Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation in Treating Patients With Hematological Cancer Who Are Undergoing Umbilical Cord Blood Transplant

PRIMARY OBJECTIVES:

I. Graft failure/rejection and secondary graft failure.

II. Day -200 non-relapse mortality.

SECONDARY OBJECTIVES:

I. Platelet engraftment by six months.

II. Grade II-IV and III-IV acute graft-versus-host disease (GVHD) at day 100 and one year.

III. Chronic GVHD.

IV. Clinically significant infections.

V. Overall survival.

VI. Relapse or disease progression.

VII. Immune reconstitution (Fred Hutchinson Cancer Research Center [FHCRC] only).

VIII. Emergence of a dominant unit (FHCRC only).

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (low risk for graft failure): Patients receive a conditioning regimen comprising
fludarabine phosphate intravenously (IV) over 1 hour once daily (QD) on days -6 to -2 and
treosulfan IV over 120 minutes on days - 6 to -4. Patients undergo TBI on day -1. Patients
then undergo donor UCBT on day 0. Patients receive GVHD prophylaxis comprising cyclosporine
IV over 1 hour or orally (PO) 2-3 times daily on days -3 to 100, followed by a taper in the
absence of GVHD. Patients also receive mycophenolate mofetil IV 3 times daily on days 0 to
40, followed by a taper in the absence of GVHD.

ARM II (high risk for graft failure): Patients receive a conditioning regimen, TBI, donor
UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I.

After completion of the study treatment, patients are followed up at 6 months and 1 and 2
years.

Inclusion Criteria:

- Acute myeloid leukemia/acute lymphoblastic leukemia, including biphenotypic acute
leukemia or mixed-lineage leukemia: Must have < 5% morphologic marrow blasts in an
evaluable marrow sample (> 25% of normal cellularity for age collected less than one
month prior to start of conditioning; patients in which adequate marrow/biopsy
specimens cannot be obtained to determine remission status by morphologic assessment,
but have fulfilled criteria of remission by flow cytometry, recovery of peripheral
blood counts with no circulating blasts, and/or normal cytogenetics (if applicable)
may still be eligible; reasonable attempts must be made to obtain an adequate specimen
for morphologic assessment, including possible repeat procedures; these patients must
be discussed with the principal investigator prior to enrollment; patients
persistently aplastic for greater than one month since completing last chemotherapy
are also eligible with principal investigator (PI) approval

- Myelodysplastic syndrome (MDS): Any 2001 World Health Organization (WHO)
classification subtype; refractory anemia with excess blasts (RAEB)-2 patients may
proceed directly to transplant, but may also be considered for induction chemotherapy
before transplant; patients with >= 20% morphologic marrow blasts require induction
therapy to reduce morphologic marrow blasts below 5% before transplant

- 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

- Patients =< 50 must have performance status score: Karnofsky (for adults) >= 70 or
Eastern Cooperative Oncology Group (ECOG) 0-1; Lansky (for children) score >= 50

- Patients > 50 must have Karnofsky performance score >= 70 or ECOG 0-1 and comorbidity
index < 5

- 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 absence of oxygen (O2) requirements and one of
the following:

- Diffusion lung capacity for carbon monoxide (DLCO) corrected >= 70% mm Hg

- DLCO corrected between 60% - 69% mm Hg and partial pressure of oxygen (pO2) >= 70
mm Hg

- DLCO corrected between 50% - 59% mm Hg and pO2 >= 80 mm Hg

- Pediatric patients unable to perform pulmonary function tests must have O2
saturation > 92% on room air; may not be on supplemental oxygen

- 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 estimated
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

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

- Prior hematopoietic cell transplant: must be >= 3 months after previous transplant

- DONOR: Human leukocyte antigen (HLA) matching:

- Minimum requirement: The cord blood (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 (above) are met

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

- Match grade

- 6/6

- Single unit allowed for total nucleated cell (TNC) dose >= 2.5 x
10^7/kg

- 5/6, 4/6

- Single unit allowed for 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

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

- DONOR: 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

- DONOR (FHCRC only): Up to 5% of the unmanipulated cord blood product (s), when ready
for infusion, may be withheld for research purposes as long as thresholds for infused
TNC dose are met; these products will be used to conduct studies involving the
kinetics of engraftment and immunobiology of double cord transplantation

Exclusion Criteria:

- 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 diseases
(ID) consult and approval

- Central nervous system (CNS) leukemic involvement not clearing with intrathecal
chemotherapy and/or cranial radiation prior to initiation of conditioning (day -6)

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

- DONOR: Any cord blood units that have not passed donor screening for infectious
disease markers as recommended by NMDP will not be used unless a waiver is signed by
the clinical attending allowing use of CB unit. Cord blood units are presumed to be
cytomegalovirus (CMV) negative regardless of serologic testing due to passive
transmission of maternal CMV antibodies