Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): DNA Microarray Gene Expression Analysis
Condition: Chronic Lymphocytic Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Rituximab; Fludarabine phosphate; Leukemic or stroma cells
Intervention description: Rituxan; Fludara; Patients are eligible to donate cells for the purpose of analyzing leukemic cells. Cells can be donated by apheresis (e.g. 60-90 minute intravenous technique), lymph node biopsy (e.g. 3 biopsy/excision of lymph nodes)bone marrow biopsy (e.g. 2-4 separate bone marrow biopsies), and bone marrow aspiration (e.g. 3 to 5cc of marrow per aspirate).
Intervention MeSH terms: Rituximab; Fludarabine; Fludarabine phosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 105.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Genetics; Bone Marrow Transplantation; Immunosuppression; T Lymphocytes; Marrow Purging

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.
    

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.