TY - JOUR
T1 - Venetoclax and dexamethasone synergize with inotuzumab ozogamicin-induced DNA damage signaling in B-lineage ALL
AU - Kirchhoff, Hanna
AU - