Results to date of umbilical cord blood transplantation in adult and fully mature adolescent patients are inferior to what is seen in children, due to a lower stem cell dosage in adults and a more toxic conditioning regimen. This phase 1 protocol will use a potentially less toxic bone marrow conditioning regimen, followed by infusion of a combined umbilical cord blood graft that will provide the patient with a higher stem cell dose than can be given with a single umbilical cord blood infusion. The subjects will be conditioned with a total body irradiation (TBI) 13.5 Gy and fludarabine. Following conditioning, up to two unrelated, partially matched umbilical cord blood grafts will be infused that will provide a minimum nucleated cell dose of 3 x 10e7/kg . The primary objective of this study is to measure the frequency of treatment-related toxicity and engraftment.

Results to date of umbilical cord blood transplantation in adult and fully mature adolescent patients are inferior to what is seen in children. There are two reasons for this. First is that the stem cell dose, measured in nucleated cells/kg body weight, is considerably lower due to the size of the recipient. This results in a higher incidence of graft failure, delayed engraftment, and impaired immune reconstitution. Multiple studies have suggested that a nucleated cell dose below 1.5 to 2 x 107/kg results in an unacceptably high risk for graft failure. Only a minority of adult patients will have a suitably matched umbilical cord blood unit that contains more than 1.5 x 107 nucleated cells/kg. The second reason for inferior outcome of umbilical cord blood transplantation in adult patients is that in comparison to children, the conventional myeloablative bone marrow conditioning regimens are more toxic. This phase 1 protocol will use a potentially less toxic bone marrow conditioning regimen, followed by infusion of a combined umbilical cord blood graft that will provide the patient with a higher stem cell dose than can be given with a single umbilical cord blood infusion. The subjects will be conditioned with a TBI 13.5 Gy and fludarabine. Fludarabine pharmacokinetics will be measured and correlated with the kinetics of donor cell engraftment as well frequency of treatment-related toxicity. Following conditioning, up to two unrelated, partially matched umbilical cord blood grafts will be infused that will provide a minimum nucleated cell dose of 3 x 10e7/kg. The primary objective of this study is to measure the frequency of treatment-related toxicity and engraftment.

Inclusion Criteria:

• Age 14 to 65 years.

• Available cord blood graft.

• Patients with high risk ALL in first complete remission, with high risk being defined by the presence of t(4;11), t(9;22) or t(1;19) or patients presenting with extreme hyperleukocytosis (WBC > 500,000/ul) or partial remission after induction therapy.

• Adult patients with acute non-lymphocytic leukemia (ANLL) in first complete remission with high-risk cytogenetics (monosomy chromosome 5 or 7, del (5q), abn (3q26), complex karyotypic abnormalities) or failure to achieve complete remission after standard induction therapy.

• All patients with ALL or ANLL in second or subsequent remission or partial remission.

• All patients with CML in chronic (failed interferon and/or Gleevec) or accelerated phase.

• Patients with myelodysplastic syndrome with International Prognostic Scoring System (IPSS) risk category of INT-1 or greater.

• Patients with severe aplastic anemia must have failed immunosuppressive therapy such as cyclosporine plus anti-thymocyte globulin.

• Non-Hodgkin's lymphoma or Hodgkin's disease:

  • High risk disease in first complete or partial remission
  • Chemotherapy-resistant relapse
  • Second or subsequent relapse or remission

• Myelofibrosis with myeloid metaplasia.

• High risk, congenital immunodeficiency disorders resulting in recurrent (> 3 episodes) life-threatening infection, known to be curable with allogeneic stem cell transplantation (to include, but not limited to; severe combined immunodeficiency disorder, combined immunodeficiency disease, Wiskott-Aldrich syndrome, Chediak-Higashi syndrome, chronic granulomatous disease, leukocyte adhesion deficiency, hemophagocytic lymphohistiocytosis).

• Patients with a history of CNS disease must have been treated and have no active CNS disease at the time of protocol treatment.

• ECOG performance status < or equal to 2.

• Patients must have adequate function of other organ systems as measured by:

  • Creatinine clearance (by Cockcroft Gault equation) > or equal to 30 ml/min. Hepatic transaminases (ALT/AST) < or equal to 4 x normal, bilirubin < or equal to 2.0 mg/dl
  • Pulmonary function tests demonstrating FVC and FEV1 of > or equal to 50% of predicted for age and DLCO > or equal to 50% of predicted
  • Ejection fraction of > or equal to 45% by echocardiogram, radionuclide scan or cardiac MRI

• Patients must be HIV negative.

• They do not have an HLA-ABC/DR identical related bone marrow or UCB donor.

• They do NOT have a 5/6 antigen matched related bone marrow or UCB donor.

• Their condition precludes waiting to search and find a donor in the National Marrow Donor Registry or an 8/8 (HLA-A, B, C, DRB1) antigen by high resolution (allele-level) typing matched unrelated donor was not found.

• Patients must not be pregnant.

Exclusion Criteria:

• Patients that have circulating antibodies specific for donor major histocompatibility antigens (as determined by panel of reactive antibody assay).
• Patients with progressive ANLL or ALL following second or third-line treatment regimens.