Hematopoietic Stem Cell Transplantation for Patients with Sickle Cell Disease: Progress and Future Directions

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Key points

  • 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

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

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References (63)

  • G. La Nasa et al.

    Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes

    Blood

    (2002)
  • C. Li et al.

    A novel conditioning regimen improves outcomes in beta-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation

    Blood

    (2012)
  • A. Ruggeri et al.

    Umbilical cord blood transplantation for children with thalassemia and sickle cell disease

    Biol Blood Marrow Transplant

    (2011)
  • L. Luznik et al.

    Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation

    Biol Blood Marrow Transplant

    (2002)
  • L. Luznik et al.

    HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide

    Biol Blood Marrow Transplant

    (2008)
  • A.T. Munchel et al.

    Treatment of hematological malignancies with nonmyeloablative, HLA-haploidentical bone marrow transplantation and high dose, post-transplantation cyclophosphamide

    Best Pract Res Clin Haematol

    (2011)
  • J. Bolanos-Meade et al.

    HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease

    Blood

    (2012)
  • M.H. Dallas et al.

    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

    (2013)
  • D.E. Gladstone et al.

    Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies

    Biol Blood Marrow Transplant

    (2013)
  • M.E. Horwitz et al.

    Fludarabine-based nonmyeloablative stem cell transplantation for sickle cell disease with and without renal failure: clinical outcome and pharmacokinetics

    Biol Blood Marrow Transplant

    (2007)
  • L. Krishnamurti et al.

    Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease

    Biol Blood Marrow Transplant

    (2008)
  • B. Brichard et al.

    Persistence of fetal hemoglobin production after successful transplantation of cord blood stem cells in a patient with sickle cell anemia

    J Pediatr

    (1996)
  • N.R. Kamani et al.

    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

    (2012)
  • K. Radhakrishnan et al.

    Busulfan, fludarabine, and alemtuzumab conditioning and unrelated cord blood transplantation in children with sickle cell disease

    Biol Blood Marrow Transplant

    (2013)
  • F.L. Johnson et al.

    Bone-marrow transplantation in a patient with sickle-cell anemia

    N Engl J Med

    (1984)
  • C. Vermylen et al.

    Bone marrow transplantation for sickle cell disease. The European experience

    Am J Pediatr Hematol Oncol

    (1994)
  • A. Ferster et al.

    Bone marrow transplantation for severe sickle cell anaemia

    Br J Haematol

    (1992)
  • F.L. Johnson et al.

    Bone marrow transplantation for sickle cell disease. The United States experience

    Am J Pediatr Hematol Oncol

    (1994)
  • M.C. Walters et al.

    Bone marrow transplantation for sickle cell disease

    N Engl J Med

    (1996)
  • M.M. Hsieh et al.

    Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype

    JAMA

    (2014)
  • A. Brand et al.

    On the role of HLA antibodies in hematopoietic stem cell transplantation

    Tissue Antigens

    (2013)
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