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Immunologic Factors

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.

Leslie Kean, MD, PhD

The primary objective of the study is to determine the safety and tolerability when adding abatacept to acute Graft versus Host Disease in transplants for malignant diseases using unrelated donor bone marrow or peripheral blood stem cell grafts.

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.

Pilot of Abatacept-based Immunosuppression for Prevention of Acute GvHD During Unrelated Donor HCT

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

Grade III-IV Acute GVHD by Day 100. The incidence of Gr III-IV acute GVHD was measured by the modified Glucksburg scale.

The rates of Grades III-IV acute GVHD were measured at 2 years according to standard Glucksberg criteria, which was 10%.

Flow cytometric analysis of CD4 t-cell t-cell reconstitution was performed at day +100 post-transplant.

Percent of CMV virus binding CD8+ t-cells at day +365 post-transplant

Boston Children's Hospital

MD, PhD

Attribution of adverse events when patients are co-enrolled on other trials: because abatacept's effects are strictly immunologic and because co-enrollment will only be allowed in trials testing agents without immunomodulatory effects, all adverse events stemming directly or indirectly from immune deficiency or immune dysregulation will be attributed (definite, probable or possible depending on the circumstances) to abatacept and not the agent being tested in the other trial.

In this trial, we will test the safety and tolerability of the addition of the CD28-B7 blockade agent, abatacept, as an adjunctive therapy for the prevention of GvHD in a high-risk BMT cohort. Four doses of abatacept will be given according to a dosing schedule based on previous trials using CD28-B7 blockade with belatacept in kidney transplantation. Pharmacokinetic and pharmakodynamic analysis of abatacept will be undertaken, as well as an evaluation of the incidence and severity of acute GvHD in this patient cohort.

Dosage: Abatacept is administered as an intravenous infusion under medically controlled conditions. Dose is 10mg/kg with a maximum dose of 1 gram. Abatacept should be administered as a 30-minute intravenous infusion. In this study, abatacept will be dosed on days -1, +5, +14, +28 post-transplant. Small adjustments in dose to accommodate abatacept vial size may be acceptable. These dose adjustments must be approved by the study PI.

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.

Abatacept: 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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pilot of Abatacept-based Immunosuppression for Prevention of Acute GvHD During Unrelated Donor HCT	NCT01012492	AML ALL Undifferentiate... Biphenotypic Le... Refractory Anem... Refractory Anem... Refractory Cyto... Ref. Cytopenia ... Refractory Anem... Refractory Anem... Myelodysplastic... MDS Associated ...	Abatacept	12 Years -	Boston Children's Hospital
Pilot of Abatacept-based Immunosuppression for Prevention of Acute GvHD During Unrelated Donor HCT	NCT01012492	AML ALL Undifferentiate... Biphenotypic Le... Refractory Anem... Refractory Anem... Refractory Cyto... Ref. Cytopenia ... Refractory Anem... Refractory Anem... Myelodysplastic... MDS Associated ...	Abatacept	12 Years -	Boston Children's Hospital

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