DA-EPOCH-R Induction Followed by Nivolumab Consolidation in Newly Diagnosed MYC, BCL2 and/or BCL6 Rearranged HGBL

Inclusion Criteria:

Inclusion Criteria for DA-EPOCH-R induction:

* High-grade B-cell lymphoma, with MYC in combination with BCL2 and/or BCL6 rearrangements as assessed by fluorescence in situ hybridization (FISH) according to the WHO 2016 classification including high-grade B-cell lymphoma with MYC and BCL2 rearrangements, transformed from previously untreated FL.
* Age ≥ 18 year.
* Patient started with or has received one course of full dose R-CHOP. \[Reversed R-CHOP (cyclophosphamide, vincristine and doxorubicin on day 5) is allowed; local radiation or short course (max 7 days) of steroids (max 100 mg/day) before R-CHOP is allowed. Mini-R-CHOP is not allowed\].
* World Health Organization (WHO) performance status 0-3 during or after the first R-CHOP cycle.
* Ann Arbor stage II-IV at diagnosis.
* 18F-FDG PET scan and contrast enhanced CT-scan performed within 21 days before start first cycle of R-CHOP.
* Measurable disease: on contrast enhanced CT-scan at least 1 lesion/node with a long axis of \>1.5 cm and at least one 18F-FDG avid lesion.
* Negative pregnancy test at study entry.
* Patient is willing and able to use adequate contraception until 6 months post last treatment administration.
* Written informed consent.
* Patient is capable of giving informed consent.

Inclusion criteria for Nivolumab consolidation:

* Complete metabolic response on end of induction 18F-FDG PET-CT assessed with the Deauville response criteria
* Patient has completed at least R-CHOP plus four cycles of DA-EPOCH-R induction treatment

Exclusion Criteria:

Exclusion Criteria for DA-EPOCH-R induction:

* All histopathological diagnoses other than DH/TH-HGBL (like testicular large B-cell lymphoma or primary mediastinal B-cell lymphoma) according to WHO 2016 classification.
* Known history of indolent lymphoma previously treated with immunochemotherapy.
* Inadequate renal function or creatinine clearance \< 30 mL/min (after rehydration). Creatinine clearance (CrCl) may be calculated by Cockcroft -Gault formula: CrCl = (140 - age \[in years\]) x weight \[kg\] (x 0.85 for females) (0.815 x serum creatinine \[μmol/L\])
* Inadequate hepatic function: bilirubin \> 3 times upper limit of normal (ULN) (total) except patients with Gilbert's syndrome as defined by \> 80% unconjugated bilirubin.
* Inadequate hematological function: absolute neutrophil count (ANC) \< 1.0x109/L or platelets \< 75x109 /L before R-CHOP unless lymphoma related.
* Central nervous system (CNS) localization of the lymphoma. Cerebrospinal fluid (CSF) analysis before start of treatment is only necessary in case of suspicion of CNS localization.
* Female subject pregnant or breast-feeding.
* History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma.
* Active symptomatic ischemic heart disease, myocardial infarction, or congestive heart failure within the past year. In case of cardiac history, an echo or multigated acquisition (MUGA) should be obtained and left ventricular ejection fraction (LVEF) should exceed 40% to be eligible.
* Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, cancer, etc.) that would jeopardize the patient's ability to receive the regimen with reasonable safety.
* HIV positivity.
* Active Hepatitis B or C infection as defined by positive serology and transaminitis. Non-active Hepatitis B carriers may be included if protected
* Severe pulmonary dysfunction (CTCAE grade III-IV).
* Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
* Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Prior treatment with an anti-PD1, anti-PDL1, anti-PDL2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways.
* Severe neurological or psychiatric disease.
* Current participation in another clinical trial interfering with this trial.
* Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
* Claustrophobia precluding PET-CT.

Exclusion criteria for Nivolumab consolidation:

* Inadequate renal function or creatinine clearance \< 30 mL/min (after rehydration). Creatinine clearance may be calculated by Cockcroft -Gault formula: CrCl = (140 - age \[in years\]) x weight \[kg\] (x 0.85 for females) (0.815 x serum creatinine \[μmol/L\])
* Inadequate hepatic function: bilirubin \> 3 times ULN (total) except patients with Gilbert's syndrome as defined by \> 80% unconjugated bilirubin.
* Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
* Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.