- •
Progenitor cells (bone marrow, cord blood [CB], or peripheral blood stem cell) from matched sibling/related donors offer the best results of transplantation.
- •
Although there are insufficient data in sickle cell disease (SCD), fully matched unrelated marrow is likely the next best option. This donor source is rare for patients with SCD.
- •
No study directly compared fully with less well-matched unrelated CB transplants. The combined data showed 50% disease-free survival, 20% acute graft-versus-host
Hematopoietic Stem Cell Transplantation for Patients with Sickle Cell Disease: Progress and Future Directions
Section snippets
Key points
Indications for transplantation
Indications for transplant are either directed to patients requiring lifelong transfusion because of an increased risk of recurrent or primary stroke (stroke and increased transcranial Doppler velocity), a significant impact on quality of life (recurrent vaso-occlusive crises, priapism, acute chest syndrome, osteonecrosis of multiple joints, and symptomatic silent infarct), difficulty maintaining transfusion therapy because of the lack compatible units (red cell alloimmunization), or an
Patient evaluation overview
SCD-related complications are important to identify before transplant. Not only do they drive the decision for transplant, but they also serve as a baseline for peritransplant and posttransplant care. Thus in addition to standard transplant-related blood (including renal/liver parameters and transfusion-related infectious pathogens), lung, and cardiac testing, evaluations for SCD-related end-organ injury should include the following:
- •
Brain MRI/MRA to establish the presence and extent of infarcts
Myeloablative
The first transplant for SCD used BM from a MSD for AML.1 The preparative regimen consisted of cyclophosphamide 120 mg/kg over 2 days and fractionated total body irradiation (TBI) of 11.5 Gy. Graft-versus-host disease (GVHD) prophylaxis was a short course of methotrexate (MTX) and 28 days of methylprednisolone. The patient was cured of both diseases. At about the same time, thalassemia major had been reported to be cured by MSD BMT, and myeloablation was achieved using the
Donor Availability
Although MSD transplants are safer, there remains the inherent problem of donor availability. The likelihood of 2 siblings being HLA identical is only 25%, and some siblings have SCD, further limiting the chance of having a suitable donor. Therefore, the field has moved to investigate alternative donor sources. Improved outcomes for malignancy and immunodeficiency have already been described with matched unrelated donor (MUD), umbilical CB, and haploidentical transplantation techniques in the
Timing and preparation for transplantation
Overall and SCD-free survival rates approaching 90% have prompted physicians to reconsider the methods and timing of treatment. The concept of transplantation earlier in the disease course was already being considered in the 1980s, as reported by investigators in Belgium.40 In this study, 50 transplanted patients belonged to 1 of 2 groups: permanent residents of a European country who had already developed a severe sickle cell phenotype before transplant, or visiting patients who were
Novel therapies and their integration in transplantation
Based on the combined studies thus far, active research is most necessary for unrelated CB and haploidentical transplantation to improve outcome. Although the data in unrelated CBT have remained the same recently, results from the Hopkins group in haploidentical transplant showed no GVHD or mortality, giving enthusiasm for that donor source. The major obstacle with both approaches remains graft failure, and there are efforts to optimize the transplant regimens.
In the haploidentical transplants,
Gene therapy
Autologous transplantation for hemoglobin disorders has only been considered in gene therapy trials. Clinical trials using lentiviral vectors to correct autologous HSCs have begun in France (NCT02151526) and New York City (Memorial Sloan Kettering Cancer Center, NCT01639690) for patients with thalassemia. Patients typically received close to myeloablative doses of Bu to enhance the engraftment of genetically modified cells. Patients achieving transfusion independence have been reported.46 A
Summary
Substantial progress in allogeneic hematopoietic stem cell transplantation has been made (Fig. 1). These transplant studies can be summarized into the following key points, and applied to children and adults (Fig. 2).
- •
Marrow, peripheral blood-derived, or CB progenitor cells from matched sibling/related donors offer the best results of transplantation.
- •
Fully matched unrelated marrow (8/8 or 10/10 allelic match) is likely the next best option, as described in patients with thalassemia from 2
References (63)
- et al.
Bone marrow transplantation in five children with sickle cell anaemia
Lancet
(1988) - et al.
Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease
Blood
(2007) - et al.
Donor-specific anti-HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation
Blood
(2011) - et al.
