Pilot Study of Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients With Life Threatening Hemophagocytic Disorders

Study Overview
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Brief Summary
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OBJECTIVES: I. Determine the efficacy of unrelated donor hematopoietic stem cell transplantation in the treatment of patients with life threatening hemophagocytic disorders. II. Determine the rate of disease free survival, incidence of graft failure, and incidence of graft versus host disease in these patients after undergoing this treatment regimen.

Detailed Description
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PROTOCOL OUTLINE: Patients receive oral busulfan twice a day on days -9 to -6; cyclophosphamide IV over 1 hour on days -5 to -2; etoposide IV over 4 hours on days -5 to -3; and anti-thymocyte globulin IV twice a day on days -2 and -1 and days 1 and 2. Patients undergo allogeneic hematopoietic stem cell transplantation on day 0. Filgrastim (G-CSF) is administered subcutaneously beginning on day 1 and continuing until blood counts recover. Patients receive graft versus host disease prophylaxis with methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1-4 hours (orally once the patients resumes eating) every 12 hours (every 8 hours for pediatric patients) starting on or prior to day -3 and continuing up to 1 year. Patients are followed at days 28 and 100, at 6 months and 1 year, and then annually for 5 years.

Conditions
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Chediak-Higashi Syndrome, Graft Versus Host Disease, X-Linked Lymphoproliferative Syndrome, Familial Erythrophagocytic Lymphohistiocytosis, Hemophagocytic Lymphohistiocytosis, Virus-Associated Hemophagocytic Syndrome

Intervention / Treatment
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* Drug: anti-thymocyte globulin
* Drug: busulfan
* Drug: cyclophosphamide
* Drug: cyclosporine
* Drug: etoposide
* Drug: filgrastim
* Drug: methotrexate
* Procedure: allogeneic hematopoietic stem cell transplantation


Participation Criteria
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Eligibility Criteria
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PROTOCOL ENTRY CRITERIA: --Disease Characteristics-- Patients diagnosed with any of the following active but stable, or nonactive/quiescent, hemophagocytic disorders: Hemophagocytic lymphohistiocytosis (HLH) Fever greater than 38.5 degrees Celsius Splenomegaly (greater than 3 cm below costal margin) Hemophagocytosis in bone marrow or spleen or lymph nodes Disease may be confirmed by positive family history No evidence of malignancy Hypertriglyceridemia and/or hypofibrinogenemia Fasting triglycerides at least 2.0 mmol/L or at least 3 standard deviations above normal for age Fibrinogen no greater than 1.5 g/L or no greater than 3 standard deviations above normal Cytopenia (affecting at least 2 of 3 lineages in the peripheral blood) Hemoglobin less than 9.0 g/L Platelet count less than 100,000/mm3 X-linked lymphoproliferative disorder (XLP) Two or more maternally related males manifesting at least one of the following XLP phenotypes: Fulminant infectious mononucleosis Dysgammaglobulinemia Malignant lymphoma/lymphoproliferative disorder Aplastic anemia Lymphoid granulomatosis/vasculitis OR A maternally related male in an established XLP kindred who has strong genetic (RFLP) linkage to the XLP locus Chediak-Higashi syndrome Partial oculocutaneous albinism (hair, skin, eyes) Frequent bacterial infections Large peroxidase positive granules in leukocytes of peripheral blood or bone marrow Positive family history or parental consanguinity is supportive of the diagnosis May not have entered accelerated phase as defined by any of the following: Lymphadenopathy Pancytopenia Histiocytes with hemophagocytosis in bone marrow, lymph nodes, liver, or spleen Viral associated hemophagocytic syndrome (VAHS) Relapsed after prior therapy or supportive care Diagnostic criteria as for HLH No hemophagocytic disorders secondary to underlying malignancy Patients 35 years of age and under must have a hematopoietic stem cell donor that is one of the following: HLA A and B identical OR Single HLA A or B serologic mismatch with DRB1 identity OR HLA A or B serologic identity with a single DRB1 mismatch Patients 36 to 55 years of age must have a hematopoietic stem cell donor that is one of the following: HLA A and B and HLA DRB1 identical OR Single HLA A or B serologic mismatch with DRB1 identity Patients receiving umbilical cord blood must have an unrelated donor with no more than two antigen HLA A, B, or DRB1 mismatches --Patient Characteristics-- Performance status: Karnofsky 70-100% OR Age less than 16 years: Lansky 50-100% Life expectancy: Not severly limited by another disease Hepatic: SGOT less than 3 times normal Bilirubin less than 2.5 mg/dL Renal: Creatinine normal OR Creatinine clearance or glomerular filtration rate greater than 50% normal Cardiovascular: If symptomatic, ventricular ejection fraction must be greater than 40% and must improve with exercise OR Shortening fraction normal on echocardiogram Pulmonary: If symptomatic, DLCO greater than 45% predicted (corrected for hemoglobin) In children unable to perform pulmonary function testing, oxygen saturation must be greater than 95% Other: HIV negative No significant active infections

Ages Eligible for Study
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Minimum Age: 0 Years
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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: anti-thymocyte globulin|nan|
|Drug: busulfan|nan|
|Drug: cyclophosphamide|nan|
|Drug: cyclosporine|nan|
|Drug: etoposide|nan|
|Drug: filgrastim|nan|
|Drug: methotrexate|nan|
|Procedure: allogeneic hematopoietic stem cell transplantation|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chediak-Higashi syndrome, X-linked lymphoproliferative syndrome, disease-related problem/condition, familial erythrophagocytic lymphohistiocytosis, genetic diseases and dysmorphic syndromes, graft versus host disease, hematologic disorders, hemophagocytic lymphohistiocytosis, histiocytosis, immunologic disorders and infectious disorders, primary immunodeficiency disease, rare disease, virus-associated hemophagocytic syndrome