Effect of Cyclosporine Therapy on Gene Expression in Patients With Large Granular Lymphocyte Leukemia
Condition: Large Granular Lymphocytic Leukemia; LGL Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Large Granular Lymphocytic
Intervention: Cyclosporine; Gene expression analysis; Microarray analysis; Laboratory biomarker analysis
Intervention description: An oral preparation given every 12 hours, 5-10 mg/kg/day in divided doses. Doses are adjusted to maintain a therapeutic level between 200-400 ng/ml. Levels will be checked twice weekly and once the patient has achieved steady state levels they shall be monitored once every 2 weeks. These therapeutic levels shall be maintained for 3 months.; A permutation test will be performed to examine whether the overall expression profile changes due to treatment. This will be done by comparing the number of significant genes to the distribution of this number if in fact there is no difference between pre-treatment and post-treatment gene expression.; Gene expression profiling will be carried out on Affymetrix microarrays to compare pretreatment and posttreatment samples.; Analysis of differential gene expression profiles in patients with LGL leukemia treated with cyclosporine.
Intervention MeSH terms: Cyclosporine; Cyclosporins
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Large Granular Lymphocyte (LGL); LGL; Leukemia; Cyclosporine; Microarray; Gene Expression; Cyclosporin; Large Granular Lymphocyte Leukemia; LGL Leukemia

Summary:

      Background:

        -  Large granular lymphocyte (LGL) leukemia is a low-grade non-Hodgkin's lymphoma.

        -  LGL is associated with low numbers of white blood cells (leading to recurring
           infections), red blood cells (causing anemia) and platelets (causing abnormal bleeding).

        -  Cyclosporine (CSA) is an immunosuppressive drug that improves low blood cell counts in
           about 50 percent of patients with LGL leukemia.

      Objectives:

        -  To identify what factors determine why cyclosporine works in some patients and not in
           others.

        -  To identify what causes low blood counts in LGL leukemia.

      Eligibility: Patients 18 years of age and older with LGL leukemia.

      Design:

        -  Patients have a medical history, physical examination blood tests, bone marrow biopsy
           and x-ray studies, including chest x-rays and computed tomography (CT) scans of the
           chest, abdomen and pelvis. Patients with an easily accessible enlarged lymph node have a
           node biopsy (removal of a small piece of tissue for microscopic examination).

        -  Patients take cyclosporine twice a day by mouth. Blood samples are taken at least weekly
           to adjust the cyclosporine dosing to maintain therapeutic serum levels.

        -  Patients undergo apheresis (collection of white blood cells) at a number of different
           time points in the study (maximum 6 times) to look at the differences in the leukemia
           cells before and during treatment with cyclosporine. For apheresis, blood is withdrawn
           through a needle in an arm vein and directed through a catheter (plastic tube) into a
           machine that separates it into its components. The white cells are extracted and the
           rest of the blood is returned through the same needle or through a second needle in the
           other arm.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. All patients must have a histologic or cytologic diagnosis of T-cell LGL leukemia
                  as determined by the Laboratory of Pathology or Hematology at the Clinical
                  Center, National Institutes of Health

               2. All patients must have hemocytopenias such as granulocyte count less than
                  1,200/ul, platelet count less than 100,000/ul or hemoglobin less than 10 g/dl, or
                  require hematopoietic support (transfusion or colony stimulating factors) to
                  maintain counts at these or higher levels.

               3. Patients must have measurable or evaluable disease

               4. Patients must have a creatinine of less than 2.0 mg/dl.

               5. Omission of cytotoxic chemotherapy for 3 weeks prior to entry into the trial is
                  required. However, patients receiving stable corticosteroids will be eligible.

               6. Age greater than 18 years

               7. Karnofsky performance greater than 70%

               8. Patients must have a life expectancy of greater than 3 months.

               9. Patients must be able to understand and sign an Informed Consent form.

              10. All female patients must use adequate contraception during participation in this
                  trial and for three months after completing therapy.

        EXCLUSION CRITERIA:

          1. Patients with uncontrolled hypertension

          2. Pregnant and nursing patients are not eligible for the study as CSA crosses the
             placenta. Based on clinical use, premature births and low birth weight were
             consistently observed. Breast-feeding is contraindicated because CSA enters the blood
             milk and may possibly be administered to the child.

          3. Underlying immunodeficiency state including human immunodeficiency virus (HIV)
             seropositivity.

          4. Positive for antibodies to hepatitis C or positive for hepatitis B surface antigen,

          5. Patients with serious intercurrent illnesses, concurrent hepatic, renal, cardiac,
             neurologic, pulmonary, infectious or metabolic disease of such severity that it would
             preclude the patients' ability to tolerate cyclosporine.

          6. Patients who received cyclosporine for LGL leukemia previously and failed to respond.