Non-myeloablative Allogeneic BMT for Children at High Risk for Complications from a Conventional Transplant

Successful allogeneic bone marrow stem cell transplant requires that two immunologic barriers be overcome: a host-versus-graft (HVG) reaction and a graft-versus-host (GVH) reaction. In conventional transplants, control of HVG has been achieved through the use of high-dose chemotherapy and radiation given before transplant in order to eradicate the host's immune system and eliminate underlying disease, e.g., leukemia. The GVH reaction is overcome by removing the donor's T-cells from the graft, or using T-cell modulating agents such as cyclosporine (CSA) or methotrexate (MTX) after the transplant.

The goals of the non-myeloablative conditioning protocol are as follows:

• To make BMT available to children who are ineligible for standard myeloablative regimens due to pre-existing organ toxicities, or who are at high risk (>30%) of toxic death with a standard transplant.
• To assess engraftment of different hematopoietic lineages after the non-myeloablative preparative regimen.
• To assess the anti-tumor effect of the non-myeloablative regimen in patients with malignancies, and the efficacy of mixed chimerism (both donor and recipient cells in the bone marrow and blood) in correcting marrow stem cell defects, severe immunodeficiency diseases and congenital cytopenias.
• To assess organ toxicities and immune reconstitution after this regimen.

Myeloablation and toxicity in standard BMT

Conditioning regimens and post-transplant T-cell modulation with cyclosporine and methotrexate lead to "myeloablation" as well as therapy-related organ toxicities, such as liver, kidney, and gastrointestinal tract toxicities. Patients with pre-existing organ failure or damage are at high risk of sustaining further organ damage during the transplant and dying from transplant-related complications. These patients are considered ineligible for conventional bone marrow stem cell transplants.

Non-myeloablative, or minimally toxic therapies

Because the risk of death from toxicity in a standard BMT is so great, the UCSF Pediatric BMT Program has developed novel protocols for using "non-myeloablative," or minimally toxic therapy, along with a bone marrow stem cell transplant. The non-myeloablative approach uses immunosuppressive drugs that have significantly fewer harsh side effects compared to the standard "myeloablative" regimens. The transplant course is thus "mild," and mucositis and related pain are avoided. T lymphocytes in the donor stem cell preparation are used to not only "create space" but to kill cancer cells. Eradication of malignancy and/or achievement of full engraftment (that is, 100% donor cells in the marrow and blood) is achieved over time by adding more donor T lymphocytes post-transplant (referred to as donor lymphocyte infusions or DLI).

Eligibility

Currently, the non-myeloablative protocol is open to children who have the following:

• a related or unrelated donor;
• high risk for a transplant-related toxic complication;
• leukemia or a non-malignant bone marrow disorder;
• the inability to withstand a standard transplant using high-dose chemotherapy.