Venetoclax and dexamethasone synergize with inotuzumab ozogamicin-induced DNA damage signaling in B-lineage ALL.
Blood
; 137(19): 2657-2661, 2021 05 13.
Article
in En
| MEDLINE
| ID: mdl-33512436
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sulfonamides
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DNA Damage
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DNA, Neoplasm
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Dexamethasone
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
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Antineoplastic Combined Chemotherapy Protocols
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Bridged Bicyclo Compounds, Heterocyclic
/
Inotuzumab Ozogamicin
Limits:
Adolescent
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Adult
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Aged
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Animals
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Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Blood
Year:
2021
Document type:
Article