Fludarabine and Rituximab With or Without Lenalidomide or Cyclophosphamide in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia
Condition: Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: Cyclophosphamide; Fludarabine Phosphate; Laboratory Biomarker Analysis; Lenalidomide; Rituximab
Intervention description: Given IV; Given IV or PO; Correlative studies; Given PO; Given IV
Intervention MeSH terms: Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate; Lenalidomide; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 418.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This randomized phase II trial studies how well fludarabine (fludarabine phosphate) and
      rituximab with or without lenalidomide or cyclophosphamide work in treating patients with
      symptomatic chronic lymphocytic leukemia. Drugs used in chemotherapy, such as fludarabine
      phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells,
      either by killing the cells, by stopping them from dividing, or by stopping them from
      spreading. Monoclonal antibodies, such as rituximab, may block cancer growth in different
      ways by targeting certain cells. Lenalidomide may stimulate the immune system in different
      ways and stop cancer cells from growing. Giving fludarabine phosphate and rituximab together
      with lenalidomide or cyclophosphamide may be an effective treatment for chronic lymphocytic
      leukemia.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Specific diagnosis of B-cell CLL:

               -  An absolute lymphocytosis of > 5,000/uL

                    -  Morphologically, the lymphocytes must appear mature with < 55%
                       prolymphocytes

                    -  Bone marrow examination must include at least a unilateral aspirate and
                       biopsy; the aspirate smear must show > 30% of all nucleated cells to be
                       lymphoid or the bone marrow core biopsy must show lymphoid infiltrates
                       compatible with marrow involvement by CLL; overall cellularity must be
                       normocellular or hypercellular

                    -  Local institution lymphocyte phenotype must reveal a predominant B-cell
                       monoclonal population sharing a B-cell marker (cluster of differentiation
                       [CD]19, 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 kappa or lambda and have surface immunoglobulin
                       expression of low density; patients with bright surface immunoglobulin
                       levels must have CD23 co-expression

          -  Patients must have symptomatic and active intermediate or high-risk categories of the
             modified three-stage Rai staging system:

               -  Not eligible: low risk, Rai stage 0, lymphocytes (L) in blood (> 5000/uL) and
                  marrow (> 30%) only

               -  Intermediate risk, Rai stage I, L + enlarged lymph nodes (LN)

               -  Intermediate risk, Rai stage II, L + spleen and/or liver (LN + or -)

               -  High risk, Rai stage III, L + anemia (hemoglobin < 11 gm/dL)

               -  High risk, Rai stage IV, L + thrombocytopenia (platelets < 100,000/uL)

          -  Patients in the intermediate-risk group must have evidence of active disease as
             demonstrated by at least one of the following criteria:

               -  Massive or progressive splenomegaly, hepatomegaly and/or lymphadenopathy

               -  Presence of weight loss > 10% over the preceding 6 month period

               -  Grade 2 or 3 fatigue

               -  Fevers > 100.5 degrees Fahrenheit (°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

          -  No prior therapy for CLL, including no corticosteroids for autoimmune complications
             that have developed since the initial diagnosis of CLL

          -  No medical condition requiring chronic use of oral corticosteroids

          -  Performance status 0 - 2

          -  Patients with human immunodeficiency virus (HIV) infection may be eligible provided
             they meet the following criteria: no evidence of infection with hepatitis B or C; CD4+
             cell count > 350/mm^3; no evidence of resistant strains of HIV; if not on anti-HIV
             therapy, an HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL; if on HIV
             therapy, HIV viral load < 50 copies HIV RNA/mL; and no history of acquired immune
             deficiency syndrome (AIDS)-defining condition; patients receiving concurrent
             zidovudine or stavudine may not be enrolled

          -  Non-pregnant and non-nursing

          -  In females of child-bearing potential randomized to Arm B or assigned to Arm D, a
             negative urine or serum pregnancy test with a sensitivity of at least 25 mIU/mL will
             be required: 1) 10-14 days prior to beginning lenalidomide consolidation therapy; and
             2) within 24 hours prior to the first dose of lenalidomide consolidation therapy; in
             addition, females of childbearing potential in Arm B and Arm D with regular menses
             must have a pregnancy test performed weekly during the first 28 days of treatment, and
             then every 28 days while taking lenalidomide (including breaks in lenalidomide), at
             discontinuation of lenalidomide, and then 28 days following discontinuation of
             lenalidomide; if menses are irregular, a pregnancy test must be performed weekly
             during the first 28 days of treatment, and then every 14 days while taking
             lenalidomide, at discontinuation of lenalidomide, and at 14 and 28 days after
             discontinuation of lenalidomide; additionally, females of childbearing potential must
             either commit to continued abstinence from heterosexual intercourse or begin TWO
             reliable methods of birth control - one highly effective method (intrauterine device
             [IUD], hormonal [birth control pills, injections, or implants], tubal ligation, or
             partner's vasectomy), and one additional effective method (latex condom, diaphragm, or
             cervical cap) - AT THE SAME TIME, at least 4 weeks before she begins lenalidomide
             therapy, while participating in the study, and for at least 4 weeks after completing
             lenalidomide therapy; "females of childbearing potential" is defined as a sexually
             mature woman who has not undergone a hysterectomy or bilateral oophorectomy, or who
             has had menses at any time in the preceding 24 consecutive months (not been naturally
             postmenopausal for at least 24 consecutive months)

          -  Male patients randomized to Arm B or reassigned to Arm D must agree not to father a
             child and to use a latex condom during any sexual contact with females of childbearing
             potential while taking lenalidomide and for at least 4 weeks following completion of
             lenalidomide therapy, even if the patient have undergone a successful vasectomy

          -  All patients randomized to Arm B or reassigned to Arm D must be counseled by a trained
             counselor every 28 days during consolidation therapy about pregnancy precautions and
             risks of fetal exposure

          -  Creatinine =< 1.5 x upper limit of normal