Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis

- Age 18 - 64 years

- Histologically confirmed CD20+ DLBCL based on revised WHO 2008 Lymphoma Classification. The following subgroups and variants can be included:

- Patients in at least stage II with age adjusted IPI score of 2 or 3:

- And/or patients with site specific risk factors for CNS recurrence defined as follows

- Previously untreated, except steroids allowed

- WHO performance status 0-3

- Written informed consent

- Severe cardiac disease: cardiac function grade 3-4, left ventricular ejection fraction <45%

- Impaired bone marrow liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule (Hemoglobin < 9 g/dL, ANC < 1.5 × 109/L, Platelet count < 75 × 109/L, creatinine clearance < 40 mL/min, ALT/AST > 2.5 x ULN, bilirubin 1.5 x ULN, INR > 1.5)

- Pregnancy/lactation

- Men and women of reproductive potential not agreeing to use effective contraception during treatment and for 18 months after completion of treatment (Effective contraception is combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), hormone-releasing IUD, bilateral tubal occlusion, vasectomised partner, or sexual abstinence

- Patients with other severe medical problems, including active infections, cardiac or pulmonary disease, history of PML and with an expected short survival for non-lymphoma reasons

- Known HIV positivity

- Active or chronic hepatitis B virus (HBV) infection (defined as positive HBsAg serology), or active hepatitis C virus (HCV) infection (defined by antibody serology testing). HBsAg, HBcAb, and HCVAb must be tested during screening. Patients who have protective titers of HBsAb along negative HBsAg after vaccination or prior but cured hepatitis B are eligible.

- Vaccination with a live vaccine within one month prior to randomization

- Patients with a malignancy that has been treated but not with curative intent, unless the malignancy has been in remission without treatment for ≥ 5 years prior to enrollment

- Earlier treatment containing anthracyclines

- Psychiatric or mental disorder which make the patient unable to give an informed consent and/or adhere to the protocol

- CNS disease as diagnosed by MRI or CSF cytology. Positive CSF flow cytometry below diagnostic threshold level by cytology is allowed

- Transformed lymphoma

- Primary mediastinal B-cell lymphoma

- Pleural or peritoneal fluid that cannot be drained safely

- Hypersensitivity to the active substance or any of the other ingredients

- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products

- Patients participating in other clinical studies, unless followed for survival

- Lower urinary tract constriction, which cannot be treated adequately

- Degenerative and toxic encephalopathy

- Neuromuscular disease