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Total Body Irradiation With Fludarabine Conditioning Followed by Transplantation With Combined Umbilical Cord Blood Grafts

Phase 1
14 Years
65 Years
Open (Enrolling)
Lymphoma, Myeloma, Leukemia, Myelodysplasia, Solid Tumors, Hodgkin's Disease, Myelofibrosis

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Trial Information

Total Body Irradiation With Fludarabine Conditioning Followed by Transplantation With Combined Umbilical Cord Blood Grafts

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

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary objective will be to measure the time to and rate of hematologic engraftment following transplant and the frequency of treatment-related mortality.

Outcome Time Frame:

3 years

Safety Issue:


Principal Investigator

Mitchell Horwitz, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University Health System


United States: Institutional Review Board

Study ID:




Start Date:

September 2005

Completion Date:

September 2014

Related Keywords:

  • Lymphoma
  • Myeloma
  • Leukemia
  • Myelodysplasia
  • Solid Tumors
  • Hodgkin's Disease
  • Myelofibrosis
  • Umbilical Cord Blood Graft
  • Stem Cell Transplantation
  • Primary Myelofibrosis
  • Hodgkin Disease
  • Leukemia
  • Lymphoma
  • Myelodysplastic Syndromes
  • Preleukemia



Duke University Health System Durham, North Carolina  27705