Myeloablative Umbilical Cord Blood Transplantation in Hematological Diseases

Study Overview
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Brief Summary
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RATIONALE: Giving chemotherapy drugs, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer cells and prepares the patient's bone marrow for the 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 cyclosporine and mycophenolate mofetil may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing an umbilical cord blood transplant for hematologic cancer.

Detailed Description
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OBJECTIVES: Primary Determine the 1-year survival of patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine, cyclophosphamide, and fractionated total-body irradiation. Secondary Determine the incidence of transplant-related mortality at 6 months after UCBT. Evaluate the pattern of chimerism after double UCBT. Determine the incidence of neutrophil engraftment at day 42 after UCBT. Determine the incidence of platelet engraftment at 6 months after UCBT. Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT. Determine the incidence of chronic GVHD at 1 year after UCBT. Determine the disease-free survival at 1 and 2 years after UCBT. Determine the incidence of relapse at 1 year after UCBT. OUTLINE: This is a nonrandomized, open-label, multicenter study. Preparative Regimen: Patients receive fludarabine IV over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients also undergo total-body irradiation twice daily on days -4 to -1. Umbilical Cord Blood Transplantation (UCBT): Patients undergo 1 or 2 units of UCBT on day 0. Patients receive filgrastim (G-CSF) IV once daily beginning on day 1 and continuing until blood counts recover. Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours 2 or 3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. Patients also receive mycophenolate mofetil IV or orally 2 or 3 times a day beginning on day -3 and continuing until day 30 or 7 days after engraftment in the absence of acute GVHD. After completion of study treatment, patients are followed periodically for at least 5 years. PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.

Official Title
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Transplantation of Unrelated Umbilical Cord Blood for Patients With Hematological Diseases With Cyclophosphamide/Fludarabine/Total Body Irradiation Myeloablative Preparative Regimen

Conditions
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Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Myelofibrosis, MDS, Refractory Anemia, Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Non-Hodgkin's Lymphoma, Leukemia, Lymphoma, Multiple Myeloma, Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: filgrastim
* Drug: cyclophosphamide
* Drug: cyclosporine
* Drug: fludarabine phosphate
* Drug: mycophenolate mofetil
* Procedure: umbilical cord blood transplantation
* Radiation: total-body irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute myeloid leukemia (AML): high risk CR1 (as evidenced by preceding myelodysplastic syndrome [MDS], high risk cytogenetics, ≥ 2 cycles to obtain complete remission [CR], erythroblastic or megakaryocytic leukemia; CR2+. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. Very high risk pediatric patients with AML. Patients <21 years, however, are eligible with (M2 marrow) with < or = 25% blasts in marrow after having failed one or more cycles of chemotherapy. This group of patients will be analyzed separately. Acute lymphocytic leukemia (ALL): high risk CR1 [t(9;22), t (1:19), t(4;11) or other MLL rearrangements] hypodiploidy, or IKZF1 abnormalities), DNA index < 0.81, > 1 cycle to obtain CR or presence minimal residual disease (MRD). Patients in CR2+ are eligible. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. Very high risk pediatric patients with ALL. patients <21 years are also considered high risk CR1 if they had M2 or M3 marrow at day 42 from the initiation of induction or M3 marrow at the end of induction. They are eligible once they achieved a complete remission Chronic myelogenous leukemia (CML) excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate. Plasma Cell leukemia after initial therapy, who achieved at least a partial remission Advanced myelofibrosis Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory anemia with severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by a representative bone marrow aspirate morphology. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma or follicular lymphoma are eligible if there was disease progression/relapse within 12 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 (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant. Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy in CR1+ or PR1+. Large cell NHL > CR2/> PR2. Patients in CR2/PR2 with initial short remission (<6 months) are eligible. Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade NHL after initial therapy if stage III/IV in CR1/PR1 or after progression if stage I/II < 1 year. Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may be considered for this protocol after initial therapy. Recipients must have a Karnofsky score (adults) ≥ 80 % or Lansky score ≥ 50% (pediatrics), and proper organ function. Exclusion Criteria Active infection at time of transplantation History of human immunodeficiency virus (HIV) infection Pregnant or breast feeding. Chemotherapy refractory large cell and high grade NHL If < or = 18 years old, prior myeloablative transplant within the last 6 months. If >18 years old prior myeloablative allotransplant or autologous transplant Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation. Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as part of their salvage therapy.

