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. Coombs; Joanna 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

doi:10.1158/1078-0432.CCR-19-3815

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

Immunology and Immunotherapy

Research output: Contribution to journal › Article › peer-review

24 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3589-3596
Number of pages	8
Journal	Clinical Cancer Research
Volume	26
Issue number	14
Early online date	20 Mar 2020
DOIs	https://doi.org/10.1158/1078-0432.CCR-19-3815
Publication status	Published - 15 Jul 2020

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1078-0432.CCR-19-3815Licence: None: All rights reserved

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Mato, A. R., Roeker, L. E., Jacobs, R., Hill, B. T., Lamanna, N., Brander, D., Shadman, M., Ujjani, C. S., Yazdy, M. S., Perini, G. F., Pinilla-ibarz, J. A., Barrientos, J., Skarbnik, A. P., Torka, P., Pu, J. J., Pagel, J. M., Gohil, S., Fakhri, B., Choi, M., ... Eyre, T. A. (2020). Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clinical Cancer Research, 26(14), 3589-3596. Advance online publication. https://doi.org/10.1158/1078-0432.CCR-19-3815

@article{b593f3a4e7d3494fa54c993d0c987838,

title = "Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy",

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 na{\"i}ve (n = 130), and 81% were idelalisib na{\"i}ve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-na{\"i}ve 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-na{\"i}ve 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 na{\"i}ve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.",

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

year = "2020",

month = jul,

day = "15",

doi = "10.1158/1078-0432.CCR-19-3815",

language = "English",

volume = "26",

pages = "3589--3596",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research",

number = "14",

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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 2020, 'Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy', Clinical Cancer Research, vol. 26, no. 14, pp. 3589-3596. https://doi.org/10.1158/1078-0432.CCR-19-3815

TY - JOUR

T1 - Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy

AU - Mato, Anthony R.

AU - Roeker, Lindsey E.

AU - Jacobs, Ryan

AU - Hill, Brian T.

AU - Lamanna, Nicole

AU - Brander, Danielle

AU - Shadman, Mazyar

AU - Ujjani, Chaitra S.

AU - Yazdy, Maryam Sarraf

AU - Perini, Guilherme Fleury

AU - Pinilla-ibarz, Javier A.

AU - Barrientos, Jacqueline

AU - Skarbnik, Alan P.

AU - Torka, Pallawi

AU - Pu, Jeffrey J.

AU - Pagel, John M.

AU - Gohil, Satyen

AU - Fakhri, Bita

AU - Choi, Michael

AU - Coombs, Catherine C.

AU - Rhodes, Joanna

AU - Barr, Paul M.

AU - Portell, Craig A.

AU - Parry, Helen

AU - Garcia, Christine A.

AU - Whitaker, Kate J.

AU - Winter, Allison M.

AU - Sitlinger, Andrea

AU - Khajavian, Sirin

AU - Grajales-cruz, Ariel F.

AU - Isaac, Krista M.

AU - Shah, Pratik

AU - Akhtar, Othman S.

AU - Pocock, Rachael

AU - Lam, Kentson

AU - Voorhees, Timothy J.

AU - Schuster, Stephen J.

AU - Rodgers, Thomas D.

AU - Fox, Christopher P.

AU - Martinez-calle, Nicolas

AU - Munir, Talha

AU - Bhavsar, Erica B.

AU - Bailey, Neil

AU - Lee, Jason C.

AU - Weissbrot, Hanna B.

AU - Nabhan, Chadi

AU - Goodfriend, Julie M.

AU - King, Amber C.

AU - Zelenetz, Andrew D.

AU - Dorsey, Colleen

AU - Bigelow, Kayla

AU - Cheson, Bruce D.

AU - Allan, John N.

AU - Eyre, Toby A.

PY - 2020/7/15

Y1 - 2020/7/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85084371263&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-19-3815

DO - 10.1158/1078-0432.CCR-19-3815

M3 - Article

C2 - 32198151

SN - 1078-0432

VL - 26

SP - 3589

EP - 3596

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 14

ER -

Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy

Abstract

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UN SDGs

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