Treatment of Single or Double Umbilical Cord Trans + Graft-versus-host Disease (GVHD) Prophylaxis w/ Tacrolimus & Mycophenolate Mofetil

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy and total-body irradiation 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 a donor 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 make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil before and after transplant may stop this from happening. PURPOSE: To look at the ability of umbilical cord blood cells from one or two unrelated donors to serve as a source of stem cells for people needing a bone marrow transplant.

Detailed Description
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OBJECTIVES: Primary To determine the safety (as assessed by the day 100 non-relapse mortality) and feasibility of single or double umbilical cord stem cell transplantation in patients with hematological malignancies receiving graft-versus-host disease (GVHD) prophylaxis comprising tacrolimus and mycophenolate mofetil (MMF). Secondary To assess sustained donor engraftment, neutrophil recovery, platelet recovery, incidence and severity of acute graft-versus-host disease (GVHD) and chronic GVHD, relapse rate, 100-day all-cause mortality, overall survival, and immune reconstitution after single or double umbilical cord stem cell transplantation in patients with hematologic malignancies receiving graft-versus-host disease(GVHD) prophylaxis comprising tacrolimus and mycophenolate mofetil (MMF). OUTLINE: Conditioning: Patients receive myeloablative or reduced-intensity conditioning regimen according to age and prior treatment. Myeloablative conditioning (pediatric patients): Patients undergo total-body irradiation on days -7 to -4, and receive cyclophosphamide IV over 1 hour on days -3 and -2, methylprednisolone IV twice daily on days -3 to -1, and anti-thymocyte globulin IV over 4 hours on days -3 to -1. Myeloablative conditioning (adult patients 18-40 years old): Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -4, cyclophosphamide IV over 1 hour on days -5 and -4, and undergo total-body irradiation on days -3 to -1. Reduced-intensity conditioning (patients over 40 and no more than 50 years old OR deemed ineligible for above myeloablative conditioning regimen due to previous treatment): Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1 hour on day -6 and undergo total-body irradiation on day -1. Umbilical cord blood transplantation (UCBT): All patients undergo single- or double-unit umbilical cord blood transplantation (UCBT)on day 0. Graft-versus-host disease prophylaxis: Patients receive tacrolimus IV continuously or orally twice daily on days -2 to 180 followed by a tapering and mycophenolate mofetil IV or orally twice daily on days 0-100 followed by a tapering over the next 3 months. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on day 0* and continuing until blood counts recover. NOTE: *In adult patients receiving a reduced intensity transplant, G-CSF will be started when the total white cell count falls below 2.5 x 109/L. After completion of study treatment, patients are followed monthly for 1 year and then every 2-4 months thereafter.

Official Title
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The Treatment of Hematologic Malignancies With Single or Double Umbilical Cord Blood Unit Transplantation Followed by Graft-versus-Host Prophylaxis With Tacrolimus and Mycophenolate Mofetil

Conditions
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Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: anti-thymocyte globulin
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Drug: methylprednisolone
* Radiation: total-body irradiation


