Inclusion Criteria:

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

• Patients must have paraffin tissue from the diagnostic or relapse biopsy available to be submitted for central pathology review.

ELIGIBILITY CRITERIA (STEP 1)

• Diagnosis of World Health Organization (WHO) diffuse large B-cell lymphoma, high grade B-cell lymphoma not otherwise specified, non-GCB by central review confirmation.
• Patient must be deemed eligible to proceed with high-dose chemotherapy and autologous stem cell transplantation by local transplant center.
• New York Heart Association class I or less; ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or angina pain; patients 60 years or older must have a left ventricular ejection fraction (LVEF) at rest ≥ 40% measured by echocardiogram or multi-gated acquisition (MUGA).
• Diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 40% of predicted (corrected for hemoglobin).
• Forced expiratory volume in 1 second (FEV1) ≥ 40% of predicted (corrected for hemoglobin).
• Forced vital capacity (FVC) ≥ 40% of predicted (corrected for hemoglobin).
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) unless isolated hyperbilirubinemia attributed to Gilbert's syndrome.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN).
• Creatinine ≤ 2.0 mg/dL OR creatinine clearance (calculated clearance permitted) ≥ 40 mL/min by Cockcroft-Gault formula.
• Prothrombin time (PT)/ international normalized ration (INR) < 1.5 x ULN and partial thromboplastin time (PTT) (activated [a]PTT) < 1.5 x ULN.
• Patient must have progressed or be refractory to prior anthracycline-containing chemotherapy (e.g., R-CHOP, DA-EPOCH-R, etc.).
• No more than 3 prior regimens for large cell component (e.g., one induction and two salvage therapies); monoclonal antibody alone or involved field/involved site radiotherapy do not count as lines of therapy.
• Prior use of ibrutinib is allowed unless patient has had disease progression while receiving ibrutinib.
• Patient must have chemosensitive disease as defined by at least a partial response to salvage therapy at their latest assessment.
• No major surgery ≤ 7 days prior to registration and no minor surgery ≤ 3 days prior to registration (with the exception of intravenous access placement; e.g., Hickman or peripherally inserted central catheter [PICC]).
• Not pregnant and not nursing; for women of childbearing potential only, a negative serum pregnancy test must be obtained within 14 days prior to registration.
  • Women of childbearing potential must use adequate contraception from study start to one month after the last dose of protocol therapy; adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence; men must practice complete abstinence or agree to use an adequate contraception method from study start to one month after the last dose of protocol therapy.
• Patients should not require chronic use of strong CYP3A inhibitors or strong CYP3A inducers.
• Patients should not require concurrent therapeutic doses of steroids (> 20 mg of prednisone/day or equivalent) unless they need them for the indications; steroids should be discontinued for 14 days before starting protocol treatment.
• Human immunodeficiency virus (HIV) infected patients are eligible provided they meet all other eligibility criteria, and:
  • There is no prior history of acquired immunodeficiency syndrome (AIDS) defining conditions other than historically low CD4+ T-cell count or B-cell lymphoma;
  • In the opinion of an expert in HIV disease, prospects for long-term survival are excellent were it not for the diagnosis of lymphoma;
  • Use of HIV protease inhibitors as part of the anti-HIV regimen OR as a pharmacologic booster is not allowed;
  • Zidovudine is not allowed;
  • Once daily combination pills for HIV containing a pharmacologic booster such as cobicistat are not allowed;
  • Patients with multi-drug resistant HIV are not eligible.
• Patients cannot have:
  • Active central nervous system or meningeal involvement by lymphoma; patients with a history of central nervous system (CNS) or meningeal involvement must be in a documented remission by cerebrospinal fluid (CSF) evaluation and contrast-enhanced magnetic resonance imaging (MRI) imaging for at least 91 days prior to registration;
  • Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy;
  • A known bleeding diathesis;
  • Requirement for warfarin or similar vitamin K antagonists; these drugs are prohibited 28 days prior to the first treatment and throughout the trial;
  • History of stroke or intracranial hemorrhage ≤ 6 months before treatment;
  • Currently active, clinically significant hepatic impairment (Child-Pugh class B or C according to the Child Pugh classification;
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study;
  • Serologic status reflecting active hepatitis B or C infection; patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment; (PCR positive patients will be excluded).
• Eastern Cooperative Oncology Group (ECOG) performance status must be ≤ 2