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Targeting MCL-1 and BCL-2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non-Hodgkin lymphoma: Results from preclinical models and a Phase Ib study
dc.contributor.authorLasater, Elisabeth A.
dc.contributor.authorAmin, Dhara N.
dc.contributor.authorBannerji, Rajat
dc.contributor.authorMali, Raghuveer Singh
dc.contributor.authorBarrett, Kathy
dc.contributor.authorRys, Ryan N.
dc.contributor.authorOeh, Jason
dc.contributor.authorLin, Eva
dc.contributor.authorSterne-Weiler, Tim
dc.contributor.authorIngalla, Ellen Rei
dc.contributor.authorGo, MaryAnn
dc.contributor.authorYu, Shang-Fan
dc.contributor.authorKrem, Maxwell M.
dc.contributor.authorArthur, Chris
dc.contributor.authorHahn, Uwe
dc.contributor.authorJohnston, Anna
dc.contributor.authorKarur, Vinit
dc.contributor.authorKhan, Nadia
dc.contributor.authorMarlton, Paula
dc.contributor.authorPhillips, Tycel
dc.contributor.authorGritti, Giuseppe
dc.contributor.authorSeymour, John F.
dc.contributor.authorTani, Monica
dc.contributor.authorYuen, Sam
dc.contributor.authorMartin, Scott
dc.contributor.authorChang, Matthew T.
dc.contributor.authorRose, Christopher M.
dc.contributor.authorPham, Victoria C.
dc.contributor.authorPolson, Andrew G.
dc.contributor.authorChang, YiMeng
dc.contributor.authorWever, Claudia
dc.contributor.authorJohnson, Nathalie A.
dc.contributor.authorJiang, Yanwen
dc.contributor.authorHirata, Jamie
dc.contributor.authorSampath, Deepak
dc.contributor.authorMusick, Lisa
dc.contributor.authorFlowers, Christopher R.
dc.contributor.authorWertz, Ingrid E.
dc.date.accessioned2023-03-03T21:10:06Z
dc.date.available2024-04-03 16:10:03en
dc.date.available2023-03-03T21:10:06Z
dc.date.issued2023-03
dc.identifier.citationLasater, Elisabeth A.; Amin, Dhara N.; Bannerji, Rajat; Mali, Raghuveer Singh; Barrett, Kathy; Rys, Ryan N.; Oeh, Jason; Lin, Eva; Sterne-Weiler, Tim ; Ingalla, Ellen Rei; Go, MaryAnn; Yu, Shang-Fan ; Krem, Maxwell M.; Arthur, Chris; Hahn, Uwe; Johnston, Anna; Karur, Vinit; Khan, Nadia; Marlton, Paula; Phillips, Tycel; Gritti, Giuseppe; Seymour, John F.; Tani, Monica; Yuen, Sam; Martin, Scott; Chang, Matthew T.; Rose, Christopher M.; Pham, Victoria C.; Polson, Andrew G.; Chang, YiMeng; Wever, Claudia; Johnson, Nathalie A.; Jiang, Yanwen; Hirata, Jamie; Sampath, Deepak; Musick, Lisa; Flowers, Christopher R.; Wertz, Ingrid E. (2023). "Targeting MCL‐1 and BCL‐2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non‐Hodgkin lymphoma: Results from preclinical models and a Phase Ib study." American Journal of Hematology 98(3): 449-463.
dc.identifier.issn0361-8609
dc.identifier.issn1096-8652
dc.identifier.urihttps://hdl.handle.net/2027.42/175920
dc.description.abstractThe treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro-survival BCL-2 protein family member MCL-1 as a resistance factor for the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system. This targeted MCL-1 antagonism, when combined with venetoclax and the anti-CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off-treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre-treated patients with relapsed or refractory NHL, 25/33 (76%) patients with follicular lymphoma and 5/17 (29%) patients with diffuse large B-cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti-CD20 antibody.
dc.publisherJohn Wiley & Sons, Inc.
dc.titleTargeting MCL-1 and BCL-2 with polatuzumab vedotin and venetoclax overcomes treatment resistance in R/R non-Hodgkin lymphoma: Results from preclinical models and a Phase Ib study
dc.typeArticle
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelOncology and Hematology
dc.subject.hlbsecondlevelMolecular, Cellular and Developmental Biology
dc.subject.hlbtoplevelScience
dc.subject.hlbtoplevelHealth Sciences
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/175920/1/ajh26809_am.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/175920/2/ajh26809.pdf
dc.identifier.doi10.1002/ajh.26809
dc.identifier.sourceAmerican Journal of Hematology
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dc.working.doiNOen
dc.owningcollnameInterdisciplinary and Peer-Reviewed


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