Umbilical Cord Blood T-Regulatory Cell Infusion Followed by Donor Umbilical Cord Blood Transplant in Treating Patients With High-Risk Leukemia or Other Hematologic Diseases

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of umbilical cord blood (UCB)-derived CD4- and
CD25-positive T-regulatory (Treg) cell infusion followed by double unrelated donor UCB
transplantation in patients with high-risk leukemia or other hematologic diseases.

Secondary

- Determine the speed of neutrophil and platelet recovery at day 42 in these patients.

- Determine the incidence of "double chimerism" (e.g., engraftment of both UCB units) at
day 21 in these patients.

- Determine the risk of severe grade III-IV acute graft-versus-host disease (GVHD) at day
100 in these patients.

- Determine the risk of chronic GVHD at 1 year post transplantation in these patients.

- Determine the probability of survival at 100 days and 1 year post transplantation in
these patients.

OUTLINE: This is an open-label, dose-escalation study of CD4- and CD25-positive umbilical
cord blood (UCB)-derived T-regulatory cells (Treg).

- Preparative therapy: Patients receive fludarabine phosphate intravenously (IV) over 1
hour on days -9 to -7 and cyclophosphamide IV over 2 hours on days -8 and -7 (1 hour
after fludarabine infusion). Patients then undergo total-body irradiation (TBI) twice
daily on days -5 to -2.

- UCB-derived Treg infusion: Patients receive UCB-derived Treg cells IV on day -1.

- Double unrelated donor UCB transplantation: Patients undergo double unrelated donor UCB
transplantation by IV infusion on day 0.

- Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2
hours or orally 2 or 3 times daily beginning on day -3 and continuing until day 100,
followed by a taper to day 180, in the absence of GVHD. Patients also receive
mycophenolate mofetil (MMF) orally or IV twice daily on days -3 to 30 or 7 days after
engraftment, whichever is later, in the absence of acute GVHD*. If no donor engraftment
occurs, MMF may be continued at the discretion of the attending physician.

NOTE: *If the patient has acute GVHD requiring systemic therapy, MMF may be stopped 7 days
after GVHD is controlled (e.g., resolution of skin rash, vomiting, and diarrhea).

Cohorts of 3-6 patients receive escalating doses of UCB-derived Treg cells until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 3 or 2 of 6 patients experience nonhematologic dose-limiting toxicity within 48 hours of
Treg cell infusion. At least 6 patients are treated at the MTD.

Inclusion Criteria:

Patient and Donor Demographic Criteria

- Patient must be 18-45 years of age.

- Patients must have three partially HLA matched UCB units. Units identified as the HSC
source must be HLA matched at 4-6 HLA- A and B (at low to intermediate resolution) and
DRB1 (at high resolution), and the units must be HLA matched at 4-6 HLA- A, B, DRB1
antigens with each other. Total cryopreserved HSC graft cell dose must be >2.5 x 107
nucleated cells per kilogram recipient body weight. Also, the two umbilical cord blood
(UCB) units must be ABO-matched.

- The UCB unit identified as the Treg source must be HLA matched at 4-6 HLA antigens
with the patient (without an HLA or ABO matching criterion with the UCB HSC source).

Disease Criteria

- Patients must have a hematological malignancy as listed below:

- Acute myelogenous leukemia: high risk CR1 (as evidenced by preceding
myelodysplastic syndrome (MDS), high risk cytogenetics such as those associated
with MDS or complex karyotype, or >2 cycles to obtain complete remission (CR);
second or greater CR. Must be in remission by morphology (<5% blasts within
normocellular marrow).

- Acute lymphocytic leukemia: high risk CR1 as evidenced by high risk cytogenetics
[t(9;22), t (1:19), t(4;11) or other MLL rearrangements] or > 1 cycle to obtain CR;
second or greater CR.

- Chronic myelogenous leukemia resistant to imatinib therapy

- Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory anemia
with severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by a
representative bone marrow aspirate morphology (otherwise induction chemotherapy to
achieve < 10% blasts is required pre-transplant).

- Advanced myelofibrosis

- Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone
B-cell lymphoma or follicular lymphoma that have progressed after at least two prior
therapies. Patients with bulky disease (nodal mass greater than 5 cm) should be
considered for debulking chemotherapy before transplant.

- Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible
after initial therapy in CR1+ or PR1+.

- Large cell non-Hodgkins lymphoma (NHL) > CR2/> PR2. Patients in CR2/PR2 with initial
short remission(<6 months) are eligible.

- Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade NHL after initial
therapy if stage III/IV in CR1/PR1 or after progression if stage I/II <1 year.

- Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first response
lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may be considered for this
protocol after initial therapy.

- Recipients will have a Karnofsky score > 80% and have acceptable organ function ie
creatinine < 2.0, bilirubin, AST/ALT, ALP < 2 x normal, pulmonary function > 50%
normal, left ventricular ejection fraction > 45%. Note: All patients with a creatinine
> 1.2 or a history of renal dysfunction must have creatinine clearance (must be > 40
ml/min to be eligible).

- Recipients will sign informed consent approved by the Committee on the Use of Human
Subjects at the University of Minnesota.

Exclusion Criteria:

- Pregnant or breastfeeding

- Evidence of HIV infection or known HIV positive serology

- Current active infection

- Available HLA matched sibling donor.

- CML in active blast crisis