Curative therapy for hemoglobinopathies: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review comparing outcomes, accessibility and cost of ex vivo stem cell gene therapy versus allogeneic hematopoietic stem cell transplantation

Abstract

Thalassemia and sickle cell disease (SCD) are the most common monogenic diseases in the world and represent a growing global health burden. Management is limited by a paucity of disease-modifying therapies; however, allogeneic hematopoietic stem cell transplantation (HSCT) and autologous HSCT after genetic modification offer patients a curative option. Allogeneic HSCT is limited by donor selection, morbidity and mortality from transplant conditioning, graft-versus-host disease and graft rejection, whereas significant concerns regarding long-term safety, efficacy and cost limit the broad applicability of gene therapy. Here the authors review current outcomes in allogeneic and autologous HSCT for transfusion-dependent thalassemia and SCD and provide our perspective on issues surrounding accessibility and costs as barriers to offering curative therapy to patients with hereditary hemoglobinopathies.

Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease

“…There is increasing interest as well as many clinical trials in progress over the last 2 to 3 years concerning gene therapy and its comparison with allogeneic HSCT, both of which can potentially offer complete therapy for TM patients [6][7][8][173][174][175][176][177][178][179][180]. The risk/benefit assessment of these two HSCT methods and their comparison with the standard therapy of regular RBC transfusion and chelation therapy are likely to be the subject of future investigations.…”

“…Genetically modified autologous HSCT via gene addition has recently received a conditional approval by the European Medicines Agency (EMA) for the treatment of TM patients [178][179][180]. This gene therapy option offers the potential for the treatment of all TM patients without the need of a bone marrow donor.…”

“…Several other products and gene editing techniques are under investigation and development. Many clinical trials for these agents are ongoing and full assessment of the results is expected in the next few years [178][179][180][188][189][190][191][192][193][194][195].…”

“…Despite the initial encouraging results there are at least three major drawbacks, which are likely to limit the gene therapy option for TM patients and will require further research and development in the coming years. One of the major drawbacks is that most of the TM patients do not achieve transfusion independence, e.g., in a recent study six of nine patients failed to achieve this goal [180,193,196]. Another drawback is the risk of hematological malignancies due to different factors including insertional mutagenesis.…”

“…Another drawback is the risk of hematological malignancies due to different factors including insertional mutagenesis. Lastly, public expenditure concerns appear to limit the overall number of TM patients that can have access to gene therapy [180,196].…”