Early or Delayed Fludarabine and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia
Condition: Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: rituximab; fludarabine phosphate
Intervention description: Given IV over 4 hours; Given IV over 30 minutes
Intervention MeSH terms: Rituximab; Fludarabine; Fludarabine phosphate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 84.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: B-cell chronic lymphocytic leukemia; stage 0 chronic lymphocytic leukemia; stage I chronic lymphocytic leukemia

Summary:

      RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop
      the growth of cancer cells, either by killing the cells or by stopping them from dividing.
      Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some
      block the ability of cancer cells to grow and spread. Others find cancer cells and help kill
      them or carry cancer-killing substances to them. Giving fludarabine together with rituximab
      may kill more cancer cells. Sometimes the cancer may not need treatment until it progresses.
      In this case, observation may be sufficient. It is not yet known whether giving fludarabine
      together with rituximab early is more effective than giving fludarabine and rituximab after
      observation in treating chronic lymphocytic leukemia.

      PURPOSE: This randomized phase III trial is studying fludarabine and rituximab to compare how
      well they work when given early or after observation in treating patients with previously
      untreated chronic lymphocytic leukemia.
    

Eligibility criteria:

        Eligibility Criteria for Pre-Registration:

          1. Patients must be within 6 months of the initial flow cytometric confirmation of B-cell
             chronic lymphocytic leukemia (CLL). This interval begins with the initial flow
             cytometric confirmation of disease.

          2. Clinical and immunophenotypic evidence of CLL including:

             2.1 An absolute lymphocytosis of > 5,000/μL

               -  Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes.

               -  Local institution lymphocyte phenotype must reveal a predominant B-cell
                  monoclonal population sharing a B-cell marker (CD19, CD20, CD23) with the CD5
                  antigen, in the absence of other pan-T-cell markers.

               -  Additionally, the B-cells must be monoclonal with regard to expression of either
                  κ or λ and have surface immunoglobulin expression of low density.

               -  Patients with bright surface immunoglobulin levels must have CD23 coexpression
                  and absence of t(11;14) on interphase cytogenetics or have negative tumor protein
                  staining for cyclin D1.

             2.2 Staging - Patients must be in the low category (i.e., only stages 0 or I) of the
             modified three-stage Rai staging system as described in the protocol.

          3. Patients should not have evidence of active disease as demonstrated by any of the
             following criteria:

               -  Splenomegaly and/or massive/progressive lymphadenopathy that would require
                  therapy

               -  Presence of weight loss > 10% over the preceding 6 month period

               -  Grade 2 or 3 fatigue

               -  Fevers > 100.5°F or night sweats for greater than 2 weeks without evidence of
                  infection

               -  Progressive lymphocytosis with an increase of > 50% over a 2 month period or an
                  anticipated doubling time of less than 6 months.

          4. Prior Treatment: No prior therapy for CLL including corticosteroids for autoimmune
             complications that have developed since the initial diagnosis of CLL.

          5. Age ≥ 18 years

          6. Performance Status 0 - 1.

          7. No HIV disease. Due to alterations in host immunity, patients known to have HIV
             infection may not be enrolled.

          8. Non-pregnant and non-nursing. Due to the unknown teratogenic potential of
             chemotherapy, pregnant or nursing women may not be enrolled. Women and men of
             reproductive potential should agree to use an effective means of birth control.

          9. Required Initial Laboratory Values:

               -  Creatinine ≤ 1.5 x upper limit of normal

        Eligibility Criteria for Registration (to Low-Risk Cohort or High-Risk Cohort Randomization
        between Early Intervention Versus Observation with Later Treatment)

          1. Successful determination of IgVH mutational status by reference laboratory.

          2. Absence of progression of CLL, i.e., absence of the following:

               -  Progressive splenomegaly and/or lymphadenopathy on two independent measures
                  spaced two weeks apart. If one assessment notes progression, this should be
                  repeated prior to re-registration.

               -  Development of anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets <
                  100,000/μL).

               -  Progressive lymphocytosis with an increase of > 50% over a 2 month period or an
                  anticipated doubling time of less than 6 months.

               -  Symptoms referable to CLL, including weight loss > 10% over the preceding 6 month
                  period; grade 2 or 3 fatigue; or fevers > 100.5°F and/or night sweats for greater
                  than 2 weeks without evidence of infection.

          3. Required Laboratory Value:

               -  Creatinine ≤ 1.5 x upper limit of normal