Faculty Collaboration Database

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy. Clin Cancer Res 2020 Jul 15;26(14):3589-3596

Date

03/22/2020

Pubmed ID

32198151

Pubmed Central ID

PMC8588795

DOI

10.1158/1078-0432.CCR-19-3815

Scopus ID

2-s2.0-85084371263 (requires institutional sign-in at Scopus site)   84 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 naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.

CONCLUSIONS: For BTKi-naïve 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 naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501.

Author List

Mato AR, Roeker LE, Jacobs R, Hill BT, Lamanna N, Brander D, Shadman M, Ujjani CS, Yazdy MS, Perini GF, Pinilla-Ibarz JA, Barrientos J, Skarbnik AP, Torka P, Pu JJ, Pagel JM, Gohil S, Fakhri B, Choi M, Coombs CC, Rhodes J, Barr PM, Portell CA, Parry H, Garcia CA, Whitaker KJ, Winter AM, Sitlinger A, Khajavian S, Grajales-Cruz AF, Isaac KM, Shah P, Akhtar OS, Pocock R, Lam K, Voorhees TJ, Schuster SJ, Rodgers TD, Fox CP, Martinez-Calle N, Munir T, Bhavsar EB, Bailey N, Lee JC, Weissbrot HB, Nabhan C, Goodfriend JM, King AC, Zelenetz AD, Dorsey C, Bigelow K, Cheson BD, Allan JN, Eyre TA

Author

Othman S. Akhtar MBBS Assistant Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Bridged Bicyclo Compounds, Heterocyclic
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Pyrazoles
Pyrimidines
Sulfonamides