Non-Myeloablative Conditioning for Unrelated Donor Umbilical Cord Blood Transplant

OBJECTIVES:

Primary

- Determine the one- and two-year survival of patients with hematologic malignancies
treated with a nonmyeloablative conditioning regimen comprising fludarabine,
cyclophosphamide, and total-body irradiation followed by umbilical cord blood
transplantation and post-transplant immunosuppression comprising sirolimus and
mycophenolate mofetil.

Secondary

- Determine the six-month nonrelapse mortality of patients treated with this regimen.

- Determine the presence of chimerism in patients treated with this regimen at days 21,
60, 100, 180, and 365.

- Determine the incidence of neutrophil engraftment by day 42 in patients treated with
this regimen.

- Determine the incidence of platelet engraftment by six months in patients treated with
this regimen.

- Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease
(GVHD) at day 100 in patients treated with this regimen.

- Determine the incidence of chronic GVHD at one year in patients treated with this
regimen.

- Determine the probability of overall survival within one or two years in patients
treated with this regimen.

- Determine the probability of progression-free survival within one or two years in
patients treated with this regimen.

- Determine the incidence of relapse or disease progression within one or two years in
patients treated with this regimen.

OUTLINE: This is a nonrandomized study. Patients are stratified into five disease groups: 1.
acute myeloid leukemia, myelodysplastic syndromes, chronic myelogenous leukemia [CML] in
first chronic phase and second chronic phase [CP2] after myeloid blast crisis; 2. acute
lymphoblastic leukemia, Burkitt's lymphoma, CML CP2 post lymphoid blast crisis, 3. large-cell
B and T-cell lymphoma, mantle cell lymphoma; 4. chronic lymphocytic leukemia/small
lymphocytic lymphoma, prolymphocytic leukemia, marginal zone B-cell lymphoma, follicular
lymphoma; 5. Hodgkin's lymphoma and multiple myeloma.

- Nonmyeloablative conditioning: Patients receive fludarabine intravenously on days -6 to
-2 and cyclophosphamide IV on day -6. Patients who did not undergo prior autologous
transplant or who received ≤ 1 course of prior multiagent chemotherapy or no severely
immunosuppressive therapy in the past 3 months also receive anti-thymocyte globulin IV
on days -6 to -4. All patients also undergo total-body irradiation on day -1.

- Umbilical cord blood transplant: Patients undergo umbilical cord blood transplantation
on day 0.

- Post-transplant immunosuppression: Sirolimus will be administered starting at day -3
with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum
concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2
weeks, weekly until day +60, and as clinically indicated until day +100
post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at
day +100 and eliminated by day +180 post-transplantation. Patients also receive
mycophenolate mofetil IV on days -3 to 5 and then orally on days 6-30.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 320 patients will be accrued for this study.

Inclusion Criteria:

Age, Graft Cell Dose and Graft HLA Criteria

- Subjects must be <70 years old. Subjects ages ≥ 70 and ≤ 75 may be eligible if they
have a Co-Morbidity Scoring (HCT-CI) score ≤ 2.

- The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient.

- Patients co-enrolled in MT-2006-01 Phase I Study of Infusion of Umbilical Cord Blood
Derived CD25+CD4+ T-Regulatory (Treg) Cells after Non-Myeloablative Cord\Blood
Transplantation will receive grafts composed of 2 UCB units.

Disease Criteria:

- Acute Leukemias:

- Acute myeloid leukemia: high risk complete remission 1 (CR1) (as evidenced by
preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those
associated with MDS or complex karyotype, > 2 cycles to obtain CR or
erythroblastic and megakaryocytic); second or greater CR.

- Acute lymphoblastic leukemia/lymphoma: high risk CR1 as evidenced by high risk
cytogenetics (e.g. t(9;22), t(1;19),t(4;11), other myeloid/lymphoid or mixed
lineage leukemia [MLL] rearrangements, hypodiploidy or Ikaros family zinc finger
1 [IKZF1]), > 1 cycle to obtain CR or evidence of minimal residual disease (MRD).
Patients in second or greater CR are also eligible.

- Burkitt's lymphoma in CR2 or subsequent CR

- Natural Killer cell malignancies

- Chronic myelogenous leukemia: all types except refractory blast crisis. Chronic phase
patients must have failed or been intolerant to Gleevec

- Myelodysplastic syndrome:

- Large-cell lymphoma, Hodgkin lymphoma and multiple myeloma with chemotherapy sensitive
disease that has failed or patients who are ineligible for an autologous transplant.

- Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone
B-cell lymphoma, follicular lymphoma, which have progressed within 12 months of
achieving a partial or complete remission. Patients who had remissions lasting > 12
months, are eligible after at least two prior therapies. Patients with bulky disease
should be considered for debulking chemotherapy before transplant. Patients with
refractory disease are eligible, unless has bulky disease and an estimated tumor
doubling time of less than one month.

- Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible
after initial therapy if chemotherapy sensitive.

- Refractory leukemia or MDS.

- Bone marrow failure syndromes, except for Fanconi Anemia

- Myeloproliferative syndromes Patients who have undergone an autologous transplant >12
months prior to allogeneic transplantation

Adequate Organ Function and Performance Status

Exclusion Criteria:

- < 70 years with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor

- Pregnancy or breastfeeding

- Evidence of human immunodeficiency virus (HIV) infection or known HIV positive
serology

- Current active serious infection

- Unless in post-chemotherapy and radioimmunoconjugated antibody induced aplasia, when
he/she would be eligible for Arm 3, patients with acute leukemia in morphologic
relapse/ persistent disease defined as > 5% blasts in normocellular 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 (CML) in refractory blast crisis

- Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressive on
salvage therapy. Stable disease is acceptable to move forward provided it is
non-bulky.

- Active central nervous system malignancy