Donor Umbilical Cord Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies

PRIMARY OBJECTIVES:

1. To establish the day +180 overall survival after a myeloablative unrelated double unit
UCBT in a single institution setting.

SECONDARY OBJECTIVES:

1. To determine the rates of hematologic and immune reconstitution in patients with high
risk hematologic malignancies, who are undergoing myeloablative chemotherapy followed by
infusion of double unit UCBT.

2. To determine the contribution of each umbilical cord unit to immune reconstitution with
a focus on both initial (day +21 BM, and +28 PB) and sustained engraftment (day +100 BM;
PB at +14, +21, +28, +35, +42, +60, +100, +180, +1 and 2 years).

3. To determine the probability of overall survival and disease free survival at one and
two years.

4. To describe the incidence of disease recurrence at one and two years in patients post
UCBT.

5. To describe the incidence of acute GVHD and chronic GVHD at 100 days and at one year,
respectively.

6. To determine the incidence of day 100 and 180 treatment related mortality.

7. To determine the incidence of serious infectious complications in the first year after
transplant.

8. To determine the incidence of donor-derived neutrophil and platelet recovery.

9. To determine the incidence of secondary lymphoproliferative diseases following
transplantation with umbilical cord blood.

OUTLINE:

PREPARATIVE REGIMEN: Patients receive oral busulfan every 6 hours on days -8 to -5,
cyclophosphamide IV on days -4 to -3, and anti-thymocyte globulin or methylprednisolone IV on
days -3 to -1.

TRANSPLANTATION: Patients undergo double-unit umbilical cord blood allogeneic stem cell
transplantation on day 0.

GRAFT-VS-HOST DISEASE PROPHYLAXIS: Beginning on day -2, patients receive cyclosporine IV and
taper beginning on day 100. Patients also receive mycophenolate mofetil IV or orally every 8
hours on days -3 to 45. After completion of study treatment, patients are followed
periodically.

Inclusion Criteria:

- Patients will be diagnosed with one of the following hematological malignancies: acute
myelogenous leukemia (AML), acute lymphoblastic leukemia, non-Hodgkin's lymphoma,
myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), and
myeloproliferative and lymphoproliferative disorders

- AML--First remission (CR1) with high risk features including a known prior diagnosis
of myelodysplasia (MDS); therapy related AML; white cell count at presentation >
100,000; presence of extramedullary leukemia at diagnosis; unfavorable AML subtype
(M0, M5-M7); poor cytogenetic markers (abnormalities of chromosome 5, 7 or 8, 11q23,
Philadelphia chromosome, complex karyotype)

- AML--Second remission (CR2) or subsequent remission

- AML--Relapse/Persistent Disease with < 20% bone marrow blasts

- ALL--First remission (CR1) at high risk for relapse as defined by: B cell ALL white
blood cell count (WBC) at presentation > 30,000 (T cell ALL WBC > 100,000); presence
of high-risk cytogenetic abnormality such as t(9;22), t(1;19), t(4;11) or other MLL
rearrangements (11q23), t(8;14)

- ALL--Second remission (CR2) or subsequent remission

- ALL--Relapse/Persistent Disease with < 20% bone marrow blasts

- Non-Hodgkin Lymphoma--Induction failure or relapse and sensitive to most recent
chemotherapy

- MDS--Low or Intermediate-1 International Prognostic Scoring System (IPSS) score with:
life-threatening cytopenia(s); and/or red cell or platelet transfusion dependence

- MDS--ANC < 500, recurrent infections, PRBC transfusions > 2 units/month, poor risk
cytogenetics, platelet transfusion dependence

- MDS--Intermediate-2 or High IPSS score

- CML--Chronic phase I (CP1) and resistant to or intolerant of tyrosine kinase
inhibitors (i.e. imatinib, dasatinib, etc.)

- CML--CP2 or subsequent chronic phase, including chronic phase achieved after induction
therapy for blast crisis

- Myeloproliferative and lymphoproliferative disorders--eligibility to be determined by
a consensus of the physicians on the Case Comprehensive Cancer Center
Leukemia/Lymphoma Multidisciplinary Committee

- Myeloproliferative and lymphoproliferative disorders--must have evidence of disease
acceleration to be a candidate for umbilical cord blood transplant; myeloproliferative
disorders eligible for transplant include chronic myelomonocytic leukemia (CMML) with
high IPSS score and myelofibrosis

- Myeloproliferative and lymphoproliferative disorders--potential lymphoproliferative
disorders eligible for transplant include chronic lymphocytic leukemia, prolymphocytic
leukemia, and large granular lymphocytic leukemia

- Good performance status: Karnofsky >= 70 % or ECOG 0-1

- Calculated creatinine clearance >= 60 mL/min, or measured creatinine clearance >= 60
mL/min (by 24-hour urine collection) if creatinine >= 1.5 or history of renal
dysfunction

- Hepatic Transaminases < 4 x upper limit normal (ULN); total bilirubin < 2.5 mg/dL,
unless the patient has a history of benign congenital hyperbilirubinemia (Gilbert's
syndrome)

- Normal cardiac function by echocardiogram or radionuclide scan, (left ventricular
ejection fraction > 45%); if the left ventricular ejection fraction is between 40-50%,
clearance by an adult cardiologist is required

- Pulmonary function tests demonstrating FEV1 > 60% of predicted for age

- Adults must have a DLCOva > 60% normal

- For patients unable to complete pulmonary function tests clearance by an adult
pulmonologist is required

- Patients will be eligible for the clinical trial under the following conditions: they
do NOT have an HLA-A/B/DR B1 identical RELATED bone marrow donor; they do NOT have a
6/6 HLA-identical matched unrelated adult donor; OR a matched related donor transplant
is not in the best interest of the patient (i.e., patient's condition precludes
waiting on the donor, too much time to prepare the donor, the donor is ineligible due
to medical reasons, or in the case of high risk disease a related donor is not
appropriated (syngeneic transplant); the decision must be agreed upon by the consensus
of physicians on the Case Comprehensive Cancer Center Leukemia/Lymphoma
Multidisciplinary Committee; OR their condition precludes waiting to search and find a
donor in the National Marrow Donor Registry

Exclusion Criteria:

- Female patients who are pregnant or breast-feeding

- HIV or HTLV-1 positivity

- Any leukemia with a morphologic relapse or persistent disease in the BM with >= 20%
blasts (cytogenetic relapse without morphologic evidence of relapse, or cytogenetic
persistent disease is acceptable)

- Active extramedullary leukemia, including CNS disease

- Prior hematopoietic stem cell transplant (autologous or allogeneic)

- Uncontrolled infection

- Patient has an identical related bone marrow donor or a 6/6 HLA-identical matched
unrelated donor

- Any patient who is unable to provide informed consent or comply with the requirements
of the protocol