T-Cell Depletion and Stem Cell Transplant for Immune Deficiencies and Histiocytic Disorders

Study Overview
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Brief Summary
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The hypothesis is to determine if a preparative regimen of busulfan, cyclophosphamide, and antithymocyte globulin (ATG) plus allogeneic stem cell transplantation will be effective in the treatment of immune deficiencies and histiocytic disorders.

Detailed Description
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Subjects will begin chemotherapy as a preparative regimen, which is intended to completely eliminate their defective immune system and bone marrow. The preparative regimen consists of the chemotherapy drugs (busulfan, cyclophosphamide, and antithymocyte globulin (ATG)). Transplantation: subjects will then have a source of blood stem cells (bone marrow) from their donor administered into their catheter. Medication will be given to help prevent Graft-Versus Host Disease (GVHD). The ATG will help to deplete the donor stem cells of the type of cells that can cause GVHD and will also help to promote engraftment of the new stem cells. Recovery Phase: The second phase of treatment consists of a period after transplantation during which we wait for the return of bone marrow function. This usually takes two to four weeks. Subjects will be given a blood cell growth factor, G-CSF, to help speed recovery of the white blood cells and potentially decrease the risk of infection and decrease the time until the bone marrow recovers.

Official Title
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In-vivo T-cell Depletion and Hematopoietic Stem Cell Transplantation for Life-Threatening Immune Deficiencies and Histiocytic Disorders

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

Intervention / Treatment
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* Procedure: Stem Cell Transplant
* Drug: Myeloablative conditioning regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any patient from birth to < 55 years of age fulfilling the following criteria will be eligible for this study. Patients meeting clinical diagnostic criteria for Hemophagocytic Lymphohistiocytosis (HLH) Patients meeting clinical diagnostic criteria or genetic diagnosis of X-linked lymphoproliferative disorder (XLP) and whose disease is ACTIVE but STABLE, or NON-ACTIVE/QUIESCENT. Patients with Chediak-Higashi Syndrome who meet the following diagnostic criteria and whose disease is ACTIVE but STABLE, or NON-ACTIVE/QUIESCENT as defined in Appendix V of the study protocol. Patients with Viral Associated Hemophagocytic Syndrome (VAHS) - if relapsed after other therapy or supportive care. Diagnostic criteria as above for HLH. Disease status must be ACTIVE but STABLE, or NON-ACTIVE/QUIESCENT as defined in Appendix V. It is cautioned that many patients with HLH or familial hemophagocytic lymphohistiocytosis (FHL) will have a viral infection at time of initial presentation and may therefore be misdiagnosed as having VAHS. Griscelli Syndrome Primary immune deficiencies with non-genotypic identical donors only. Progressive Langerhans cell histiocytosis unresponsive to standard therapy. Other non-malignant hematological disorders in which stem cell transplant with a myeloablative regimen is indicated. Diamond Blackfan Anemia if transfusion dependent Schwachman Diamond Syndrome: with cytopenias or transformation to myelodysplastic syndrome (MDS) Kostman's Syndrome (if ANC <500 without GCSF support, or transformation to MDS) Congenital dyserythropoietic anemia if transfusion dependent Amegakaryocytic thrombocytopenia if baseline platelet counts <20,000 or requiring transfusions. Cardiac, hepatic, renal and pulmonary function deemed adequate for high dose chemotherapy with stem cell rescue as per institutional standards. General guidelines are as follows: Cardiac: Asymptomatic or, if symptomatic, then left ventricular ejection fraction at rest must be > 40% and must improve with exercise, or shortening fraction by echocardiogram must be within institutional normals Hepatic: < 3 x normal SGOT and < 2.5 mg/dL serum bilirubin Renal: Serum creatinine within normal range, or if serum creatinine outside normal range then creatinine clearance or glomerular filtration study should be > 50% of normal. Pulmonary: Asymptomatic or, if symptomatic, diffusing capacity of the lung for carbon monoxide (DLCO) > 45% of predicted (corrected for hemoglobin). For children unable to perform pulmonary function testing, then oxygen saturation should be >95%. Availability of a suitable allogeneic bone marrow donor as per current institutional guidelines for non-T cell depleted hematopoietic stem cell transplant (HSCT). Patients who have undergone previous stem cell transplant (SCT) and failed engraftment or who had relapse of their disease are considered eligible if they meet other eligibility criteria and if the second SCT would occur 6 months or more after the first. If the first SCT preparative regimen was of a non-myeloablative intensity then the second SCT could be performed earlier when the acute toxicity from that procedure was resolved. Exclusion Criteria: Patients who are moribund or whose life expectancy is severely limited by disease other than their underlying disorder. Karnofsky performance status < 70% or Lansky < 50% for patients < 16 years. Patients with hemophagocytic disorders secondary to underlying malignancy. Patients who have ACTIVE/UNSTABLE disease as defined in Appendix V. Significant active infections, including Human Immunodeficiency Virus (HIV). Age > 55 years. Not providing informed consent.

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: Intent-To-Treat<br>Patients who were treated with chemotherapies (myeloablative conditioning regimen) and stem cell transplant. Busulfan intravenously for 4 days followed by cyclophosphamide intravenously for 4 days. Rabbit ATG is given intravenously for 4 doses pre-transplant. | Procedure: Stem Cell Transplant<br>* Infusion of hematopoietic stem cells (bone marrow, cord blood, peripheral blood stem cells) following myeloablative conditioning regimen.<br>* Other names: HSCT;Drug: Myeloablative conditioning regimen<br>* Busulfan intravenously for 4 days followed by cyclophosphamide intravenously for 4 days. Rabbit ATG is given intravenously for 4 doses pre-transplant.<br>* Other names: ATG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Transplant Engraftment |  | Day 100 Post Transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Treatment Related Mortality. |  | Day 100 Post Transplant | 
| Number of Patients Surviving (Disease-free) |  | 1 year | 
| Number of Patients With Grade II-IV Graft-Versus-Host Disease (GVHD) |  | Day 100 Post Transplant | 
| Number of Patients With Graft Failure |  | Day 100 Post transplant | 
| Number of Patients With III-IV Graft-Versus-Host Disease (GVHD) |  | Day 100 Post Transplant | 
| Number of Patients Surviving (Disease-free) |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stem Cell Transplant, T-cell depletion, immune deficiencies, Busulfan pharmacokinetics, Non-Malignant Hematological Disorders