HOVON 152 DLBCL. A phase II study evaluating the effect of DA-EPOCH-R induction followed by nivolumab consolidation in patients with newly diagnosed high grade B cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements

Prior treatment

• 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.
• 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.
• Known history of indolent lymphoma previously treated with immunochemotherapy

Other illness

• 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
• 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.
• Severe neurological or psychiatric disease.
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• History of active malignancy during the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma

Lab values

• Inadequate renal function or creatinine clearance < 30 mL/min (after rehydration)
• Inadequate hepatic function: bilirubin > 3 times ULN (total) except patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin.
• Inadequate hematological function: ANC < 1.0x109/L or platelets < 75x109 /L before induction cycle 1 unless lymphoma related.
• Active symptomatic ischemic heart disease, myocardial infarction, or congestive heart failure within the past year. In case of cardiac history, an echo or MUGA should be obtained and LVEF should exceed 40% to be eligible.

Other

• 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.
• Severe pulmonary dysfunction (CTCAE grade III-IV)
• Current participation in another clinical trial interfering with this trial.
• Claustrophobia precluding PET-CT.
• CNS localization of the lymphoma. CSF analysis before start of treatment is only necessary in case of suspicion of CNS localization.
• Female subject pregnant or breast-feeding.

• High-grade B-cell lymphoma, with MYC in combination with BCL2 and/or BCL6 rearrangements as assessed by FISH according to the WHO 2016 classification including high-grade B-cell lymphoma with MYC and BCL2 rearrangements, transformed from previously untreated FL.
• Written informed consent
• Patient is capable of giving informed consent
• Age ≥ 18 year.
• Patient started with or has received one course of full dose R-CHOP or DA-EPOCH-R (cycle 1).Starting with DA-EPOCH-R in cycle 1 is only allowed when FISH results (confirming DH/TH diagnosis) are directly available at diagnosis. [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].
• WHO performance status 0-3 during or after induction cycle 1
• Ann Arbor stage II-IV at diagnosis
• 18F-FDG PET scan and contrast enhanced CT-scan performed preferably within 28 days before start first induction cycle
• 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