Donor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer

• Survival at 1 year [ Designated as safety issue: No ]
• Engraftment rates [ Designated as safety issue: No ]

• Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Incidence of non-relapse mortality [ Time Frame: 6 months ] [ Designated as safety issue: No ]
• Incidence of non-relapse mortality [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• Incidence of graft failure/rejection [ Time Frame: By day 55 ] [ Designated as safety issue: No ]
• Incidence of neutrophil engraftment [ Time Frame: By day 42 ] [ Designated as safety issue: No ]
• Incidence of platelet engraftment [ Time Frame: By 6 months ] [ Designated as safety issue: No ]
• Incidence of grade II-IV and III-IV acute GVHD for each arm [ Time Frame: By day 100 ] [ Designated as safety issue: Yes ]
• Incidence of chronic GVHD for each arm [ Time Frame: At 1 year ] [ Designated as safety issue: Yes ]
• Incidence of one and two year relapse or disease progression [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Progression-free survival [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Incidence of clinically significant infections [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]

• Overall survival (i.e., beyond 1 year) [ Designated as safety issue: No ]
• Nonrelapse mortality at 6 months, 1 year, and overall [ Designated as safety issue: No ]
• Incidence of graft failure/rejection [ Designated as safety issue: Yes ]
• Neutrophil and platelet engraftment [ Designated as safety issue: Yes ]
• Acute and chronic GVHD [ Designated as safety issue: Yes ]
• Relapse [ Designated as safety issue: No ]
• Progression-free survival [ Designated as safety issue: No ]
• Clinically significant infections [ Designated as safety issue: Yes ]

This phase II trial is studying how well umbilical cord blood transplant from a donor works in treating patients with hematological cancer. Giving chemotherapy and total-body irradiation (TBI) before a donor umbilical cord blood transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from an 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 cell from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening

PRIMARY OBJECTIVES:

I. Estimate probability of one year survival.

II. Demonstrate equivalent or improved engraftment rates with a non-anti-thymocyte globulin (ATG) based conditioning regimen. Patients will be considered graft failure/rejections provided they meet any of the criteria listed below:

• Absence of 3 consecutive days with neutrophils >= 500/ul combined with host CD3 peripheral blood chimerism >= 50% at day 42
• Absence of 3 consecutive days with neutrophils >= 500/ul under any circumstances at day 55
• Death after day 28 with neutrophil count < 100/ul without any evidence of engraftment (< 5% donor CD3)
• Primary autologous count recovery with < 5% donor CD3 peripheral blood chimerism at count recovery and without relapse

SECONDARY OBJECTIVES:

I. Six month non-relapse mortality.

II. Overall incidence of graft failure/rejection. Patients will be considered graft failure/rejections provided they meet any of the criteria listed below:

• Absence of 3 consecutive days with neutrophils >= 500/ul combined with host CD3 peripheral blood chimerism >= 50% at day 42
• Absence of 3 consecutive days with neutrophils >= 500/ul under any circumstances at day 55
• Death after day 28 with neutrophil count < 100/ul without any evidence of engraftment (< 5% donor CD3)
• Primary autologous count recovery with < 5% donor CD3 peripheral blood chimerism at count recovery and without relapse.

III. Kinetics of chimeric reconstitution.

IV. Incidence of neutrophil engraftment by day 42.

V. Incidence of platelet engraftment by six months.

VI. Incidence of grade II-IV and III-IV acute graft-versus-host disease (GvHD) for each arm at day 100.

VII. Incidence of one year chronic GvHD for each arm.

VIII. Incidence of clinically significant infections at 6 months, 1 year, 2 years for each arm.

IX. Probability of one and two year survival.

X. Incidence of one and two year relapse or disease progression.

XI. Fred Hutchinson Cancer Research Center (FHCRC) patients: Kinetics of immune reconstitution, with both functional and quantitative assays.

XII. FHCRC patients: Examination of possible immunologic factors leading to emergence of a dominant unit.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM I:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -6 to -2 and cyclophosphamide IV on day -6. Patients undergo a lower dose of total-body irradiation (TBI) on day -1.

UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0.

IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to +180 and mycophenolate mofetil IV or orally (PO) every 8 hours on days -3 to +96.

ARM II:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate and cyclophosphamide as in Arm I. Patients undergo a higher dose of TBI on day -1.

UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion as in Arm I.

IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine and mycophenolate mofetil as in Arm I.

After completion of study treatment, patients are followed periodically for up to 2 years.

