Stem Cell Transplantation for Fanconi Anemia

Study Overview
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Brief Summary
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The purpose of this study is to determine whether thymic shielding during total body irradiation can be given and whether it will reduce the risk of infections in Fanconi Anemia patients undergoing alternate donor (not a matched sibling) stem cell transplants.

Detailed Description
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All subjects will be given the same treatment regimen of total body irradiation (TBI), Fludarabine, Cyclophosphamide, and anti-thymocyte globulin (ATG), followed by an alternate donor stem cell transplant. Since this treatment regimen has been given before, without thymic shielding, we will compare the outcomes of these patients with the historical data from subjects who did not receive thymic shielding.

Official Title
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A Study of Thymic Shielding in Recipients of Total Body Irradiation, Cyclophosphamide, and Fludarabine Followed by Alternate Donor Hematopoietic Stem Cell Transplantation in Patients With Fanconi Anemia

Conditions
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Fanconi Anemia

Intervention / Treatment
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* Procedure: Hematopoietic Stem Cell Transplant
* Procedure: Thymic Shielding During Radiation
* Procedure: Total Body Irradiation
* Drug: Cyclophosphamide, Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be less than (<) 18 years of age with a diagnosis of Fanconi anemia. Patients must have an HLA-A, B, DRB1 identical unrelated donor or less than or equal to (≤)1 antigen mismatched related (non-HLA-matched sibling) or <1 antigen mismatched unrelated UCB donor. Patients and donors will be typed for HLA-A and B using serological or molecular techniques and for DRB1 using high resolution molecular typing. Patients with FA must have aplastic anemia (AA), myelodysplastic syndrome without excess blasts, or high risk genotype as defined below. Aplastic anemia is defined as having at least one of the following when not receiving growth factors or transfusions Platelet count <20 x 10^9/L ANC <5 x 10^8/L Hgb <8 g/dL Myelodysplastic syndrome with multilineage dysplasia with or without chromosomal anomalies High risk genotype (e.g. IVS-4 or exon 14 FANCC mutations, or BRCA1 or 2 mutations) Adequate major organ function including Cardiac: ejection fraction greater than (>)45% Hepatic: bilirubin, AST/ALT, ALP <2 x normal Karnofsky performance status >70% or Lansky performance status >50% Women of child-bearing age must be using adequate birth control and have a negative pregnancy test Exclusion Criteria: Available HLA-genotypically identical related donor History of gram negative sepsis or systemic fungal infection (proven or suspected based on radiographic studies) Refractory anemia with excess blasts, or leukemia Active central nervous system (CNS) leukemia at time of hematopoietic cell transplant (HCT) History of squamous cell carcinoma of the head/neck/cervix within 2 years of HCT Pregnant or lactating female Prior radiation therapy preventing use of total body irradiation (TBI) 450 centigray (cGy)

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 18 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HSCT Patients<br>Patients who received total body irradiation (450 cGy [centigray]) with thymic shielding prior to chemotherapy regimen and Hematopoietic Stem Cell Transplant (HSCT) | Procedure: Hematopoietic Stem Cell Transplant<br>* Bone marrow failure may be treated by giving patients stem cells that come from someone else. This is called a stem-cell transplant. As part of the transplant process, patients receive high doses of chemotherapy and/or radiation to treat their underlying disease. As one of its effects, this treatment also kills the healthy stem cells that are already in the marrow. The transplant provides new stem cells for the patient from a healthy donor; that replace the bone marrow and allow the blood counts to recover.<br>* Other names: Bone Marrow Transplant;Procedure: Thymic Shielding During Radiation<br>* protecting the thymus during total body radiation (450 cGy administered)<br>* Other names: TBI;Procedure: Total Body Irradiation<br>* Six days before the stem cells are given (day -6), subjects will receive total body irradiation with thymic shielding. Thymic shielding is done by placing a piece of lead on the chest during the irradiation treatment so that the irradiation beams do not go to the thymus.<br>* Other names: Radiation Therapy, Therapuetic Radiation;Drug: Cyclophosphamide, Fludarabine<br>* Day -5 through Day -2, subjects will receive a chemotherapy regimen of Fludarabine, Cyclophosphamide via central line<br>* Other names: Cytoxan, Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Exhibited Hematopoietic Recovery and Engraftment | Calculated from Day 1 of hematopoietic cell transplant to Day 42 post-transplant. Hematopoietic recovery and engraftment is defined as the first of three consecutive days the patient's absolute neutrophil count is greater than or equal to 0.5X10^9/Liter. | Day 42 after hematopoietic cell transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Who Exhibited Secondary Graft Failure | Calculated from Day 1 of hematopoietic cell transplant to Day 100 after transplant. A complication after Bone Marrow Transplant in which the transplanted stem cells do not grow in the recipient's bone marrow and thus do not produce new blood cells. | Day 100 after hematopoietic cell transplant | 
| Number of Patients With Acute Graft Versus-Host Disease (aGVHD) | Calculated from Day 1 of hematopoietic cell transplant to Day 100 after transplant. GVHD is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as foreign and mount an immunologic attack. | Day 100 after hematopoietic cell transplant | 
| Number of Patients With Chronic Graft Versus-Host Disease (GVHD) | Calculated from Day 1 of hematopoietic cell transplant to 1 year after transplant. GVHD is a common complication of allogeneic bone marrow transplantation in which functional immune cells in the transplanted marrow recognize the recipient as foreign and mount an immunologic attack. | 1 year after hematopoietic cell transplant | 
| Number of Patients Who Exhibited Regimen-related Toxicity (RRT) | Calculated from Day 1 of hematopoietic cell transplant to 1 year after transplant. Regimen-related toxicity involves harmful effects in an organism through exposure to the treatment given. | 1 year after hematopoietic cell transplant | 
| Immune Reconstitution - Mean Value (1 Year) | Calculated mean value of patient CD4 values collected at intervals from Day 30 through 1 year post-transplant. | 1 year post-transplant. | 
| Immune Reconstitution - Mean Value (2 Years) | Calculated mean value of patient CD4 values collected at intervals from Day 30 through 2 years post-transplant. | at 2 years after transplant | 
| Number of Patients Alive at 1 Year | Calculated from Day 1 of hematopoietic cell transplant to 1 year post-transplant. | 1 year after transplant | 
| Number of Patients Alive at 2 Years | Calculated from Day 1 of hematopoietic cell transplant to 2 years post-transplant. | 2 years after transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem Cell Transplant, Thymic Shielding, Total Body Irradiation, Chemotherapy