Clinical trial NCT00001586: Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): DNA Microarray Gene Expression Analysis
Official title: Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): DNA Microarray Gene Expression Analysis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Keywords: Genetics
Bone Marrow Transplantation
Immunosuppression
T Lymphocytes
Marrow Purging
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 1999-11-04
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

* Combined therapy with rituximab and fludarabine is the treatment of choice for advanced stage chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
* A new technology called deoxyribonucleic acid (DNA) microarray can be used to gain knowledge about the genetic basis of CLL/SLL.
* Genetic studies of CLL/SLL may improve our understanding of what happens in the disease, help determine which patients are most likely to respond to treatment with fludarabine and rituximab, and identify new treatments.

Objectives:

-To gain further knowledge about CLL/SLL and the role of rituximab and fludarabine in treating the disease.

Eligibility:

-Patients 18 years of age and older with low, intermediate or high-risk CLL/SLL.

Design:

* Patients with low-risk CLL/SLL do not receive treatment, but are followed every 3 to 6 months and donate cells (through apheresis) or lymph nodes, or both, for research purposes.
* Patients with intermediate or high-risk CLL/SLL receive standard treatment with rituximab and fludarabine for six 28-day treatment cycles. Rituximab is given on day 1 and fludarabine is given on days 1-5. (For the first cycle only, fludarabine treatment starts on day 2. This delay permits blood sampling on day 1 for the effect of rituximab on white blood cells.)
* Laboratory tests and imaging studies are done periodically to monitor drug side effects and the response to treatment. Tests include bone marrow biopsy and aspiration, blood tests and x-rays, including positron emission tomography (PET) and computed tomography (CT) scans.

Detailed description: 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.

Eligibility 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.

Primary outcomes:
measure: Change in Gene Expression Post Chemo
timeFrame: 6 hours post treatment, and 24 hours post treatment
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 13 years, 10.5 months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute, National Institutes of Health
name: Wyndham H Wilson, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
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