Infusion of Off-the-Shelf Expanded Cord Blood Cells to Augment Cord Blood Transplant in Patients With Hematologic Malignancies

PRIMARY OBJECTIVES:

I. Examine the safety and toxicity when ex vivo expanded cord blood cells are infused as an
off-the-shelf non-human leukocyte antigen (HLA) matched product with the goal of providing
rapid but transient myelopoiesis in the setting of a single or double umbilical cord blood
transplant.

II. Examine the in vivo persistence of the ex vivo expanded cord blood product. The kinetics
and durability of hematopoietic reconstitution will be determined and the relative
contribution to engraftment of the expanded cord blood product and the unmanipulated cord
blood unit(s) in early and long-term engraftment will be determined by frequent determination
of donor chimerisms in the peripheral blood.

SECONDARY OBJECTIVES

I. Estimate the incidence and severity of acute and chronic graft-versus-host-disease (GVHD)
in patients receiving off-the-shelf ex vivo expanded and cryopreserved cord blood cells.

II. Estimate the incidence of transplant related mortality at day 100.

III. Estimate the incidence of malignant relapse and probabilities of overall and event-free
survival at 1 and 2 years post transplant.

IV. Obtain preliminary data on the incidence of infections/viral reactivation from the start
of conditioning to 100 days post transplant and then at 6 months, 1 year and 2 years post
transplant as possible.

V. Obtain preliminary data on the phenotype and function of immune cells recovering in
patients receiving expanded and unmanipulated cord blood grafts.

VI. Examination of possible immunologic factors leading to emergence of a dominant unit.

OUTLINE:

MYELOABLATIVE CONDITIONING: Patients receive fludarabine phosphate intravenously (IV) over 1
hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients undergo total-body
irradiation (TBI) twice daily on days -4 to -1.

TRANSPLANTATION: Patients undergo unmanipulated single- or double-unit umbilical cord blood
transplantation on day 0 and receive ex vivo-expanded cord blood progenitor cells IV over 4
hours following the last unmanipulated cord blood infusion.

GVHD PROPHYLAXIS: Patients initially receive cyclosporine (CSP) IV over 1 hour beginning on
day -3. CSP may be given orally (PO) when the patient can tolerate oral medications and has a
normal gastrointestinal transit time. CSP is given until day 100, and may taper on day 101 if
there is no graft versus host disease. Patients also receive mycophenolate mofetil (MMF) IV
every 8 hours on days 0 to 7 and then may receive MMF PO beginning day 8 to 30. MMF is
continued for a minimum of 30 days or until 7 days after blood counts recover whichever is
later. If there is no evidence of acute GVHD and donor cluster of differentiation (CD)3
engraftment is at least 50% from one donor MMF may be tapered.

Inclusion Criteria:

- Acute myeloid leukemia:

- High risk complete response (CR)1 as evidenced by preceding myelodysplastic
syndromes (MDS), high risk cytogenetics (for example, monosomy 5 or 7, or as
defined by referring institution treatment protocol), >= 2 cycles to obtain CR,
erythroblastic or megakaryocytic leukemia; >= CR2

- All patients must be in CR as defined by hematologic recovery and < 5% blasts by
morphology within the bone marrow and a cellularity of >= 15%

- Patients in which adequate marrow/biopsy specimens cannot be obtained to
determine remission status by morphologic assessment, but have fulfilled criteria
of remission by flow cytometry, recovery of peripheral blood counts with no
circulating blasts, and/or normal cytogenetics (if applicable) may still be
eligible; reasonable attempts must be made to obtain an adequate specimen for
morphologic assessment, including possible repeat procedures; these patients must
be discussed with the Principal Investigator, Colleen Delaney prior to enrollment

- Acute lymphoblastic leukemia:

- High risk CR1 [for example, but not limited to: t(9;22), t(1;19), t(4;11) or
other mixed lineage leukemia (MLL) rearrangements, hypodiploid]

- Greater than 1 cycle to obtain CR

- >= CR2

- All patients must be in CR as defined by hematologic recovery and < 5% blasts by
morphology within the bone marrow and a cellularity of >= 15%

- Patients in which adequate marrow/biopsy specimens cannot be obtained to
determine remission status by morphologic assessment, but have fulfilled criteria
of remission by flow cytometry, recovery of peripheral blood counts with no
circulating blasts, and/or normal cytogenetics (if applicable) may still be
eligible; reasonable attempts must be made to obtain an adequate specimen for
morphologic assessment, including possible repeat procedures; these patients must
be discussed with the Principal Investigator, Colleen Delaney prior to enrollment

- Chronic myelogenous leukemia excluding refractory blast crisis; to be eligible in
first chronic phase (CP1) patient must have failed or be intolerant to imatinib
mesylate

- Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate 2
(Int-2) or high risk (i.e., refractory anemia with excess myeloblasts [RAEB],
refractory anemia with excess blasts in transformation [RAEB-T]) or refractory anemia
with severe pancytopenia or high risk cytogenetics; blasts must be < 10% by a
representative bone marrow aspirate morphology

- Karnofsky (>= 16 years old) >= 70%

- Lansky (< 16 years old) >= 50%

- Calculated creatinine clearance must be > 60 mL and serum creatinine =< 2 mg/dL
(adults)

- Calculated creatinine clearance must be > 60 mL/min (children < 18 years old)

- Total serum bilirubin must be < 3 mg/dl

- Transaminases must be < 3 x the upper limit of normal

- Diffusion capacity of the lung for carbon monoxide (DLCO) corrected > 50% normal

- For pediatric patients unable to perform pulmonary function tests, oxygen (O2)
saturation > 92% on room air

- Left ventricular ejection fraction > 45% OR shortening fraction > 26%

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Uncontrolled viral or bacterial infection at the time of study enrollment

- Active or recent (prior 6 month) invasive fungal infection without infectious disease
(ID) consult and approval

- History of human immunodeficiency virus (HIV) infection

- Pregnant or breastfeeding

- If =< 18 years old, prior myeloablative transplant within the last 6 months

- If > 18 years old prior myeloablative allotransplant or autologous transplant

- Extensive prior therapy including > 12 months alkylator therapy or > 6 months
alkylator therapy with extensive radiation