This randomized phase III trial studies ibrutinib to see how well it works compared to placebo when given before and after stem cell transplant in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Before transplant, stem cells are taken from patients and stored. Patients then receive high doses of chemotherapy to kill cancer cells and make room for healthy cells. After treatment, the stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Ibrutinib is a drug that may stop the growth of cancer cells by blocking a protein that is needed for cell growth. It is not yet known whether adding ibrutinib to chemotherapy before and after stem cell transplant may help the transplant work better in patients with relapsed or refractory diffuse large B-cell lymphoma.

PRIMARY OBJECTIVE:

I. To evaluate the ability of ibrutinib to improve 24-month progression free survival (PFS) compared to placebo in patients with non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) as determined by immunohistochemistry (IHC).

SECONDARY OBJECTIVES:

I. To evaluate the ability of ibrutinib to improve overall survival (OS) compared to placebo.

II. To evaluate the ability of ibrutinib to improve progression free survival (PFS) compared to placebo.

III. To evaluate the ability of ibrutinib to improve post-transplant response rates compared to placebo.

IV. To evaluate time to hematopoietic recovery in the two arms. V. To evaluate the safety and tolerability of ibrutinib compared to placebo. VI. To evaluate the incidence of secondary malignancies in the two arms. VII. To evaluate immune reconstitution in the two arms.

CORRELATIVE SCIENCE OBJECTIVES:

I. To assess whether pre-autologous hematopoietic stem cell transplantation (AutoHCT) positive fludeoxyglucose F-18 (FDG)-positron emission tomography (PET) is associated with inferior 24-month PFS as well as PFS and OS.

II. To assess whether pre-AutoHCT FDG-PET results are differentially associated with 24-month PFS, PFS and OS in the ibrutinib versus placebo arms.

III. To evaluate the application of the Lugano criteria and change in quantitative measurements between pre-AutoHCT and post AutoHCT (e.g. delta standard uptake variable [SUV], %SUV decline and %metabolic tumor volume [MTV] decline, and other available applicable quantitative measurements) to assess the association between changes in these variables and outcomes, such as PFS and OS.

IV. To assess whether the GSTT1 null polymorphism is correlated with pulmonary toxicity after BCNU (carmustine)-containing conditioning regimens as part of autologous stem cell transplantation.

V. To assess whether other polymorphisms in the BCNU metabolism pathway or BCNU damage repair pathway(s) are associated with pulmonary toxicity after BCNU-containing conditioning regimens as part of autologous stem cell transplantation.

VI. To evaluate whether any of the proposed deoxyribonucleic acid (DNA) polymorphisms are associated with other toxicities.

VII. To assess whether DLBCL subtype based on the lymphoma subtyping test (LST) is associated with 24-month PFS, PFS, and OS with ibrutinib compared to placebo in patients treated on this protocol.

VIII. To assess whether activating mutations in the BCR pathway are associated with response to ibrutinib and with clinical outcomes in patients treated on this protocol.

IX. To assess whether there are any phenotypic associations with IHC markers (particularly MYC protein expression level) and presence of these mutations.

X. To assess whether BCL2, MYC, and Ki67 expression by IHC affect clinical outcomes in patients treated on this protocol.

XI. To assess whether translocations in MYC with or without BCL2 and BC6 have poor outcomes in patients treated on this protocol and whether ibrutinib modifies the prognosis.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

CONDITIONING REGIMEN:

ARM I: Investigators may choose to use either the BEAMi (carmustine, etoposide, cytarabine, melphalan, ibrutinib) or CBVi (cyclophosphamide, carmustine, etoposide, ibrutinib) regimen.

BEAMi: Patients receive ibrutinib orally (PO) on days -6 to -1, carmustine intravenously (IV) over 2 hours on day -6, etoposide IV twice daily (BID) over 1-2 hours and cytarabine IV BID over 1-2 hours on days -5 to -2, and melphalan IV over 20-30 minutes on day -1. Optionally, if a day of rest is planned, patients may receive BEAMi on days -7 to -2.

CBVi: Patients receive ibrutinib PO on days -6 to -1, carmustine IV over 2 hours on day -6, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2. Optionally, if a day of rest is planned, patients may receive CBVi on days -7 to -2.

ARM II: Patients receive placebo PO on days -6 to -1 and receive 1 of the 2 conditioning regimens as in Arm I.

TRANSPLANT: In both arms, patients undergo autologous hematopoietic progenitor cell or bone marrow transplant on day 0.

CONTINUATION REGIMEN:

ARM I: Beginning 30-60 days after transplant, patients receive ibrutinib PO on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

ARM II: Beginning 30-60 days after transplant, patients receive placebo PO on days 1-28. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients experiencing disease progression may crossover Arm I.

After completion of treatment, patients are followed up every 6 months for up to 60 months from registration.

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; this review is mandatory prior to registration to confirm eligibility and should be initiated as soon as possible

• ELIGIBILITY CRITERIA (STEP 1)

• Diagnosis of World Health Organization (WHO) diffuse large B-cell lymphoma, 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 or uncorrected for hemoglobin per institutional standards)

• Forced expiratory volume in 1 second (FEV1) >= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards)

• Forced vital capacity (FVC) >= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards)

• 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. rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone [R-CHOP], dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [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 CART therapy is allowed and counts as one line 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, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects; therefore, 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

• Age >= 18 years

• 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