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Umbilical Cord Blood Transplant With Co-Infusion of T Regulatory Cells

Phase 1
18 Years
45 Years
Not Enrolling
Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Secondary Myelofibrosis

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Trial Information

Umbilical Cord Blood Transplant With Co-Infusion of T Regulatory Cells



- Determine the maximum tolerated dose of umbilical cord blood (UCB)-derived CD4- and
CD25-positive T-regulatory (Treg) cell infusion followed by double unrelated donor UCB
transplantation in patients with high-risk leukemia or other hematologic diseases.


- Determine the speed of neutrophil and platelet recovery at day 42 in these patients.

- Determine the incidence of "double chimerism" (e.g., engraftment of both UCB units) at
day 21 in these patients.

- Determine the risk of severe grade III-IV acute graft-versus-host disease (GVHD) at day
100 in these patients.

- Determine the risk of chronic GVHD at 1 year post transplantation in these patients.

- Determine the probability of survival at 100 days and 1 year post transplantation in
these patients.

OUTLINE: This is an open-label, dose-escalation study of CD4- and CD25-positive umbilical
cord blood (UCB)-derived T-regulatory cells (Treg).

- Preparative therapy: Patients receive fludarabine phosphate intravenously (IV) over 1
hour on days -9 to -7 and cyclophosphamide IV over 2 hours on days -8 and -7 (1 hour
after fludarabine infusion). Patients then undergo total-body irradiation (TBI) twice
daily on days -5 to -2.

- UCB-derived Treg infusion: Patients receive UCB-derived Treg cells IV on day -1.

- Double unrelated donor UCB transplantation: Patients undergo double unrelated donor UCB
transplantation by IV infusion on day 0.

- Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2
hours or orally 2 or 3 times daily beginning on day -3 and continuing until day 100,
followed by a taper to day 180, in the absence of GVHD. Patients also receive
mycophenolate mofetil (MMF) orally or IV twice daily on days -3 to 30 or 7 days after
engraftment, whichever is later, in the absence of acute GVHD*. If no donor engraftment
occurs, MMF may be continued at the discretion of the attending physician.

NOTE: *If the patient has acute GVHD requiring systemic therapy, MMF may be stopped 7 days
after GVHD is controlled (e.g., resolution of skin rash, vomiting, and diarrhea).

Cohorts of 3-6 patients receive escalating doses of UCB-derived Treg cells until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 3 or 2 of 6 patients experience nonhematologic dose-limiting toxicity within 48 hours of
Treg cell infusion. At least 6 patients are treated at the MTD.

Inclusion Criteria:

Patient and Donor Demographic Criteria

- Patient must be 18-45 years of age.

- Patients must have three partially HLA matched UCB units. Units identified as the HSC
source must be HLA matched at 4-6 HLA- A and B (at low to intermediate resolution)
and DRB1 (at high resolution), and the units must be HLA matched at 4-6 HLA- A, B,
DRB1 antigens with each other. Total cryopreserved HSC graft cell dose must be >2.5 x
107 nucleated cells per kilogram recipient body weight. Also, the two umbilical cord
blood (UCB) units must be ABO-matched.

- The UCB unit identified as the Treg source must be HLA matched at 4-6 HLA antigens
with the patient (without an HLA or ABO matching criterion with the UCB HSC source).

Disease Criteria

- Patients must have a hematological malignancy as listed below:

- Acute myelogenous leukemia: high risk CR1 (as evidenced by preceding
myelodysplastic syndrome (MDS), high risk cytogenetics such as those associated
with MDS or complex karyotype, or >2 cycles to obtain complete remission (CR);
second or greater CR. Must be in remission by morphology (<5% blasts within
normocellular marrow).

- Acute lymphocytic leukemia: high risk CR1 as evidenced by high risk cytogenetics
[t(9;22), t (1:19), t(4;11) or other MLL rearrangements] or > 1 cycle to obtain CR;
second or greater CR.

- Chronic myelogenous leukemia resistant to imatinib therapy

- Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory anemia
with severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by a
representative bone marrow aspirate morphology (otherwise induction chemotherapy to
achieve < 10% blasts is required pre-transplant).

- Advanced myelofibrosis

- Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone
B-cell lymphoma or follicular lymphoma that have progressed after at least two prior
therapies. Patients with bulky disease (nodal mass greater than 5 cm) should be
considered for debulking chemotherapy before transplant.

- Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are
eligible after initial therapy in CR1+ or PR1+.

- Large cell non-Hodgkins lymphoma (NHL) > CR2/> PR2. Patients in CR2/PR2 with initial
short remission(<6 months) are eligible.

- Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade NHL after initial
therapy if stage III/IV in CR1/PR1 or after progression if stage I/II <1 year.

- Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first
response lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may be considered
for this protocol after initial therapy.

- Recipients will have a Karnofsky score > 80% and have acceptable organ function ie
creatinine < 2.0, bilirubin, AST/ALT, ALP < 2 x normal, pulmonary function > 50%
normal, left ventricular ejection fraction > 45%. Note: All patients with a
creatinine > 1.2 or a history of renal dysfunction must have creatinine clearance
(must be > 40 ml/min to be eligible).

- Recipients will sign informed consent approved by the Committee on the Use of Human
Subjects at the University of Minnesota.

Exclusion Criteria:

- Pregnant or breastfeeding

- Evidence of HIV infection or known HIV positive serology

- Current active infection

- Available HLA matched sibling donor.

- CML in active blast crisis

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose of T-regulatory cells

Outcome Description:

Dose limiting toxicities (DLT) are defined as any grade 3-4 toxicity within 24 hours of Treg cell infusion, excluding hematological .

Outcome Time Frame:

Within 24 Hours

Safety Issue:


Principal Investigator

Claudio G. Brunstein, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota


United States: Food and Drug Administration

Study ID:




Start Date:

May 2007

Completion Date:

March 2008

Related Keywords:

  • Graft Versus Host Disease
  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • Secondary Myelofibrosis
  • graft versus host disease
  • adult acute lymphoblastic leukemia in remission
  • adult acute myeloid leukemia in remission
  • secondary acute myeloid leukemia
  • refractory anemia with excess blasts
  • myelodysplastic syndromes
  • chronic myelogenous leukemia
  • refractory anemia
  • prolymphocytic leukemia
  • stage IV adult lymphoblastic lymphoma
  • recurrent adult Burkitt lymphoma
  • stage I adult Burkitt lymphoma
  • stage III adult Burkitt lymphoma
  • stage IV adult Burkitt lymphoma
  • follicular lymphoma
  • mantle cell lymphoma
  • chronic idiopathic myelofibrosis
  • secondary myelofibrosis
  • refractory chronic lymphocytic leukemia
  • recurrent small lymphocytic lymphoma
  • recurrent marginal zone lymphoma
  • marginal zone lymphoma
  • diffuse large cell lymphoma
  • anaplastic large cell lymphoma
  • lymphoblastic lymphoma
  • immunoblastic large cell lymphoma
  • multiple myeloma
  • Primary Myelofibrosis
  • Neoplasms
  • Graft vs Host Disease
  • Hematologic Diseases
  • Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Myelodysplastic Syndromes
  • Preleukemia



Masonic Cancer Center at University of Minnesota Minneapolis, Minnesota  55455