Effect of Cyclosporine Therapy on Gene Expression in Patients With Large Granular Lymphocyte Leukemia

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00363779
First received: August 10, 2006
Last updated: July 6, 2012
Last verified: July 2012

August 10, 2006
July 6, 2012
June 2006
November 2010   (final data collection date for primary outcome measure)
Changes in Gene Expression Patterns [ Time Frame: Baseline and 12 weeks ] [ Designated as safety issue: No ]
Differences (2 fold) in mean gene expression between pre-treatment and post treatment.
Not Provided
Complete list of historical versions of study NCT00363779 on ClinicalTrials.gov Archive Site
Number of Participants With Adverse Events [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Not Provided
Not Provided
Not Provided
 
Effect of Cyclosporine Therapy on Gene Expression in Patients With Large Granular Lymphocyte Leukemia
Microarray Analysis of the Effect of Cyclosporine Therapy on Gene Expression Patterns in Large Granular Lymphocytic Leukemia

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.

Background:

  • LGL leukemia is a low grade non-Hodgkins Lymphoma characterized by tissue invasion of the marrow, spleen and liver
  • Recurrent infections due to chronic neutropenia and transfusion-dependent anemia are the principal causes for initiation of therapy
  • Approximately 50% of patients treated with cyclosporine (CSA) respond to treatment. CSA appears to correct the associated cytopenia without decreasing LGL numbers, suggesting it may inhibit LGL secretion of yet unidentified mediators of neutropenia and anemia.
  • Analysis of differential gene expression profiles in patients with LGL leukemia treated with cyclosporine has the potential to detect as yet unidentified, therapeutic targets and possibly provide predictors of CSA responsiveness.

Objective:

  • Identify changes in gene expression patterns induced by cyclosporine therapy in patients with LGL leukemia
  • Identify differences between responding and non-responding patients

Eligibility:

-Patients with Large Granular Lymphocyte leukemia

Design:

  • Patients will be treated with cyclosporine at a dose of 5-10mg/kg/day in divided doses, with doses adjusted to maintain a therapeutic serum level between 200-400ng/ml. These therapeutic levels shall be maintained for 3 months.
  • Tumor response will be evaluated after 3 months therapy, the dose of CsA may then be tapered to that required to sustain a response or discontinued if no evidence of response, or after relapse.
  • Blood sampling or Lymphapheresis for collection of circulating malignant cells will be performed at a number of different time points. Gene expression profiling will be carried out on Affymetrix microarrays to compare pretreatment and post-treatment samples.
Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Large Granular Lymphocytic Leukemia
  • LGL Leukemia
  • Drug: Cyclosporine
    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.
    Other Name: Ciclosporin
  • Genetic: Gene expression analysis
    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.
  • Genetic: Microarray analysis
    Gene expression profiling will be carried out on Affymetrix microarrays to compare pretreatment and posttreatment samples.
  • Other: Laboratory biomarker analysis
    Analysis of differential gene expression profiles in patients with LGL leukemia treated with cyclosporine.
Experimental: LGL Patients administered cyclosporine
Large Granular Lymphocyte Leukemia (LGL) is a low grade non-Hodgkins lymphoma characterized by tissue invasion of the marrow, spleen, and liver. Cyclosporine 5-10 mg/kg/day was administered as an oral preparation given every 12 hours. Doses are adjusted to maintain a therapeutic level between 200-400 ng/ml.
Interventions:
  • Drug: Cyclosporine
  • Genetic: Gene expression analysis
  • Genetic: Microarray analysis
  • Other: Laboratory biomarker analysis

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
5
November 2010
November 2010   (final data collection date for primary outcome measure)
  • 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.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00363779
060177, 06-C-0177
No
John E. Janik, M.D./National Cancer Institute, National Institutes of Health
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Thomas Waldmann, M.D. National Cancer Institute, National Institutes of Health
National Institutes of Health Clinical Center (CC)
July 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP