Clinical Trial: Treatment of Sickle Cell Anemia With Stem Cell Transplant

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Sickle Cell Anemia From HLA Matched or Partially-Matched Related Donors

Brief Summary:

This is a clinical research trial in which a novel preparatory regimen was developed for bone marrow transplant (BMT) which eliminates the primary obstacle to transplant, the lack of a matched sibling donor. It is believed this regimen is sufficiently efficacious and sufficiently gentle to apply to patients with sickle cell anemia and related disorders. It is proposed to characterize the efficacy and toxicity of this regimen in high risk patients with sickle cell anemia using criteria for patient selection that have been accepted in prior BMT trials in patients with sickle cell disease, specifically only the subset of patients whose prior clinical behavior indicates that they are at high risk for serious morbidity and early mortality. In addition, it is proposed to characterize the pathophysiology of a consistent febrile response seen in the haploidentical BMT regimen the investigators have developed at Thomas Jefferson University (TJU).

The primary goal of this study is to determine the response rate to a reduced intensity conditioning regimen which consists of fludarabine, cytarabine, low dose total body irradiation and cyclophosphamide in patients with severe sickle cell anemia.


Detailed Summary:

Hemoglobinopathies, such as sickle cell disease and thalassemia major, constitute a group of genetic diseases associated with significant morbidity and premature death. In the 1970s, the mean survival of patients with sickle cell disease was 14.3 years. With improvements in medical practice, this has improved such that estimates are now into the third decade of life.

In patients with sickle cell disease, a single amino acid substitution in beta-hemoglobin causes erythrocytes to sickle in response to oxidative stress. The sequelae of this defect are vaso-occlusive crises, resulting in episodes of bony pain and infarction, acute chest syndrome, and strokes. Life long need for transfusion leads to complications including alloimmunization and iron overload. The latter condition is frequently associated with significant end-organ damage.

In recent years, new strategies in supportive care, such as the use of hydroxyurea to stimulate fetal hemoglobin production in patients with sickle cell anemia, have resulted in the amelioration of some of the devastating manifestations of this disease. However, this therapy does not benefit all patients, and there have been concerns about the possible risk of latent transformation to leukemia with prolonged use of this drug. Clearly, better treatment strategies are needed for this devastating group of diseases.

Patients with sickle cell anemia will be offered enrollment on a clinical trial of reduced intensity stem cell transplant. The transplant donors will be either HLA matched siblings or family members who are 50% matched for HLA. Patients will receive therapy in 2 steps.

For patients who are allo-immunized against the donor (patients who have made an immune response already against the dono
Sponsor: Sidney Kimmel Cancer Center at Thomas Jefferson University

Current Primary Outcome: Stable Engraftment [ Time Frame: 180 days post-infusion ]

To determine if the reduced intensity preparative regimen of fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation will generate stable engraftment with donor hematopoietic stem cells in at least 80% of patients with severe sickle cell anemia.


Original Primary Outcome:

Current Secondary Outcome:

  • Organ Toxicity [ Time Frame: 30 days post infusion ]
    To assess organ toxicity related to fludarabine, cytarabine, cyclophosphamide and low-dose total body irradiation in a population with severe sickle cell anemia.
  • Overall Survival [ Time Frame: 6 months post infusion ]
    To determine the overall survival at 6 months post-transplant in patients receiving a matched or partially-matched related donor transplant after reduced-intensity conditioning.
  • Acute Graft Versus Host Disease [ Time Frame: 100 days post infusion ]
    To describe the incidence and severity of acute and chronic GVHD following this reduced intensity transplant from partially matched related donors using a combination of cyclophosphamide, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.
  • Correction of Hemoglobinopathy [ Time Frame: 100 days post infusion through 5 years post infusion ]
    To evaluate the extent of correction of hemoglobinopathy following this reduced intensity transplant.
  • Immune Recovery [ Time Frame: 100 days post infusion through 5 years post infusion ]
    To assess the pace of lymphoid recovery and associated risk for opportunistic infections and relapse (return to recipient erythropoiesis) in this patient population.
  • Quality of Life [ Time Frame: Through 5 years post infusion ]
    To describe the quality of life and functional status following transplantation.
  • Cytokine Profile [ Time Frame: Through 5 years after infusion ]
    To characterize the profiles of cytokines released following administration of the lymphoid portion of the transplant (donor lymphocyte infusion [DLI]).


Original Secondary Outcome:

Information By: Thomas Jefferson University

Dates:
Date Received: May 4, 2011
Date Started: September 2009
Date Completion:
Last Updated: October 19, 2016
Last Verified: October 2016