Trial Information

Transplantation of Expanded and Unexpanded Umbilical Cord Blood Units Following Myeloablative Chemotherapy for Hematologic Malignancies

The success of BMT as a curative option for patients with malignancies is frequently limited
by the inability to identify an appropriate donor in time for transplantation.

Transplantations utilizing umbilical cord blood stem cells are increasingly successful.
Data suggest that there are fewer and less developed T-cells in cord products when compared
to bone marrow and so are likely to produce less graft-vs.-host disease (GVHD) even in the
mismatched setting. In addition, the grafts are easily available second to the ease of
collection as compared with other sources such as bone marrow and peripheral blood stem
cells (PBSCs). The ability to build cord blood repositories containing samples with HLA
types from minorities has and will continue to increase the likelihood of finding suitable
products for under represented minorities such as African-Americans, Hispanic populations
and mixed ethnic populations.

Unfortunately, limitations remain, secondary to the time to engraftment when the cell dose
is less than optimal, resulting in delayed or failed engraftment. In addition, increased
cell dose appears to be associated with disease free survival. Therefore, this modality of
transplant is generally limited to smaller patients. This protocol evaluates the infusion
and engraftment of two cord blood products - one that has been expanded ex vivo and one that
has not been expanded following myeloablative chemotherapy for the treatment of
hematological malignancies.

Primary Objective:

-To evaluate the safety of transplantation of two cord products including an expanded unit
including infusional toxicities and potential immunologic competition.

Secondary Objective:

-To determine if the use of two cord products results in an improvement in neutrophil
engraftment (ANC>500) in subjects as demonstrated by engraftment <=21 days.

Tertiary Objectives:

Patients will be compared with patients participating in other trials at our institution and
to those who receive therapy as per standard of care.

- To evaluate the rate, extent, and durability of hematopoietic reconstitution and in
particular to determine the relative contribution of each cord unit in early
engraftment and long-term engraftment

- To estimate the rate and severity of graft-vs-host disease

- To estimate the rates of infectious complications

- To obtain preliminary data regarding disease-free and overall survival

- To collect samples for future studies of immune reconstitution and for future studies
in the laboratory regarding disease and the immune system

We will be able to track the fate of both the unmanipulated and expanded CB progenitors by
evaluating differences in the cord products and the recipient by evaluation of sex mismatch,
HLA type and/or restriction length polymorphisms (RFLPs). If the expanded CB cells are
detected in the patients long-term, this will give us confidence to use expanded CB as the
sole hematopoietic progenitor cell support, in future studies.

The major risk is non-engraftment of either one or both of the cord blood units.
Non-engraftment of one of the units may lead to prolonged cytopenia and a marked increased
risk for infection. Failure of either unit to engraft as defined as failure to detect cells
from either cord blood product at Day +60 is likely to result in the death of the subject.
There is the possibility of failure of long-term engraftment from both cords. This would be
fatal unless an alternative donor option was identified or the unlikely event of autologous
reconstitution of bone marrow. There is a possibility of an immune competition of both
cord blood products . This could result in the loss of the cord product that would have
been responsible for long term engraftment. There is a possibility of the expanded cord
product to fail release testing. In this event, only the unexpanded cord would be infused
and would likely result in delayed engraftment.

As with all cellular products there are risks associated with the infusion including but not
limited to anaphylaxis, transfusion reaction, hemolysis, side-effects of the DMSO that the
product is stored in (bradycardia, hypothermia, neurologic changes). The expanded product
will be washed however there remains a small chance that a small amount of growth factor
remains. The risk associated with these will be allergic.

Busulfan toxicity

1. Nausea and vomiting

2. Myeloablation

3. Pulmonary complications

4. Seizures

5. Other toxic effects which may be produced by Busulfan erythematous skin rash,
hyperpigmentation, hepatic dysfunction, amenorrhea, testicular atrophy, gynecomastia,
myasthenia symptoms, cataract and atrophic bronchitis associated with cytologic
dysplasia.

Cyclophosphamide Toxicity

1. Leukopenia, anemia

2. Alopecia

3. Nausea, vomiting, increased AST, ALT, mucositis, diarrhea

4. Headache, dizziness

5. Cardiac necrosis rarely with high dose cyclophosphamide

6. Hemorrhagic cystitis, SIADH

7. Teratogenic, may cause secondary neoplasms, anaphylaxis (rare)

8. Fluid retention.

9. Cardiomyopathy.

10. Hemorrhagic Cystitis.

At the doses used for uroprotection mesna is virtually non-toxic. However, adverse effects
which may be attributable to mesna include nausea and vomiting, diarrhea, abdominal pain,
altered taste, rash, urticaria, headache, joint or limb pain, hypotension and fatigue.

Total Body Irradiation Toxicity:

1. Nausea and Vomiting

2. Alopecia

3. Parotitis and Pancreatitis

4. Diarrhea

5. Fever

6. Erythema

7. Hyperpigmentation

8. Mucositis

9. Late Effects - cataract formation, growth retardation, carcinogenesis and the
probability of sterilization.