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Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): DNA Microarray Gene Expression Analysis


Phase 2
18 Years
N/A
Not Enrolling
Both
Chronic Lymphocytic Leukemia

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Trial Information

Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): DNA Microarray Gene Expression Analysis


Background:

- Due to their synergistic action and non-overlapping toxicity profiles, the combination
of Rituximab and Fludarabine is the treatment of choice for advanced stage chronic
lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL).

- As such, we have designed this protocol to better understand the genetic basis of
CLL/SLL, to identify predictors of treatment response and to study the molecular
effects of Rituximab Fludarabine on the leukemic cells.

- A new technology utilizing complementary deoxyribonucleic acid (cDNA) microarrays now
permits the simultaneous quantitation of the expression of thousands of genes; this
methodology can evaluate defined cellular pathways, and also discover novel genes
influencing cell biology.

- In addition to improving our understanding of the pathogenesis of CLL/SLL, these
molecular studies may identify new therapeutic targets in CLL/SLL, and may help to
identify those CLL/SLL patients most likely to respond to the combination of
Fludarabine and Rituximab.

Objectives:

- Evaluate CLL/SLL patients during and following Rituximab Fludarabine chemotherapy for
changes in lymphocyte gene expression using DNA microarray analysis.

- Evaluate gene expression by DNA microarray analysis of leukemic cells in blood, bone
marrow and lymph nodes.

Eligibility:

- Low, Intermediate or High-Risk Category of CLL/SLL, using the Modified Three- Stage Rai
Staging System

- Age greater than or equal to 18 years.

- Patients must have received no previous cytotoxic or monoclonal antibody therapy.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

- Patients must not be pregnant or breast-feeding.

- Patients with active autoimmune hemolytic anemia (AIHA)) grade III or higher
(transfusion or steroids indicated) or immune thrombocytopenia (ITP) grade III or
higher (platelets less than 50,000/microL) shall not be enrolled.

- Any patient with a medical condition that requires chronic use of corticosteroids shall
not be enrolled.

Design:

- Patients who do not require treatment will be followed every 3-6 months and will donate
cellular products, bone marrow biopsies, bone marrow aspirates and/or lymph nodes for
research purposes.

- Patients who do require treatment will received the standard dose of the Rituximab
monoclonal antibody and the standard dose of Fludarabine for a total of six cycles. In
the first cycle, Rituximab will be given on day 1 with Fludarabine being given on days
2-6. This will allow for appropriate samplings of the effects of Rituximab on
lymphocytes before during and at the end of the first 24 hours. In subsequent cycles
2-6, the Rituximab and day 1 Fludarabine can both be given on day 1.

Inclusion Criteria


- INCLUSION CRITERIA:

Diagnosis of chronic lymphocytic lymphoma (CLL)/small lymphocytic lymphoma (SLL) will be
made according to the World Health Organization (WHO) diagnostic classification. A
lymphocyte count in excess of 5000/mcl is typically found in the leukemic variant but is
not a pre-requisite for a diagnosis of SLL. Low, Intermediate or High-Risk Category of
CLL/SLL, using the Modified Three-Stage Rai Staging System as follows:

Risk Category: Low Risk

Rai Stage: 0

Clinical Features: Elevated blood and marrow lymphocyte numbers only (L). (lymphocytes
greater than 5000/microl in blood, and lymphocytes greater than 30 percent in marrow).

Risk Category: Intermediate Risk

Rai Stage: I

Clinical Features: L + enlarged lymph nodes (LN)

Risk Category: Intermediate Risk

Rai Stage: II

Clinical Features: L + enlarged spleen or liver

Risk Category: High Risk

Rai Stage: III

Clinical Features: L + anemia (Hemoglobin less than 11 gm/dl)

Risk Category: High Risk

Rai Stage: IV

Clinical Features: L + thrombocytopenia (platelets less than 100,000/microl)

Patients in the modified Rai high risk group and select patients in the intermediate risk
group will undergo treatment with Rituximab Fludarabine. To meet treatment criteria
patients in the intermediate risk group should have evidence of active disease as
demonstrated by at least one of the following criteria:

