This pilot phase II trial studies ibrutinib in treating patients with transformed indolent (a type of cancer that grows slowly) B-cell non-Hodgkin lymphoma that have returned after a period of improvement (relapsed) or do not respond to treatment (refractory). Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes (proteins) needed for cell growth.

OUTLINE:

Patients receive ibrutinib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for up to 5 years.

Inclusion Criteria:

• Patients must have histologically confirmed transformed indolent B-cell non-Hodgkin lymphoma that is relapsed or refractory to at least one line of therapy
• Patients must have a computed tomography (CT) (preferred) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis within 28 days of enrollment
• Patients must have measurable disease defined as lesions greater than 1.5 cm that can be accurately measured in two dimensions by CT (preferred), or MRI
• Patients must have a positron emission tomography (PET) scan within 56 days of enrollment
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• Absolute neutrophil count (ANC) >= 1000/mm^3 or >= 750/mm^3 in the setting of marrow involvement by disease
• Platelets >= 50,000/mm^3 or >= 30,000/mm^3 in the setting of marrow involvement by disease or splenomegaly due to disease
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
• Creatinine clearance (Clcr) > 25 mL/min
• Patients must be anticipated to complete 2 cycles of therapy in the opinion of the treating physician
• Women of childbearing potential and men who are sexually active must affirm they are practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials; men must agree to not donate sperm during or after the study; for females, these restrictions apply for 1 month after the last dose of study drug; for males, these restrictions apply for 3 months after the last dose of the study drug
• Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening; women who are pregnant or breastfeeding are ineligible for this study
• Sign (or their legally-acceptable representatives must sign) an informed consent document in accordance with institutional and federal guidelines indicating that they understand the investigational nature of and procedures required for the study, including biomarkers, and are willing to participate in and comply with the guidelines of the study

Exclusion Criteria:

• Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection
• Major surgery or a wound that has not fully healed within 4 weeks of initiation of therapy
• Known central nervous system lymphoma
• History of stroke or intracranial hemorrhage within 6 months of screening
• Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon)
• Requires chronic treatment with strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
• Vaccinated with live, attenuated vaccines within 4 weeks of initiation of therapy
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
• Patients with other prior malignancies except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, breast or cervical cancer in situ, or other cancer from which the patient has been disease-free for 5 years or greater, unless approved by the protocol sponsor-investigator/lead-sub-investigator
• Patients that previously were treated with ibrutinib for > 7 days
• Previous chemotherapy, immunotherapy, biologically targeted therapy, other investigational agent, or radiation therapy within 3 weeks of initiation of ibrutinib therapy or radio-immunotherapy within 12 weeks of initiation of ibrutinib therapy
• Prior allogeneic transplant with graft-versus-host disease (GVHD) requiring immunosuppressive therapy