Ages Eligible for Study
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Maximum Age: 55 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Unrelated UCBT for Blood Cancers<br>Patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine phosphate, mycophenolate mofetil, filgrastim, cyclophosphamide, cyclosporine and fractionated total-body irradiation. | Biological: filgrastim<br>* All patients will receive G-CSF 5 mcg/kg/day intravenously(IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10^9/L for three consecutive days.<br>* Other names: G-CSF;Drug: cyclophosphamide<br>* Cyclophosphamide to be administered with high volume fluid flush and mesna (MT(S) 9006) at 10:00am, or per institutional routine, on days-7 and -6 after fludarabine. Cyclophosphamide 60mg/kg/day intravenous (IV) x 2 days, total dose 120 mg/kg (days -7 and -6) Dosing is calculated based on Actual BodyWeight (ABW) unless ABW > 30 kg above Ideal BodyWeight (IBW), in which case the dose should be computed using adjusted body weight.<br>* Other names: Cytoxan;Drug: cyclosporine<br>* Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of > 200 ng/mL. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours.<br>* Other names: CSA;Drug: fludarabine phosphate<br>* Fludarabine 25 mg/m2/day intravenously (IV) x 3 days, total dose 75 mg/m2 (days -8 to -6);<br>* Other names: Fludara;Drug: mycophenolate mofetil<br>* All patients will begin mycophenolate mofetil (MMF) on day -3. Patients ≥ 40 kilograms will receive MMF at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours). Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg three times a day.<br>* Other names: MMF;Procedure: umbilical cord blood transplantation<br>* The product is infused via intravenous (IV) drip directly into the central line without a needle, pump or filter.<br>* Other names: UCBT;Radiation: total-body irradiation<br>* The recommended TBI is 165 cGy given twice daily for a total dose of 1320 cGy (days -4 to -1).<br>* Other names: TBI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Were Alive at 1 Year Transplant Overall Survival | Number of patients alive at 1 year after transplant. | at 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died Due to Transplant | Determine the incidence of transplant-related mortality at 6 months after UCBT | At Month 6 | 
| Number of Participants With Platelet Engraftment | Determine the incidence of platelet engraftment (platelet recovery >50,000/uL) at 6 months after UCBT. | 6 months | 
| Number of Participants With Neutrophil Engraftment | Determine the incidence of neutrophil engraftment at day 42 after UCBT Patients diagnosed with graft failure (failure of absolute neutrophil count ANC > 5 x 10^8/L of donor origin by day +42) | Day 42 | 
| Number of Participants With Acute Graft-Versus-Host Disease | Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria following Przepiorka et al, 1995, Consensus Clinical Stage and Grade of Acute GVHD. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. | Day 100 | 
| Number of Participants With Chronic Graft-Versus-Host Disease | Determine the incidence of chronic GVHD at 1 year after UCBT. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. | Year 1 | 
| Percentage Chimerism on Day 21 | Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28. | Day 21 | 
| Percentage Chimerism on Day 100 | Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28. | Day 100 | 
| Percentage Chimerism at 6 Months | Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28. | Month 6 | 
| Percentage Chimerism at 1 Year | Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28. | 1 Year | 
| Percentage Chimerism at 2 Years | Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28. | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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blastic phase chronic myelogenous leukemia, primary myelofibrosis, chronic myelomonocytic leukemia, myelodysplastic syndromes, juvenile myelomonocytic leukemia, recurrent adult Burkitt lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent lymphoblastic lymphoma, recurrent childhood acute myeloid leukemia, recurrent childhood large cell lymphoma, recurrent follicular lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, refractory multiple myeloma, chronic myelogenous leukemia, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, multiple myeloma, adult lymphoblastic lymphoma, refractory anemia with excess blasts, refractory anemia, Burkitt lymphoma, childhood large cell lymphoma, adult Burkitt lymphoma, mantle cell lymphoma, childhood lymphoblastic lymphoma, childhood myelodysplastic syndromes