Umbilical Cord Blood Transplant for Children With Myeloid Hematological Malignancies

Study Overview
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Brief Summary
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In this study, the investigators will use busulfan and cyclophosphamide (BuCy) backbone with the addition of fludarabine as the preparative Stem Cell Transplant (SCT) regimen. As an attempt to improve engraftment rate and reduce infections, the investigators are going to incorporate fludarabine in the conditioning regimen. The use of a BuCy backbone has been widely used and comparable to total body irradiation and cyclophosphamide (Cy/TBI) regimen. Encouraging data on adding fludarabine to the SCT regimen have been reported. A fludarabine-based, conditioning regimen, with adequate immunosuppressive activity could conceivably allow engraftment of stem cells from alternative donors in hematologic malignancies patients with acceptable engraftment rates and low transplant-related mortality. Regimen-related toxicity is believed to be a major contributing factor to GVHD. Therefore this approach may also lead to reduced GVHD, as some investigators have suggested. In an attempt to decrease the rate of viral infection and reactivation, the investigators will avoid ATG (Thymoglobulin) / Campath (anti-CD52), and instead administer Mycophenolate Mofetil (MMF). The addition of fludarabine should compensate any increase risk of graft failure with the removal of the ATG/Campath. The investigators anticipate that the removal of ATG/Campath will facilitate immune reconstitution more efficiently after receiving a UCBT.

Detailed Description
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The following will be given as the conditioning regimen for the transplant: BUSULFAN: Busulfan (intravenous BUSULFEX) dosing will be as follows: patients <12 kg: 1.1 mg/kg/dose IV every 6 hours for 16 doses total; patients >12 kg: 0.8 mg/kg/dose IV every 6 hours for 16 doses. Administration and pharmacokinetic monitoring will be performed as per standard practice. Anticonvulsants will be given in accordance with standard Blood and Marrow Transplant Program recommendations. CYCLOPHOSPHAMIDE: Cyclophosphamide (50 mg/kg/dose) will be given IV on Days -5, - 4, -3, and -2 over 1 hour. The total dose to be given over 4 days is 200 mg/kg. Mesna will be given in accordance with standard Blood and Marrow Transplant. FLUDARABINE: Fludarabine will be given IV daily over 1 hour for 3 days. Dosing will be as follows: for patients ≤ 10 kg: 1.3 mg/kg; for patients > 10 kg: 40 mg/m2. Preparation, administration and monitoring will be according to standard practice procedure POST-TRANSPLANT IMMUNOSUPPRESSION: CSA will begin on Day -3. For children < 40 kg, the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. Dose adjustments will be made to maintain levels above 200 ng/mL. Levels will be done on Day 0 and then as clinical indicated. CSA will be tapered per institutional SOP. Once the patient can tolerate oral medications and has a normal gastrointestinal transit time, CSA will be converted to an oral form. MMF will begin on Day 0 at a dose of 15 mg/Kg IV or orally TID, and will be discontinued on Day +45 unless GVHD is present. CNS Disease: Patients with CNS relapse or primary CNS disease that is symptomatic or associated to radiological changes will receive additional irradiation to the craniospinal axis. SUPPORTIVE CARE: Supportive care will be provided as per standard practice of the Blood and Marrow Stem Cell Transplant program at the Texas Children's Hospital, including all prophylactic and therapeutic clinical care issues. These practices may be modified if necessary for any individual patient in order to provide optimum care for that particular patient. IVIG: Intravenous immunoglobulin (500 mg/kg per dose) will be given monthly until discontinuation of GVHD therapy and documentation of antibody production. CB-CTLs: Patients enrolled in this protocol may also be eligible for infusion of CB-derived multivirus-specific CTL to provide virus-specific immune reconstitution and treatment of viral infections after CBT. EVALUATIONS DURING THE STUDY: Screening Procedures; Pre-HCT: Physical examination Pregnancy test Complete blood count and chemistries Electrocardiogram Echocardiograph PT/PTT/Fibrinogen/Anti-Thrombin III/von Willebrand Factor Viral tests Bone marrow aspirate and biopsy/Lumbar puncture Renal Function (GFR) Lumbar puncture will be performed Pulmonary Function test EVALUATIONS BETWEEN DAY 0 AND DAY 100: Physical examination Complete blood count and chemistries Lytes/BUN/Cr Peripheral blood for STRs or FISH analysis for molecular diagnostics Lymphocyte phenotype testing and lymphoproliferative responses Bone marrow aspirate and biopsy for assessment of leukemia status and UCB engraftment Lumbar puncture Immunoglobulins EVALUATIONS AFTER DAY 100: Physical examination Complete blood count and chemistries Lytes/BUN/Cr Serum chemistries Peripheral blood with assessment of engraftment by STRs or FISH analysis and enzyme levels Echocardiograph with LVEF Bone marrow aspirate and biopsy assessment of leukemia status and UCB engraftment Lymphocyte phenotype testing (CD3, CD4, CD8, CD19 and CD56) and lymphoproliferative responses Immunoglobulins FOLLOW-UP INTERVAL: Patients will be seen in the hospital everyday until discharge. After discharge from the hospital, the patient will be following on the BMT clinics on a regular basis as recommended by the primary physician.

