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)

Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation (Impact Factor: 3.4). 02/2012; 18(8):1265-72. DOI: 10.1016/j.bbmt.2012.01.019
Source: PubMed


The Sickle Cell Unrelated Donor Transplant Trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a phase II study of the toxicity and efficacy of unrelated donor hematopoietic cell transplantation in children with severe sickle cell disease (SCD) using a reduced-intensity conditioning regimen. Here we report the results for the cord blood cohort of this trial. Eight children with severe SCD underwent unrelated donor cord blood transplantation (CBT) following alemtuzumab, fludarabine, and melphalan. Cyclosporine or tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. Donor/recipient HLA match status was 6 of 6 (n = 1) or 5 of 6 (n = 7), based on low/intermediate-resolution molecular typing at HLA -A, -B, and high-resolution typing at -DRB1. Median recipient age was 13.7 years (range: 7.4-16.2 years), and median weight was 35.0 kg (range: 25.2-90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 10(7) /kg (range: 3.1-7.6), and the median postthaw infused CD34 cell dose was 1.5 × 10(5) /kg (range: 0.2-2.3). All patients achieved neutrophil recovery (absolute neutrophil count >500/mm(3)) by day 33 (median: 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained, and 5 patients had autologous hematopoietic recovery. Six of 8 patients had a platelet recovery to >50,000/mm(3) by day 100. Two patients developed grade II acute GVHD. Of these, 1 developed extensive chronic GVHD and died of respiratory failure 14 months posttransplantation. With a median follow-up of 1.8 years (range: 1-2.6), 7 patients are alive with a 1-year survival of 100%, and 3 of 8 are alive without graft failure or disease recurrence. Based upon the high incidence of graft rejection after unrelated donor CBT, enrollment onto the cord blood arm of the SCURT trial was suspended. However, because this reduced-intensity regimen has demonstrated a favorable safety profile, this trial remains open to enrollment for unrelated marrow donor transplants. Novel approaches aimed at improving engraftment will be needed before unrelated CBT can be widely adopted for transplanting patients with severe SCD.

2 Reads
  • Source
    • "In the case of severe Sickle cell disease (SCD), the cytokine milieu of SCD, which activates the inflammation and the immune activation might also promote a host-versus-graft reaction and interfere with engraftment even after myeloablative preparation [32]. In a recent phase II (BMT CTN) study of the toxicity and efficacy of unrelated donor HSCT in children with SCD, using a reduced-intensity condition regimen, one patient had 6/6 HLA antigen matching with his donor (using low-intermediate resolution typing for HLA-A-B and high resolution for HLA-DRB1), while seven patients had 5/6 HLA antigen mismatching. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, umbilical cord blood (CB), a rich source of hematopoietic stem cells (HSC), has been used successfully as an alternative HSC source to treat a variety of hematologic, immunologic, genetic, and oncologic disorders. CB has several advantages, including prompt availability of the transplant, decrease of graft versus host disease (GVHD) and better long-term immune recovery, resulting in a similar long-term survival. Studies have shown that some degree of HLA mismatches is acceptable. This review is intended to outline the main aspects of HLA matching in different settings (related, pediatric, adult, or double-unit HSCT), its effect on transplantation outcome and the role of HLA in donor selection.
    10/2012; 2012:485160. DOI:10.1155/2012/485160
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this issue of Blood, Bolaños-Meade et al report promising results using a pioneering HLA-haploidentical bone marrow transplantation protocol in adults with sickle cell disease (SCD), including nonmyeloablative conditioning and posttransplantation high-dose cyclophosphamide.
    Blood 11/2012; 120(22):4276-7. DOI:10.1182/blood-2012-09-455832 · 10.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: High-level production of β-globin, γ-globin, or therapeutic mutant globins in the RBC lineage by hematopoietic stem cell gene therapy ameliorates or cures the hemoglobinopathies sickle cell disease and beta thalassemia, which are major causes of morbidity and mortality worldwide. Considerable efforts have been made in the last 2 decades in devising suitable gene-transfer vectors and protocols to achieve this goal. Five years ago, the first β(E)/β(0)-thalassemia major (transfusion-dependent) patient was treated by globin lentiviral gene therapy without injection of backup cells. This patient has become completely transfusion independent for the past 4 years and has global amelioration of the thalassemic phenotype. Partial clonal dominance for an intragenic site (HMGA2) of chromosomal integration of the vector was observed in this patient without a loss of hematopoietic homeostasis. Other patients are now receiving transplantations while researchers are carefully weighing the benefit/risk ratio and continuing the development of further modified vectors and protocols to improve outcomes further with respect to safety and efficacy.
    Hematology 12/2012; 2012:276-83. DOI:10.1182/asheducation-2012.1.276 · 0.81 Impact Factor
Show more