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 HLA-matched (defined as matched in HLA A, B, C, and DRB1) related or unrelated donors, those who elect to undergo UCB even if they have a MRD or MUD, or patients who require a UCB either for emergency indications such as primary graft failure.
• 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 2.0x107TNC/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