key: cord-0856117-9ggxgdfq authors: Northend, Michael; Wilson, William; Osborne, Wendy; Fox, Christopher P.; Davies, Andrew J.; El-Sharkawi, Dima; Phillips, Elizabeth H.; Sim, Hau Wui; Sadullah, Shalal; Shah, Nimish; Peng, Ying Ying; Qureshi, Iman; Addada, Juanah; Mora, Rocio Figueroa; Phillips, Neil; Kuhnl, Andrea; Davies, Elizabeth; Wrench, David; McKay, Pamela; Karpha, Indrani; Cowley, Anna; Karim, Richard; Challenor, Sarah; Singh, Vikram; Burton, Cathy; Auer, Rebecca; Williams, Chris; Cunningham, Joel; Broom, Angus; Arasaretnam, Anita; Roddie, Claire; Menne, Tobias; Townsend, William title: Results of a United Kingdom real-world study of polatuzumab vedotin, bendamustine, and rituximab for relapsed/refractory DLBCL date: 2022-05-09 journal: Blood Adv DOI: 10.1182/bloodadvances.2021005953 sha: 06b84f2656753b26af59a5b2954176b5486c93b4 doc_id: 856117 cord_uid: 9ggxgdfq The addition of polatuzumab vedotin to bendamustine and rituximab (Pola-BR) has been shown to improve overall survival (OS) in stem cell transplant (SCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). It is also increasingly used as bridging to CAR T-cell therapy (CAR-T). We retrospectively analysed the efficacy of Pola-BR in 133 patients at 28 UK institutions. Treatment intent was bridging to CAR-T for N=40, re-induction with planned SCT for N=13 and stand-alone treatment for N=78. The overall response rate (ORR) was 57.0% (complete response (CR) 32.8%). After median 7.7 months follow-up, median PFS and OS were 4.8 months and 8.2 months respectively. For stand-alone treatment shortened PFS was associated with bulk disease (>7.5cm) (HR 2.32 (95% CI 1.23-4.38), p=0.009), >1 prior treatment (HR 2.17 (95% CI 1.19-3.95), p=0.01) and refractoriness to the last treatment (HR 3.48 (95% CI 1.79-6.76), p<0.001). For CAR-T bridging the ORR was 42.1% (CR 18.4%) and for treatment after CAR-T failure the ORR was 43.8% (CR 18.8%). These data demonstrate efficacy for Pola-BR as a treatment for SCT-ineligible patients with R/R DLBCL, help to delineate which patients may benefit most, and provide preliminary evidence of efficacy as bridging to CAR-T and after CAR-T failure. Before regulatory approval in the United Kingdom, Pola-BR was available via the Early Access to Medicines Scheme (EAMS) between June 2019 and January 2020 in line with the intended label. 11 Subsequently, interim funding (from March to August 2020) was provided via the Cancer Drugs Fund (CDF) for Pola-BR because of potential delays in CAR T-cell therapy delivery during the Covid-19 pandemic. We analyzed outcomes of patients treated on these schemes. Anonymized data were collected retrospectively from 28 United Kingdom hospitals for consecutive patients treated with Pola-BR via EAMS or CDF interim funding. All patients who started Pola-BR treatment via either scheme were eligible (for EAMS: patients with R/R DLBCL after $1 previous treatments who were ineligible for SCT; for CDF: patients with R/R DLBCL after $2 previous treatments and who were approved to receive CAR T-cell therapy). Polatuzumab was given on day 1 or 2 of a 28-day cycle at a dose of 1.8 mg/kg for a maximum of 6 cycles. Dose reduction or treatment delay because of adverse events was permitted according to physician discretion. Response assessment was performed according to local policy. The collection and analysis of the data were part of routine National Health Service (NHS) evaluation and did not require ethical review. Full methods, statistical analysis, and treatment details are listed in the supplemental Data. Data were collected from 133 patients (EAMS, n 5 106; CDF, n 5 27) treated from June 2019 to October 2020. Treatment intent was bridging to CAR T-cell therapy for 30.1% (n 5 40), re-induction therapy with planned SCT consolidation for 9.8% (n 5 13), and stand-alone treatment (no planned CAR T-cell therapy or SCT) for 58.6% (n 5 78). Table 1 summarizes patient characteristics. Figure 1A shows subgroups according to treatment intent. A median of 4 cycles (range, 1-6 cycles) were given (median, 1 for CAR T-cell therapy bridging vs 4 for stand-alone treatment, and 5 when SCT consolidation was planned). Pola-BR was initiated with full-dose bendamustine for 91 patients (68.4%), reduced-dose bendamustine for 24 patients (18.0%), bendamustine was omitted for 5 patients (3.8%), and data were missing for 13 patients (9.8%). The investigator-assessed best ORR was 57.0% (CR, 31.6%). Response rates for predefined subgroups are provided in Figure 1B . Median follow-up duration was 7.7 months, median PFS was 4.8 months (95% confidence interval [CI], 3.7-9.3 months), and median OS was 8.2 months (95% CI, 5.9-14.3 months) ( Figure 1C ). For stand-alone Pola-BR (no planned CAR T-cell therapy or SCT [n 5 78]), a majority of patients were ineligible for SCT because of age (55.1%) or comorbidities (21.8%), but for 17.9% of patients, this was a result of insufficient response to previous therapy. Primary reasons