Stem Cell Transplant for Immunologic or Histiocytic Disorders

Study Overview
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Brief Summary
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This study tests the clinical outcomes of a preparative regimen of fludarabine (FLU), anti-thymocyte globulin (ATG)/or Campath, and melphalan; followed by hematopoietic stem cell transplant, and a post transplant regimen of Cyclosporin A (CsA) in patients with immunologic or histiocytic disorders. The researchers hypothesize that this regimen will have a positive effect on post transplant engraftment and the incidence of graft-versus-host-disease (GVHD). Patients will be randomized biologically into one of 3 arms based upon donor availability: (a) human leukocyte antigen (HLA) genotypic matched sibling donor, (b) HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor, (c) two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord).

Detailed Description
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Prior to transplantation, subjects will receive Melphalan, Fludarabine and Anti-Thymocyte Globulin (ATG) or Campath. These three drugs are being given to subjects to help the new stem cells take and grow. On the day of transplantation, subjects will receive stem cells transfused via intravenous (IV) catheter. After stem cell transplantation, subjects will be given Cyclosporin A (CsA) and mycophenolate mofetil (MMF) to reduce the risk of graft-versus-host disease, the complication that occurs when the donor's stem cells react against the patient.

Official Title
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Allogeneic Hematopoietic Stem Cell Transplant for Patients With Immunologic or Histiocytic Disorders Using a Non-Myeloablative Preparative Regimen to Achieve Stable Mixed Chimerism

Conditions
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Hemophagocytic Lymphohistiocytosis, X-Linked Lymphoproliferative Disorders, Chediak-Higashi Syndrome, Griscelli Syndrome, Immunologic Deficiency Syndromes, Langerhans-Cell Histiocytosis

Intervention / Treatment
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* Procedure: Stem Cell Transplant
* Drug: Fludarabine
* Drug: Melphalan
* Drug: Anti-thymocyte globulin (ATG)
* Drug: Campath 1H
* Drug: Cyclosporin A
* Drug: Mycophenolate mofetil
* Drug: Intravenous immunoglobulin (IVIG)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with immunodeficiencies or histiocytic disorders 0-35 years of age with an acceptable stem cell donor and disease characteristic defined by the following: Patients with histocytic disorders (hemophagocytic lymphohistiocytosis of any etiology and refractory Langerhans cell histiocytosis) who do not meet eligibility criteria for a myeloablative transplant procedure Patients with immunodeficiency disorders in whom residual immune function may not require a fully myeloablative preparative regimen or patient is ineligible for standard myeloablative preparative regimen (any form of severe combined immunodeficiency [SCID], or other immunodeficiency with T cell defect) Patients with immunodeficiency disorders that have had poor outcome with myeloablative stem cell transplants (including, but not limited to, common variable immunodeficiency [CVID], Wiskott Aldrich Syndrome [WAS] if > 5 years of age, ataxia telangiectasia) Patients with immunodeficiencies or histocytic disorders that require a second stem cell transplant (SCT) for any reason Exclusion Criteria: Karnofsky or Lansky performance score <70 Glomerular filtration rate (GFR)<30% predicted Cardiac function <50% normal by echocardiogram Serum creatinine > 2x normal for age/weight Pregnant or lactating females Active serious infection that has not had an adequate course of therapy pre-SCT. Any patient with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) or human immunodeficiency virus (HIV) seropositivity

