Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer

PRIMARY OBJECTIVES:

I. Estimate probability of one year survival.

II. Demonstrate equivalent or improved engraftment rates with a non-anti-thymocyte globulin
(ATG) based conditioning regimen. Patients will be considered graft failure/rejections
provided they meet any of the criteria listed below:

- Absence of 3 consecutive days with neutrophils >= 500/ul combined with host cluster of
differentiation (CD)3 peripheral blood chimerism >= 50% at day 42

- Absence of 3 consecutive days with neutrophils >= 500/ul under any circumstances at day
55

- Death after day 28 with neutrophil count < 100/ul without any evidence of engraftment (<
5% donor CD3)

- Primary autologous count recovery with < 5% donor CD3 peripheral blood chimerism at
count recovery and without relapse

SECONDARY OBJECTIVES:

I. Six month non-relapse mortality.

II. Overall incidence of graft failure/rejection. Patients will be considered graft
failure/rejections provided they meet any of the criteria listed below:

- Absence of 3 consecutive days with neutrophils >= 500/ul combined with host CD3
peripheral blood chimerism >= 50% at day 42

- Absence of 3 consecutive days with neutrophils >= 500/ul under any circumstances at day
55

- Death after day 28 with neutrophil count < 100/ul without any evidence of engraftment (<
5% donor CD3)

- Primary autologous count recovery with < 5% donor CD3 peripheral blood chimerism at
count recovery and without relapse

III. Kinetics of chimeric reconstitution.

IV. Incidence of neutrophil engraftment by day 42.

V. Incidence of platelet engraftment by six months.

VI. Incidence of grade II-IV and III-IV acute graft-versus-host disease (GvHD) at day 100.

VII. Incidence of one year chronic GvHD.

VIII. Incidence of clinically significant infections at 6 months, 1 year, 2 years.

IX. Probability of one and two year survival.

X. Incidence of one and two year relapse or disease progression.

XI. Fred Hutchinson Cancer Research Center (FHCRC) patients: Kinetics of immune
reconstitution, with both functional and quantitative assays.

XII. FHCRC patients: Examination of possible immunologic factors leading to emergence of a
dominant unit.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 1 hour
on days -6 to -2 and cyclophosphamide IV over 1-2 hours on day -6. Patients undergo a lower
dose of total-body irradiation (TBI) on day -1.

UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day
0.

IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on
days -3 to +180 and mycophenolate mofetil IV or orally (PO) every 8 hours on days 0 to +96.

After completion of study treatment, patients are followed periodically for up to 2 years.

Inclusion Criteria:

- Patients > 70 may be considered if performance status > 80% or Eastern Cooperative
Oncology Group (ECOG) =< 1 and comorbidity score < 3; these patients must be discussed
with the principal investigator (PI), Rachel Salit prior to enrollment

- Adequate cardiac function defined as absence of decompensated congestive heart
failure, or uncontrolled arrhythmia and:

- Left ventricular ejection fraction >= 35% or

- Fractional shortening > 22%

- Adequate pulmonary function defined as diffusion capacity of carbon monoxide (DLCO) >
30% predicted, and absence of oxygen (O2) requirements

- Adequate hepatic function; patients with clinical or laboratory evidence of liver
disease will be evaluated for the cause of liver disease, its clinical severity in
terms of liver function, histology, and the degree of portal hypertension; patients
with fulminant liver failure, cirrhosis with evidence of portal hypertension or
bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding
esophageal varices, hepatic encephalopathy, or correctable hepatic synthetic
dysfunction evidenced by prolongation of the prothrombin time, ascites related to
portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral
hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease will
be excluded

- Adequate renal function defined as creatinine =< 2.0 mg/dl (adults) or creatinine
clearance > 40 ml/min (pediatrics)

- All adults with a creatinine > 1.2 or a history of renal dysfunction must have
estimated creatinine clearance > 40 ml/min

- Performance status score: Karnofsky (for adults) >= 60 or ECOG 0-2; Lansky (for
children) score >= 50

- If recent mold infection, e.g., Aspergillus, must be cleared by infectious disease

- Second hematopoietic cell transplant: Must be >= 3 months after prior myeloablative
transplant

- Patients who have received < 2 cycles of multiagent chemotherapy and patients who have
received no multiagent chemotherapy within the 3 months previous to umbilical cord
blood transplant (UCBT) as well as patients experiencing graft failure following
previous allogeneic transplant

- Acute myeloid leukemia/acute lymphoblastic leukemia, including biphenotypic acute
leukemia or mixed-lineage leukemia: Must have < 5% morphologic marrow blasts in an
evaluable marrow (> 25% of normal cellularity for age) collected less than one month
prior to start of conditioning; patients persistently aplastic for greater than one
month since completing last chemotherapy are also eligible with the approval of the PI
or designee

