Stem cell transplantation and gene therapy for telomere biology disorders: Historical perspective, current approaches, and emerging strategies

Telomere biology disorders (TBDs) are inherited conditions characterized by defective telomere maintenance, leading to critically short telomeres and multisystem disease, with hematologic complications representing a major cause of morbidity and mortality. Bone marrow failure, myelodysplastic syndrome, and acute myeloid leukemia occur at markedly increased rates in affected individuals, and hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for these hematologic manifestations. Historically, outcomes following HSCT in TBDs were poor, largely due to heightened sensitivity to myeloablative conditioning regimens, resulting in excessive early mortality, graft failure, graft-versus-host disease, and severe pulmonary and hepatic toxicity. Advances in disease recognition, donor selection, conditioning regimens, and supportive care have substantially improved transplant outcomes over the last several decades. Contemporary strategies emphasize reduced-intensity or reduced-toxicity approaches, with growing experience in the use of alkylator- and radiation-free platforms. Despite improved early survival, long-term outcomes remain limited by progressive non-hematologic organ dysfunction, vascular complications, and secondary malignancies inherent to telomere-mediated disease and potentially accelerated by transplantation. Optimal management of patients with TBDs undergoing HSCT requires careful patient selection, thorough pre-transplant evaluation, exclusion of occult TBDs in related donors, preference for bone marrow grafts, and aggressive strategies to prevent graft-versus-host disease. Lifelong, multidisciplinary posttransplant surveillance focused on multiorgan complications is essential. Emerging gene and cellular therapies, including autologous telomere-elongation approaches, offer promising alternatives for select patients and may further expand the therapeutic landscape. Continued progress will depend on disease-specific, multi-institutional prospective studies aimed at optimizing transplant strategies, minimizing long-term toxicity, and improving survival and quality of life for patients with TBDs.