Umbilical Cord Blood Transplantation From Unrelated Donors

Study Overview
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Brief Summary
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This study is a single-center, treatment protocol with 4 possible preparative regimens, designed to validate the process of umbilical cord blood stem cell transplantation at our institution.

Detailed Description
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This study is a single-center treatment protocol with four possible preparative regimens, designed to validate the process of umbilical cord blood stem cell transplantation at our institution. Enrolled patients will receive chemotherapy +/-total body radiation as a pre-transplant conditioning regimen. Patients will then receive cord blood stem cells followed by GvHD prophylaxis that will include Tacrolimus and Mycophenolate Mofetil, or Cyclosporin A and Methylprednisolone. Multiple data points will be collected prior to, during, and following transplantation to ensure safety of the process and to evaluate the stated objectives.

Official Title
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Umbilical Cord Blood Transplantation From Unrelated Donors

Conditions
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Acute Leukemia, Immune Deficiency Disorder, Congenital Hematological Disorder, Metabolism Disorder, Aplastic Anemia, Myelodysplastic Syndromes, Chronic Leukemia, Lymphoma, Multiple Myeloma, Solid Tumor

Intervention / Treatment
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* Radiation: Total Body Irradiation 1200 cGy
* Radiation: Total Body Irradiation 200 cGy
* Drug: Cyclophosphamide
* Drug: Mesna
* Procedure: Cord Blood Infusion
* Drug: Busulfan
* Drug: Fludarabine
* Drug: Melphalan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Appropriate diagnosis: Patients must have a disease or syndrome amenable to therapy with hematopoietic stem cell transplantation. Diagnoses include, but are not limited to: Congenital and Other Non-malignant Disorders: Immunodeficiency disorders (e.g. Severe Combined Immunodeficiency, Wiskott-Aldrich Syndrome) Congenital hematopoietic stem cell defects (e.g. Chediak-Higashi Syndrome, Congenital Osteopetrosis, Osteogenesis Imperfecta) Metabolic disorders (e.g. Hurler's Syndrome) Severe aplastic anemia High-Risk Leukemia: Acute Myelogenous Leukemia Refractory to standard induction therapy (more than 1 cycle required to achieve remission) Recurrent (in CR ≥ 2) Treatment-related AML or MDS Evolved from myelodysplastic syndrome Presence of FLT3 abnormalities FAB M6 or M7 Adverse cytogenetics Myelodysplastic Syndrome Acute Lymphoblastic Leukemia including T lymphoblastic leukemia: Refractory to standard induction therapy (time to CR >4 weeks) Recurrent (in CR ≥ 2) WBC count >30,000/mcL at diagnosis Age >30 at diagnosis Adverse cytogenetics, such as t(9:22), t(1:19), t(4:11), and other MLL rearrangements. Chronic Myelogenous Leukemia in accelerated phase or blast crisis Biphenotypic or undifferentiated leukemia Burkitt's leukemia or lymphoma Lymphoma: Large cell, Mantle cell, Hodgkin lymphoma refractory or recurrent, chemo-sensitive, and ineligible for an autologous stem cell transplant or previously treated with autologous SCT Marginal zone or follicular lymphoma that is progressive after at least two prior therapies Multiple Myeloma, recurrent following high-dose therapy and autologous SCT or ineligible for an autologous HSCT Solid tumors, with efficacy of allogeneic HSCT demonstrated for the specific disease and disease status Adequate organ function: Cardiac - LVEF >45%, or shortening fraction >25%, Absence of congestive heart failure or conduction disturbances with high risk for sudden death Pulmonary - DLCO (corrected for hemoglobin), FEV1 and FVC ≥ 50% predicted; Renal - serum Cr < 1.5 times the upper limit of normal for age or GFR ≥ 50 ml/min/1.73m2 Hepatic - total bilirubin level < 2 times the upper limit of normal (except for patients with Gilbert's syndrome or hemolysis); if the primary disease process is causal, this criterion will be reconsidered. ALT, AST, and Alkaline phosphatase ≤ 5 times upper limit of normal. Performance Status Karnofsky or Lansky score ≥ 70%. Informed Consent must be obtained prior to initiating conditioning therapy. Receipt of viable cord blood product(s), single or dual, must be confirmed with the stem cell processing laboratory prior to initiating conditioning therapy. Exclusion Criteria: Availability of 10/10 or 9/10 HLA-matched related or unrelated donor within a reasonable timeframe dictated by the clinical urgency of the transplant Autologous HSCT < 6 months prior to proposed UCB transplant Pregnant or breast feeding Current uncontrolled infection Evidence of HIV infection or positive HIV serology

