This review examines the central role of conditioning in enabling durable engraftment of gene-modified hematopoietic stem cells, emphasizing the narrow therapeutic window between insufficient niche clearance and excessive toxicity.
Abstract
Abstract Gene therapy for sickle cell disease and transfusion-dependent thalassemia is now widely available, yet its broader application is constrained by the need for effective and tolerable conditioning. This review examines the central role of conditioning in enabling durable engraftment of gene-modified hematopoietic stem cells, emphasizing the narrow therapeutic window between insufficient niche clearance and excessive toxicity. Busulfan remains the standard conditioning agent, supported by consistent engraftment and clinical efficacy, but its use is limited by acute and long-term toxicities, including infertility and potential genotoxicity. Emerging strategies aim to mitigate these risks. Reduced-intensity melphalan shows early promise but raises concerns regarding the durability of engraftment, whereas treosulfan offers a potentially safer profile, although data in the autologous setting are lacking. Antibody-based, nongenotoxic approaches represent a transformative direction but remain investigational. Refining conditioning through comparative trials and long-term follow-up will be critical to fully realize the curative potential of gene therapy.
The landscape of pediatric hematopoietic cell transplantation for nonmalignant disorders has evolved through disease-adapted conditioning, pharmacokinetic-guided dosing, expanded donor options, and gene therapy (GT). These advances have transformed curative strategies for children with select inborn errors of immunity, hemophagocytic lymphohistiocytosis, hemoglobinopathies, bone marrow failure syndromes, and select metabolic disorders. Early diagnosis, especially newborn screening for severe combined immunodeficiency, enables timely intervention, with contemporary series reporting more than 90% survival in select early-treated infants. Similarly, modern matched related donor transplantation for pediatric severe aplastic anemia approaches 98% 3-year survival. Fludarabine-based platforms combined with busulfan, melphalan, or treosulfan support durable engraftment with reduced toxicity, while matched unrelated, haploidentical, and cord blood donors expand access. GT now offers a parallel curative platform for select sickle cell disease, transfusion-dependent beta-thalassemia, and immunodeficiencies. For pediatricians, early referral before irreversible complications is critical. This review proposes a five-axis framework to guide referral, treatment selection, and survivorship planning.
Eman M. Elsabbagh, A. Shawky, Christopher C. Dvorak· Pediatric annals· 1 citation
The therapeutic landscape of β-thalassemia has evolved rapidly over the past decade, shifting from a historical reliance on transfusion support and iron chelation toward disease-modifying and potentially curative therapies. This review summarizes the clinical development of novel treatments for both non-transfusion-dependent and transfusion-dependent β-thalassemia, including approved therapies, agents in active development, and programs that have been discontinued. Disease-modifying strategies have focused on improving ineffective erythropoiesis, correcting iron dysregulation, and restoring red blood cell metabolism. Luspatercept and mitapivat have demonstrated clinically meaningful improvements in hemoglobin levels and reduction of transfusion burden and are now approved in multiple jurisdictions. Additional pyruvate kinase activators, such as etavopivat, are undergoing clinical evaluation. Curative approaches have advanced substantially through gene addition, gene editing, and base editing technologies. Approved therapies, including betibeglogene autotemcel and exagamglogene autotemcel, have achieved high rates of durable transfusion independence, while emerging platforms aim to further improve efficacy, safety, and accessibility. At the same time, several promising approaches targeting fetal hemoglobin induction, iron metabolism, and ineffective erythropoiesis have failed to demonstrate sufficient clinical benefit despite preclinical proof of concept, highlighting the complexity of therapeutic development in β-thalassemia. Future priorities include refining patient selection, generating real-world and comparative effectiveness data, developing clinically meaningful response criteria, expanding pediatric access, and addressing the substantial cost and accessibility challenges associated with novel therapies.
K. M. Musallam, F. Locatelli, M. Algeri et al.· American journal of hematolo...· 0 citations
Recent developments and refinements in gene transfer and editing technologies for HSPCs are reviewed, while also discussing the critical limitations and hurdles to clinical translation, as recently presented at the New Investigator Committee Gene Therapy webinar.
