Low Intensity Non-Myeloablative Preparative Conditioning Followed by Transplantation of Genetically Modified HLA-Matched Peripheral Blood Hematopoietic Precursor Cells (PBPC) for Hematologic Malignancies in HIV Positive Adults
Adult patients with myelodysplasia, leukemia, and non-Hodgkin's lymphoma can be cured by
allogeneic bone marrow transplantation (BMT). This curative effect has until now been
ascribed to the intense chemoradiotherapy used to condition the recipient for
transplantation. The assumption that the curative effect of allogeneic transplantation
rests in the ability to deliver very high doses of chemoradiotherapy has led to the
restriction of allogeneic transplantation to those recipient patients whose overall status
would permit the use of such intense conditioning. As a result, HIV positivity has
generally appeared as an exclusion criteria to allogeneic transplantation for hematologic
malignancies. Additionally, early studies of allogeneic BMT in HIV patients suggested no
benefit in controlling the progression to AIDS.
Several in vitro studies have demonstrated the existence of donor derived CD4 and CD8
positive lymphocytes with specific reactivity to recipient leukemia providing a potent graft
versus leukemia (GVL) effect, and this GVL effect is area of intense interest both at the
NIH and elsewhere. In fact, early attempts to decrease treatment related mortality in
chronic myelogenous leukemia (CML) patients undergoing allogeneic BMT by T-cell depletion of
the graft resulted in an unacceptably high rate of relapse suggesting that alloreactivity in
the donor graft accounted for a significant portion of the cure rate in this disease. This
GVL effect is most dramatically demonstrated among relapsed allogeneic bone marrow
transplant recipients transplanted for CML in whom a simple infusion of donor lymphocytes
can induce a complete and durable remission.
Non-myeloablative allogeneic peripheral blood stem cell transplants are currently being
investigated for engraftment efficacy and toxicity in a number of transplant centers.
Preliminary data including our own experience with 13 patients undergoing this type of
procedure have shown a high rate of complete donor engraftment, low toxicity, and
preservation of the GVL effect. Two recent published studies investigating
non-myeloablative allo-transplantation in standard risk patients revealed an extremely low
rate of transplant related complications and mortality.
The decreased risk of transplant related complications associated with non-myeloablative
transplants expands the eligibility of transplant candidates and may allow successful
application in patients infected with HIV. In this study, we will assess the safety and
efficacy of nonmyeloablative transplantation in patients with HIV infection. Moreover, the
introduction of an HIV resistance vector into a portion of the allogeneic graft provides a
unique opportunity to test the in vivo efficacy of introducing resistance to HIV through the
self renewing stem cell.
The end points of this study are engraftment, degree of donor-host chimerism, incidence of
acute and chronic GVHD, transplant related morbidity and mortality, disease free survival,
as well as overall survival, and overall level and persistence of progeny of gene modified
Endpoint Classification: Safety Study, Primary Purpose: Treatment
United States: Federal Government
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