1. massive or progressive splenomegaly or lymphadenopathy;

2. presence of weight loss greater than 10% over the preceding 6 months;

3. constitutional symptoms of extreme fatigue, night sweats or recurrent fever of
greater than 100 degrees F (documented fevers must be occurring without evidence of
specific infection), and bone pain;

4. progressive lymphocytosis with an increase of greater than 50% over a 2 month period,
or an anticipated doubling time of less than 6 months;

5. chronic infections either increased number or prolonged infections;

6. other high risk prognostic indicators such as excess elevation of
beta-2-microglobulin, cluster differentiation 38 (CD38) expression and adverse
cytogenetics may be used to better appraise the risk in each individual patient.

Patients with a diagnosis of CLL/SLL who do not meet the eligibility criteria for
receiving Rituximab and Fludarabine (are not intermediate- or high-risk CLL/SLL), can
enroll on the protocol for the purpose of donating cellular products. Such patients will
not receive rituximab and fludarabine chemotherapy. At a later date, if it is documented
that the patient does meet the criteria, then the patient may receive Rituximab and
Fludarabine (after discussion with the Principal Investigator).

In a limited number of cases, patients with low-risk CLL/SLL may be initiated on Rituximab
and Fludarabine treatment. For example, individuals who are candidates for bone marrow
transplantation may be started on Rituximab Fludarabine as an induction regimen prior to
transplantation. Additionally, some low-risk patients may be started on Rituximab and
Fludarabine for psychological reasons (patient insistence on starting chemotherapy prior
to disease progression). However, it must be stressed that low-risk CLL/SLL patients will
be discouraged from initiating therapy except in these specific cases.

Age greater than or equal to 18 years of age.

Patients must have received no prior cytotoxic or monoclonal antibody therapy.

Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

Required initial laboratory tests: Blood urea nitrogen (BUN) and Creatinine values must
be less than or equal to 1.5 times the normal values; alternatively, patients with
creatinine clearance of greater than 50 ml per minute will also be eligible. Aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) values must be less than or
equal to 2.0 times normal values; patients with laboratory values greater than these
levels may be enrolled on the protocol (after a specific approval from the Principal
Investigator) if the values are due to a known, pre-existing liver disease. Bilirubin
must be less than or equal to 2.0 mg/dl unless due to Gilbert's disease.

The patient must be competent to sign an informed consent, and sign the protocol consent
form.

EXCLUSION CRITERIA:

Patients must not be pregnant or breastfeeding.

Patients with active autoimmune hemolytic anemia (AIHA)) grade III or higher (transfusion
or steroids indicated) or immune thrombocytopenia (ITP) grade III or higher (platelets
less than 50,000/microL) shall not be enrolled. Patients with a history of prior therapy
to control either AIHA or ITP will be eligible, provided they do not require maintenance
corticosteroids, and have not received monoclonal antibody therapy in the past 6 months.
Patients developing AIHA or ITP on protocol may be managed as medically indicated on
protocol but will generally not undergo fludarabine/rituximab treatment until resolution
of hemolysis or thrombocytopenia to less than grade III.

Any patient with a medical condition that requires chronic use of corticosteroids shall
not be enrolled.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Change in Gene Expression Post Chemo

Outcome Description:

Changes in lymphocyte gene expression was measured by deoxyribonucleic acid (DNA) microarray analysis of circulating leukemic cells after completion of study treatment. A change in expression is defined as a >50% increase in circulating leukemic cells or a 30% decrease in circulating leukemic cells.

Outcome Time Frame:

6 hours post treatment, and 24 hours post treatment

Safety Issue:

No

Principal Investigator

Wyndham H Wilson, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health

Authority:

United States: Federal Government

Study ID:

970178

NCT ID:

NCT00001586

Start Date:

September 1997

Completion Date:

November 2011

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • Genetics
  • Bone Marrow Transplantation
  • Immunosuppression
  • T Lymphocytes
  • Marrow Purging
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892