Transformative Therapies Advance Treatment for Sickle Cell Disease

Transformative therapies for sickle cell disease include allogeneic hematopoietic stem cell transplant and gene therapy, offering patients the potential to no longer demonstrate an SCD phenotype and experience reductions in disease-related morbidities with improved quality of life. These therapies address the mutated β-globin gene in bone marrow stem cells through different mechanisms, though they can be associated with major adverse events including death.

Allogeneic hematopoietic stem cell transplant replaces the patient's stem cells with those of a donor unaffected by SCD or who has sickle cell trait. After successful transplant, the patient's blood cell production mirrors that of the donor. Transplant requires conditioning before the procedure and immunosuppressive therapy for 1 to 2 years after transplant to prevent rejection of donor stem cells and graft-versus-host disease. Conditioning can be myeloablative or nonmyeloablative, with nonmyeloablative conditioning increasingly used in the current era.

About 90% of patients successfully switch to donor blood cell production and no longer demonstrate an SCD phenotype. After successful transplant, patients demonstrate improvements in quality of life, resolution of acute complications of SCD, and stability or improvement in end-organ function. Unfortunately, only 18% of people with SCD have a matched sibling donor. Recent studies have established transplant from a haploidentical donor as an alternative for those without a matched sibling, with more than 90% of people with SCD expected to have at least one haploidentical donor.

After nonmyeloablative conditioning, about 90% of adults who undergo transplant from a haploidentical donor successfully switch to donor blood cell production. However, 25% of children experience transplant rejection, and further research is needed to determine whether haploidentical transplant is suitable for people younger than 18 years.

Gene therapy represents another transformative therapy for SCD, with two gene therapies currently marketed worldwide. In contrast to transplant, gene therapies are autologous stem cell products. The patient's own stem cells are collected via apheresis, shipped to a manufacturing facility where gene editing is applied, then returned for infusion. One available product deactivates BCL11A, a suppressor of fetal hemoglobin production, thereby reconstituting erythropoiesis with about 40% fetal hemoglobin. Fetal hemoglobin prevents sickling and reduces morbidity and mortality in SCD. Another product introduces a novel β-globin gene, which leads to production of an antisickling hemoglobin.

Sickle cell disease occurs when a DNA base pair substitution in the β-globin gene results in the formation of hemoglobin S, which polymerizes when deoxygenated, leading to deformation and hemolysis of red blood cells. The disease results in recurrent acute complications like pain crises, acute chest syndrome, and stroke, as well as chronic end-organ injury affecting the heart, lungs, kidneys, bones, and retina. Recent American data indicate that the life expectancy of people with SCD is 52.6 years, though life expectancy varies considerably depending on disease-related factors and access to health care.

An estimated 6000 people live with SCD in Canada, with increasing prevalence owing to immigration. The decision to proceed with a transformative therapy must take into careful consideration the severity of the SCD, the risk of future SCD complications, and the risks of available transformative therapies. The expertise and infrastructure to deliver transformative therapies lies within existing Canadian cancer care programs.