for treatment discontinuation were completion of 6 cycles (n 5 33; 42.3%), PD (n 5 25; 32.1%), treatment-related toxicity (n 5 14; 17.9%), patient death (n 5 2; 2.6%), achieving CR (n 5 2; 2.6%), and other (n 5 2; 2.6%). In the stand-alone group, 26 patients (33.3%) experienced treatment delay because of adverse events, most commonly infection (n 5 14; 17.9%) and hematologic toxicity (n 5 11; 14.1%), as well as nausea (n 5 1), diarrhea (n 5 1), fatigue (n 5 4), and peripheral neuropathy (PN; n 5 1). Bendamustine dose was reduced for 33 patients (42.3%) and omitted for 4 patients (5.1%) in at least 1 cycle. Reported reasons for bendamustine dose reduction or omission were hematologic toxicity (n 5 7), patient age (n 5 7), infection (n 5 6), frailty (n 5 4), diarrhea (n 5 3), increased bilirubin (n 5 2), • Prior SCT (N=0) • Prior CAR-T (N=6) • Reason ineligible for SCT: • Median cycles completed: 4 (1-6) • Reasons for stopping treatment: Progression-free survival 3 according to treatment response. CR=complete response, PR=partial response, HR=hazard ratio, CI=confidence interval. iv: Overall survival for patients in the 'stand-alone' Pola-BR cohort (no planned stem cell transplant or CAR T-cell therapy) according to treatment response. infusion-related reaction (n 5 1), comorbidities (n 5 1), and unknown (n 5 6). These outcome data for 133 consecutive patients treated with Pola-BR add substantially to evidence from the registration trial and other studies. 9,10,12-15 Within its limitations (investigator-reported outcomes and limited toxicity data), this retrospective study supports Pola-BR as a treatment for patients with R/R DLBCL who are ineligible for SCT and provides preliminary evidence of efficacy for CAR T-cell therapy bridging and after CAR T-cell therapy failure. A median of 1 cycle was given as bridging to CAR T-cell therapy. The ORR was 42.1% and the CR rate was 18.4%, similar to rates for the post-CAR T-cell therapy group. A majority (31 [77.5%] of 40) proceeded to cell infusion; thus, Pola-BR seems to be a feasible bridging strategy. Further studies are required to define who is most likely to benefit from this treatment and to assess other approaches for this chemotherapyrefractory group. [16] [17] [18] This is the largest data set of patients treated with Pola-BR to date. Other series report broadly similar outcomes, but this study is unique in its sample size and inclusion of patients at different stages in the DLBCL treatment pathway. [12] [13] [14] [15] These outcomes support Pola-BR as a treatment for patients who are ineligible for SCT, help to delineate which groups stand to benefit most, and show efficacy in transformed low-grade lymphoma and double-hit lymphoma which were not represented in the G029365 trial. Furthermore, these data offer new insights into the role of Pola-BR as CAR T-cell therapy bridging and as treatment after CAR T-cell therapy failure. PFS seems shorter in this study than in the G029365 trial, which possibly reflects patient characteristics, including an older median age in this study (72 vs 67 years), a higher proportion of patients with PS $2 (30.1% vs 15%), and the inclusion of 16 patients with previous CAR T-cell therapy. The optimal partner agents for polatuzumab and its place in the DLBCL treatment algorithm remain open questions worthy of further study. Conflict-of-interest disclosure: C.P.F served as a consultant for, had an advisory role with, and received research funding and travel grants from Roche. A.J.D. served as a consultant for or had an advisory role with Celgene, Roche, Kite Pharma, Takeda, Karyopharm Therapeutics, and Incyte; received honoraria from Celgene, Roche, Kite Pharma, Takeda, Janssen, Acerta Pharma/AstraZeneca, and ADC Therapeutics; received research funding from Celgene, Roche, Karyopharm Therapeutics, Janssen, Acerta Pharma/ AstraZeneca, ADC Therapeutics, and BioInvent; and received travel grants from Celgene and Roche. D.E.-S. served as a consultant or had an advisory role with AbbVie, Astex Therapeutics, AstraZeneca, BeiGene, Janssen, and Kyowa Kirin; received honoraria from AbbVie, AstraZeneca, Janssen, Roche, and Takeda; and received travel grants from AbbVie and Novartis. N.S. served as a consultant for, had an advisory role with, and received travel grants from AbbVie, Janssen, and Roche. A.K. received honoraria from Kite Pharma, Novartis, and Celgene. P.M. served as a consultant for, had an advisory role with, or received honoraria from Roche. R.K. received honoraria from Bristol Myers Squibb and Roche. V.S. received travel grants from Gilead, Novartis, and AbbVie. R.A. served as a consultant for or had an advisory role with BeiGene and received research funding from Janssen. W.T. served as a consultant for, had an advisory role with, and received honoraria from Roche, Gilead, Celgene, and Janssen. The remaining authors declare no competing financial interests. 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