OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I: Patients receive myeloablative conditioning comprising fludarabine intravenously (IV)
over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo
high-dose TBI twice daily (BID) on days -4 to -1. Patients then undergo single- or
double-unit UCBT on day 0.
ARM II: Patients receive myeloablative conditioning comprising fludarabine IV over 30-60
minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 2-4 hours on days
-5 and -4, and middle-intensity TBI once daily (QD) on days -2 and -1. Patients then undergo
single- or double-unit UCBT on day 0.
Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours,
then cyclosporine orally (PO) (if tolerated), on days -3 to 100 with taper on day 101.
Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if
tolerated) three times daily (TID) on days 8-30. Mycophenolate mofetil is tapered to BID on
day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks
beginning on day 45 (or 15 days after engraftment if engraftment occurred > day 30) after
engraftment if there continues to be no evidence of acute GVHD.
After completion of study treatment, patients are followed up at 6 months, 1 year, and 2
years.
Inclusion Criteria:
- GRAFT CRITERIA:
- UCB units will be selected according to current umbilical cord blood graft
selection algorithm; one or 2 UCB units may be used to achieve the required cell
dose
- The UCB graft is matched at 4-6 human leukocyte antigen (HLA)-A, B, DRB1 antigens
with the recipient; this may include 0-2 antigen mismatches at the A or B or DRB1
loci; unit selection based on cryopreserved nucleated cell dose and HLA-A,B, DRB1
using intermediate resolution A, B antigen and DRB1 allele typing
- If 2 UCB units are required to reach the target cell dose, each unit must be a
4-6 antigen match to the recipient
- Age and Disease Criteria:
- High-dose TBI regimen: 6 months to =< 45 years
- Middle-intensity TBI regimen: 6 months to =< 65 years
- Conditioning regimen selection should be based on the underlying disease,
presence of minimum residual disease (MRD), age, co-morbidities, and attending
physician
- Acute myeloid leukemia, including biphenotypic acute leukemia or mixed-lineage
leukemia:
- All patients must be in complete remission (CR) as defined by hematologic
recovery and < 5% blasts by morphology/flow cytometry in a representative bone
marrow sample with cellularity >= 15% for age; patients who do not have high-risk
features (for example preceding myelodysplastic syndrome [MDS], high-risk
cytogenetics, >= 2 cycles to obtain CR, erythroblastic or megakaryocytic leukemia
or >= CR2) must be discussed with the principal investigator (PI) prior to
enrollment and at the Patient Care Conference or equivalent group such as the
pediatric leukemia board as an alternative
- Patients in whom 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 PI prior to enrollment; patients persistently aplastic for
greater than one month since completing last chemotherapy are also eligible with
PI approval
- Very high risk pediatric/young adult patients with acute myeloid leukemia (AML):
Patients =< 25 years, however, are eligible with (M2 marrow) with =< 25% blasts in
marrow after having failed one or more cycles of chemotherapy; this group of patients
will be analyzed separately
- Acute lymphoblastic leukemia, including biphenotypic acute leukemia or mixed-lineage
leukemia:
- All patients must be in CR as defined by < 5% blasts by morphology; flow
cytometry in a representative bone marrow sample with cellularity >= 15% for age;
patients who do not have high-risk disease (high risk CR1, greater than one cycle
to obtain CR or >= CR2) must be discussed with the PI prior to enrollment and at
the Patient Care Conference or equivalent group such as the pediatric leukemia
board as an alternative
- Patients in whom 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 Ann Dahlberg prior to enrollment;
patients persistently aplastic for greater than one month since completing last
chemotherapy are also eligible with PI approval
- Chronic myelogenous leukemia excluding refractory blast crisis; to be eligible in
first chronic phase (CP1) patient must have failed or be intolerant to imatinib
mesylate
- Advanced myelofibrosis
- Myelodysplasia (MDS) International Prognostic Scoring System (IPSS) intermediate
(Int)-2 or high risk (i.e., refractory anemia with excess blasts [RAEB], RAEB in
transformation [RAEBt]) or refractory anemia with severe pancytopenia or high risk
cytogenetics; blasts must be < 10% by a representative bone marrow aspirate morphology
- Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade non-Hodgkin lymphoma
(NHL) after initial therapy if stage III/IV in first partial response (PR1) or after
progression if stage I/II < 1 year; stage III/IV patients are eligible after
progression in CR/PR
- Chronic lymphocytic leukemia /small lymphocytic lymphoma (CLL/SLL), marginal zone
B-cell lymphoma, lymphoplasmacytic lymphoma or follicular lymphoma that have
progressed after at least two different prior therapies; patients with bulky disease
(nodal mass greater than 5 cm) should be considered for debulking chemotherapy before
transplant; these patients must be presented at primary care center (PCC) prior to
enrollment, given potential competing eligibility on autotransplant protocols
- Mantle-cell lymphoma, prolymphocytic leukemia: Eligible after initial therapy in >=
CR1 or >= PR1
- Large cell NHL > CR2/> second partial response (PR2):
- Patients in CR2/PR2 with initial short remission (< 6 months) are eligible
- These patients must be presented at PCC prior to enrollment, given potential
competing eligibility on autotransplant protocols
- Multiple myeloma beyond PR2: Patients with chromosome 13 abnormalities, first response
lasting less than 6 months, or beta-2 microglobulin > 3 mg/L, may be considered for
this protocol after initial therapy
- Performance status score: Karnofsky (for adults) >= 70% or Eastern Cooperative
Oncology Group (ECOG) 0-1 or Lansky (for children) >= 50%
- Creatinine < 2.0 mg/dL (for adults) or creatinine clearance > 60 ml/min (for children)
- 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
- Diffusion capacity for carbon monoxide corrected (DLCOcorr) > 50% normal or a
pediatric patient who is unable to perform pulmonary function tests (PFTs) but has
adequate pulmonary function
- Left ventricular ejection fraction > 45% or shortening fraction > 26%
Exclusion Criteria:
- Uncontrolled viral or bacterial infection at the time of study enrollment
- Active or recent (prior 6 month) invasive fungal infection without interdisciplinary
(ID) consult and approval
- History of human immunodeficiency virus (HIV) infection
- Pregnant or breastfeeding
- Chemotherapy refractory large cell and high grade NHL (i.e., progressive disease after
> 2 salvage regimens)
- Patients with history of prior myeloablative transplant containing full dose TBI
(greater than 8 gray [Gy]) will not be eligible for Regimen A; however, they may still
enroll on Regimen B if they otherwise meet inclusion and exclusion criteria
- Any prior myeloablative transplant within the last 6 months
- Patients >= 45 years: comorbidity score of 5 or higher
- Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as
part of their salvage therapy are not eligible for Regimen A
