Open-label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-naive CLL or SLL

Inclusion Criteria:

1. Males or females of 65 years of age or greater. Patients between the ages of 65 and 70years of age must have 1 or more of the following comorbidities that may preclude theuse of frontline chemo-immunotherapy with fludarabine, cyclophosphamide, or rituximab:

• creatinine clearance < 70 mL/min using the Cockcroft-Gault equation

• platelet count < 100,000/μL or hemoglobin < 10 g/dL

• clinically apparent autoimmune cytopenia (autoimmune hemolytic anemia or immunethrombocytopenia)

• ECOG performance score = 1 or 2

2. Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008)

3. Active disease meeting at least 1 of the following IWCLL criteria (Hallek 2008) forrequiring treatment:

• Evidence of progressive marrow failure as manifested by the development of, orworsening of, anemia and/or thrombocytopenia Massive, progressive, or symptomaticsplenomegaly

• Massive nodes or progressive or symptomatic lymphadenopathy

• Progressive lymphocytosis

• Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorlyresponsive to corticosteroids or standard therapy

• Constitutional symptoms

4. Measurable nodal disease by computed tomography (CT)

5. ECOG performance status of 0-2

6. Life expectancy > 4 months from randomization

7. Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1,000/μL (independent of growth factor support for at least 7 days prior to screening) andplatelet count ≥ 50,000/μL (independent of transfusion and growth factor support forat least 7 days prior to screening)

8. Adequate hepatic function, defined as serum aspartate transaminase (AST) and alaninetransaminase (ALT) < 2.5 x upper limit of normal (ULN), and total bilirubin ≤ 1.5 xULN

9. Adequate renal function, defined as estimated creatinine clearance ≥ 30 mL/min usingthe Cockcroft-Gault equation

10. Willingness to receive all outpatient treatment, all laboratory monitoring, and allradiological evaluations at the institution that administers study drug for the entirestudy

11. Willingness of male patients, if sexually active with a female of childbearingpotential, to use an effective barrier method of contraception during the study andfor 3 months following the last dose of study drug

12. Ability to provide written informed consent and to understand and comply with therequirements of the study

Exclusion Criteria:

1. Known involvement of the central nervous system by lymphoma or leukemia

2. History or current evidence of Richter's transformation or prolymphocytic leukemia

3. Documentation of deletion of the short arm of chromosome 17: del(17p13.1) in more than 20% of cells examined on any pretreatment fluorescence in situ hybridization (FISH) orcytogenetic evaluation

4. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura

5. Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies)intended specifically to treat CLL/SLL

6. Received any immunotherapy, vaccine, or investigational drug within 4 weeks prior torandomization

7. Corticosteroid use within 1 week prior to first dose of study drug, with the exceptionof inhaled, topical, or other local administrations. Patients requiring systemicsteroids at daily doses > 20 mg prednisone (or corticosteroid equivalent, see AppendixN), or those who are administered steroids for leukemia control or white blood cell (WBC)-count-lowering are excluded.

8. Major surgery within 4 weeks prior to randomization

9. History of prior malignancy, with the exception of the following:

• malignancy treated with curative intent and with no evidence of active diseasepresent for more than 3 years prior to screening and felt to be at low risk forrecurrence by treating physician

• adequately treated nonmelanomatous skin cancer or lentigo maligna melanomawithout current evidence of disease

• adequately treated cervical carcinoma in situ without current evidence of disease

10. Currently active, clinically significant cardiovascular disease or a history ofmyocardial infarction within 6 months prior to randomization

11. Inability to swallow capsules or tablets, or disease significantly affectinggastrointestinal function

12. Uncontrolled active systemic fungal, bacterial, viral, or other infection orrequirement for intravenous (IV) antibiotics

13. Known history of infection with human immunodeficiency virus (HIV)

14. Serologic status reflecting active hepatitis B or C infection

15. History of stroke or intracranial hemorrhage within 6 months prior to enrollment

16. Current life-threatening illness, medical condition, or organ-system dysfunction thatcould compromise patient safety or put the study at risk

17. Requirement for anticoagulation with warfarin

18. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor