Venetoclax and dexamethasone synergize with inotuzumab ozogamicin-induced DNA damage signaling in B-lineage ALL

被引：24

作者：

Kirchhoff, Hanna ^{[1
]}

Karsli, Uemran ^{[1
]}

Schoenherr, Caroline ^{[1
]}

Battmer, Karin ^{[1
]}

Erschow, Sergej ^{[2
]}

Talbot, Steven R. ^{[3
]}

Steinemann, Doris ^{[4
]}

Heuser, Michael ^{[1
]}

Heidenreich, Olaf ^{[5
]}

Hilfiker-Kleiner, Denise ^{[2
]}

Ganser, Arnold ^{[1
]}

Eder, Matthias ^{[1
]}

Scherr, Michaela ^{[1
]}

机构：

[1] Hannover Med Sch, Dept Hematol Hemostasis Oncol & Stem Cell Transpl, Carl Neuberg Str 1, D-30625 Hannover, Germany

[2] Hannover Med Sch, Dept Cardiol & Angiol, Hannover, Germany

[3] Hannover Med Sch, Inst Lab Anim Sci, Hannover, Germany

[4] Hannover Med Sch, Dept Human Genet, Hannover, Germany

[5] Newcastle Univ, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

来源：

BLOOD | 2021年 / 137卷 / 19期

关键词：

CELLS;

D O I：

10.1182/blood.2020008544

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Adult patients with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy, we analyzed induction of apoptosis by venetoclax and inotuzumab ozogamicin in terms of cytotoxicity and mode of action. Flow cytometry-based analyses of mitochondrial outer membrane permeabilization (MOMP) and ataxia telangiectasia mutated activation demonstrate rapid induction of MOMP by venetoclax and DNA damage signaling by inotuzumab ozogamicin, respectively. In primary ALL samples and patient-derived xenograft (PDX) models, venetoclax and inotuzumab ozogamicin cooperated and synergized in combination with dexamethasone in vitro in all tested samples of ALL. In murine PDX models, inotuzumab ozogamicin, but not venetoclax, induced complete remission in a dose-dependent manner but constantly failed to achieve relapse-free survival. In contrast, combination therapy with venetoclax, dexamethasone, and inotuzumab ozogamicin induced long-term leukemia-free survival and treatment-free survival in all 3 ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualify for evaluation in clinical trials.

引用

页码：2657 / 2661

页数：5

共 17 条

[1] ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response [J].

Blackford, Andrew N. ;

Jackson, Stephen P. .

MOLECULAR CELL, 2017, 66 (06) :801-817

[2] Lentiviral marking of patient-derived acute lymphoblastic leukaemic cells allows in vivo tracking of disease progression [J].

Bomken, S. ;

Buechler, L. ;

Rehe, K. ;

Ponthan, F. ;

Elder, A. ;

Blair, H. ;

Bacon, C. M. ;

Vormoor, J. ;

Heidenreich, O. .

LEUKEMIA, 2013, 27 (03) :718-721

[3] Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method [J].

Chou, Ting-Chao .

CANCER RESEARCH, 2010, 70 (02) :440-446

[4] Targeting the B-Cell Lymphoma/Leukemia 2 Family in Cancer [J].

Davids, Matthew S. ;

Letai, Anthony .

JOURNAL OF CLINICAL ONCOLOGY, 2012, 30 (25) :3127-3135

[5] Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options [J].

Fischer, Ute ;

Forster, Michael ;

Rinaldi, Anna ;

Risch, Thomas ;

Sungalee, Stephanie ;

Warnatz, Hans-Joerg ;

Bornhauser, Beat ;

Gombert, Michael ;

Kratsch, Christina ;

Stuetz, Adrian M. ;

Sultan, Marc ;

Tchinda, Joelle ;

Worth, Catherine L. ;

Amstislavskiy, Vyacheslav ;

Badarinarayan, Nandini ;

Baruchel, Andre ;

Bartram, Thies ;

Basso, Giuseppe ;

Canpolat, Cengiz ;

Cario, Gunnar ;

Cave, Helene ;

Dakaj, Dardane ;

Delorenzi, Mauro ;

Dobay, Maria Pamela ;

Eckert, Cornelia ;

Ellinghaus, Eva ;

Eugster, Sabrina ;

Frismantas, Viktoras ;

Ginzel, Sebastian ;

Haas, Oskar A. ;

Heidenreich, Olaf ;

Hemmrich-Stanisak, Georg ;

Hezaveh, Kebria ;

Hoell, Jessica I. ;

Hornhardt, Sabine ;

Husemann, Peter ;

Kachroo, Priyadarshini ;

Kratz, Christian P. ;

te Kronnie, Geertruy ;

Marovca, Blerim ;

Niggli, Felix ;

McHardy, Alice C. ;

Moorman, Anthony V. ;

Panzer-Gruemayer, Renate ;

Petersen, Britt S. ;

Raeder, Benjamin ;

Ralser, Meryem ;

Rosenstiel, Philip ;

Schaefer, Daniel ;

Schrappe, Martin .

NATURE GENETICS, 2015, 47 (09) :1020-+

[6] An optimized method for detecting gamma-H2AX in blood cells reveals a significant interindividual variation in the gamma-H2AX response among humans [J].

Ismail, Ismail Hassan ;

Wadhra, Tabasum Imran ;

Hammarsten, Ola .

NUCLEIC ACIDS RESEARCH, 2007, 35 (05)

[7] Inotuzumab Ozogamicin for Acute Lymphoblastic Leukemia Reply [J].

Kantarjian, Hagop M. ;

Vandendries, Erik ;

Advani, Anjali S. .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (21) :2100-2101

[8] Targeting BCL-2 and ABL/LYN in Philadelphia chromosome-positive acute lymphoblastic leukemia [J].

Leonard, Jessica T. ;

Rowley, Joelle S. J. ;

Eide, Christopher A. ;

Traer, Elie ;

Hayes-Lattin, Brandon ;

Loriaux, Marc ;

Spurgeon, Stephen E. ;

Druker, Brian J. ;

Tyner, Jeffrey W. ;

Chang, Bill H. .

SCIENCE TRANSLATIONAL MEDICINE, 2016, 8 (354)

[9] Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax [J].

Matulis, S. M. ;

Gupta, V. A. ;

Nooka, A. K. ;

Hollen, H. V. ;

Kaufman, J. L. ;

Lonial, S. ;

Boise, L. H. .

LEUKEMIA, 2016, 30 (05) :1086-1093

[10] Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia [J].

Maude, S. L. ;

Laetsch, T. W. ;

Buechner, J. ;

Rives, S. ;

Boyer, M. ;

Bittencourt, H. ;

Bader, P. ;

Verneris, M. R. ;

Stefanski, H. E. ;

Myers, G. D. ;

Qayed, M. ;

De Moerloose, B. ;

Hiramatsu, H. ;

Schlis, K. ;

Davis, K. L. ;

Martin, P. L. ;

Nemecek, E. R. ;

Yanik, G. A. ;

Peters, C. ;

Baruchel, A. ;

Boissel, N. ;

Mechinaud, F. ;

Balduzzi, A. ;

Krueger, J. ;

June, C. H. ;

Levine, B. L. ;

Wood, P. ;

Taran, T. ;

Leung, M. ;

Mueller, K. T. ;

Zhang, Y. ;

Sen, K. ;

Lebwohl, D. ;

Pulsipher, M. A. ;

Grupp, S. A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2018, 378 (05) :439-448

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