Although allogeneic hematopoietic stem cell transplantation has long been the only curative therapy for non-malignant blood diseases, recent clinical successes have demonstrated the transformative potential of autologous gene therapies as definitive treatments for these disorders. By providing durable life-changing clinical benefit while reducing the need for suitable allogeneic donors and avoiding immunologic complications like graft rejection and graft-versus-host disease, autologous transplantation with genetically modified hematopoietic stem cells provides a potentially safer and, in some respects, more accessible pathway to cure. However, several formidable barriers still prevent broader use of autologous gene therapy, including the risk of adverse acute and chronic effects from the busulfan-based conditioning regimens used to deplete host hematopoietic stem cells before transplant. In this article, we define the role transplant conditioning regimens play in autologous gene therapy, including contrasting the goals of care in this setting with those for stem cell transplantation for malignancies. We also discuss the conditioning strategies that are used by approved and select investigational autologous gene therapies to date, while highlighting exciting preclinical and clinical advances aimed at making transplant conditioning safer for myriad non-malignant and malignant disease applications.
Cerebral complications are among the most devastating manifestations of sickle cell disease (SCD), affecting children and adults with a spectrum that includes overt ischemic and hemorrhagic stroke, silent cerebral infarcts, vasculopathy, and long-term neurocognitive impairment. Advances in screening, primary and secondary stroke prevention, and acute stroke care have reduced risk for some patients, yet cerebrovascular injury remains common and likely underdiagnosed. The pathophysiology of cerebral injury in SCD is multifactorial, resulting from chronic hemolytic anemia, vaso-occlusion, large- and small-vessel vasculopathy, endothelial dysfunction, inflammation, and altered cerebral hemodynamics. Emerging data suggest stabilization or reduced incidence of new infarcts and preservation of neurocognitive function after successful hematopoietic cell transplantation (HCT), although some neurodevelopmental deficits may persist. This review synthesizes contemporary epidemiology, pathophysiology, diagnostic strategies, prevention and treatment, in the context of HCT. Key gaps for future research include optimizing screening strategies, quantifying neurocognitive benefit of curative therapy, and improving access to prevention in resource-limited settings.
Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by dysregulated myeloid proliferation and hyperactive JAK-STAT signaling pathway. While JAK inhibitors have become standard therapies for the management of these conditions, significant challenges remain due to resistance to these medications and adverse effects such as cytopenias and infectious complications. This review explores novel therapeutic strategies that target pathways beyond JAK-STAT signaling.We discuss BET inhibitors (pelabresib), PIM kinase inhibitors (TP-3654), telomerase inhibition (imetelstat), nuclear export inhibition (selinexor), LSD1 inhibition (bomedemstat), MDM2 antagonism (navtemadlin), mutant CALR-directed immunotherapies, and activin receptor ligand traps (elritercept). Emerging data suggest that pairing JAK inhibitors with agents that target transcriptional regulation, clonal persistence, anemia, or fibrosis can demonstrate improved responses and enhance safety profiles. Strategies such as high-molecular-risk mutation profiling and variant allele frequency monitoring to assess disease progression and clonal burden will also be discussed. As the focus of MPN management shifts towards curative non-transplant options, a combination of improved access to clinical trials and accounting for patient-reported outcomes will be vital if we are to realize the promise of these next-generation therapies.
Transfusion therapy remains a cornerstone in the management of sickle cell disease (SCD). Yet, repeated exposure to donor red blood cells poses a substantial risk for alloimmunization against red blood cell antigens. Patients with SCD exhibit a disproportionately high incidence of alloimmunization and often experience more severe clinical consequences than other transfusion-dependent populations. This review explores the multifactorial mechanisms underlying this heightened immunogenicity, the clinical and immunologic sequelae that result, and the factors contributing to the under-recognition of alloimmunization's impact in SCD. It will also highlight current and emerging strategies to prevent alloimmunization and advances in the management of its complications, including delayed hemolytic transfusion reactions.
