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

NCT00363779 | Terminated Phase 2 Results

• 2 other identifiers: 06017706-C-0177
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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 For apheresis, blood is withdrawn through a needle in an arm vein and directed through a catheter (plastic tube) into a machine that separates it into its components.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

Conditions

Large Granular Lymphocytic Leukemia; LGL Leukemia

Keywords

Large Granular Lymphocyte (LGL); LGL; Leukemia; Cyclosporine; Microarray; Gene Expression; Cyclosporin; Large Granular Lymphocyte Leukemia; LGL Leukemia

Outcome Measures

Primary Outcomes (1)

• Changes in Gene Expression Patterns

  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.

  Baseline and 12 weeks

Secondary Outcomes (1)

• Number of Participants With Adverse Events

  3 months

Study Arms (1)

LGL Patients administered cyclosporine

EXPERIMENTAL

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; Genetic: Gene expression analysis; Genetic: Microarray analysis; Other: Laboratory biomarker analysis

Interventions

Cyclosporine DRUG

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.

Also known as: Ciclosporin

LGL Patients administered cyclosporine

Gene expression analysis GENETIC

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.

LGL Patients administered cyclosporine

Microarray analysis GENETIC

Gene expression profiling will be carried out on Affymetrix microarrays to compare pretreatment and posttreatment samples.

LGL Patients administered cyclosporine

Laboratory biomarker analysis OTHER

Analysis of differential gene expression profiles in patients with LGL leukemia treated with cyclosporine.

LGL Patients administered cyclosporine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.
• Patients must have measurable or evaluable disease
• Patients must have a creatinine of less than 2.0 mg/dl.
• Omission of cytotoxic chemotherapy for 3 weeks prior to entry into the trial is required. However, patients receiving stable corticosteroids will be eligible.
• Age greater than 18 years
• Karnofsky performance greater than 70%
• Patients must have a life expectancy of greater than 3 months.
• Patients must be able to understand and sign an Informed Consent form.
• All female patients must use adequate contraception during participation in this trial and for three months after completing therapy.

You may not qualify if:

• Patients with uncontrolled hypertension
• 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.
• Underlying immunodeficiency state including human immunodeficiency virus (HIV) seropositivity.
• Positive for antibodies to hepatitis C or positive for hepatitis B surface antigen,
• 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.
• Patients who received cyclosporine for LGL leukemia previously and failed to respond.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Lamy T, Loughran TP Jr. Clinical features of large granular lymphocyte leukemia. Semin Hematol. 2003 Jul;40(3):185-95. doi: 10.1016/s0037-1963(03)00133-1.

  PMID: 12876667 BACKGROUND

• Vie H, Chevalier S, Garand R, Moisan JP, Praloran V, Devilder MC, Moreau JF, Soulillou JP. Clonal expansion of lymphocytes bearing the gamma delta T-cell receptor in a patient with large granular lymphocyte disorder. Blood. 1989 Jul;74(1):285-90.

  PMID: 2546620 BACKGROUND

• Lamy T, Dauriac C, Le Prise PY. Long-term survival in chronic granulocytic leukaemia. Br J Haematol. 1989 Oct;73(2):279. doi: 10.1111/j.1365-2141.1989.tb00270.x. No abstract available.

  PMID: 2818949 BACKGROUND

Related Links

• Genetics Home Reference
• Medline Plus
• Drug Information
• US FDA Resources

MeSH Terms

Conditions

Leukemia, Large Granular Lymphocytic; Leukemia

Interventions

Cyclosporine; Gene Expression Profiling; Microarray Analysis

Condition Hierarchy (Ancestors)

Leukemia, T-Cell; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Genetic Techniques; Investigative Techniques; Microchip Analytical Procedures

Limitations and Caveats

As there were only 5 patients treated, the primary endpoints of this protocol were not met and there is not enough data generated for statistical analysis. This protocol is being terminated due to low accrual and the investigator leaving the NIH.

Results Point of Contact

• Title: Thomas Waldmann, M.D.
• Organization: National Cancer Institute (NCI), National Institutes of Health (NIH)

Thomas_Waldmann@nih.gov

301-496-6653

Study Officials

• Thomas Waldmann, M.D.

  National Cancer Institute, National Institutes of Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 10, 2006
• First Posted: August 15, 2006
• Study Start: June 1, 2006
• Primary Completion: November 1, 2010
• Study Completion: November 1, 2010
• Last Updated: July 21, 2015
• Results First Posted: July 6, 2012

Record last verified: 2015-06

Locations

US (1)