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

Hanna Kirchhoff, Uemran Karsli, Caroline Schoenherr, Karin Battmer, Sergej Erschow, Steven R Talbot, Doris Steinemann, Michael Heuser, Olaf Heidenreich, Denise Hilfiker-Kleiner, Arnold Ganser, Matthias Eder, Michaela Scherr

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)2657-2661
Aantal pagina's5
TijdschriftBlood
Volume137
Nummer van het tijdschrift19
DOI's
StatusGepubliceerd - 13 mei 2021
Extern gepubliceerdJa

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