Intra-Osseous Co-Transplant of UCB and hMSC

PRIMARY OBJECTIVES:

I. To estimate the feasibility of combining intra-osseous umbilical cord blood (UCB)
hematopoietic stem cells and human mesenchymal stromal cells (hMSC) following reduced
intensity conditioning (RIC).

SECONDARY OBJECTIVES:

I. To estimate the time to engraftment of intra-osseous (IO) UCB transplant combined with
hMSC following RIC.

II. To estimate the safety profile of IO UBC transplant combined with hMSC.

OUTLINE:

REDUCED INTENSITY CONDITIONING: Patients receive cyclophosphamide intravenously (IV) over 2
hours on day -6 and fludarabine phosphate IV on days -6 to -2 and undergo total body
irradiation (TBI) on day -1.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive cyclosporine orally (PO) or IV
over 2 hours every 12 hours on beginning on days -5 to 100 with taper beginning on day 100
and mycophenolate mofetil IV or PO twice daily (BID) on days -5 to 100.

TRANSPLANT: Patients undergo intra-osseous UCB and hMSC co-transplant on day 0.

After completion of study treatment, patients are followed up at days 28 and 100, and then at
6, 9, and 12 months.

Inclusion Criteria:

- Patients must have one of the following malignancies:

- Acute myelogenous leukemia (AML): high-risk AML including:

- Antecedent hematological disease (e.g., myelodysplasia [MDS])

- Treatment-related leukemia

- Complete remission (first complete remission [CR1]) with poor-risk
cytogenetics or molecular markers (e.g. fms-related tyrosine kinase 3 [Flt
3] mutation, 11q23, del 5, del 7, complex cytogenetics)

- Second complete remission (CR2) or third complete remission (CR3)

- Induction failure or first relapse with either

- ≤ 10% blasts in the marrow and/or

- ≤ 5% blasts in the peripheral blood

- Acute lymphoblastic leukemia (ALL)

- High-risk CR1 including:

- Poor-risk cytogenetics (e.g., Philadelphia chromosome t(9;22)or 11q23
rearrangements)

- Presence of minimal disease by flow cytometry after 2 or more cycles of
chemotherapy

- No complete remission (CR) within 4 weeks of initial treatment

- Induction failure

- CR2 or CR3 with either:

- ≤ 10% blasts in the marrow and/or

- ≤ 5% blasts in the peripheral blood

- Myelodysplastic syndromes (MDS), Intermediate-1 (INT-1), intermediate-2 (INT-2)
or high Revised International Prognostic Scoring System (IPSS-R) score that has
failed at least 1 first line therapy

- Myelofibrosis (MF):

- Intermediate-2 or high risk by Dynamic International Prognostic Scoring
System (DIPSS)-plus

- Monosomal karyotype

- Presence of inv(3)/i(17q) abnormalities

- Other unfavorable karyotype OR leukocytes ≥40 X 10^9/L AND

- Circulating blasts ≤ 9%

- Relapsed or refractory lymphoid malignancies (including non-Hodgkin lymphoma,
Hodgkin lymphoma and chronic lymphocytic leukemia) meeting the following
criteria:

- Disease status: stable disease, partial remission or 2nd and 3rd complete
remission

- Chronic myelogenous leukemia (CML) in second chronic phase after accelerated or
blast crisis; blast crisis defined as:

- Blast count ≥ 20% in the peripheral blood or bone marrow

- Large foci of blasts on bone marrow

- Presence of extra-medullary blastic infiltrate (myeloid sarcoma or chloroma)

- Recipients of prior autologous or allogeneic transplant are eligible, as long as
at least 3 months have passed since the transplant, and the patient fulfills
other eligibility criteria

- Eastern Cooperative Oncology Group (ECOG) performance status ≤2

- Candidates for reduced intensity conditioning regimens

- Patients who do not have human leukocyte antigen (HLA)-matched (defined as
matched in HLA A, B, C, and DRB1) related or unrelated donors

- Cord Blood Units available through NMDP with the following minimal criteria:

- HLA Match: 4/6 or better match (HLA A, B, DRB1)

- Cell dose: Minimum of 2x107TNC/kg pre thaw

- Concurrent therapy for extramedullary leukemia or central nervous system (CNS)
lymphoma: concurrent therapy or prophylaxis for testicular leukemia, CNS
leukemia, and CNS lymphoma including standard intrathecal chemotherapy and/or
radiation therapy will be allowed as clinically indicated; such treatment may
continue until the planned course is completed; subjects must be in CNS remission
at the time of protocol enrollment if there is a history of CNS involvement

- Subjects must have a back-up umbilical cord on the registry in addition to the
umbilical cord being used in this study

- Subjects must have the ability to understand and the willingness to sign a
written informed consent document

Exclusion Criteria:

- Patients with inadequate Organ Function as defined by:

- Creatinine clearance < 30 ml/min

- Bilirubin ≥ 2 x institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])
≥ 2 x institutional upper limit of normal

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≥ 2
x institutional upper limit of normal

- Corrected diffusing capacity of the lung for carbon monoxide (DLCOcorr) < 40%
normal

- Left ventricular ejection fraction < 35%

- Patients with uncontrolled inter-current illness including, but not limited to ongoing
or active infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements

- Pregnant or breastfeeding women are excluded from this study