• Probability of survival at 2 years [ Designated as safety issue: No ]
• Survival at 1 and 2 years [ Designated as safety issue: No ]
• Non-relapse mortality at 6 months after study completion [ Designated as safety issue: No ]
• Chimerism at days 7, 14, 21, 60, 100, 180, and 365 [ Designated as safety issue: No ]
• Incidence of neutrophil engraftment at day 42 [ Designated as safety issue: No ]
• Incidence of platelet engraftment at 6 months [ Designated as safety issue: No ]
• Incidence of acute graft-versus-host disease (GVHD) at day 100 [ Designated as safety issue: No ]
• Incidence of extensive GVHD at 1 year [ Designated as safety issue: No ]
• Probability of progression-free survival at 1 and 2 years [ Designated as safety issue: No ]
• Incidence of relapse at 1 and 2 years [ Designated as safety issue: No ]

• Non-relapse mortality at 6 months after study completion
• Chimerism at days 21, 60, 100, 180, and 365

RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. An umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by an umbilical cord blood transplant, cyclosporine, and mycophenolate mofetil works in treating patients with hematologic cancer.

OBJECTIVES:

Primary

• Determine the one- and two-year survival of patients with hematologic malignancies treated with a nonmyeloablative conditioning regimen comprising fludarabine, cyclophosphamide, and total-body irradiation followed by umbilical cord blood transplantation and post-transplant immunosuppression comprising cyclosporine and mycophenolate mofetil.

Secondary

• Determine the six-month nonrelapse mortality of patients treated with this regimen.
• Determine the presence of chimerism in patients treated with this regimen at days 7, 14, 21, 60, 100, 180, and 365.
• Determine the incidence of neutrophil engraftment by day 42 in patients treated with this regimen.
• Determine the incidence of platelet engraftment by six months in patients treated with this regimen.
• Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 in patients treated with this regimen.
• Determine the incidence of chronic GVHD at one year in patients treated with this regimen.
• Determine the probability of overall survival and progression-free survival within one or two years in patients treated with this regimen.
• Determine the incidence of relapse or disease progression within one or two years in patients treated with this regimen.

OUTLINE: This is a nonrandomized study. Patients are stratified according to disease (acute myeloid leukemia, myelodysplastic syndromes, chronic myelogenous leukemia [CML] in first chronic phase and second chronic phase [CP2] after myeloid blast crisis vs acute lymphoblastic leukemia, CML CP2 post lymphoid blast crisis, lymphoblastic lymphoma, and Burkitt's lymphoma vs large cell B- and T-cell lymphomas and mantle cell lymphoma vs chronic lymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, lymphoplasmacytic lymphoma, and prolymphocytic leukemia vs Hodgkin's lymphoma and multiple myeloma).

• Nonmyeloablative conditioning: Patients receive fludarabine IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on day -6. Patients who did not undergo prior autologous transplant or who received ≤ 1 course of prior multiagent chemotherapy or no severely immunosuppressive therapy in the past 3 months also receive anti-thymocyte globulin IV over 4-6 hours twice daily on days -6 to -4. All patients also undergo total-body irradiation on day -1.
• Umbilical cord blood transplant: Patients undergo umbilical cord blood transplantation on day 0.
• Post-transplant immunosuppression: Patients receive cyclosporine IV over 1 hour 2-3 times daily beginning on day -3 and continuing until approximately day 100, followed by a taper until day 180. Patients also receive mycophenolate mofetil IV on days -3 to 5 and then orally on days 6-30.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

• Chronic Myeloproliferative Disorders
• Leukemia
• Lymphoma
• Multiple Myeloma and Plasma Cell Neoplasm
• Myelodysplastic Syndromes
• Myelodysplastic/Myeloproliferative Diseases

• Biological: anti-thymocyte globulin
• Drug: cyclophosphamide
• Drug: cyclosporine
• Drug: fludarabine phosphate
• Drug: mycophenolate mofetil
• Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
• Procedure: umbilical cord blood transplantation
• Radiation: total-body irradiation

• Brunstein CG, Cantero S, Cao Q, Majhail N, McClune B, Burns LJ, Tomblyn M, Miller JS, Blazar BR, McGlave PB, Weisdorf DJ, Wagner JE. Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2009 Feb;15(2):214-22.
• Bachanova V, Verneris MR, DeFor T, Brunstein CG, Weisdorf DJ. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation. Blood. 2009 Mar 26;113(13):2902-5. Epub 2009 Jan 28.
• MacMillan ML, Weisdorf DJ, Brunstein CG, Cao Q, DeFor TE, Verneris MR, Blazar BR, Wagner JE. Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood. 2009 Mar 12;113(11):2410-5. Epub 2008 Nov 7.