• Accelerated Phase Chronic Myelogenous Leukemia
• Adult Acute Lymphoblastic Leukemia in Remission
• Adult Acute Myeloid Leukemia in Remission
• Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
• Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
• Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
• Anaplastic Large Cell Lymphoma
• Angioimmunoblastic T-cell Lymphoma
• Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative
• Blastic Phase Chronic Myelogenous Leukemia
• Childhood Acute Lymphoblastic Leukemia in Remission
• Childhood Acute Myeloid Leukemia in Remission
• Childhood Acute Myelomonocytic Leukemia (M4)
• Childhood Anaplastic Large Cell Lymphoma
• Childhood Diffuse Large Cell Lymphoma
• Childhood Immunoblastic Large Cell Lymphoma
• Childhood Myelodysplastic Syndromes
• Chronic Myelomonocytic Leukemia
• Chronic Phase Chronic Myelogenous Leukemia
• Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
• Contiguous Stage II Adult Lymphoblastic Lymphoma
• Contiguous Stage II Grade 1 Follicular Lymphoma
• Contiguous Stage II Grade 2 Follicular Lymphoma
• de Novo Myelodysplastic Syndromes
• Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
• Juvenile Myelomonocytic Leukemia
• Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
• Nodal Marginal Zone B-cell Lymphoma
• Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
• Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma
• Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
• Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma
• Noncontiguous Stage II Adult Lymphoblastic Lymphoma
• Noncontiguous Stage II Grade 1 Follicular Lymphoma
• Noncontiguous Stage II Grade 2 Follicular Lymphoma
• Noncontiguous Stage II Grade 3 Follicular Lymphoma
• Noncontiguous Stage II Mantle Cell Lymphoma
• Noncontiguous Stage II Marginal Zone Lymphoma
• Noncontiguous Stage II Small Lymphocytic Lymphoma
• Previously Treated Myelodysplastic Syndromes
• Recurrent Adult Acute Lymphoblastic Leukemia
• Recurrent Adult Acute Myeloid Leukemia
• Recurrent Adult Diffuse Large Cell Lymphoma
• Recurrent Adult Diffuse Mixed Cell Lymphoma
• Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
• Recurrent Adult Grade III Lymphomatoid Granulomatosis
• Recurrent Adult Hodgkin Lymphoma
• Recurrent Adult Immunoblastic Large Cell Lymphoma
• Recurrent Adult Lymphoblastic Lymphoma
• Recurrent Adult T-cell Leukemia/Lymphoma
• Recurrent Childhood Acute Lymphoblastic Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Recurrent Childhood Anaplastic Large Cell Lymphoma
• Recurrent Childhood Grade III Lymphomatoid Granulomatosis
• Recurrent Childhood Large Cell Lymphoma
• Recurrent Childhood Lymphoblastic Lymphoma
• Recurrent Childhood Small Noncleaved Cell Lymphoma
• Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma
• Recurrent Grade 1 Follicular Lymphoma
• Recurrent Grade 2 Follicular Lymphoma
• Recurrent Grade 3 Follicular Lymphoma
• Recurrent Mantle Cell Lymphoma
• Recurrent Marginal Zone Lymphoma
• Recurrent Mycosis Fungoides/Sezary Syndrome
• Recurrent Small Lymphocytic Lymphoma
• Recurrent/Refractory Childhood Hodgkin Lymphoma
• Refractory Anemia
• Refractory Anemia With Excess Blasts
