Clinical trial NCT00006056: Pilot Study of Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients With Life Threatening Hemophagocytic Disorders
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Chediak-Higashi Syndrome
Graft Versus Host Disease
X-Linked Lymphoproliferative Syndrome
Familial Erythrophagocytic Lymphohistiocytosis
Hemophagocytic Lymphohistiocytosis
Virus-Associated Hemophagocytic Syndrome
Keywords: 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
Lead sponsor: Office of Rare Diseases (ORD)
Sponsor class: NIH
First posted: 2000-07-06
Enrollment: 40
Sex: ALL
Minimum age (years): 0
Maximum age (years): 55
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Fairview University Medical Center
state: Minnesota
Study officials:
affiliation: Fairview University Medical Center
name: K. Scott Baker
role: STUDY_CHAIR
References: