This document addresses gene therapy for sickle cell disease (SCD) which is a genetic disease involving variations in the human beta-globin gene (HBB) that reduce an individual’s ability to produce functional hemoglobin leading to a shortage of mature red blood cells and a lack of sufficient oxygen circulation. The characteristic sickle-shaped red blood cells are rigid and can block small blood vessels (vaso-occlusion), causing severe pain and organ damage.

Two hematopoietic stem cell-based gene therapy products have been approved by the U.S. Food and Drug Administration (FDA) to treat SCD, exagamglogene autotemcel (Casgevy^™) and lovotibeglogene autotemcel (Lyfgenia^®). In Casgevy therapy, the BCL11A gene, which encodes a repressor of fetal hemoglobin (HbF) levels, is edited in an individual’s own hematopoietic stem cells using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) nuclease system to produce high levels of HbF in red blood cells. Lyfgenia therapy involves using a modified lentivirus to deliver a functional copy of the beta-globin HBB gene to the individual’s cells. Both therapies produce functional hemoglobin proteins that may compensate for defective beta-globin, thereby reducing painful and debilitating sickle cell crises for those with SCD.

Note: Please see the following related documents for additional information:

• CG-MED-68 Therapeutic Apheresis
• CG-MED-90 Chelation Therapy
• MED.00140 Gene Therapy for Beta Thalassemia
• TRANS.00029 Hematopoietic Stem Cell Transplantation for Genetic Diseases and Aplastic Anemias

Position Statement

Medically Necessary:

A one-time infusion of exagamglogene autotemcel is considered medically necessary in individuals when all of the following criteria are met:

1. Diagnosis of sickle cell disease; and
2. At least 4 severe vaso-occlusive crises in the previous 2 years; and
3. 12 years of age and older; and
4. Hydroxyurea therapy failure or intolerance; and
5. The individual is a candidate for an allogeneic hematopoietic cell transplantation, but ineligible due the absence of a donor*; and
6. No serious concomitant illness (for example, advanced liver disease, clinically significant active infection, severe cerebral vasculopathy, clinically significant pulmonary hypertension, inadequate pulmonary or cardiac function, prior or current malignancy other than previously treated non-life-threatening tumors, immunodeficiency disorder); and
7. No prior receipt of gene therapy.

A one-time infusion of lovotibeglogene autotemcel is considered medically necessary in individuals when all of the following criteria are met:

1. Diagnosis of sickle cell disease; and
2. At least 4 severe vaso-occlusive crises in the previous 2 years; and
3. 12 years of age and older; and
4. Hydroxyurea therapy failure or intolerance; and
5. The individual is a candidate for an allogeneic hematopoietic cell transplantation, but ineligible due the absence of a donor*; and
6. No serious concomitant illness (for example, advanced liver disease, clinically significant active infection, severe cerebral vasculopathy, clinically significant pulmonary hypertension, inadequate pulmonary or cardiac function, prior or current malignancy other than previously treated non-life-threatening tumors, immunodeficiency disorder) and
7. No prior receipt of gene therapy.

*Documentation that a suitable donor has not been identified, for example, a matched related donor or matched (HLA 8/8 or 7/8) unrelated donor.

Investigational and Not Medically Necessary:

Gene therapy for sickle cell disease is considered investigational and not medically necessary when the criteria above are not met.