Non-Myeloablative HLA-Mismatched Ex-Vivo T-cell Depleted Stem Cell Transplantation for Hematologic Malignancies

One major obstacle to further advancement in the role of bone marrow transplant (BMT) in
hematological malignancies is graft-versus-host-disease (GVHD), which can best be prevented
by removing T-cells from the donor stem cell product. However, previous experience with
T-cell depletion has been associated with an increased rate of engraftment failure and
leukemic relapse. Another obstacle is that a large fraction of leukemia and lymphomas afflict
older patients who are more prone to GVHD and have co-morbid conditions that prevent them
from being a candidate for BMT.

This trial uses a non-myeloablative conditioning regimen with cyclophosphamide, MEDI-507,
fludarabine, and thymic irradiation followed by a T-cell depleted PBSC infusion. Cyclosporine
is used for GVHD prophylaxis, and tapered beginning on day 35. Data from our mouse model and
previous clinical trials have demonstrated that this approach can induce mixed chimerism
without GVHD, with the potential for conversion of mixed chimerism to full donor
hematopoiesis following donor leukocyte infusions.

Inclusion Criteria:

- Disease Status: NHL, HD, MM that are chemorefractory or relapsed; CLL that is Rai
stage III or IV, or lymphocyte doubling time of 6 months, or stage I/II resistant to >
2 cycles of chemotherapy regimens; CML in accelerated or blast phase; MDS with
life-threatening cytopenias; patients who have had a previous autologous or allogeneic
bone marrow or stem cell transplant; other hematological disorders where allogeneic
transplant is appropriate and the risk of conventional transplantation is considered
to be unacceptably high.

- estimated disease free survival of less than one year

- ECOG performance status of 0, 1, or 2

- HLA 1 to 3 mismatched (at A, B, DR loci) related donor

Exclusion Criteria:

- Cardiac disease: symptomatic congestive heart failure, ejection fraction of < 45%,
active angina pectoris or uncontrolled hypertension.

- Pulmonary disease: severe chronic obstructive lung disease, or symptomatic restrictive
lung disease, or corrected DLCO of < 50%

- Renal disease: serum creatinine > 2.0 mg/dl or creatinine clearance < 50 ml/min

- Hepatic disease: serum bilirubin > 2.0 mg/dl or alkaline phosphate, SGPT or SGOT > 3 x
normal

- Neurologic disease: symptomatic leukoencephalopathy, active CNS malignancy or other
neuropsychiatric abnormalities believed to preclude transplantation

- HIV antibody or Hepatitis B surface antigen positivity

- Uncontrolled infection

- Presence of HAMA or HAHA in patient previously treated with monoclonal antibody
therapy or who have received a product in which the preparation involved a monoclonal
antibody affinity step