• Refractory Anemia With Excess Blasts in Transformation
• Refractory Anemia With Ringed Sideroblasts
• Refractory Chronic Lymphocytic Leukemia
• Refractory Cytopenia With Multilineage Dysplasia
• Refractory Hairy Cell Leukemia
• Refractory Multiple Myeloma
• Relapsing Chronic Myelogenous Leukemia
• Secondary Acute Myeloid Leukemia
• Secondary Myelodysplastic Syndromes
• Splenic Marginal Zone Lymphoma
• Stage I Adult Diffuse Large Cell Lymphoma
• Stage I Adult Diffuse Mixed Cell Lymphoma
• Stage I Adult Diffuse Small Cleaved Cell Lymphoma
• Stage I Adult Hodgkin Lymphoma
• Stage I Adult Immunoblastic Large Cell Lymphoma
• Stage I Adult Lymphoblastic Lymphoma
• Stage I Childhood Anaplastic Large Cell Lymphoma
• Stage I Childhood Hodgkin Lymphoma
• Stage I Childhood Large Cell Lymphoma
• Stage I Childhood Lymphoblastic Lymphoma
• Stage I Childhood Small Noncleaved Cell Lymphoma
• Stage I Cutaneous T-cell Non-Hodgkin Lymphoma
• Stage I Grade 1 Follicular Lymphoma
• Stage I Grade 2 Follicular Lymphoma
• Stage I Grade 3 Follicular Lymphoma
• Stage I Marginal Zone Lymphoma
• Stage I Multiple Myeloma
• Stage I Mycosis Fungoides/Sezary Syndrome
• Stage I Small Lymphocytic Lymphoma
• Stage II Adult Hodgkin Lymphoma
• Stage II Childhood Anaplastic Large Cell Lymphoma
• Stage II Childhood Hodgkin Lymphoma
• Stage II Childhood Large Cell Lymphoma
• Stage II Childhood Lymphoblastic Lymphoma
• Stage II Cutaneous T-cell Non-Hodgkin Lymphoma
• Stage II Multiple Myeloma
• Stage II Mycosis Fungoides/Sezary Syndrome
• Stage III Adult Diffuse Large Cell Lymphoma
• Stage III Adult Diffuse Mixed Cell Lymphoma
• Stage III Adult Diffuse Small Cleaved Cell Lymphoma
• Stage III Adult Hodgkin Lymphoma
• Stage III Adult Immunoblastic Large Cell Lymphoma
• Stage III Adult Lymphoblastic Lymphoma
• Stage III Childhood Anaplastic Large Cell Lymphoma
• Stage III Childhood Hodgkin Lymphoma
• Stage III Childhood Large Cell Lymphoma
• Stage III Childhood Lymphoblastic Lymphoma
• Stage III Chronic Lymphocytic Leukemia
• Stage III Cutaneous T-cell Non-Hodgkin Lymphoma
• Stage III Grade 1 Follicular Lymphoma
• Stage III Grade 2 Follicular Lymphoma
• Stage III Grade 3 Follicular Lymphoma
• Stage III Marginal Zone Lymphoma
• Stage III Multiple Myeloma
• Stage III Mycosis Fungoides/Sezary Syndrome
• Stage III Small Lymphocytic Lymphoma
• Stage IV Adult Diffuse Large Cell Lymphoma
• Stage IV Adult Diffuse Mixed Cell Lymphoma
• Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
• Stage IV Adult Hodgkin Lymphoma
• Stage IV Adult Immunoblastic Large Cell Lymphoma
• Stage IV Adult Lymphoblastic Lymphoma
• Stage IV Childhood Anaplastic Large Cell Lymphoma
• Stage IV Childhood Hodgkin Lymphoma
• Stage IV Childhood Large Cell Lymphoma
• Stage IV Childhood Lymphoblastic Lymphoma
• Stage IV Chronic Lymphocytic Leukemia
• Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma
• Stage IV Grade 1 Follicular Lymphoma
• Stage IV Grade 2 Follicular Lymphoma
• Stage IV Grade 3 Follicular Lymphoma
• Stage IV Mantle Cell Lymphoma
• Stage IV Marginal Zone Lymphoma
• Stage IV Mycosis Fungoides/Sezary Syndrome
• Stage IV Small Lymphocytic Lymphoma
• Waldenström Macroglobulinemia

