Biomarker Driven Intensified ChemoImmunotherapy With Early CNS Prophylaxis

Inclusion Criteria:

* Age 18 - 64 years
* Histologically confirmed CD20+ DLBCL based on revised WHO 2008 Lymphoma Classification. The following subgroups and variants can be included:

  * ALK-positive large B-cell lymphoma
  * Intravascular large B-cell lymphoma
  * T-cell rich B-cell lymphoma
  * Myc/BCL-2 double hit lymphoma
  * Follicular lymphomas grade 3b
  * DLBCL with previously undiagnosed concurrent small cell infiltration in bone marrow, lymph node, or extranodal site and lymphomas intermediate between DLBCL and Burkitt's lymphoma are allowed
  * Posttransplantation lymphoma (PTLD), discordant or transformed lymphoma are NOT allowed
* Patients in at least stage II with age adjusted IPI score of 2 or 3:

  * Stage III /IV and elevated LDH
  * Stage III/IV and WHO performance status 2 - 3
  * Stage II and elevated LDH and WHO performance status 2 - 3
* And/or patients with site specific risk factors for CNS recurrence defined as follows

  * More than one extranodal site
  * Testicular lymphoma, stage IIE and higher
  * Paranasal sinus and orbital lymphoma with destruction of bone
  * Large cell lymphoma infiltration of the bone marrow
* Previously untreated, except steroids allowed
* WHO performance status 0-3
* Written informed consent

Exclusion Criteria:

* 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