Current Results and Future Research Priorities in Late Effects after Hematopoietic Stem Cell Transplantation for Children with Sickle Cell Disease and Thalassemia: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Stem Cell Transplantation

Abstract

Sustained donor engraftment after allogeneic hematopoietic cell transplantation (HCT) converts to healthy donor hemoglobin synthesis and halts disease symptoms in patients with sickle cell disease and thalassemia major. A disease-free survival probability that exceeds 90% has been reported when HCT using an HLA-matched sibling donor is performed in young patients with low-risk disease or treatment-related risk factors. Alternate donor HCT and HCT in adults is performed infrequently because of a higher risk profile. Transplant-specific risks include conditioning regimen-related toxicity, graft-versus-host disease, graft rejection with marrow aplasia or disease recurrence, and infections associated with immunosuppression and delayed immune reconstitution. The magnitude of risk depends on patient age, clinical status of the underlying disease (eg, organ injury from vasculopathy and iron overload), donor source, and intensity of the conditioning regimen. These risks are commonly monitored and reported in the short term. Documenting very late outcomes is important, but these data are rarely reported because of challenges imposed by patient drop-out and insufficient resources. This report summarizes long-term follow-up results after HCT for hemoglobin disorders, identifies gaps in knowledge, and discusses opportunities for future investigations. This consensus summary will be followed by a second article detailing comprehensive long-term follow-up recommendations to aid in maintaining health in these individuals and identifying late complication risks that could facilitate interventions to improve outcomes.

Bone Marrow Transplantation after Nonmyeloablative Treosulfan Conditioning Is Curative in a Murine Model of Sickle Cell Disease

“…Of particular importance is the effect on fertility. It is well established in murine and human studies that both myeloablative and nonmyeloablative doses of busulfan may impact fertility [8,9,46]. Much less information exists on the gonadal toxicities of treosulfan.…”

“…Allogeneic HSCT for SCD has been performed for over 30 years, with close to 1000 transplants to date [1]. Although often successful, transplants are limited to patients with severe disease because of pretransplant comorbidities and unacceptable toxicities associated with myeloablative conditioning [1,8]. Post-transplant complications include infection, neurologic sequelae, infertility, and a high incidence of graft failure [9][10][11][12].…”

“…To this end, efforts to decrease morbidity by reducing the intensity of the preparative regimen have been used. In several reports, reduced-intensity conditioning HSCT in SCD was well tolerated, and levels of donor chimerism > 50% HbA appeared to be sufficient to reverse the SCD phenotype [8,15,16]. More recently, myeloablative conditioning with busulfan has been used before infusion of autologous SCD gene-modified bone marrow (BM) or peripheral blood (PB) stem cells with expected toxicities, although limited expression of modified Hb has been observed [17,18].…”

Advances in transplantation and gene therapy in transfusion-dependent β-thalassemia

“…These are related to pretransplant characteristics for example, years and type of therapy . Detailed surveillance and intervention guidelines in this area have been published and should be followed to assure complication‐free cure after allo‐HCT . It is important to re‐emphasize that transplantation is always encouraged in early first few years of life …”

Complication free survival long-term after hemopoietic cell transplantation in thalassemia

“…7) Specific follow-up guidelines and screening recommendations can be proposed and can be used specifically for this category of patients in order to prevent / cure the complications that are known today. 15,16 8) Recent data on the emerging gene therapy approach clearly indicate that a myeloablative preparative regime is necessary to allow gene-modified autologous stem cell engraftment. Therefore, if the long follow up confirms current safety data on the cellular product, 17 complications relating to the conditioning regimen, such as those reported here, can be foreseen and similar screening programs can be set up.…”