Participation Criteria
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Eligibility Criteria
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Patient and UCB Unit Selection: Inclusion Criteria: General (Adults and Pediatrics) Only one of the following should be present: Acute leukemia (lymphocytic or myeloid or undifferentiated or biphenotypic) in complete remission 2 or beyond Acute lymphocytic leukemia, Philadelphia chromosome positive in complete remission 1 or beyond Acute myeloid leukemia in complete remission 1 if it has evolved from a myeloproliferative disorder (MPD) or myelodysplastic syndrome (MDS). Acute leukemia in complete remission 1 if there is a failure to recover normal blood counts or the development of MDS following induction chemotherapy. Therapy related acute leukemia in complete remission 1 or beyond Chronic myeloid leukemia (CML) chronic phase-1 (imatinib failures, imatinib intolerance), or any CML beyond first chronic phase Myelodysplastic syndromes (Intermediate -1 or higher risk by IPSS) Therapy related MDS (irrespective of IPSS) Multiple myeloma must have had prior chemotherapy or autologous transplant Chronic lymphocytic leukemia must have failed two lines of conventional therapy but still chemosensitive to third line therapy. Chemosensitive Non-Hodgkin's lymphoma or Hodgkin's lymphoma in CR or PR after failing induction therapy. High risk acute leukemia/lymphoma eg Nk/T cell, HTLV associated leukemia/lymphoma, other T cell lymphoma/leukemia in first best response For patients with acute leukemia-they must be in a remission (less than 5% leukemic marrow blasts) at time of study entry. Inclusion Criteria (Adults - 18 years or older) Karnofsky score of > 70% Estimated creatinine clearance of > 60 ml/min Left ventricular ejection fraction of >50% Pulmonary function test with DLCO, FEV1 and FVC of >60% Total bilirubin and SGOT of < 3.0 x upper limits of normal Note: Age 18- 40 years for adult myeloablative conditioning Age > 40 -50 years for adult reduced intensity conditioning Inclusion Criteria (Pediatrics - 18 years and younger) Karnofsky or Lansky score of > 70% Estimated Creatinine clearance of > 60 ml/min Left ventricular ejection fraction of >50% Pulmonary function test with FEV1 and FVC of >60% (for patients >6 years of age) Total bilirubin and SGOT of < 3.0 x upper limits of normal Note: All pediatric patients will receive myeloablative conditioning Inclusion Criteria - Donor Issues No available HLA identical or 1 antigen/allele mismatched (Class I-A, B or Class II DR locus) related donor Inclusion Criteria: Umbilical Cord Blood Unit-HLA Typing At least a HLA 4/6 match (Class I-A, B by low resolution, Class II-DR by high resolution) to recipient For double UCB SCT each unit should be at least a 4/6 match (Class I-A,B by low resolution, Class II-DR by high resolution) to recipient, and should be at least a 4/6 match (Class I-A,B by low resolution, Class II-DR by high resolution) to each other Inclusion Criteria: Umbilical Cord Blood Unit-Cell dose For Single UCB SCT: the unit will have ≥ 3.5 X 107 NC/kg of recipient body weight (For pediatric patients a cell dose ≥ 3.0 X 107 NC/kg of recipient body weight is acceptable). Recipient body weight will be determined as per standard guidelines. For Double UCB SCT: (done only if no single UCB unit ≥ 3.5 X 107 NC/kg of recipient body weight is available for adults, and ≥ 3.0 X 107 NC/kg of recipient body weight is available for pediatric patients ) The larger of the two units (UCB1) will have a minimum cell dose of 2.0 X 107 NC/kg of recipient body weight. The smaller of the two units (UCB2) will have a minimum of 0.5 X 107 NC/kg of recipient body weight. The total cell dose UCB1 + UCB2 will be ≥ 2.5 X 107 NC/kg of recipient body weight. -Adult patients eligible for a double UCB SCT but without an appropriate second UCB unit will be enrolled in the study if their single UCB unit contains ≥ 2.5 x 107 NC/kg recipient body weight. Exclusion Criteria Organ dysfunction as per standard guidelines. Unable to give informed consent (for adults only) Pregnant or lactating Sexually active individuals capable of becoming pregnant or causing a pregnancy who are unable or unwilling to use appropriate contraceptives. Active use of illicit drugs as evidenced by a positive toxicology screen for a substance not prescribed by a medical professional just prior to initiating the preparative regimen Actively smoking as evidenced by a positive nicotine screen just prior to initiating the preparative regimen HIV positive Patients with other unrelated malignancies will be excluded except: diagnosis of skin cancer (squamous cell or basal cell) diagnosis of cervical dysplasia (CIN I-III) any other malignancy which is currently in remission and was treated with curative intent more than 5 years preceding study entry In patients with secondary MDS or secondary acute leukemias-the previous non-hematopoietic neoplasm should be in remission but can be within 5 years of study entry