Ages Eligible for Study
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Maximum Age: 35 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 - Matched sibling donor<br>Stem Cell Transplant: human leukocyte antigen (HLA) genotypic matched sibling donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG) | Procedure: Stem Cell Transplant<br>* IV on Day 0<br>* Other names: hematopoietic stem cell transplant;Drug: Fludarabine<br>* 30mg/m^2 IV Day -7 through Day -3<br>* Other names: Fludara;Drug: Melphalan<br>* 140 mg/m^2 IV Day -1<br>* Other names: Alkeran;Drug: Anti-thymocyte globulin (ATG)<br>* 30 mg/kg IV Day -5 through Day -1<br>* Other names: ATGAM;Drug: Campath 1H<br>* 0.2 mg/kg IV X 5 days (used as an alternative to Anti-thymocyte globulin (ATG) if unable to tolerate ATG) Day -10 through Day -6<br>* Other names: Alemtuzumab;Drug: Cyclosporin A<br>* 2.5 mg/kg IV every 12 hours (adults) or every 8 hours (children <40 kg) maintaining a level of >200mg/L Day -3 until Day +180 when, if no GVHD, the dose will be tapered 10% per week beginning on day 181<br>Drug: Mycophenolate mofetil<br>* 15 mg/kg IV or orally bid and discontinued on Day +45 unless GVHD is present<br>* Other names: CellCept;Drug: Intravenous immunoglobulin (IVIG)<br>* 500 mg/kg IV weekly beginning on Day +7 until Day +100<br>|
| Active Comparator: Arm 2 - Matched unrelated donor<br>Stem Cell Transplant: HLA phenotypic matched unrelated peripheral blood stem cell (PBSC) donor and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG) | Procedure: Stem Cell Transplant<br>* IV on Day 0<br>* Other names: hematopoietic stem cell transplant;Drug: Fludarabine<br>* 30mg/m^2 IV Day -7 through Day -3<br>* Other names: Fludara;Drug: Melphalan<br>* 140 mg/m^2 IV Day -1<br>* Other names: Alkeran;Drug: Anti-thymocyte globulin (ATG)<br>* 30 mg/kg IV Day -5 through Day -1<br>* Other names: ATGAM;Drug: Campath 1H<br>* 0.2 mg/kg IV X 5 days (used as an alternative to Anti-thymocyte globulin (ATG) if unable to tolerate ATG) Day -10 through Day -6<br>* Other names: Alemtuzumab;Drug: Cyclosporin A<br>* 2.5 mg/kg IV every 12 hours (adults) or every 8 hours (children <40 kg) maintaining a level of >200mg/L Day -3 until Day +180 when, if no GVHD, the dose will be tapered 10% per week beginning on day 181<br>Drug: Mycophenolate mofetil<br>* 15 mg/kg IV or orally bid and discontinued on Day +45 unless GVHD is present<br>* Other names: CellCept;Drug: Intravenous immunoglobulin (IVIG)<br>* 500 mg/kg IV weekly beginning on Day +7 until Day +100<br>|
| Active Comparator: Arm 3 - Mismatched double cord donors<br>Stem Cell Transplant: two HLA 0-2 antigen mismatched unrelated cord blood donors (double cord) and pre-treatment with fludarabine, melphalan, anti-thymocyte globulin or Campath 1H and post-treatment with Cyclosporin A, mycophenolate mofetil and Intravenous immunoglobulin (IVIG) | Procedure: Stem Cell Transplant<br>* IV on Day 0<br>* Other names: hematopoietic stem cell transplant;Drug: Fludarabine<br>* 30mg/m^2 IV Day -7 through Day -3<br>* Other names: Fludara;Drug: Melphalan<br>* 140 mg/m^2 IV Day -1<br>* Other names: Alkeran;Drug: Anti-thymocyte globulin (ATG)<br>* 30 mg/kg IV Day -5 through Day -1<br>* Other names: ATGAM;Drug: Campath 1H<br>* 0.2 mg/kg IV X 5 days (used as an alternative to Anti-thymocyte globulin (ATG) if unable to tolerate ATG) Day -10 through Day -6<br>* Other names: Alemtuzumab;Drug: Cyclosporin A<br>* 2.5 mg/kg IV every 12 hours (adults) or every 8 hours (children <40 kg) maintaining a level of >200mg/L Day -3 until Day +180 when, if no GVHD, the dose will be tapered 10% per week beginning on day 181<br>Drug: Mycophenolate mofetil<br>* 15 mg/kg IV or orally bid and discontinued on Day +45 unless GVHD is present<br>* Other names: CellCept;Drug: Intravenous immunoglobulin (IVIG)<br>* 500 mg/kg IV weekly beginning on Day +7 until Day +100<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Mixed Chimerism | >10% Donor Cells at Day 100 | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Donor Chimerism at 100 Days | The percent of recipient bone marrow and blood cells that are of donor origin. | Day 100 | 
| Percentage of Donor Chimerism at 180 Days | The percent of recipient bone marrow and blood cells that are of donor origin. | Day 180 | 
| Percentage of Donor Chimerism at 365 Days | The percent of recipient bone marrow and blood cells that are of donor origin. | Day 365 | 
| Incidence of Grade 2-4 Acute Graft Versus Host Disease (aGVHD) | Acute graft versus host disease (aGVHD) is a reaction occurring within the first 100 days after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. The severity of aGVHD is graded on a scale of 1 - 4 with the highest number representing the most severe disease. | Day 100 | 
| Incidence of Grade 3-4 Acute Graft Versus Host Disease (aGVHD) | Acute graft versus host disease (aGVHD) is a reaction occurring within the first 100 days after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. The severity of aGVHD is graded on a scale of 1 - 4 with the highest number representing the most severe disease. | Day 100 | 
| Incidence of Chronic Graft Versus Host Disease (cGVHD) | Chronic graft versus host disease (cGVHD) is a reaction which typically develops 3 to 6 months after transplant where the T- cells of the donor graft attacks the recipient's (host's) skin, GI tract, liver and other organs. | 6 months and 1 year | 
| Number of Subjects Alive at 100 Days |  | Day 100 | 
| Number of Subjects Alive at One Year |  | Day 365 | 
| Compare Quality of Life (QOL) |  | Pretransplant, 1 year, 2 years and 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem cell transplant, immunodeficiency, donor lymphocyte infusion