Treosulfan, Fludarabine Phosphate, and Total-Body Irradiation in Treating Patients With Hematological Cancer Who Are Undergoing Umbilical Cord Blood Transplant
Condition: Acute Biphenotypic Leukemia; Acute Lymphoblastic Leukemia in Remission; Acute Myeloid Leukemia in Remission; Blasts Under 5 Percent of Bone Marrow Nucleated Cells; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Myelodysplastic Syndrome (MDS)
MeSH terms: Leukemia; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Leukemia, Biphenotypic, Acute; Myelodysplastic Syndromes
Intervention: Cyclosporine; Fludarabine Phosphate; Laboratory Biomarker Analysis; Mycophenolate Mofetil; Total-Body Irradiation; Treosulfan; Umbilical Cord Blood Transplantation
Intervention description: Given IV or PO; Given IV; Correlative studies; Given IV; TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section); Given IV; Undergo single or double unit UCBT
Intervention MeSH terms: Cyclosporine; Mycophenolic Acid; Fludarabine; Fludarabine phosphate; Treosulfan; Busulfan; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 130.0
Sex: All
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well giving treosulfan together with fludarabine phosphate
      and total-body irradiation (TBI) works in treating patients with hematological cancer who are
      undergoing umbilical cord blood transplant (UCBT). Giving chemotherapy, such as treosulfan
      and fludarabine phosphate, and TBI before a donor UCBT helps stop the growth of cancer cells
      and helps stop the patient's immune system from rejecting the donor's stem cells. When the
      stem cells from a related or unrelated donor, that do not exactly match the patient's blood,
      are infused into the patient, they may help the patient's bone marrow make stem cells, red
      blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor
      can also make an immune response against the body's normal cells. Giving cyclosporine (CsA)
      and mycophenolate mofetil (MMF) after the transplant may stop this from happening.
    

Eligibility criteria:

        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