Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL

Wei D Ding, Betsy R. LaPlant, Timothy G. Call, Sameer A Parikh, Jose F. Leis, Rong He, Tait D. Shanafelt, Sutapa Sinha, Jennifer Le-Rademacher, Andrew L Feldman, Thomas Matthew Habermann, Thomas Elmer Witzig, Gregory A. Wiseman, Yi Lin, Erik Asmus, Grzegorz S Nowakowski, Michael J. Conte, Deborah A. Bowen, Casey N. Aitken, Daniel L. Van DykePatricia T Greipp, Xin Liu, Xiaosheng Wu, Henan Zhang, Charla R. Secreto, Shulan Tian, Esteban D Braggio, Linda E. Wellik, Ivana Micallef, David S. Viswanatha, Huihuang D Yan, Asher A Chanan Khan, Neil Elliot Kay, Haidong M Dong, Stephen Maxted Ansell

Research output: Contribution to journalArticle

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Abstract

Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often develop Richter transformation (RT) with a short survival of about 4 months. Preclinical studies suggest thatprogrammed death 1 (PD-1) pathwayis critical to inhibitimmunesurveillance in CLL. This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL patients (0%). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a medianfollow-up time of 11months, themedianoverall survival in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated.

Original languageEnglish (US)
Pages (from-to)3419-3427
Number of pages9
JournalBlood
Volume129
Issue number26
DOIs
StatePublished - Jun 29 2017

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
Tumors
Blocking Antibodies
Ligands
pembrolizumab
PCI 32765
Tumor Microenvironment
Survival
Lymphoma, Large B-Cell, Diffuse
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. / Ding, Wei D; LaPlant, Betsy R.; Call, Timothy G.; Parikh, Sameer A; Leis, Jose F.; He, Rong; Shanafelt, Tait D.; Sinha, Sutapa; Le-Rademacher, Jennifer; Feldman, Andrew L; Habermann, Thomas Matthew; Witzig, Thomas Elmer; Wiseman, Gregory A.; Lin, Yi; Asmus, Erik; Nowakowski, Grzegorz S; Conte, Michael J.; Bowen, Deborah A.; Aitken, Casey N.; Van Dyke, Daniel L.; Greipp, Patricia T; Liu, Xin; Wu, Xiaosheng; Zhang, Henan; Secreto, Charla R.; Tian, Shulan; Braggio, Esteban D; Wellik, Linda E.; Micallef, Ivana; Viswanatha, David S.; Yan, Huihuang D; Chanan Khan, Asher A; Kay, Neil Elliot; Dong, Haidong M; Ansell, Stephen Maxted.

In: Blood, Vol. 129, No. 26, 29.06.2017, p. 3419-3427.

Research output: Contribution to journalArticle

Ding, WD, LaPlant, BR, Call, TG, Parikh, SA, Leis, JF, He, R, Shanafelt, TD, Sinha, S, Le-Rademacher, J, Feldman, AL, Habermann, TM, Witzig, TE, Wiseman, GA, Lin, Y, Asmus, E, Nowakowski, GS, Conte, MJ, Bowen, DA, Aitken, CN, Van Dyke, DL, Greipp, PT, Liu, X, Wu, X, Zhang, H, Secreto, CR, Tian, S, Braggio, ED, Wellik, LE, Micallef, I, Viswanatha, DS, Yan, HD, Chanan Khan, AA, Kay, NE, Dong, HM & Ansell, SM 2017, 'Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL', Blood, vol. 129, no. 26, pp. 3419-3427. https://doi.org/10.1182/blood-2017-02-765685
Ding, Wei D ; LaPlant, Betsy R. ; Call, Timothy G. ; Parikh, Sameer A ; Leis, Jose F. ; He, Rong ; Shanafelt, Tait D. ; Sinha, Sutapa ; Le-Rademacher, Jennifer ; Feldman, Andrew L ; Habermann, Thomas Matthew ; Witzig, Thomas Elmer ; Wiseman, Gregory A. ; Lin, Yi ; Asmus, Erik ; Nowakowski, Grzegorz S ; Conte, Michael J. ; Bowen, Deborah A. ; Aitken, Casey N. ; Van Dyke, Daniel L. ; Greipp, Patricia T ; Liu, Xin ; Wu, Xiaosheng ; Zhang, Henan ; Secreto, Charla R. ; Tian, Shulan ; Braggio, Esteban D ; Wellik, Linda E. ; Micallef, Ivana ; Viswanatha, David S. ; Yan, Huihuang D ; Chanan Khan, Asher A ; Kay, Neil Elliot ; Dong, Haidong M ; Ansell, Stephen Maxted. / Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. In: Blood. 2017 ; Vol. 129, No. 26. pp. 3419-3427.
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abstract = "Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often develop Richter transformation (RT) with a short survival of about 4 months. Preclinical studies suggest thatprogrammed death 1 (PD-1) pathwayis critical to inhibitimmunesurveillance in CLL. This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60{\%} received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44{\%}) and in 0 out of 16 CLL patients (0{\%}). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a medianfollow-up time of 11months, themedianoverall survival in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60{\%}) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated.",
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AU - Ding, Wei D

AU - LaPlant, Betsy R.

AU - Call, Timothy G.

AU - Parikh, Sameer A

AU - Leis, Jose F.

AU - He, Rong

AU - Shanafelt, Tait D.

AU - Sinha, Sutapa

AU - Le-Rademacher, Jennifer

AU - Feldman, Andrew L

AU - Habermann, Thomas Matthew

AU - Witzig, Thomas Elmer

AU - Wiseman, Gregory A.

AU - Lin, Yi

AU - Asmus, Erik

AU - Nowakowski, Grzegorz S

AU - Conte, Michael J.

AU - Bowen, Deborah A.

AU - Aitken, Casey N.

AU - Van Dyke, Daniel L.

AU - Greipp, Patricia T

AU - Liu, Xin

AU - Wu, Xiaosheng

AU - Zhang, Henan

AU - Secreto, Charla R.

AU - Tian, Shulan

AU - Braggio, Esteban D

AU - Wellik, Linda E.

AU - Micallef, Ivana

AU - Viswanatha, David S.

AU - Yan, Huihuang D

AU - Chanan Khan, Asher A

AU - Kay, Neil Elliot

AU - Dong, Haidong M

AU - Ansell, Stephen Maxted

PY - 2017/6/29

Y1 - 2017/6/29

N2 - Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often develop Richter transformation (RT) with a short survival of about 4 months. Preclinical studies suggest thatprogrammed death 1 (PD-1) pathwayis critical to inhibitimmunesurveillance in CLL. This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL patients (0%). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a medianfollow-up time of 11months, themedianoverall survival in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated.

AB - Chronic lymphocytic leukemia (CLL) patients progressed early on ibrutinib often develop Richter transformation (RT) with a short survival of about 4 months. Preclinical studies suggest thatprogrammed death 1 (PD-1) pathwayis critical to inhibitimmunesurveillance in CLL. This phase 2 study was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT patients (44%) and in 0 out of 16 CLL patients (0%). All responses were observed in RT patients who had progression after prior therapy with ibrutinib. After a medianfollow-up time of 11months, themedianoverall survival in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) patients and were manageable. Analyses of pretreatment tumor specimens from available patients revealed increased expression of PD-ligand 1 (PD-L1) and a trend of increased expression in PD-1 in the tumor microenvironment in patients who had confirmed responses. Overall, pembrolizumab exhibited selective efficacy in CLL patients with RT. The results of this study are the first to demonstrate the benefit of PD-1 blockade in CLL patients with RT, and could change the landscape of therapy for RT patients if further validated.

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