Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated 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: Bendamustine Hydrochloride; Ibrutinib; Laboratory Biomarker Analysis; Quality-of-Life Assessment; Rituximab
Intervention description: Given IV; Given PO; Correlative studies; Ancillary studies; Given IV
Intervention MeSH terms: Rituximab; Antineoplastic Agents, Immunological; Bendamustine Hydrochloride; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 547.0
Sex: All
Minimum age: 65 Years
Healthy volunteers: No

Summary:

      This randomized phase III trial studies rituximab with bendamustine hydrochloride or
      ibrutinib to see how well they work compared to ibrutinib alone in treating older patients
      with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as
      rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used
      in chemotherapy, such as bendamustine hydrochloride, 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. Ibrutinib may stop the growth of cancer cells by blocking some
      of the enzymes needed for cell growth. It is not yet known whether rituximab with
      bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in
      treating chronic lymphocytic leukemia.
    

Eligibility criteria:

        Inclusion Criteria:

          -  PRE-REGISTRATION (STEP 0)

          -  All patients are REQUIRED to be pre-registered to A041202 in order to submit
             peripheral blood to the Alliance Hematologic Malignancy Biorepository (HEME) for
             central Zap-70 methylation. This specimen submission is mandatory prior to
             registration as results will be used for stratification

          -  REGISTRATION (STEP 1)

          -  Patients must be diagnosed with CLL in accordance with International Workshop on
             Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that includes all of the following:

               -  >= 5 x 10^9 B lymphocytes (5000/uL) in the peripheral blood

               -  On morphologic review, the leukemic cells must be small mature lymphocytes, and
                  prolymphocytes must not exceed 55% of the blood lymphocytes

               -  CLL cells on immunophenotype (performed locally) must reveal a clonal B-cell
                  population, which express the B cell surface markers of CD19 and CD20, as well as
                  the T-cell antigen CD5; patients with bright surface immunoglobulin expression or
                  lack of CD23 expression in > 10% of cells must lack t(11;14) translocation by
                  interphase cytogenetics

          -  Patients must be intermediate or high-risk Rai stage CLL

               -  Intermediate risk (formerly Rai stage I/II) is defined by lymphocytosis plus
                  enlarged lymph nodes at any site, with or without hepatomegaly or splenomegaly

               -  High risk (formerly Rai stage III/IV) is defined by lymphocytosis with or without
                  enlarged nodes and spleen plus disease-related anemia (hemoglobin < 11 g/dL) or
                  thrombocytopenia (platelet count < 100 x 10^9/L) that is not attributable to
                  autoimmune hemolytic anemia or thrombocytopenia

          -  Patients must meet criteria for treatment as defined by IWCLL 2008 guidelines which
             includes at least one of the following criteria:

               -  Evidence of marrow failure as manifested by the development or worsening of
                  anemia or thrombocytopenia (not attributable to autoimmune hemolytic anemia or
                  thrombocytopenia)

               -  Massive (>= 6 cm below the costal margin), progressive or symptomatic
                  splenomegaly

               -  Massive nodes (>= 10 cm) or progressive or symptomatic lymphadenopathy

               -  Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard
                  therapy

               -  Constitutional symptoms, which include any of the following:

                    -  Unintentional weight loss of 10% or more within 6 months

                    -  Significant fatigue

                    -  Fevers > 100.5 degrees F for 2 weeks or more without evidence of infection

                    -  Night sweats > 1 month without evidence of infection

          -  Age >= 65 years

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Patients with active hepatitis B defined by hepatitis B surface antigen positivity or
             core antibody positivity in the presence of hepatitis B DNA are not eligible for this
             study; patients with a positive hepatitis B core antibody but with negative hepatitis
             B DNA may participate, but must have hepatitis serologies and hepatitis B DNA
             monitored periodically by the treating physician

               -  Intravenous immunoglobulin (IVIG) can cause a false positive hepatitis B
                  serology; if patients receiving routine IVIG have core antibody or surface
                  antigen positivity without evidence of active viremia (negative hepatitis B DNA)
                  they may still participate in the study, but should have hepatitis serologies and
                  hepatitis B DNA monitored periodically by the treating physician

          -  Patients with class III or class IV heart failure by New York Heart Association, those
             with unstable angina, and those with uncontrolled arrhythmia are not eligible

          -  Patients who have had a myocardial infarction, intracranial bleed, or stroke within
             the past 6 months are not eligible

          -  Patients with known human immunodeficiency virus (HIV) are eligible if their CD4 count
             is >= 350 cells/mm^3 and if they are not taking prohibited CYP-interacting medications

          -  Patients may not have had major surgery within 10 days of enrollment, or minor surgery
             within 7 days of enrollment; examples of minor surgery include dental surgery,
             insertion of a venous access device, skin biopsy, or aspiration of a joint; the
             decision about whether a surgery is major or minor can be made at the discretion of
             the treating physician

          -  Absolute neutrophil count (ANC) >= 1,000/uL unless due to bone marrow involvement

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (AST) =< 2.5 x upper
             limits of normal except if due to disease infiltration of the liver

          -  Bilirubin =< 1.5 x upper limits of normal (unless due to liver involvement, hemolysis,
             or Gilbert's disease)

          -  Creatinine clearance >= 40 mL/min

               -  To be calculated by modified Cockcroft-Gault formula

          -  Platelet count (untransfused) >= 30,000/uL

        Exclusion Criteria:

          -  Prior treatment

               -  Patients must not have had prior therapy for CLL (except palliative steroids or
                  treatment of autoimmune complications of CLL with rituximab or steroids)

               -  Treatment with rituximab and/or high dose corticosteroids for autoimmune
                  complications of CLL must be complete at least 4 weeks prior to enrollment;
                  palliative steroids must be at a dose not higher than 20 mg/day of prednisone or
                  equivalent corticosteroid at the time of registration

          -  Patients must not be receiving active systemic anticoagulation with heparin or
             warfarin; patients must be off warfarin therapy for at least 30 days prior to
             enrollment

          -  Patients must not have any history of Richter's transformation or prolymphocytic
             leukemia (prolymphocytes in blood > 55%)

          -  Patients must not require more than 20 mg prednisone or equivalent corticosteroid
             daily

          -  Patients must not have uncontrolled active systemic infection requiring intravenous
             antibiotics

          -  Patients must not have continued requirement for therapy with a strong cytochrome P450
             3A4/5 (CYP3A4/5) inhibitor or inducer

          -  Patients must not have a known allergy to mannitol

          -  Patients must not have prior significant hypersensitivity to rituximab (not including
             infusion reactions)