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The efficacy of polatuzumab vedotin in relapsed/refractory diffuse large B-cell lymphoma outside clinical study are undetermined. This retrospective study examined the efficacy and safety of polatuzumab vedotin administered in real life settings. Forty-seven patients, 31 with de-novo DLBCL and 16 with transformed lymphoma, treated with polatuzumab-based regimen in 14 Israeli centers between June 2018 and November 2019, were included. Median age was 66.1 years (60.4–78.8) and median number of prior lines was 3 (2–7). The overall response rate was 61% (n = 29), including 40% complete responses (n = 19) and 21% (n = 10) partial responses. The median overall survival and progression-free survival were 8.3 months and 5.6 months, respectively. An ECOG PS ≥2 predicted a decreased overall survival (p = 0.045). Primary refractory vs relapsed disease (p = 0.005) and transformed vs de-novo DLBCL (p = 0.039) were associated with shorter PFS (p = 0.027). Our data show that polatuzumab-based regimen is an effective and tolerable treatment in relapsed/refractory DLBCL. [ABSTRACT FROM AUTHOR]