Official Title
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Umbilical Cord Blood Transplant for Children With Myeloid Hematological Malignancies (UCAML)

Conditions
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Myeloid Hematological Malignancies

Intervention / Treatment
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* Drug: Busulfan
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Procedure: Cord Blood Stem Cell Infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a myeloid hematologic malignancy (acute myelogenous leukemia, secondary myelogenous leukemia or myelodysplastic syndrome) unlikely to be cure by standard chemotherapy. This includes patients who have relapsed after standard chemotherapy treatments and patients in first remission with unfavorable prognostics features. Related or Unrelated Umbilical Cord Blood Unit with 0-1 antigen mismatch at HLA-A and B (at low resolution) and DRB1 (at high resolution), with a total nucleated cell dose of ≥ 4 x 10^7/kg. Lansky/Karnofsky scores at least 60. Written informed consent and/or signed assent line from patient, parent or guardian. Negative pregnancy test, if applicable. Exclusion Criteria: Patients with uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections, patients must be receiving definitive systemic antifungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection. Severe renal disease (Creatinine > 3X normal for age). Severe hepatic disease (direct bilirubin > 3 mg/dL or SGOT > 500). Patient has DLCO < 50% predicted or FEV1 < 50% of predicted, if applicable. Patients with symptomatic cardiac failure unrelieved by medical therapy or evidence of significant cardiac dysfunction by echocardiogram (shortening fraction < 20%). HIV positive.

Ages Eligible for Study
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Maximum Age: 17 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: Umbilical Cord Blood Transplant<br>Busulfan,Cyclophosphamide, Fludarabine, Cord Blood Stem Cell Infusion | Drug: Busulfan<br>* Busulfan dosing will be as follows: Patients < 12 kg: 1.1 mg/kg/dose IV every 6 hours for 16 doses total; patients > 12 kg: 0.8 mg/kg/dose IV every 6 hours for 16 doses. It will be given on Days -9, -8, -7 and -6.<br>* Other names: Busulfex;Drug: Cyclophosphamide<br>* Cyclophosphamide (50 mg/kg/dose) will be given IV on Days -5, - 4, -3, and -2 over 1 hour. The total dose to be given over 4 days is 200 mg/kg.<br>* Other names: CTX, Cytoxan;Drug: Fludarabine<br>* Fludarabine will be given IV daily over 1 hour for 3 days. Dosing will be as follows: for patients ≤ 10 kg: 1.3 mg/kg; for patients > 10 kg: 40 mg/m^2.<br>* Other names: Fludera;Procedure: Cord Blood Stem Cell Infusion<br>* The cord blood stem cells will be infused on Day 0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at 100 Days, 1 Year, and 3 Years After Umbilical Cord Blood Transplant in Pediatric Patients. | To determine the overall survival rate at 1 year after umbilical cord blood transplant in pediatric patients with myeloid hematological malignancies. | 100 days, 1 year, and 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Severe Acute GVHD Grade III-IV | Number of participants with acute GVHD graded by the method of Przepiorka et al, which evaluates skin involvement, lower and upper GI, and liver function (bilirubin), each being graded in stages from 0 to 4, where 0 means no acute GVHD, and 4 is the highest stage of acute GVHD. | Day 100 | 
| Number of Participants With Chronic GvHD | Number of participants with chronic GVHD graded by the method of Przepiorka et al, which evaluates skin, joints, oral, ocular, hepatic, esophagus, GI, respiratory, platelet, and musculoskeletal involvement, in stages from 0 to 3. | 1 year | 
| Number of Participants With Relapse Rate After Transplant | To assess relapse rate at 1 and 3 years after transplant. Cumulative incidence of relapse was calculated from the date of umbilical cord blood transplant using the competing risk method as described in Gray(1988) with death prior to relapse as the competing risk. Participants still alive without a date of relapse were censored at the time of the last follow-up. | 1 and 3 years | 
| Number of Participants With Donor Engraftment After Transplant. | To evaluate donor engraftment at 100 days, 6, 9, 12, 24, and 36 months after transplant. | 100 days, 6, 9, 12, 24 and 36 months | 
| Number of Participants With Platelet Engraftment | Achievement of untransfused platelet count > 20 x 10^9/L on three consecutive days | Day 180 | 
| Number of Participants With Neutrophil Engraftment | Achievement of absolute neutrophil count > 0.5 x 10^9/L on three consecutive days | Day 42 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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UCB, Umbilical Cord Blood, Transplant, Umbilical Cord Blood Transplant, Cord Blood Stem Cell Transplantation, Pediatric, Myeloid Hematological Malignancies, Busulfan, Cytoxan, Cyclophosphamide, Fludarabine