The purpose of this study is to improve the outcome of elderly patients with CD20-Aggressive B-Cell Lymphoma and to reduce the toxicity of standard used Immuno-Chemotherapy by using an optimised schedule of the monoclonal antibody Rituximab, substituting conventional by Liposomal Vincristine and by a PET-guided reduction of therapy in Combination with Vitamin D Substitution.

Primary objective of study:

"OPTIMAL>60 Less Favourable" Patients with less favourable prognosis: To test whether progression-free survival (PFS) can be improved by substituting conventional by liposomal vincristine; To test whether PFS can be improved by 12 optimised applications instead of 8 2-week applications of rituximab.

"OPTIMAL>60 Favourable": Patients with favourable prognosis: Comparison of neurotoxicity of conventional and liposomal vincristine; Determination of PFS for the treatment strategy of reducing treatment in patients with negative FDG-PET after 4 x R-CHOP/CHLIP-14 (PET-4) and comparison with the corresponding patient population in RICOVER-60.

Secondary objectives: "OPTIMAL>60 Favourable" and "OPTIMAL>60 Less Favourable":

Comparison of the prognostic value of a pre-treatment FDG-PET (PET-0) with conventional CT/MRT.

Prospective evaluation on the role of (metabolic) tumor volume to confirm or refuse the hypothesis that optimized rituximab should improve the outcome of patients with a high (metabolic) tumor volume more than that of patients with low MTV and to analyse the substitution of conventional vincristine by liposomal. • Estimation of the vincristine-related neurotoxicity ("OPTIMAL>60 Less Favourable only, since vincristine related neurotoxicity is primary objective of the study in favourable patients") and other toxicities (all patients).

Determination of the therapeutic efficacy of a vitamin D substitution.

Comparison of the FDG-PET-based individualised treatment strategy in OPTIMAL>60 with the fixed (pre-defined) treatment strategy in RICOVER>60.

Investigation of the prognostic value of different FDG-PET derived imaging biomarkers for lymphoma load (SUV, MTV, TLG).

Comparison of the vincristine related neurotoxicity before and after amendment 4.

Comparison of CNS events before and after amendment 4. Comparison of the Cheson, Lugano and RECIL response criteria. Prospective evaluation of the improvement of the prognostic value of ECOG performance status during prephase treatment.

Prospective evaluation of reference pathology biomarkes. Prospective evaluation of circulating tumor DNA (ctDNA), correlation and comparison with PET.

Prospective evaluation of the role of 2 additional cycles of CHOP/CHLIP-14 and involved node radiotherapy in PET-positive patients after 4xR-CHOP/CHLIP-14 in favourable patients.

Evaluation of the role of radiotherapy to PET-positive bulky disease patients after 6xR-CHOP/CHLIP-14 in less favourable patients.

Quality assurance of the performed radiotherapy, including in in-field and outfield relapses.

Investigation of the effect of cross-site ComBat harmonization. Analysis of FDG-PET derived biomarkers in combination with clinical and laboratory variables as distance of lesions and Ann-Arbor stage.

Estimation of the prognostic value of a pre-treatment FDG-PET (PET-0) compared to conventional imaging with CT/MRT.

Prospective evaluation of the prediction of the probability of time-to-progression (TTP) within 2 years by a convolutional neural network trained to analyze maximum intensity projection images from baseline PET.

Analysis regarding molecular subtype, transcriptomics, methylome analysis, spatious analysis of interaction of tumor cells and microenvironment by cyTOF, 3D-morphology (AI-based) or similar techniques, viruses (EBV, HHV6, HHV7), micro-RNA in tumor samples.

Analysis of ctDNA analysis by i) digital droplet PCR, ii) e.g. CAPP or similar methods and iii) methylome analysis as prognostic and predictive marker and comparison with imaging biomarkers.

Analysis special focus on refractory, relapsed courses (including specific patterns of relapse regarding location and time) compared to matched controls and regarding comparison with imaging biomarkers.

Analysis of specific BCR-antigens of aggressive B-NHL as Ars2, SAMD14/neurabin-I in tissue and blood. of initial samples of cases with refractory, relapsing course (including specific patterns of relapse regarding location and time).

Analysis of factors influencing immune effector cells e.g.KIR2DS1 and homozygous HLA-C2, PRF1 A91V or other fHLH variants and prognostic and predictive markers in comparison to RICOVER-60.

Investigation of possible prognostic, or predictive markers of treatment related toxicity as: Neurofilament light chain (NfL) to estimate vincristine-related neurotoxicity, or as clonal hematopoiesis with indeterminate potential (CHIP) and association with cardiovascular events.

Investigation of specific concomitant medication and possible impact on outcome.