Kohei Shiroshita, A. Stolz, C. Malouf et al.· Experimental Hematology· 0 citations
ABSTRACT Background and Aims Thalassemia is an inherited hemoglobin disorder characterized by ineffective erythropoiesis, chronic anemia, and progressive multisystem complications that require lifelong management. Current treatment relies on regular red blood cell transfusions, iron chelation therapy, and supportive multidisciplinary care, while hematopoietic stem cell transplantation offers a curative option for selected patients. Although gene‐based therapies and novel pharmacological agents have expanded therapeutic options, their widespread implementation is limited by cost, accessibility, and long‐term safety considerations. This article summarizes contemporary management strategies for α and β thalassemia, with particular emphasis on the recent emergence of the FDA‐approved oral pyruvate kinase activator, mitapivat. Methods A structured literature review was conducted using PubMed and PubMed Central. Searches included the terms “thalassemia,” “mitapivat,” “pyruvate kinase activator,” “gene therapy,” “hydroxyurea,” and “luspatercept.” Priority was given to recent systematic reviews, clinical practice guidelines, pivotal phase II and III clinical trials, regulatory publications, and peer‐reviewed studies relevant to current therapeutic practice. Results Conventional therapies remain essential but are associated with significant limitations, including transfusion dependence, iron overload, and treatment‐related complications. Curative strategies such as hematopoietic stem cell transplantation and gene therapy are effective in selected patients but remain constrained by donor availability, toxicity, cost, and limited accessibility. Emerging pharmacological therapies target ineffective erythropoiesis and iron dysregulation. Phase III ENERGIZE and ENERGIZE‐T trials demonstrated that mitapivat significantly improved hemoglobin response in non‐transfusion‐dependent disease and reduced transfusion burden in transfusion‐dependent disease, with an acceptable safety profile, leading to FDA approval as the first oral therapy for adults with α or β thalassemia. Conclusion Mitapivat represents a significant advance in thalassemia management by targeting erythrocyte metabolism and providing the first FDA‐approved oral treatment for anemia in adults with α or β thalassemia. Multi‐year follow‐up and real‐world studies are needed to further define its durability, safety, and role within evolving treatment strategies.
Fnu Zainab, Abdul Haseeb Hasan, Muhammad Hafi Abid et al.· Health Science Reports· 0 citations
OBJECTIVES
Genetic rare diseases (GRDs), including chronic granulomatous disease, familial hemophagocytic lymphohistiocytosis, and congenital neutropenia, often require hematopoietic stem cell transplantation (HSCT) as the only curative option. Conventional myeloablative regimens are associated with considerable toxicity, whereas reduced-intensity regimens carry an increased risk of graft failure. To address the narrow therapeutic window of busulfan, we developed a pharmacokinetic-guided dosing strategy and evaluated it in a prospective study.
METHODS
Children with GRDs undergoing HSCT received a conditioning regimen comprising fludarabine 40 mg/m2 (days -8 to -4), anti-thymocyte globulin 2.5 mg/kg (days -4 to -2), and once-daily busulfan (days -9 to -6), with intensive pharmacokinetic monitoring and dose adjustments to achieve target exposure.
RESULTS
Twenty patients with GRDs (median age, 3.6 years) received HSCT with a targeted busulfan-based myeloablative regimen. No engraftment failure occurred. Cumulative incidences of Grade II-IV and Grade III-IV acute graft-versus-host disease and moderate-to-severe chronic graft-versus-host disease were 25%, 5%, and 23%, respectively. Ten-year overall survival, event-free survival, and transplant-related mortality rates were 90%, 90%, and 5%, respectively.
CONCLUSIONS
Pharmacokinetic-guided busulfan-fludarabine conditioning achieved reliable engraftment with acceptable toxicity in children with GRDs, supporting its use as a safe, effective HSCT conditioning strategy in vulnerable populations.
B. Kim, K. Hong, J. Choi et al.· European Journal of Haematol...· 0 citations
Introduction: Sickle cell disease is the most prevalent inherited hemoglobinopathy worldwide, characterized by chronic
hemolysis, systemic inflammation, and recurrent episodes of vaso-occlusion, which are responsible for high morbidity
and mortality. In recent decades, therapeutic advances have expanded treatment options, including disease-modifying
therapies, hematopoietic stem cell transplantation, and gene therapy.
Objective: To analyze the scientific evidence regarding therapeutic advances, disease-modifying therapies, and future
prospects for the treatment of sickle cell anemia.
Methods: A systematic review conducted in accordance with PRISMA guidelines, using the databases PubMed, Scopus,
Web of Science, Embase, the Cochrane Library, and ScienceDirect. Studies published between 2016 and 2026 were
included, covering pharmacological therapies, hematopoietic stem cell transplantation, gene therapy, and gene editing.
After the selection process, 124 studies comprised the final sample.
Results: Hydroxyurea remained the primary disease-modifying drug, while crizanlizumab, voxelotor, and L-glutamine
demonstrated additional benefits in reducing vaso-occlusive crises, hemolysis, and clinical complications. Hematopoietic
stem cell transplantation showed the greatest curative potential, and gene therapies based on lentiviral vectors and
CRISPR-Cas9 revealed promising results in terms of reducing clinical events and achieving transfusion independence.
However, limitations related to cost, specialized infrastructure, access, and the lack of long-term follow-up still restrict
their widespread implementation.
Conclusion: The evidence demonstrates that advances in disease-modifying therapies and potentially curative strategies
are transforming the management of sickle cell disease, reinforcing the need for long-term studies and public policies
that expand access to innovative technologies.
Rosane Rezende de Souza Giuliani, Felipe Santos Teixeira Martiniano, Nicole Mioto Medeiros et al.· Advances in Hematology and O...· 0 citations
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