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We initiated an international, investigator-initiated, prospective, open-label phase 2 study in which patients with RT received a combination of the PD-1 inhibitor tislelizumab plus the BTK inhibitor zanubrutinib for 12 cycles. Patients responding to treatment underwent maintenance treatment with both agents. The primary end point was overall response rate after six cycles. Of 59 enrolled patients, 48 patients received at least two cycles of treatment and comprised the analysis population according to the study protocol. The median observation time was 13.9 months, the median age was 67 (range 45\u201382) years. Ten patients (20.8%) had received previous RT-directed therapy. In total, 28 out of 48 patients responded to induction therapy with an overall response rate of 58.3% (95% confidence interval (CI) 43.2\u201372.4), including 9 (18.8%) complete reponse and 19 (39.6%) partial response, meeting the study\u2019s primary end point by rejecting the predefined null hypothesis of 40% (<jats:italic>P<\/jats:italic>\u2009=\u20090.008). Secondary end points included duration of response, progression-free survival and overall survival. The median duration of response was not reached, the median progression-free survival was 10.0 months (95% CI 3.8\u201316.3). Median overall survival was not reached with a 12-month overall survival rate of 74.7% (95% CI 58.4\u201391.0). The most common adverse events were infections (18.0%), gastrointestinal disorders (13.0%) and hematological toxicities (11.4%). These data suggest that combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\/study\/NCT04271956\">NCT04271956<\/jats:ext-link>.<\/jats:p>","DOI":"10.1038\/s41591-023-02722-9","type":"journal-article","created":{"date-parts":[[2023,12,9]],"date-time":"2023-12-09T23:01:21Z","timestamp":1702162881000},"page":"240-248","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9895-0570","authenticated-orcid":false,"given":"Othman","family":"Al-Sawaf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6546-0911","authenticated-orcid":false,"given":"Rudy","family":"Ligtvoet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Robrecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janina","family":"Stumpf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Maria","family":"Fink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugen","family":"Tausch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Boettcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Mikusko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Ritgen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2780-2981","authenticated-orcid":false,"given":"Johannes","family":"Schetelig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"von Tresckow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Vehling-Kaiser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Gaska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens Martin","family":"Wendtner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bjoern","family":"Chapuy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6169-9152","authenticated-orcid":false,"given":"Kirsten","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl-Anton","family":"Kreuzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6830-9296","authenticated-orcid":false,"given":"Stephan","family":"Stilgenbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6729-7708","authenticated-orcid":false,"given":"Philipp","family":"Staber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9880-5242","authenticated-orcid":false,"given":"Carsten","family":"Niemann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hallek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Eichhorst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,9]]},"reference":[{"key":"2722_CR1","doi-asserted-by":"publisher","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","volume":"36","author":"R Alaggio","year":"2022","unstructured":"Alaggio, R. et al. 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A.M.F. received research funding from Celgene; is on the advisory board of Janssen; and received travel grants from AbbVie. E.T. reports advisory board (AbbVie, Janssen-Cilag and BeiGene), speaker honoraria (AstraZeneca, AbbVie, BeiGene, Gilead, Janssen and Roche) and research funding (Roche, AbbVie and Gilead). C.S. reports speaker honoraria (AstraZeneca and AbbVie). S.B. received payment or honoraria for lectures, presentations, speaker\u2019s bureaus, manuscript writing or educational events from Roche, AbbVie, Novartis, Becton Dickinson, Janssen, AstraZeneca and Sanofi; and received grants or contracts from Janssen-Cilag. M.R. reports grants from F. Hoffman-La Roche; and personal fees from F. Hoffmann-La Roche and AbbVie. J.S. reports consultancy honoraria from AstraZeneca, Janssen, Roche, Gilead, AbbVie and Sanofi. J.v.T. received research support from Janssen\/Roche; received travel grants from AbbVie, Janssen, Roche and Celgene; received honoraria from Roche, Janssen, AbbVie and AstraZeneca; and is on the advisory boards of Janssen, Roche and AbbVie. C.M.W. reports grants and personal fees from Janssen-Cilag during the conduct of the study; and grants and personal fees from Janssen-Cilag, Hoffmann-La Roche, AbbVie and Gilead outside the submitted work. K.F. reports honoraria by AbbVie and Roche and is an advisor for AstraZeneca. B.C. reports grants from Gilead Sciences and personal fees and honoraria from Janssen, F. Hoffmann-La Roche, AstraZeneca, AbbVie, BMS, Gilead, Sobi and Incyte. K.A.K. reports grants from F. Hoffmann-La Roche and AbbVie, during the conduct of the study; and personal fees from F. Hoffmann-La Roche and AbbVie. S.S. received advisory board honoraria, research support, travel support and speaker fees from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis and Sunesis. P.S. has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Takeda, Bristol Myers Squibb, Novartis, BeiGene, Incyte, GlaxoSmithKline, Janssen, Roche, MedMedia, AstraZeneca, AbbVie, Amgen, Medahead, Sanofi and Merck Sharp & Dome. C.N. received research funding from Novo Nordisk Foundation grant NF16OC0019302 and research support, consultancy fees and\/or travel grants from AbbVie, Gilead, Janssen, Roche, CSL Behring, Genmab, Sunesis and Acerta\/AstraZeneca. M.H. is an advisor or consultant for Roche, Gilead, Janssen, Bristol Myers Squibb, AbbVie and AstraZeneca and reports honoraria from Roche, Gilead, Janssen, Bristol Myers Squibb, AbbVie and AstraZeneca. A.-M.F. reports research funding by AstraZeneca and Celgene and travel support by AbbVie. B.E. is an advisor or consultant for Janssen, AbbVie, Kite, AstraZeneca, MSD and Miltenyi and received honoraria from Janssen, Roche, AbbVie, Lilly, Kite, AstraZeneca, BeiGene and MSD; and reports research funding by Janssen, Gilead, Roche, AbbVie, BeiGene and AstraZeneca. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}