Assessing a ctDNA and PET-oriented Therapy in Patients With DLBCL A Multicenter, Open-label, Phase II Trial.

Despite advances in the clinical care of patients with DLBCL and in understanding the biology of this disease, cure rates have remained the same since the introduction of rituximab to CHOP chemotherapy, and R-CHOP chemoimmunotherapy remains the standard of care. Over the last years many phase III trials investigating new agents added to R-CHOP have been performed but they have all invariably failed to improve treatment outcomes. Importantly, three of the most recently completed phase III trials that were developed based on the cell of origin distinction of DLBCL and aimed to improve treatment outcome in the ABC (or non- Germinal center B-Cell (GCB)) subtype by adding a targeted agent to R-CHOP have also failed. This provides clinical evidence that cell of origin may not be an accurate biomarker for treatment decisions. The R - CHOP + investigational drug approach has thus failed either when broadly applied to unselected DLBCL patients or when applied to DLBCL patients selected according to inaccurate biomarkers such as COO. Within this exploratory multicohort phase II trial, SAKK aims to evaluate a PET/CT and ctDNA oriented therapy in DLBCL in order to test the following working hypothesis. * acalabrutinib-R-CHOP may improve the progression free survival in genetically defined DLBCL harboring the MYD88 L265P and/or CD79A/B mutations; * treatment escalation to acalabrutinib-R-CHOP in DLBCL patients who have positive PET/CT (with residual disease scored as Deauville score 4 or 5 with centrally defined response) and no molecular response (\<2log10 reduction of ctDNA) after two courses of R-CHOP could improve the anti-tumour activity of R-CHOP; * treatment de-escalation to 4 total R-CHOP courses plus 2 rituximab single agent infusions does not compromise the outcome in patients lacking both MYD88 L265P and CD79A/B mutations and quickly obtaining both negative PET/CT (Deauville score 1-3) and molecular response (\>2log10 reduction of ctDNA) after two courses R-CHOP. Primary objectives: * Assessing the efficacy of acalabrutinib-R-CHOP in DLBCL harboring MYD88 L265P and/or CD79A/B mutations (cohort A) * Assessing the activity of treatment escalation to acalabrutinib-R-CHOP followed by acalabrutinib monotherapy in DLBCL patients who are double positive: PET/CT positive (Deauville score 4 or 5 with centrally defined response) and no molecular response (\<2log10 fold reduction) after two courses of R-CHOP (cohort B) * Exploring the feasibility of treatment de-escalation to 4 total R-CHOP courses plus two infusions of single agent rituximab in patients lacking both MYD88 L265P and CD79A/B mutations and quickly obtaining both negative PET/CT (Deauville score 1-3) and molecular response (\>2log10 reduction of ctDNA) after two cycles of R-CHOP (cohort C). * Exploring clinical implications of having a negative PET/CT (Deauville score 1-3) but no molecular response (\<2log10 reduction of ctDNA) vs a positive PET/CT (Deauville score 4 or 5 with centrally defined response) but molecular response (\>2log10 reduction of ctDNA) after two R-CHOP courses (cohort D) Secondary objectives: * Safety and tolerability of acalabrutinib-R-CHOP * Assessment of prognostic value of baseline PET radiomics indexes, alone or in association with other parameters