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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00363779
Recruitment Status : Terminated (Study terminated due to low accrual and the investigator left the NIH.)
First Posted : August 15, 2006
Results First Posted : July 6, 2012
Last Update Posted : July 21, 2015
Information provided by (Responsible Party):
Thomas Waldmann, M.D., National Institutes of Health Clinical Center (CC)

Brief Summary:


  • 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.


  • 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.


  • 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 For apheresis, blood is withdrawn through a needle in an arm vein and directed through a catheter (plastic tube) into a machine that separates it into its components.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.

Condition or disease Intervention/treatment Phase
Large Granular Lymphocytic Leukemia LGL Leukemia Drug: Cyclosporine Genetic: Gene expression analysis Genetic: Microarray analysis Other: Laboratory biomarker analysis Phase 2

Detailed Description:


  • 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.


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


-Patients with Large Granular Lymphocyte leukemia


  • 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Microarray Analysis of the Effect of Cyclosporine Therapy on Gene Expression Patterns in Large Granular Lymphocytic Leukemia
Study Start Date : June 2006
Actual Primary Completion Date : November 2010
Actual Study Completion Date : November 2010

Arm Intervention/treatment
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.
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.

Primary Outcome Measures :
  1. Changes in Gene Expression Patterns [ Time Frame: Baseline and 12 weeks ]
    The goal was to examine which genes had a 2-fold gene expression between pre-treatment (baseline) and post treatment (12 weeks). Genes significant at the 0.001 level will be considered as differentially expressed due to treatment.

Secondary Outcome Measures :
  1. Number of Participants With Adverse Events [ Time Frame: 3 months ]
    Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

    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.


  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00363779

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Thomas Waldmann, M.D. National Cancer Institute, National Institutes of Health
Additional Information:
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Responsible Party: Thomas Waldmann, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC) Identifier: NCT00363779    
Other Study ID Numbers: 060177
First Posted: August 15, 2006    Key Record Dates
Results First Posted: July 6, 2012
Last Update Posted: July 21, 2015
Last Verified: June 2015
Keywords provided by Thomas Waldmann, M.D., National Institutes of Health Clinical Center (CC):
Large Granular Lymphocyte (LGL)
Gene Expression
Large Granular Lymphocyte Leukemia
LGL Leukemia
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Large Granular Lymphocytic
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, T-Cell
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Calcineurin Inhibitors