Table 2.
Comparison of the two curative therapies for adults with severe SCD.
| Variables | Haploidentical BMT with Post-Transplant Cyclophosphamide |
Current Gene Therapy Approaches |
|---|---|---|
| Curative | Yes | Yet to be validated |
| Intensity of regimen | Non-myeloablative | Myeloablative |
| Eligibility | Most adults with organ dysfunction | Limited to children with no organ dysfunction |
| Donor availability | >90% will have eligible related haploidentical donors |
None needed (autologous) |
| Stem cell procurement | Single bone marrow harvest or peripheral stem cell mobilization of eligible family donor | Requires multiple apheresis cycles |
| Toxicity of regimen | High-dose Cytoxan short-term toxicity (hemorrhagic cystitis, cardiotoxicity, pulmonary fibrosis, immunosuppression, increased hepatic enzymes and syndrome of inappropriate anti-diuretic hormone (SIADH), which is limited with supportive care. | High-dose busulfan toxicity (short-term—seizures, cardiovascular, gastrointestinal, bronchopulmonary dysplasia with pulmonary fibrosis and hepatic sinusoidal obstruction syndrome). |
| Outcomes | Evidence that a successful transplant attenuates progressive vasculopathy and end-organ damage | Unknown impact on progressive vasculopathy and end-organ damage in adults |
| Complications | Risk of GVHD and graft rejection | Avoids immunologic complications (GVHD or graft rejection) Poor phenotypic correction Poor consistency, integration, and site-independence Poor-level expression of the inserted gene Poor erythroid lineage specificity; developmental stage-specific expression of the inserted gene. |
| Late-effects | Long-term—less risk of ovarian failure, puberty, amenorrhea, or development of myeloid disorders from recipient derived clonal hematopoiesis of indeterminate potential (CHIP) in engrafted patients with current NMA approaches. | Long-term—ovarian failure, failure to achieve puberty and amenorrhea, secondary malignancies with current myeloablative conditioning with Busulfan. Chromosomal alterations may also occur; possible genotoxic effects; creation of DSBs at locations other than the desired genomic location; risk of clonal hematopoiesis of indeterminate potential (CHIP) prior to HSCT |
| Requirements | Requires only a FACT-accredited facility | Requires both GMP and FACT accredited facilities |
Legend: GVHD, graft-versus-host disease; SCD, sickle cell disease; HSPCs, hematopoietic stem and progenitor cells; iPSCs, induced pluripotent stem cells; DSBs, double-strand breaks; GMP, good manufacturing practice; FACT, Foundation for the Accreditation of Cellular Therapy; HSCT, hematopoietic stem cell transplant.