Investigation of the efficacy of the modified mandatory infectious prophylaxis OPTIMAL compared to the RICOVER trial with a focus on mandatory chinolon prophylaxis.

Investigation of COVID-19-reated events Impact of interval of diagnosis to time to treatment. Comparison with similar patient populations treated in real-world or prospective clinical trials.

Analysis of EFS and PFS at 24 months (EFS24/PFS24) and its impact on subsequent outcome.

Inclusion Criteria:

1. Age: 61-80 years

2. All risk groups (IPI 1-5)

3. Diagnosis of aggressive CD20+ B-NHL, based on an excisional biopsy of a lymph node or on an appropriate sample of a lymph node or of an extranodal involvement. It will be possible to treat the following entities in this study as defined by the new WHO classification of 200870:

   B-NHL:

   • Foll. lymphoma grade IIIb

   • DLBCL, not otherwise specified (NOS)

     • common morphologic variants:

       • centroblastic
       • immunoblastic
       • anaplastic

     • rare morphologic variants

   • DLBCL subtypes/entities:

     • T-cell/histiocyte-rich large B-cell lymphoma
     • primary cutaneous DLBCL, leg type
     • EBV-pos. DLBCL of the elderly

   • DLBCL associated with chronic inflammation

   • primary mediastinal (thymic) LBCL

   • intravascular large B-cell-lymphoma

   • ALK-positive large B-cell-lymphoma

   • plasmoblastic lymphoma

   • primary effusion lymphoma

   • transformed indolent lymphoma secondary or simultaneous high grade B-cell-lymphoma

   • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma

   • B-cell lymphoma, unclassifiable, with features intermediate between DLCBL and Hodgkin lymphoma

4. Performance status ECOG 0 - 2 after prephase treatment. The performance status of each patient must be assessed before the initiation and after the end of prephase treatment which, as experience has shown, can result in a significant improvement of the patient's performance status. The pre-treatment performance status which can range from ECOG 0 to ECOG 4 must be documented in the Staging CRF (see ISF); the performance status after the prephase treatment must be documented in the respective Prephase Treatment CRF (PT form: see ISF). A definition of the performance status is provided in Appendix 28.10.

5. Written informed consent of the patient

6. Contract of participation signed by the study centre and sponsor

Exclusion Criteria:

1. Already initiated lymphoma therapy (except for the prephase treatment)

2. Serious accompanying disorder or impaired organ function (except when due to lymphoma involvement), in particular:

   • heart: angina pectoris CCS >2, cardiac failure e.g. NYHA >2 and/or EF <50% or FS<25% in nuclear medicine examination/echocardiography
   • lungs: if respiratory problems are suspected the patient is to be excluded if the resultant pulmonary function test shows FeV1<50% or a diffusion capacity <50% of the reference values
   • kidneys: creatinine >2 times the upper reference limit
   • liver: bilirubin >2 times the upper reference limit, aspartate transaminase (AST, SGOT) or alanine transaminase (ALT, SGPT) >3 x institutional upper reference limit
   • uncontrollable diabetes mellitus (prephase treatment with predniso[lo]ne!)

3. Platelets <75 000/mm3, leukocytes <2 500/mm3 (if not due to lymphoma)

4. Known hypersensitivity to the medications to be used

5. Known HIV-positivity

6. Patients with severe impairment of immune defense

7. Patients with constipation with imminent risk of ileus

8. Chronic active hepatitis

9. Poor patient compliance

10. Simultaneous participation in other treatment studies or in another clinical trial within the last 6 months

11. Prior chemo- or radiotherapy, long-term use of corticosteroids or anti-neoplastic drugs for previous disorder

12. Other concomitant tumour disease and/or tumour disease in the past 5 years (except for localised skin tumors other than melanoma and carcinomas in situ of any other origin)

13. CNS involvement of lymphoma (intracerebral, meningeal, intraspinal intradural) or primary CNS lymphoma

14. Persistent neuropathy grade ≥2 (NCI CTC-AE v4.03) (unless due to lymphoma involvement)

15. History of persistent active neurologic disorders grade >2 including demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, or other demyelinating condition

16. Pregnancy or breast-feeding women

17. Active serious infections not controlled by oral and/or intravenous antibiotics or anti-fungal medication

18. Any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities.

19. MALT lymphoma

20. Non-conformity to eligibility criteria

21. Persons not able to understand the impact, nature, risks and consequences of the trial (including language barrier)

22. Persons not agreeing to the transmission of their pseudonymous data

23. Persons depending on sponsor or investigator

24. Persons from highly protected groups. Pts. with CNS lymphoma should not be included in this study.