Assessment of the Efficacy of Therapies following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy

Anthony R. Mato, Lindsey E. Roeker, Ryan Jacobs, Brian T. Hill, Nicole Lamanna, Danielle Brander, Mazyar Shadman, Chaitra S. Ujjani, Maryam Sarraf Yazdy, Guilherme Fleury Perini, Javier A. Pinilla-Ibarz, Jacqueline Barrientos, Alan P. Skarbnik, Pallawi Torka, Jeffrey J. Pu, John M. Pagel, Satyen Gohil, Bita Fakhri, Michael Choi, Catherine C. CoombsJoanna Rhodes, Paul M. Barr, Craig A. Portell, Helen Parry, Christine A. Garcia, Kate J. Whitaker, Allison M. Winter, Andrea Sitlinger, Sirin Khajavian, Ariel F. Grajales-Cruz, Krista M. Isaac, Pratik Shah, Othman S. Akhtar, Rachael Pocock, Kentson Lam, Timothy J. Voorhees, Stephen J. Schuster, Thomas D. Rodgers, Christopher P. Fox, Nicolas Martinez-Calle, Talha Munir, Erica B. Bhavsar, Neil Bailey, Jason C. Lee, Hanna B. Weissbrot, Chadi Nabhan, Julie M. Goodfriend, Amber C. King, Andrew D. Zelenetz, Colleen Dorsey, Kayla Bigelow, Bruce D. Cheson, John N. Allan, Toby A. Eyre

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood. Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]. Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi nave (n ¼ 130), and 81% were idelalisib nave (n ¼ 263). ORR to BTKi was 84% (n ¼ 44) in BTKi-nave patients versus 54% (n ¼ 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. Conclusions: For BTKi-nave patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in nave or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.

Original languageEnglish (US)
Pages (from-to)3589-3596
Number of pages8
JournalClinical Cancer Research
Volume26
Issue number14
DOIs
StatePublished - Jul 15 2020
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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