Trial Information

Reduced-Intensity Preparative Regiment With Fludarabine, Busulfan, And Alemtuzumab (Campath 1H) Followed By Allogeneic Hematopoietic Stem Cell Transplant For Malignant And Non-Malignant Hematological Diseases

Allogeneic stem cell transplantation with high-dose chemotherapy affords a better chance of
cure of malignant and non-malignant hematological diseases compared to autologous
transplantation, because of the lack of stem cell contamination and the immune mediated
graft vs. leukemia effect. Unfortunately, high-dose chemotherapy and allogeneic stem cell
transplantation has a substantial treatment related mortality, that is particularly high in
older patients (greater than 50 yrs of age), or in those with co-morbidities such as
congestive heart disease and pulmonary disease. Patients who have pre-existing infections or
who have had multiple relapses with prior chemotherapy are also at high risk. In all these
groups, treatment related mortality may exceed 50%, making them ineligible for high-dose
chemotherapy and allogeneic stem cell transplantation.

Recently interest has increased in using less toxic chemotherapy protocols that are termed
submyeloablative. The intent is to allow partial engraftment of a donor immune and
hemopoietic systems with subsequent progressive replacement of the host's own hemopoiesis
and immunity. As the donor immune system becomes established, patients may develop full
donor chimerism, without passing through the period of prolonged aplasia associated with
conventional conditioning regimens, and with less of the associated toxicity. Preliminary
results in high-risk patients have shown treatment related mortality (TRM) of 15-20%, versus
50% expected, with an overall survival rate of 70-80% at 1-2 years post transplant.

As might be anticipated, the major problem with sub-ablative conditioning is that the graft
failure rate is increased, with published figures of 5-30% versus 1-5% predicted in fully
ablated patients. The incorporation of lymphodepleting antibodies in the preliminary
conditioning regimen may allow these rejection rates to be diminished. Moreover, a highly
efficient lymphodepleting MAb or MAb combination might be successfully substituted in part
or in whole for cytotoxic and immunosuppressive drugs, further increasing the safety and
efficacy of the subablative approach to stem cell transplantation. Our own data using the
crude polyclonal mixture of antibodies in ATG as a component of pre-transplant conditioning
revealed an improvement in engraftment during matched unrelated donor transplantation.The
lymphodepleting monoclonal antibody Campath IH has many of the properties desired for this
application, and we propose to incorporate it in our conditioning regimen. Since CAMPATH1H
persists after infusion, we would expect it to have additional anti-GvHD effector function,
further reducing treatment related mortality (TRM).

The following preparative regimen will be delivered to all patients:

1. Busulfan 3.2 mg/kg/day IV daily for 2 days, infused over 3 hours, on Day -5 and Day -4

2. Fludarabine 30mg/m2/day IV daily for 4 days on Day -5 to D -2

3. Campath 10 mg/day IV daily for 3 days on days -6 to D-4.

Because CAMPATH-1H infusions will provide a persisting level of antibody over the transplant
period, it will contribute to anti-GvHD activity. Additional Graft vs. host disease
prophylaxis will consist of FK506 administered from Day-2.

The stem cells will be infused on day 0.