The impact of anti-HLA antibodies on unrelated cord blood transplantations
Blood
(2010) - et al.
Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia
Biol Blood Marrow Transplant
(2001) - et al.
Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia
Biol Blood Marrow Transplant
(2003) - et al.
Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling
Blood
(2013) - et al.
Related umbilical cord blood transplantation in patients with thalassemia and sickle cell disease
Blood
(2003) - et al.
Umbilical cord blood transplantation: the first 25 years and beyond
Blood
(2013) - et al.
Unrelated donor allogeneic hematopoietic stem cell transplantation for patients with hemoglobinopathies using a reduced-intensity conditioning regimen and third-party mesenchymal stromal cells
Biol Blood Marrow Transplant
(2014)
Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes
Blood
A novel conditioning regimen improves outcomes in beta-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation
Blood
Umbilical cord blood transplantation for children with thalassemia and sickle cell disease
Biol Blood Marrow Transplant
Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation
Biol Blood Marrow Transplant
HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide
Biol Blood Marrow Transplant
Treatment of hematological malignancies with nonmyeloablative, HLA-haploidentical bone marrow transplantation and high dose, post-transplantation cyclophosphamide
Best Pract Res Clin Haematol
HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease
Blood
Long-term outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease
Biol Blood Marrow Transplant
Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies
Biol Blood Marrow Transplant
Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics
Biol Blood Marrow Transplant
Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease
Biol Blood Marrow Transplant
Persistence of fetal hemoglobin production after successful transplantation of cord blood stem cells in a patient with sickle cell anemia
J Pediatr
Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)
Biol Blood Marrow Transplant
Busulfan, fludarabine, and alemtuzumab conditioning and unrelated cord blood transplantation in children with sickle cell disease
Biol Blood Marrow Transplant
Bone-marrow transplantation in a patient with sickle-cell anemia
N Engl J Med
Bone marrow transplantation for sickle cell disease. The European experience
Am J Pediatr Hematol Oncol
Bone marrow transplantation for severe sickle cell anaemia
Br J Haematol
Bone marrow transplantation for sickle cell disease. The United States experience
Am J Pediatr Hematol Oncol
Bone marrow transplantation for sickle cell disease
N Engl J Med
Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype
JAMA
On the role of HLA antibodies in hematopoietic stem cell transplantation
Tissue Antigens
Cited by (47)
The Evolving Landscape of Drug Therapies for Sickle Cell Disease
2022, Hematology/Oncology Clinics of North AmericaCitation Excerpt :Furthermore, SCD results in an enormous economic burden,9,10 with a substantial number of patients experiencing frequent absences from school and work, and physical impairment limiting the ability to obtain employment. SCD can be cured using allogeneic stem cell transplantation (ASCT), and recent evidence supports the curative potential of gene therapy and gene editing.11–13 Unfortunately, these curative modalities are unavailable to most patients, the vast majority of whom reside in resource-limited countries.
Allogeneic Transplant and Gene Therapy: Evolving Toward a Cure
2022, Hematology/Oncology Clinics of North AmericaCitation Excerpt :However, compelling comparative information is not yet available for individuals lacking an MSD that would facilitate selecting one curative therapy over another. The success rate of HCT in the pediatric population with HLA-matched donors is promising.18,24,34,50,51 However, GVHD continues to be an obstacle.
Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease
2020, Molecular Therapy Methods and Clinical DevelopmentAdvances in Sickle Cell Disease Management
2020, Advances in PediatricsMobilization and collection of cells in the hematologic compartment for cellular therapies: Stem cell collection with G-CSF/plerixafor, collecting lymphocytes/monocytes
2019, Seminars in HematologyCitation Excerpt :HPCT begins with a conditioning regimen to fully or partially ablate the recipient's bone marrow, creating space for HPCs to engraft and begin producing all lineages of blood cells. Often utilized as definitive treatment for hematologic malignancies, HPCT is increasingly being investigated and employed for other hematologic and immunologic disorders including sickle cell disease [1], beta thalassemia [2], chronic granulomatous disease [3], severe combined immunodeficiency [4], multiple sclerosis, systemic sclerosis, systemic lupus erythematosus [5], and HIV infection. An entirely nonphysiologic process, HPCT has a broad array of hematologic and immunologic effects which are incompletely understood and have ramifications throughout the body.