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

This randomized phase II trial studies how well ibrutinib works when given together with vaccine therapies in treating patients without clinical signs or indications that raise the possibility of a particular disorder or dysfunction (asymptomatic) who have high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Vaccines, such as pneumococcal 13-valent conjugate vaccine, trivalent influenza vaccine, and diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine adsorbed, may help the body build an effective immune response to kill cancer cells. Giving ibrutinib together with vaccine therapies may be a better treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma.

PRIMARY OBJECTIVES:

I. To determine the 2-year progression-free survival of asymptomatic, high-risk genomic chronic lymphocytic leukemia (CLL) patients treated with ibrutinib.

SECONDARY OBJECTIVES:

I. To determine whether concurrent administration of ibrutinib with 2 doses of the pneumococcal vaccine (pneumococcal 13-valent conjugate vaccine) does not negatively impact the immune response compared to those who receive the pneumococcal vaccination with sequential therapy.

II. To determine the safety and toxicity associated with administering ibrutinib to asymptomatic, high-risk genomic CLL patients.

III. To determine the response pattern (complete response \[CR\] minimal residual disease \[MRD\]-, CR, partial response \[PR\], PR with lymphocytosis, stable disease \[SD\]) in asymptomatic, genomic high-risk patients treated with ibrutinib.

VI. To determine changes in the stress, anxiety and depressive symptoms, and related quality of life indicators from patients treated with ibrutinib.

Eligibility Criteria:
Inclusion Criteria:

* Patients must have histologically identified chronic lymphocytic leukemia (CLL) or small 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 genomic features:

  * Del17p13.1(tumor protein p53 \[TP53\]) as detected by fluorescence in-situ hybridization (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% sequence homology compared with germline sequence)
  * Zeta-chain (TCR) associated protein kinase 70kDa (ZAP-70) gene promoter hypomethylation \< 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's disease
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 2.5X institutional upper limit of normal
* Serum creatinine =\< 2 md/dL or estimated creatinine clearance (CrCl) \> 50ml/min/body surface area (BSA)
* Prothrombin time (PT)/international normalized ratio (INR) \< 1.5 x ULN and partial thromboplastin time (PTT) (activated partial thromboplastin time \[aPTT\]) \< 1.5 x ULN
* Able to swallow capsules without difficulty and no history of malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or active ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction
* Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for \>= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female subjects of childbearing 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 intrauterine devices \[IUDs\], sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug

Exclusion Criteria:

* Patients meeting any of the following consensus criteria for initiating treatment for their CLL:

  * Progressive symptomatic splenomegaly and/or lymphadenopathy identified by physical examination
  * Anemia ( \< 11g/dL) or thrombocytopenia ( \< 100,000/uL) due to bone marrow involvement
  * 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 to chemotherapy, radiotherapy, or immunotherapy, prior to entering the study
* No corticosteroid use will be permitted within two weeks prior to study, except for maintenance therapy for a non-malignant disease; maintenance therapy dose may not exceed 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 or biologic composition to ibrutinib or any component of pneumococcal, influenza and DTaP vaccines
* Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject is considered by his or her physician to have a less than 2-year survival expectation
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection and/or psychiatric illness/social situations that would limit compliance with study requirements
* Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
* Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration \[\> 14 days\] of \> 20mg/day of prednisone) within 14 days of the 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 8 weeks of starting treatment on the study
* Recent infection requiring systemic treatment that was completed =\< 14 days before starting 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 with hepatitis C virus (HCV) or hepatitis B virus (HBV); patients who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will 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 the study 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 and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)