Background: The prognostic significance of end-of-treatment PET/CT (EOT-PET) has been already evaluated in PMLBCL under R-CHOP or R-MACOP-B. Patients with clearly positive scans have inferior outcomes even after consolidative radiotherapy (RT). However, after R-da-EPOCH, the prognostic significance of PET/CT may be modulated, since most patients with positive scans achieve durable remissions without consolidative RT, pointing out to false-positive results. The omission of RT in patients with Deauville 5-point scale score (D5PSS) 4 often causes anxiety to the treating physicians, while handling of patients with D5PSS5 is controversial (RT vs high dose chemotherapy and autologous stem cell transplantation). Accumulation of real-world experience is required to provide answers to these dilemmas. Aims: To assess the clinical and prognostic significance of EOT-PET imaging and its effect on further treatment guidance of patients with PMLBCL under R-da-EPOCH in a real-life setting. Methods: Among 119 patients with PMLBCL treated with R-da-EPOCH in 19 Greek Centers (2014-2021), 107 were evaluated with EOT-PET-scan after 6 cycles (2/107 with clearly progressive disease did not undergo PET/CT and they were considered as D5PSS-5), 10 patients have not completed therapy yet and 2 did not undergo EOT-PET (technical issues/early death). D5PSS-4 category was evaluated visually (visual assessment) and additionally according to the criterion of “1.4x”. Results: The median follow-up after EOT-PET was 21.8 months (1-85). Among 107 evaluable patients, 17 had an EOT-PET D5PSS-1 (16%), 21 D5PSS-2 (20%), 33 D5PSS-3 (31%), 21 D5PSS-4 (20%) and 15 D5PSS-5 (14%). D5PSS-1-3:Only one relapse was reported among 71 D5PSS-1-3 patients during a median follow-up of 24.2 months (0.5-85). D5PSS-4: Among 19 D5PSS-4 patients, who were evaluable according to the “1.4x” criterion, 12 (63%) remained D5PSS-4 (SUVmax>1.4xSUVmaxliver) and 7 (37%) were reclassified as D5PSS-3 (SUVmax<1.4x). 5/21 patients with D5PSS4 (24% of total) actually received RT, without significant difference based on the “1.4” criterion” (29% vs 17%, p=0.54). The median SUVmax of D5PSS-4 patients who received RT or not was 4.3 (2.9-6.0) vs 4.0 (2.5-5.6) (p=0.84), respectively. After a 35-month median follow-up (2-65), 2/16 patients who did not receive RT relapsed (13% or 10% of D5PSS4 patients) and 1/2 received later on treatment RT and achieved complete remission (CR). Overall, RT was omitted in 84/92 (91%) patients with D5PSS-1-4 and only 2/92 developed disease progression. D5PSS-5:10/15 patients with D5PSS-5 received salvage chemotherapy [9 with stable/progressive disease (SD/PD) and 1 with partial response (PR)], whereas 5 patients with PR underwent RT. Median SUVmax values for these 2 groups was 17.2 (12.8-27.7) vs 10.4 (7.7-11.7) respectively (p<0.001). All 5 patients with PR who received RT remain in remission compared to 3/10 patients who received salvage chemotherapy after SD/PD (6/10 died). Summary/Conclusion: PET/CT is a valuable tool for response assessment in PMBCL after R-da-EPOCH, facilitating clinical decision making regarding further consolidative RT, which can be minimized. In a real-life setting, RT was safely omitted in the vast majority (91%) of patients with EOT-PET D5PSS-1-4 with only 2% treatment failure. Handling of D5PSS-4 subgroup requires further study in larger case series. Patients with D5PSS5 are rather rare; consolidative RT appears extremely effective in conventional responders but those with SD/PD still have poor outcomes irrespectively of treatment.