-modifying treatments have been approved by the FDA for treatment of complications resulting from sickle cell disease. L-glutamine supplementation is used to decrease the frequency of acute pain crises.9, It was approved by the FDA on July 7, 2017 to reduce the acute complications of sickle cell disease in adult and pediatric individuals 5 years of age and older. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin.10, It was approved by the FDA on November 15, 2019 to reduce the frequency of vaso-occlusive crises in adults and pediatric individuals aged 16 years and older with sickle cell disease. It is administered intravenously in 2 loading doses 2 weeks apart and then every 4 weeks thereafter. Voxelotor is an HbS polymerization inhibitor that reversibly binds to hemoglobin to stabilize the oxygenated hemoglobin state, thus shifting the oxyhemoglobin dissociation curve.11, Voxelotor was approved by the FDA on November 25, 2019 for the treatment of sickle cell disease in adults and pediatric individuals 12 years of age and older.
On December 8, 2023, lovotibeglogene autotemcel (Lyfgenia) was approved by the FDA for the treatment of sickle cell disease in patients 12 years or older and a history of vaso-occlusive events.
On December 8, 2023, exagamglogene autotemcel (Casgevy) was approved by the FDA for the treatment of sickle cell disease in patients 12 years and older with recurrent vaso-occlusive crises. On January 16, 2024, the FDA expanded the approved indication to include treatment of patients age 12 years and older with transfusion-dependent β-thalassemia.
