Factors affecting subsequent autologous gene therapy after graft failure with a previous allogeneic HCT in individuals with SCD and thalassemia. Persistent systemic and bone marrow niche sterile inflammation, constant erythroid development pressure, iron overload, and associated toxicity from blood transfusions, as well as exposure to chemotherapy and radiation during an allogeneic HCT may cause damage to the HSCs, inducing accelerated senescence or clonal evolution. This may make the HSCs unsuitable for use in manufacturing of a genetically modified product. At the same time, exposure to alloantigens in the transfused blood units may induce anti-HLA antibodies, and damage to various organ systems from chemoradiotherapy exposure may affect the ability of an individual to receive a subsequent allogeneic HCT or autologous gene therapy.