- Chronic myelogenous leukemia: All types, except refractory blast crisis; chronic phase
patients must have failed or been intolerant to Gleevec or other tyrosine kinase
inhibitors; at time of transplant, patients must have < 5% blasts in an evaluable
marrow (> 25% of normal cellularity for age) by morphology within the bone marrow

- Myelodysplastic syndrome (MDS): Any subtype; morphologic blasts must be less than 5%
in an evaluable marrow (> 25% of normal cellularity for age); if blasts are 5% or
more, patient requires induction chemotherapy pre-transplant to reduce blast count to
less than 5%; patients who have a hypocellular marrow in the absence of excess blasts
that is related to the underlying disease or as a result of treatment for MDS may also
be eligible with the approval of the PI or designee

- Large-cell lymphoma and aggressive T-cell lymphoma: With chemotherapy sensitive
disease that has failed autologous transplant or patients who are ineligible for an
autologous transplant; chemotherapy sensitive disease is defined as >= 50% reduction
in the size of the tumor with the chemotherapy regimen immediately preceding
transplant

- Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Must be refractory
to fludarabine (fludarabine phosphate) or fail to have a complete or partial response
after therapy with a regimen containing fludarabine (or another nucleoside analog,
e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months
after completing therapy with a regimen containing fludarabine (or another nucleoside
analog)

- Hodgkin disease: Must have received and failed frontline therapy

- Follicular lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma,
mantle-cell lymphoma, and indolent T-cell lymphomas: Must have progressed with the
most recent remission duration being < 6 months; patients with bulky disease should be
considered for debulking chemotherapy before transplant; patients with refractory
disease are eligible, unless they have bulky disease and an estimated tumor doubling
time of less than one month

- Multiple myeloma: Must have received prior chemotherapy; consolidation of chemotherapy
by autografting prior to nonmyeloablative hematopoietic cell transplant (HCT) is
permitted

- Myeloproliferative syndromes

- DONOR: Cord blood (CB) donor selection will be based on institutional guidelines and
in general should be selected to optimize both human leukocyte antigen (HLA) match and
cell dose; additionally, CB grafts shall consist of one or two CB donors based on, but
not exclusively determined by, cell dose (total nucleated cell [TNC]/kg and CD34/kg),
HLA matching and disease status and indication for transplant; attending preference
will be allowed for single versus double unit as well as the degree of mismatching
based on patient specific factors, as long as the following minimum criteria are met:

- HLA matching

- Minimum requirement: The CB graft(s) must be matched at a minimum at 4/6
HLA-A, B, DRB1 loci with the recipient. Therefore 0-2 mismatches at the A or
B or DRB1 loci based on intermediate resolution A, B antigen and DRB1 allele
typing for determination of HLA-match is allowed

- HLA-matching determined by high-resolution typing is allowed per
institutional guidelines as long as the minimum criteria are met

- Selection of two CB units is mandatory when a single cord blood unit does not
meet the following criteria:

- Match grade 6/6; TNC Dose >= 2.5 x 10^7/kg

- Match grade 5/6 or 4/6; TNC dose >= 4.0 (+/- 0.5) x 10^7/kg

- If two CB units are used, the total cell dose of the combined units must be at
least 3.0 x 10^7 TNC per kilogram recipient weight based on pre-cryopreservation
numbers, with each CB unit containing a MINIMUM of 1.5 x 10^7 TNC/kg

- The minimum recommended CD34/kg cell dose should be 2 x 10^5 CD34/kg, total dose
from a single or combined double

- The unmanipulated CB unit(s) will be Food and Drug Administration (FDA) licensed
or will be obtained under a separate investigational new drug (IND), such as the
National Marrow Donor Program (NMDP) Protocol 10-CBA conducted under BB IND-7555
or another IND sponsored by (1) a participating institution or (2) an
investigator at FHCRC or one of the participating institutions

- FHCRC only: Up to 5% of cord blood product, when ready for infusion, may be
withheld for research purposes as long as thresholds for infused TNC dose are
met; threshold for double unit transplantation is >= 3.0 x 10^7/kg; these
products will be used to conduct studies involving the immunobiology of double
cord transplantation and kinetics of engraftment

Exclusion Criteria:

- Patients 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

- Uncontrolled viral or bacterial infection at the time of study enrollment

- Active or recent (prior 6 month) invasive fungal infection without infectious disease
(ID) consult and approval

- Active central nervous system malignancy

- Patients who have received >= 2 cycles of multiagent chemotherapy within the 3 months
previous to UCBT; patients who have had previous autologous transplant within 12
months of UCBT are excluded regardless of history of recent treatment

- DONOR: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram
recipient weight

- DONOR: Any cord blood units without the full maternal testing and negative results for
hepatitis A, B, C, HIV, and human T-lymphotropic virus (HTLV-1) viruses; any
additional available virology results on the unit itself will be reviewed but are not
mandated, complete or always available; cord blood units are presumed to be
cytomegalovirus (CMV) negative regardless of serologic testing due to passive
transmission of maternal CMV antibodies