Fludarabine, Cyclophosphamide, and Total-Body Irradiation Followed By an Umbilical Cord Blood Transplant, Sirolimus, and Mycophenolate Mofetil in Treating Patients With Hematologic Cancer

Inclusion Criteria:

Age, Graft Cell Dose and Graft HLA Criteria (all patients: Arms 1, 2, 3)

• Subjects must be <70 years old. Subjects ages ≥ 70 and ≤ 75 may be eligible if they have a Co-Morbidity Scoring (HCT-CI) score ≤ 2.
• Umbilical cord blood (UCB) units will be selected according to current University of Minnesota 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 HLA-A, B, DRB1 antigens with the recipient. This may include 0-2 antigen mismatches at the A or B or DRB1 loci. If 2 UCB units are required to reach the target cell dose, each unit must be a 4-6 HLA-A, B, DRB1 antigen match to each other, as well as a 4-6 antigen match to the recipient.
• Patients co-enrolled in MT-2006-01 Phase I Study of Infusion of Umbilical Cord Blood Derived CD25+CD4+ T-Regulatory (Treg) Cells after Non-Myeloablative Cord\Blood Transplantation will receive grafts composed of 2 UCB units.

Disease Criteria: All diseases listed below are advanced hematologic malignancies not curable by conventional chemotherapy. Responses to conventional treatment range from zero to 30% but are typically short lived.

• Acute Leukemias: Must be in remission by morphology (<5% blasts). Note cytogenetic relapse or persistent disease without morphologic relapse is acceptable. Also a small percentage of blasts that is equivocal between marrow regeneration vs. early relapse are acceptable provided there are no associated cytogenetic markers consistent with relapse.

  • Acute myeloid leukemia: high risk complete remission 1 (CR1) (as evidenced by preceding myelodysplastic syndrome (MDS), high risk cytogenetics such as those associated with MDS or complex karyotype, > 2 cycles to obtain CR or erythroblastic and megakaryocytic); second or greater CR.
  • Acute lymphoblastic leukemia/lymphoma: high risk CR1 as evidenced by high risk cytogenetics (e.g. t(9;22), t(1;19),t(4;11), other myeloid/lymphoid or mixed lineage leukemia [MLL] rearrangements, hypodiploidy or Ikaros family zinc finger 1 [IKZF1]), > 1 cycle to obtain CR or evidence of minimal residual disease (MRD). Patients in second or greater CR are also eligible.
• Burkitt's lymphoma in CR2 or subsequent CR
• Natural Killer cell malignancies
• Chronic myelogenous leukemia: all types except refractory blast crisis. Chronic phase patients must have failed or been intolerant to Gleevec

• Myelodysplastic syndrome: any subtype including refractory anemia (RA) if severe pancytopenia or complex cytogenetics. Blasts must be less than 5%. If 5% or more requires induction therapy pre-transplant to reduce blast count to

  ≤5%.

• Large-cell lymphoma, Hodgkin lymphoma and multiple myeloma with chemotherapy sensitive disease that has failed or patients who are ineligible for an autologous transplant.
• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma, which have progressed within 12 months of achieving a partial or complete remission. Patients who had remissions lasting > 12 months, are eligible after at least two prior therapies. Patients with bulky disease should be considered for debulking chemotherapy before transplant. Patients with refractory disease are eligible, unless has bulky disease and an estimated tumor doubling time of less than one month.
• Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy if chemotherapy sensitive.
• Refractory leukemia or MDS. These patients may be taken to transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody. These high risk patients will be analyzed separately (Arm 3).
• Bone marrow failure syndromes, except for Fanconi Anemia
• Myeloproliferative syndromes Patients who have undergone an autologous transplant >12 months prior to allogeneic transplantation and who have not received multi-agent or immunosuppressive chemotherapy within the preceding 3 months must receive ATG as part of the preparative regimen (Arm 2).

Organ Function and Performance Status Criteria (all patients)

• Adequate organ function is defined as:

  • Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 35%. For children that are not able to cooperate with multigated acquisition scan (MUGA) and echocardiography, such should be clearly stated in the physician's note
  • Pulmonary: Carbon Monoxide Diffusing Capacity (DLCO) > 30% predicted, and absence of oxygen (O2) requirements. For children that are not able to cooperate with pulmonary function tests (PFTs), a pulse oximetry with exercise should be attempted. If nether test can be obtained it should be clearly stated in the physician's note.
  • Liver: Transaminases < 5 x upper limit of normal and bilirubin < 3 x upper limit of normal
  • Renal: Creatinine < 2.0 mg/dl (adults) and creatinine clearance > 40 ml/min (pediatrics). Adults with a creatinine > 1.2 or a history of renal dysfunction must have estimated creatinine clearance > 40 ml/min.
  • Adequate performance status is defined as Karnofsky score > or = 60% or Lansky score > or = 50 (pediatrics)

Other Inclusion Criteria (all patients)

• If recent mold infection (e.g. Aspergillus) - must have minimum of 30 days of appropriate treatment before bone marrow transplant (BMT) and infection controlled and be cleared by Infectious Disease.
• Second BMT: Must be > 3 months after prior myeloablative transplant.
• Patients must be ineligible for autologous transplantation due to prior autologous transplant, an inadequate autologous stem cell harvest, inability to withstand a myeloablative preparative regimen, or clinically aggressive/high risk disease.
• Patients are eligible for transplantation if there is no evidence of progressive disease by imaging modalities or biopsy. Persistent positron emission tomography scan (PET) activity, though possibly related to lymphoma, is not an exclusion criterion in the absence of computated tomography scan (CT) changes indicating progression.
• Patients with stable disease are eligible for transplantation if the largest residual nodal mass is < 5 cm (approximately). For patients who have responded to preceding therapy, the largest residual mass must represent a 50% reduction and be < 7.5 cm (approximately).

Exclusion Criteria:

• < 70 years 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
• Current active serious infection
• Unless in post-chemotherapy and radioimmunoconjugated antibody induced aplasia, when he/she would be eligible for Arm 3, patients with acute leukemia in morphologic relapse/ persistent disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have unique morphologic markers (e.g. Auer rods) or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible.
• Chronic myelogenous leukemia (CML) in refractory blast crisis
• Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is progressive on salvage therapy. Stable disease is acceptable to move forward provided it is non-bulky.
• Active central nervous system malignancy