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

Lookup NU author(s): Professor Olaf Heidenreich


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© 2021 American Society of HematologyAdult 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.

Publication metadata

Author(s): Kirchhoff H, Karsli U, Schoenherr C, Battmer K, Erschow S, Talbot SR, Steinemann D, Heuser M, Heidenreich O, Hilfiker-Kleiner D, Ganser A, Eder M, Scherr M

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2021

Volume: 137

Issue: 19

Pages: 2657-2661

Online publication date: 13/05/2021

Acceptance date: 04/12/2020

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: Elsevier B.V.


DOI: 10.1182/blood.2020008544

PubMed id: 33512436


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