Trial Information

Safety and Tolerability Trial of Abatacept-based Immunosuppression for Prevention of Acute GvHD During Unrelated Donor Hematopoietic Stem Cell Transplant

Acute Graft versus Host Disease (aGvHD) is the most deadly complication facing children who
have allogeneic hematopoietic stem cell transplant (HSCT). aGvHD occurs, in large part,
because the T cells in the bone marrow graft do not "accept" the presence of the transplant
recipient's cells, and mount a severe, debilitating, and often deadly attack against the
recipient, striking the skin, the liver, and the gastrointestinal track, most prominently.
For patients receiving bone marrow from an unrelated donor, the rate of aGvHD can reach as
high as 80%, with up to half of patients dying from this complication. These serious
outcomes occur despite our best efforts at aGvHD prevention. Given the lack of success in
preventing aGvHD with current therapies, novel therapies to prevent this disease are
desperately needed.

In this study, we plan to test a novel drug to prevent aGvHD. This drug, known as
abatacept, specifically blocks the activation pathway critical to T cell function known as
"T cell costimulation." In particular, it blocks the CD28-mediated costimulation pathway
that is critical for optimal T cell activation and proliferation. My research group has
done extensive pre-clinical work with this compound. Our work has demonstrated its efficacy
in inducing immune tolerance after transplantation in both mouse models and primate models.
In addition, patient trials have demonstrated that blocking CD28-directed T cell
costimulation can prevent T cell-mediated diseases, including rheumatoid arthritis and
psoriasis, and can improve solid organ transplant acceptance. Abatacept is currently FDA
approved for use in rheumatoid arthritis. Given this drug's safety and efficacy profile, we
have been granted an IND-exemption from the FDA for the inclusion of abatacept in a
GvHD-prevention strategy.

This is a safety and tolerability study of the addition of abatacept to a GvHD-prophylaxis
regimen. Thus, the primary objective of the study is to determine the safety and
tolerability of the addition of abatacept to aGvHD prophylaxis in transplants for malignant
hematologic disease using unrelated donor bone marrow or peripheral blood stem cell grafts.

Three secondary objectives will also be addressed:

1. We will estimate the incidence and severity of aGvHD in patients receiving the
abatacept-based protocol.

2. We will determine the immune phenotype of donor cells in patients receiving abatacept.

3. We will determine the ability of donor T-cells in patients receiving abatacept to
respond to both polyclonal and recipient-specific immune stimulation.

These secondary objectives will allow us to determine the impact of abatacept-containing
GvHD prevention on both T cell alloreactivity and on T cell-mediated protective immunity.

This study is for patients older than 12 who have been diagnosed with high-risk leukemia and
for whom an unrelated bone marrow transplant is planned. We plan to enroll 10 patients on
the study, over a 1-year period from the opening of the trial. Of these ten patients, at
least five will be pediatric patients; the other five may be from adult patients taken care
of by Winship Cancer Center physicians. All clinical study coordination and biologic
studies will be performed by CHOA personnel.

Participants will receive one of two standard myeloablative conditioning regimens for their
stem cell transplant, and will receive an aGvHD prophylaxis regimen including cyclosporine,
methotrexate, and abatacept. They will have immunologic analysis for 1 year after
transplant and clinical analysis for 3 years after transplant.