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

NCT ID: NCT00363779

Last Updated: 2015-07-21

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-06-30
• Study Completion Date: 2010-11-30

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 For apheresis, blood is withdrawn through a needle in an arm vein and directed through a catheter (plastic tube) into a machine that separates it into its components.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

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.

Conditions

Large Granular Lymphocytic Leukemia; LGL Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cyclosporine

Intervention Type: 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.

Gene expression analysis

Intervention Type: 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.

Microarray analysis

Intervention Type: GENETIC

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

Laboratory biomarker analysis

Intervention Type: OTHER

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

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: GENETIC

Microarray analysis

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

Intervention Type: GENETIC

Laboratory biomarker analysis

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

Intervention Type: OTHER

Other Intervention Names

Ciclosporin

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Thomas Waldmann, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Thomas Waldmann, M.D.

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute, National Institutes of Health

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 12876667 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 2546620 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 2818949 (View on PubMed)

Related Links

http://ghr.nlm.nih.gov/

Genetics Home Reference

http://www.nlm.nih.gov/medlineplus/

Medline Plus

http://druginfo.nlm.nih.gov/drugportal/drugportal.jsp

Drug Information

http://www.clinicaltrials.gov/ct2/info/fdalinks

US FDA Resources

Other Identifiers

06-C-0177

Identifier Type: -

Identifier Source: secondary_id

060177

Identifier Type: -

Identifier Source: org_study_id