This study will investigate if treatment results obtained with R-CHOEP in young high-risk patients with diffuse large B-cell lymphoma can be further improved by the addition of ibrutinib to this regimen.

Encouraging results have been achieved in younger high-risk patients with newly diagnosed diffuse large B-cell lymphoma treated with R-CHOEP. However, more than one fourth of patients still relapse or show primary progressive disease. The outcome of such patients is poor, in particular if first-line therapy contained rituximab. In order to avoid such detrimental situations, we seek to further improve progression-free survival and overall survival by combining R-CHOEP with ibrutinib.

Ibrutinib is a first-in-class, orally administered, potent, small-molecule inhibitor of Bruton's tyrosine kinase, a mediator of critical B-cell signaling pathways implicated in the pathogenesis of B-cell cancers.

Inclusion Criteria:

1. Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
2. Age between 18-60 years
3. Risk score 2 or 3 according to age-adjusted International Prognostic Index
4. Histology: Primary diagnosis of diffuse large B-cell lymphoma
5. Performance status: ECOG (toxicity and response criteria of the eastern cooperative oncology group) 0-3
6. Stage: all stages according Ann Arbor
7. Absolute neutrophil count: > 1000 cells/microliter (independent of growth factor support)
8. Platelet count ≥ 100.000/mm³ or ≥ 50.000/mm³ if bone marrow involvement independent of transfusion support in either situation.
9. Alanine-aminotransferase and Aspartate-aminotransferase: < 3 x Upper limit of normal value
10. Total Bilirubin: < 1.5 x Upper limit of normal value
11. Serum Creatinine: < 2 x Upper limit of normal value or estimated Glomerular filtration rate (Glomerular filtration rate [Cockcroft-Gault]) ≥ 40 ml/min
12. Women of childbearing potential and men who are sexually active must be practising 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 and after the study. For male subjects, these restrictions apply for 6 months after last dose of study drug. For female subjects, they apply for 12 months after last dose of study drug.
13. Women of childbearing potential must have negative serum or urine beta-human chorionic gonadotropin pregnancy test at screening. Women who are pregnant or breast-feeding are ineligible for this study.
14. Willing/ able to adhere to the prohibitions and restrictions specified in this protocol.

Exclusion Criteria:

1. Vaccinated with live, attenuated vaccines within 4 weeks of inclusion.
2. Major surgery within 4 weeks of inclusion.
3. Any prior lymphoma-directed therapy (except pre-phase treatment).
4. Known central nervous system involvement.
5. Diagnosed or treated for malignancy other than diffuse large B-cell lymphoma, in particular any other (indolent) lymphoma.
6. 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 or 4 cardiac disease as defined by the New York Heart Association Functional classification.
7. Bone marrow involvement > 25%
8. History of stroke or intracranial hemorrhage within six months of inclusion.
9. Requires anticoagulation with warfarin or equivalent vitamin K antagonist.
10. Known history of human immunodeficiency virus or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection requiring IV antibiotics.
11. Requires treatment with strong CYP3A inhibitors.
12. Use of preparations containing St. John's Wort.
13. 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.
14. Concurrent treatment with other investigational agent or X-ray therapy.
15. Previous chemo- or radiotherapy for any other malignancy, in particular indolent lymphoma.
16. Any psychological, cognitive, familial, sociological or geographical condition that, in the investigator's opinion, compromises the patient's ability to understand the patient information, to give informed consent or to comply with the study protocol.
17. Participation in another interventional clinical trial during this trial. There may be exceptions at the discretion of the coordinating investigator.