• Drug: cyclophosphamide
  Given IV
  Other Names:

  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
• Drug: cyclosporine
  Given IV
  Other Names:

  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
• Drug: fludarabine phosphate
  Given IV
  Other Names:

  • 2-F-ara-AMP
  • Beneflur
  • Fludara
• Drug: mycophenolate mofetil
  Given IV or PO
  Other Names:

  • Cellcept
  • MMF
• Procedure: allogeneic hematopoietic stem cell transplantation
  Undergo umbilical cord blood transplant
• Procedure: umbilical cord blood transplantation
  Undergo umbilical cord blood transplant
  Other Names:

  • cord blood transplantation
  • transplantation, umbilical cord blood
  • UCB transplantation
• Radiation: total-body irradiation
  Undergo TBI
  Other Name: TBI

• Experimental: Arm I (lower dose of TBI)

  CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -6 to -2 and cyclophosphamide IV on day -6. Patients undergo a lower dose of TBI on day -1.

  UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion on day 0.

  IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine IV over 1 hour every 8-12 hours on days -3 to +180 and mycophenolate mofetil IV or PO every 8 hours on days -3 to +96.

  Interventions:

  • Drug: cyclophosphamide
  • Drug: cyclosporine
  • Drug: fludarabine phosphate
  • Drug: mycophenolate mofetil
  • Procedure: allogeneic hematopoietic stem cell transplantation
  • Procedure: umbilical cord blood transplantation
  • Radiation: total-body irradiation
• Experimental: Arm II (higher dose of TBI)

  CONDITIONING REGIMEN: Patients receive fludarabine phosphate and cyclophosphamide as in Arm I. Patients undergo a higher dose of TBI on day -1.

  UMBILICAL CORD BLOOD TRANSPLANT: Patients undergo donor umbilical cord blood infusion as in Arm I.

  IMMUNOSUPRESSIVE THERAPIES: Patients receive cyclosporine and mycophenolate mofetil as in Arm I.

  Interventions:

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

Inclusion Criteria:

• Patients > 70 may be considered if Performance Status > 80% and Comorbidity Score < 3

• 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 diffusion capacity of carbon monoxide (DLCO) > 30% predicted, and absence of oxygen (O2) requirements
• 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
• Adequate renal function defined as creatinine =< 2.0 mg/dl (adults) or 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
• Performance status score: Karnofsky (for adults) >= 60; Lansky (for children) score >= 50
• If recent mold infection, e.g., Aspergillus, must be cleared by infectious disease
• Second hematopoietic cell transplant: Must be >= 3 months after prior myeloablative transplant
• Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia: Must have < 5% morphologic marrow blasts in an evaluable marrow (> 25% of normal cellularity for age) collected less than one month prior to start of conditioning; patients persistently aplastic for greater than one month since completing last chemotherapy are also eligible with the approval of the principal investigator (PI) or designee
• 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; at time of transplant, patients must have < 5% blasts in an evaluable marrow (> 25% of normal cellularity for age) by morphology within the bone marrow
• Myelodysplastic syndrome (MDS): Any subtype; morphologic blasts must be less than 5% in an evaluable marrow (> 25% of normal cellularity for age); if blasts are 5% or more, patient requires induction chemotherapy pre-transplant to reduce blast count to =< 5%; patients who have a hypocellular marrow in the absence of excess blasts that is related to the underlying disease or as a result of treatment for MDS may also be eligible with the approval of the principal investigator (PI) or designee
• Large-cell lymphoma and aggressive T-cell lymphoma: With chemotherapy sensitive disease that has failed autologous transplant or patients who are ineligible for an autologous transplant; chemotherapy sensitive disease is defined as >= 50% reduction in the size of the tumor with the chemotherapy regimen immediately preceding transplant
• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Must be refractory to fludarabine or fail to have a complete or partial response after therapy with a regimen containing fludarabine (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing fludarabine (or another nucleoside analog)
• Hodgkin Disease: Must have received and failed frontline therapy
• Follicular lymphoma, marginal zone B-Cell lymphoma, lymphoplasmacytic lymphoma, mantle-cell lymphoma, and indolent T-cell lymphomas: Must have progressed with the most recent remission duration being < 6 months
• Follicular lymphoma, marginal zone B-Cell lymphoma, lymphoplasmacytic lymphoma, mantle-cell lymphoma, and indolent T-cell lymphomas: Patients with bulky disease should be considered for debulking chemotherapy before transplant; patients with refractory disease are eligible, unless they have bulky disease and an estimated tumor doubling time of less than one month
• Multiple Myeloma: Must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted
• Myeloproliferative syndromes
• DONOR: Unit selection is based on the cryopreserved total nucleated cell (TNC) dose and matching at HLA-A, B antigen level and DRB1 allele level typing; while HLA-C antigen/allele level typing is not considered in the matching criteria, if available, may be used to optimize unit selection
• DONOR: The patient and the cord blood unit(s) must be matched for at least 4 of 6 loci as defined above
• DONOR: Selection of two umbilical cord blood (UCB) units is allowed to provide sufficient cell dose

Exclusion Criteria:

• 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 will be excluded
• Patients with ascites related to portal hypertension, bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3mg/dL, and symptomatic biliary disease will be excluded
• Patients with an available 5-6/6 human leukocyte antigen (HLA)-A, B, DRB1 matched sibling donor
• 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 disease (ID) consult and approval
• Active central nervous system malignancy
• DONOR: Any cord blood units with < 1.5 x 10^7 total nucleated cells per kilogram recipient weight
• DONOR: Any cord blood units without the full maternal testing and negative results for hepatitis A, B, C, HIV, and human T-lymphotropic virus (HTLV-1) viruses