DISEASE CHARACTERISTICS:

• Diagnosis of one of the following advanced hematologic malignancies:

  • Acute leukemia in remission by morphology (< 5% blasts) OR cytogenetic relapse or persistent disease without morphologic relapse*

    • Acute myeloid leukemia, meeting 1 of the following criteria:

      • High-risk disease as evidenced by 1 of the following criteria:

        • In first complete remission (CR) as evidenced by preceding myelodysplastic syndromes (MDS)
        • High-risk cytogenetics such as ones associated with MDS or complex karyotype
        • Required at least 2 courses to achieve CR
        • Erythroblastic and megakaryocytic
      • In second or greater CR

    • Acute lymphoblastic leukemia/lymphoma, meeting 1 of the following criteria:

      • High-risk disease in first CR, as evidenced by 1 of the following:

        • High-risk cytogenetics (e.g., t[9;22], t[1;19], t[4;11] or other mixed-lineage leukemia rearrangements)
        • More than 1 course to achieve CR
      • In second or greater CR NOTE: *Small percentage of blasts that is equivocal between marrow regeneration vs early relapse allowed provided there are no cytogenetic markers consistent with relapse

  • Chronic myelogenous leukemia

    • Patients with chronic phase disease must have failed or been intolerant to imatinib mesylate
    • No refractory blast crisis

  • Myelodysplastic syndromes (MDS)

    • Blasts must be < 5% (may achieve with induction therapy prior to transplant)
    • Any subtype including refractory anemia if severe pancytopenia or complex cytogenetics present

  • Large cell lymphoma*, Hodgkin's lymphoma*, or multiple myeloma, meeting 1 of the following criteria:

    • Chemotherapy-sensitive disease that has failed therapy
    • Patient ineligible for autologous transplantation

  • Lymphoplasmacytic lymphoma, mantle cell lymphoma*, or prolymphocytic leukemia

    • Must be chemotherapy sensitive after initial therapy NOTE: *No disease that has progressed on salvage therapy unless disease is stable and nonbulky.

  • Chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone B-cell lymphoma, or follicular lymphoma, meeting 1 of the following criteria:

    • Disease progression after ≥ 2 prior therapies
    • Refractory disease allowed provided disease is nonbulky and an estimated tumor doubling time is ≥ 1 month
    • Patients with bulky disease (nodal areas > 5 cm) should undergo debulking chemotherapy before transplantation
  • Bone marrow failure syndromes (no Fanconi's anemia)

  • Burkitt Lymphoma

    • In CR2 or subsequent CR
  • Natural killer cell malignancy
  • Myeloproliferative syndromes

• Stable disease allowed provided the largest residual nodal mass is approximately < 5 cm

  • Largest residual mass must represent a 50% reduction and be approximately < 7.5 cm for patients who have responded to preceding therapy
• Disease not curable by conventional chemotherapy
• Patients with refractory leukemia or MDS may undergo transplant in aplasia after induction or re-induction chemotherapy or radiolabeled antibody

• Must be ineligible for autologous transplantation due to one of the following criteria:

  • Prior autologous transplantation
  • Inadequate autologous stem cell harvest
  • Inability to withstand a myeloablative preparative regimen
  • Clinically aggressive/high-risk disease

• No evidence of progressive disease by imaging modalities or biopsy

  • Persistent PET activity is not an exclusion criteria in the absence of CT changes indicating progression
• No available 5-6/6 HLA-A, -B, -DRB1 matched sibling donor
• No active CNS malignancy

• Umbilical cord blood graft must match at 4-6 HLA-A, B, DRB1 antigens

  • Antigen mismatches of 0-2 at the A, B, or DRB1 loci allowed
  • Each unit must be a 4-6 HLA-A, B, DRB1 antigen match to each other AND a 4-6 antigen match to the recipient

PATIENT CHARACTERISTICS:

• No decompensated congestive heart failure
• No uncontrolled arrhythmia
• LVEF ≥ 35%
• DLCO > 30% of predicted
• AST and ALT < 5 times upper limit of normal (ULN)
• Bilirubin < 3 times ULN

• Creatinine ≤ 2.0 mg/dL (adults) OR creatinine clearance > 40 mL/min (pediatrics)

  • Adults with creatinine > 1.2 mg/dL or a history of renal dysfunction must have creatinine clearance > 40 mL/min
• Karnofsky performance status (PS) 60-100% OR
• Lansky PS 50-100% (pediatrics)
• Prior mold infection (e.g., Aspergillus) must be cleared by Infectious Disease after receiving 1 month of treatment and infection controlled
• Not pregnant or nursing
• No evidence of HIV infection or known HIV-positive serology
• No current active serious infection
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 3 months since prior myeloablative transplant if this is the patient's second bone marrow transplant
• At least 3 months since multiagent chemotherapy (patients allowed provided they receive anti-thymocyte globulin during the preparative regimen)
• No oxygen requirements