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 75 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 |
| --- | --- |
| Other: Full Intensity, TBI-based Conditioning<br>Full Intensity TBI-based Conditioning Total Body Irradiation 1200 cGy in fractions of 150 cGy days -8 or -7 to -4 Cyclophosphamide 60 mg/kg/day x 2 doses days -3 and -2 Mesna 60 mg/kg/day with 20% loading dose with first Cyclophosphamide followed by continuous infusion over 24 hours x 2 doses [to be completed 24 hours after final Cyclophosphamide dose] followed by Cord Blood Infusion Other names: TBI/Cy | Radiation: Total Body Irradiation 1200 cGy<br>* Total Body Irradiation 1200 cGy in 8 fractions<br>* Other names: TBI 1200 cGy;Drug: Cyclophosphamide<br>* 50 mg/kg or 60 mg/kg<br>* Other names: Cy;Drug: Mesna<br>* 50 mg/kg or 60 mg/kg plus 10% loading dose<br>* Other names: Pre-Mesna;Procedure: Cord Blood Infusion<br>* Intravenous infusion of cord blood stem cells<br>|
| Other: Full Intensity, Chemo-based Conditioning<br>Full Intensity, Chemotherapy Conditioning Busulfan days -7 to -4 Recipients <5 years - 1 mg/kg/dose x 16 doses every 6 hours Recipients >/= 5 years - 0.8 mg/kg/dose x 16 doses every 6 hours Cyclophosphamide 60 mg/kg/day x 2 doses days -3 and -2 Mesna 60 mg/kg/day with 20% loading dose with first Cyclophosphamide followed by continuous infusion over 24 hours x 2 doses [to be completed 24 hours after final Cyclophosphamide dose] followed by Cord Blood Infusion Other names: Bu/Cy | Drug: Cyclophosphamide<br>* 50 mg/kg or 60 mg/kg<br>* Other names: Cy;Drug: Mesna<br>* 50 mg/kg or 60 mg/kg plus 10% loading dose<br>* Other names: Pre-Mesna;Procedure: Cord Blood Infusion<br>* Intravenous infusion of cord blood stem cells<br>Drug: Busulfan<br>* 0.8 mg/kg x 16 doses<br>* Other names: Bu;|
| Other: Reduced Intensity Chemotherapy<br>Reduced Intensity Chemotherapy Fludarabine 30 mg/m2/day x 5 doses days -6 to -2 Melphalan 140 mg/m2/day x 1 dose day -2 Cord Blood Infusion Other names: Flu/Mel | Procedure: Cord Blood Infusion<br>* Intravenous infusion of cord blood stem cells<br>Drug: Fludarabine<br>* 30 mg/m2/day x 5 or 40 mg/m2/day x 5<br>* Other names: Flu;Drug: Melphalan<br>* 140 mg/m2<br>* Other names: Mel;|
| Other: Non-Myeloablative Conditioning<br>Fludarabine 40 mg/m2/day x 5 doses days -6 to -2 Cyclophosphamide 50 mg/kg/day x 1 dose day -6 Mesna 50 mg/kg/day with 20% loading dose with Cyclophosphamide dose followed by continuous infusion over 24 hours x 1 dose [to be completed 24 hours after Cyclophosphamide dose] Total Body Irradiation 200 cGy in a single fraction day -1 Cord Blood Infusion Other names: Flu/Cy/TBI | Radiation: Total Body Irradiation 200 cGy<br>* Total Body Irradiation 200 cGy in one fraction<br>* Other names: TBI 200 cGy;Drug: Cyclophosphamide<br>* 50 mg/kg or 60 mg/kg<br>* Other names: Cy;Drug: Mesna<br>* 50 mg/kg or 60 mg/kg plus 10% loading dose<br>* Other names: Pre-Mesna;Drug: Fludarabine<br>* 30 mg/m2/day x 5 or 40 mg/m2/day x 5<br>* Other names: Flu;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Engraftment of ANC and Platelets | The date of engraftment of ANC is the first of 3 consecutive days of ANC of 500 or higher based on daily CBC and Differential Counts. The date of engraftment of platelets is the first of three consecutive days of platelet counts of 20,000 or higher in the absence of platelet transfusions for a t least 7 days prior. | 42 days following the infusion of stem cells for ANC [If engraftment of ANC does not occur within 42 days, a subsequent transplant will be performed if a donor is available.] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of non-engraftment and of secondary graft failure | The percentage of patients who fail to initially engraft ANC will be tabulated as well as the percentage of patients who have primary engraftment of ANC but whose graft fails as evidenced by pancytopenia, failure of bone marrow function and loss of donor chimerism following initial engraftment of ANC. | At 30 days, 100 days, 6 months and yearly from the date of transplant until the date of documented graft failure or the subject's death up to 120 months. | 
| Incidence of acute graft-versus-host disease | Routine physical exams, liver function tests, and clinical history of diarrhea and upper GI symptoms will be used to assess the presence of, the maximum severity of and the date of onset of Acute GvHD based on the criteria published by Przepioka et al., Bone Marrow Transplant 1995; 15(6):825-8 as used by the Center for International Blood & Marrow Transplant Research. The percentage of patients developing symptoms of acute graft-versus-host disease will be tabulated. | At 30 days and 100 days after transplant from the date of transplant until the date of documented acute GvHD. | 
| Incidence of chronic graft-versus-host disease | Assess the presence of and the maximum severity of and the date of onset of chronic GvHD based on Sullivan KM, Blood 1981;57-267 as used by the Cneter for International Blood & Marrow Transplant Research. | At 100 days, 6 months and yearly after transplant from the date of transplant until the date of documented graft failure or the subject's death up to 120 months. | 
| Disease-free survival | Document and update the length of time a subject survives without recurrence of the disease for which they were transplanted at 30 days, 100 days, 6 months and yearly following the infusion of cord blood stem cells for as long as the subjects survive and remain disease-free. | At 30 days, 100 days, 6 months and yearly after transplant from the date of transplant until the date of documented graft failure or the subject's death up to 120 months. |