Ages Eligible for Study
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Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pediatric Myeloablative conditioning<br>Patients undergo total-body irradiation on days -7 to -4, and receive cyclophosphamide IV over 1 hour on days -3 and -2, methylprednisolone IV twice daily on days -3 to -1, and anti-thymocyte globulin IV over 4 hours on days -3 to -1. | Biological: anti-thymocyte globulin<br>* Given IV<br>* Other names: ATG;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Cytoxin;Drug: methylprednisolone<br>* Given IV<br>* Other names: Medrol;Radiation: total-body irradiation<br>* Given daily for 1-4 days<br>|
| Experimental: Adult Myeloablative conditioning<br>Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -4, cyclophosphamide IV over 1 hour on days -5 and -4, and undergo total-body irradiation on days -3 to -1. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: Cytoxin;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Given daily for 1-4 days<br>|
| Experimental: Reduced-intensity conditioning<br>Patients receive fludarabine phosphate IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1 hour on day -6 and undergo total-body irradiation on day -1. | Drug: cyclophosphamide<br>* Given IV<br>* Other names: Cytoxin;Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Radiation: total-body irradiation<br>* Given daily for 1-4 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 100-day Non-relapse Mortality | Evaluate the safety (as determined by the day 100 non-relapse mortality) and feasibility of single or double umbilical cord blood (UCB)stem cell transplant (SCT) in adult or pediatric patients with hematologic malignancies receiving graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil (MMF). | 100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Sustained Donor Engraftment of Umbilical Cord Blood Stem Cells | Recovery of the neutrophil portion of white blood cells and showing complete donor cells. | 42 days | 
| Number of Participants With Acute Graft-versus-host Disease (GVHD) | Participants who exhibit acute GVHD. | 100 days | 
| Number of Participants Who Relapsed at 1 Year |  | 1 year | 
| Number of Subjects With All-cause Mortality | Death from any cause at 100 days | at 100 days | 
| Overall Survival | Overall survival at 1 year | 1 year | 
| Number of Participants With Chronic Graft Versus Host Disease (GVHD) | As opposed to acute GVHD, which is characterized by rash, cholestasis, and enteritis, chronic GVHD is characterized by nausea, anorexia, ocular and oral sicca, and other organ involvement | 100 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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graft versus host disease, 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), blastic phase chronic myelogenous leukemia, childhood acute lymphoblastic leukemia in remission, childhood acute myeloid leukemia in remission, childhood chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, de novo myelodysplastic syndromes, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, myelodysplastic/myeloproliferative disease, unclassifiable, nodal marginal zone B-cell lymphoma, noncontiguous stage II adult Burkitt 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 adult non-Hodgkin 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, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, splenic marginal zone lymphoma, stage I multiple myeloma, stage II multiple myeloma, refractory multiple myeloma, stage III adult Burkitt lymphoma, stage III adult Hodgkin lymphoma, 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 immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III chronic lymphocytic leukemia, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage III marginal zone lymphoma, stage III multiple myeloma, stage III small lymphocytic lymphoma, stage IV adult Burkitt lymphoma, stage IV adult Hodgkin 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 immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage IV chronic lymphocytic leukemia, 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 small lymphocytic lymphoma, Philadelphia chromosome positive adult precursor acute lymphoblastic leukemia, Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia, refractory chronic lymphocytic leukemia, childhood myelodysplastic syndromes, stage III adult T-cell leukemia/lymphoma, stage IV adult T-cell leukemia/lymphoma, adult nasal type extranodal NK/T-cell lymphoma, childhood nasal type extranodal NK/T-cell lymphoma, stage III cutaneous T-cell non-Hodgkin lymphoma, stage IV cutaneous T-cell non-Hodgkin lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent adult T-cell leukemia/lymphoma