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
  Purpose

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 For apheresis, blood is withdrawn through a needle in an arm vein and directed through a catheter (plastic tube) into a machine that separates it into its components.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

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

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Microarray Analysis of the Effect of Cyclosporine Therapy on Gene Expression Patterns in Large Granular Lymphocytic Leukemia

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 5
Study Start Date: June 2006
Study Completion Date: November 2010
Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Detailed Description:

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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00363779

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Thomas Waldmann, M.D. National Cancer Institute, National Institutes of Health
  More Information

Additional Information:
Publications:
Responsible Party: John E. Janik, M.D./National Cancer Institute, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00363779     History of Changes
Other Study ID Numbers: 060177, 06-C-0177
Study First Received: August 10, 2006
Results First Received: March 30, 2012
Last Updated: July 6, 2012
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Large Granular Lymphocyte (LGL)
LGL
Leukemia
Cyclosporine
Microarray
Gene Expression
Cyclosporin
Large Granular Lymphocyte Leukemia
LGL Leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Large Granular Lymphocytic
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, T-Cell
Cyclosporins
Cyclosporine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on August 26, 2014