Busulfan, Fludarabine, Antithymocyte Globulin (ATG) & Cyclophosphamide Conditioning Bone Marrow Transplant (BMT) for Patients With Sickle Cell Disease (SCD)

Summary

Some of the drugs used in the conditioning treatment injure blood vessels. This damage may be responsible for transplant-related neurological problems seen in patients with sickle cell disease. The reason that patients with sickle cell disease are more prone to the effects of the conditioning treatment drugs may be that many of them have pre-existing damage to the blood vessels that supply their brains.

The primary goal of this study is to develop a conditioning treatment that causes less blood vessel injury and, thus, fewer neurological problems. The secondary goal is to develop a better understanding of why neurological problems happen after transplant, using blood tests and a specialized type of MRI scan (weighted perfusion MR).

Description

By replacing the abnormal sickle cell producing hematopoietic stem cells, HLA matched related bone marrow and umbilical cord blood transplantation can cure sickle cell disease. The standard transplant approach relies on the use of high dose busulfan, which eliminates host hematopoietic stem cells, as well as anti-thymocyte globulin and high dose cyclophosphamide, which abolish host immunity, for pre-transplant conditioning. This myeloablative (ablates the host marrow or more precisely the host hematopoietic stem cells) regimen ensures the stable engraftment of the vast majority of transplants. The standard approach also utilizes cyclosporine and low dose methotrexate post-transplant for graft versus host prophylaxis. Most children and adolescents who undergo hematopoietic stem cell transplantation using this approach, many of whom have cerebrovascular disease, are cured; many of these patients, however, suffer neurological complications, including seizures, encephalopathy and sub-clinical ischemic brain injury, post-transplant. Circumstantial evidence suggests that these neurological complications are attributable to the vasculopathic effects of busulfan, cyclophosphamide and cyclosporine, which exacerbate the pre-existing vascular injury from sickle cell disease. We intend to conduct a pilot trial, adding fludarabine to the standard conditioning regimen in order to reduce the dose of one of these three agents, cyclophosphamide. Fludarabine is a highly immunosuppressive agent, which amplifies the immunosuppressive effects, but not the vasculopathic effects, of cyclophosphamide. The regimen will retain the standard, myeloablative dose of busulfan. Our goal, then, is to reduce the toxicity, specifically the vascular toxicity, of conditioning without diminishing its myeloreductive and immunoreductive potency. The total cyclophosphamide dose used in most regimens for sickle cell disease is 200 mg/kg. In this trial the starting dose will be 135 mg/kg (dose level 1).and it will be reduced to 90 mg/kg (dose level 2) and then to 45 mg/kg (dose level 3) using a dose de-escalation schema. In addition, plasma markers of vascular injury will be monitored longitudinally and perfusion weighted MRI scanning performed before and after transplant to further our understanding of how bone marrow transplant affects the cerebral vasculature in patients with sickle cell disease. This study will serve as the forerunner to a second pilot trial, in which Abatacept (CTLA4-Ig) will be incorporated into the post-transplant immune suppression, and the cyclosporine dose will be reduced with the intent of further lowering the incidence of neurological complications.

Study Design

Allocation: Non-Randomized, Control: Dose Comparison, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Bone Marrow Transplantation

Intervention

fludarabine

Location

Children's Healthcare of Atlanta
Atlanta
Georgia
United States
30322

Status

Recruiting

Source

Emory University

Results (where available)

View Results

Links

• Source: http://clinicaltrials.gov/show/NCT00968162
• Information obtained from ClinicalTrials.gov on July 15, 2010

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