Ibrutinib as an Immune Modulating Agent for Patients With Asymptomatic, High-risk CLL/SLL Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Inclusion Criteria:

• Patients must have histologically identified chronic lymphocytic leukemia (CLL) orsmall lymphocytic lymphoma (SLL) as defined by the World Health Organization (WHO)classification of hematopoietic neoplasms

• CLL/SLL cells must demonstrate one or more of the following high-risk genomicfeatures:

• Del17p13.1(tumor protein p53 [TP53]) as detected by fluorescence in-situhybridization (FISH)

• Del11q22.3 ataxia telangiectasia mutated (ATM) as detected by FISH

• Complex karyotype (>= 3 cytogenetic abnormalities on stimulated karyotype)

• Unmutated immunoglobulin variable region heavy chain (IgVH) ( >= 98% sequencehomology compared with germline sequence)

• Zeta-chain (TCR) associated protein kinase 70kDa (ZAP-70) gene promoterhypomethylation < 20%

• No prior therapy for CLL/SLL, including chemotherapy and/or radiotherapy is allowed

• Estimated life expectancy of greater than 24 months

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Total bilirubin =< 1.5X upper limit of normal (ULN) unless secondary to Gilbert'sdisease

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5Xinstitutional upper limit of normal

• Serum creatinine =< 2 md/dL or estimated creatinine clearance (CrCl) > 50ml/min/bodysurface area (BSA)

• Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partialthromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) < 1.5 x ULN

• Able to swallow capsules without difficulty and no history of malabsorptionsyndrome, disease significantly affecting gastrointestinal function, or resection ofthe stomach or small bowel or active ulcerative colitis, symptomatic inflammatorybowel disease, or partial or complete bowel obstruction

• Female subjects who are of non-reproductive potential (i.e., post-menopausal byhistory - no menses for >= 1 year; OR history of hysterectomy; OR history ofbilateral tubal ligation; OR history of bilateral oophorectomy); female subjects ofchildbearing potential must have a negative serum pregnancy test upon study entry

• Male and female subjects who agree to use highly effective methods of birth control (eg, condoms, implants, injectables, combined oral contraceptives, some intrauterinedevices [IUDs], sexual abstinence, or sterilized partner) during the period oftherapy and for 30 days after the last dose of study drug

Exclusion Criteria:

• Patients meeting any of the following consensus criteria for initiating treatmentfor their CLL:

• Progressive symptomatic splenomegaly and/or lymphadenopathy identified byphysical examination

• Anemia ( < 11g/dL) or thrombocytopenia ( < 100,000/uL) due to bone marrowinvolvement

• Presence of unintentional weight loss > 10% over the preceding 6 months

• National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 3 fatigue

• Fevers > 100.5°F or night sweats for > 2 weeks without evidence of infection

• Patients who have had any treatment for their CLL/SLL, including but not limited tochemotherapy, radiotherapy, or immunotherapy, prior to entering the study

• No corticosteroid use will be permitted within two weeks prior to study, except formaintenance therapy for a non-malignant disease; maintenance therapy dose may notexceed 20 mg/day prednisone or equivalent

• Patients may not be receiving any other investigational agents

• History of allergic reactions attributable to compounds of similar chemical orbiologic composition to ibrutinib or any component of pneumococcal, influenza andDTaP vaccines

• Prior malignancy, except for adequately treated basal cell or squamous cell skincancer, in situ cervical cancer, or other cancer from which the subject isconsidered by his or her physician to have a less than 2-year survival expectation

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection and/or psychiatric illness/social situations that would limit compliancewith study requirements

• Currently active, clinically significant cardiovascular disease, such asuncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by theNew York Heart Association Functional Classification; or a history of myocardialinfarction, unstable angina, or acute coronary syndrome within 6 months prior torandomization

• Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.,or chronic administration [> 14 days] of > 20mg/day of prednisone) within 14 days ofthe first dose of study drug

• Patients must discontinue treatment with H2-blockers (cimetidine, ranitidine, etc.)prior to beginning protocol therapy

• Vaccinated with any of the vaccines planned for administration in the trial within 8weeks of starting treatment on the study

• Recent infection requiring systemic treatment that was completed =< 14 days beforestarting treatment on the study

• Concomitant use of warfarin or other vitamin K antagonists

• Patients who require treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor

• Known bleeding disorders (eg, von Willebrand's disease) or hemophilia

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

• Known history of human immunodeficiency virus (HIV) or active infection withhepatitis C virus (HCV) or hepatitis B virus (HBV); patients who are positive forhepatitis B core antibody or hepatitis B surface antigen must have a negativepolymerase chain reaction (PCR) result before enrollment; those who are PCR positivewill be excluded

• Major surgery within 4 weeks of starting trial

• Any life-threatening illness, medical condition, or organ system dysfunction that,in the investigator's opinion, could compromise the subject's safety or put thestudy outcomes at undue risk

• Lactating or pregnant

• Unwilling or unable to participate in all required study evaluations and procedures

• Unable to understand the purpose and risks of the study and to provide a signed anddated informed consent form (ICF) and authorization to use protected healthinformation (in accordance with national and local subject privacy regulations)