RATIONALE: Giving chemotherapy, such as fludarabine and cyclophosphamide, and total-body
irradiation before a donor umbilical cord blood transplant helps stop the patient's immune
system from rejecting the donor's stem cells. The donated stem cells may replace the
patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor
effect). Giving an infusion of the donor's T-regulatory cells after the transplant may
decrease this effect. Sometimes the transplanted cells from a donor can also make an immune
response against the body's normal cells. However, the donor immune system may also react
against the recipient's tissues (graft-versus-host disease).
PURPOSE: This phase I trial is studying the side effects and best dose of donor T-regulatory
cells after an umbilical cord blood transplant in treating patients with advanced hematologic
cancer or other disorder.
- Determine the maximum tolerated dose (MTD) of umbilical cord blood (UCB)-derived
T-regulatory (Treg) cells.
- Estimate the proportion of patients with detectable circulating Treg cells at 0, 1, 3,
7, and 14 days after infusion.
- Estimate the risk of grades II-IV and III-IV acute graft versus host disease (GVHD) at
day +100 with the infusion of Treg cells.
- Estimate the proportion of patients with sustained donor engraftment.
- Estimate the proportion of patients with double chimerism at 6 months and 1 year.
- Determine the speed and cumulative incidence of neutrophil recovery by day 42 and
platelet recovery by 6 months after UCB transplantation.
- Estimate the risk of chronic GVHD at 1 year.
- Estimate the probability of disease-free survival at 100 days and 1 year.
- Estimate the risk of fungal and viral infections at 1 year
- Estimate the risk of relapse at 1 year
- Characterize the pattern of immune cell recovery over 1 year
OUTLINE: This is a dose-escalation study of umbilical cord blood (UCB)-derived T-regulatory
(Treg) cells. Patients receive nonmyeloablative UCB transplantation and post-transplant
immunosuppression as in protocol UMN-2005LS036 (without antithymocyte globulin during
- Nonmyeloablative conditioning and UCB transplantation: Patients receive allopurinol on
days -7 to day 0, fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2
and cyclophosphamide IV over 2 hours on day -6; undergo total-body irradiation (TBI)
once on day -1; and undergo UCB transplantation on day 0.
- Immunosuppression therapy: Beginning on day -3 and continuing until day +100, patients
receive sirolimus intravenously (IV) with 8-12 mg oral loading dose followed by a single
dose of 4mg/day with a target serum concentration of 3-12 mg/mL with a taper until day
+180. Patients also receive mycophenolate mofetil IV or orally every 8 hours on days -3
- Radiation therapy: total body irradiation is administered on Day -1 of 200 cGy.
- UCB Treg cell infusion: Patients receive escalating doses of UCB-derived CD4+ CD25+ Treg
cells IV on day +1 (and Day +15 for dose level 5 only) until the maximum tolerated dose
After completion of study treatment, patients are followed at day 180, 360, and 720.
- Ages 18 to 75 years old
- Eligible for and co-enrolled on protocol UMN-2005LS036, for treatment of any of the
following advanced hematologic malignancies:
- Acute leukemias in complete remission (high risk CR1 or subsequent CR); chronic
myelogenous leukemia (except refractory blast crisis); myelodysplastic syndrome
with severe pancytopenia or complex cytogenetics, large-cell lymphoma, Hodgkin's
lymphoma and multiple myeloma, chronic lymphocytic leukemia/small lymphocytic
lymphoma, marginal zone b-cell lymphoma, follicular lymphoma, lymphoplasmacytic
lymphoma, mantle-cell lymphoma, prolymphocytic leukemia may be eligible after
- Have three partially HLA matched umbilical cord blood (UCB) units (1-2 units for UCB
transplantation per MT2005-02 and 1 unit for the Treg cell infusion.)
- Adequate organ function
- Patients not exposed to highly immunosuppressive single agent or multi-agent
chemotherapy within 3 months, or an ablative preparative regimen for autologous
hematopoietic stem cell transplant (HCT) within 1 year.
- Pregnancy or breastfeeding
- Current active serious infection
- Evidence of human immunodeficiency virus (HIV) or known HIV positive serology
- Patients with acute leukemia in morphologic relapse/persistent disease defined as >5%
blasts in a > or = 15% cellular bone marrow or any % blasts if blasts have unique
morphologic markers (e.g., Auer rods) or associated cytogenetic markers that allows
morphologic relapse to be distinguished are not eligible.
- Chronic myelogenous leukemia in refractory blast crisis.
- Active central nervous system malignancy.
Claudio G. Brunstein, MD, PhD
Masonic Cancer Center, University of Minnesota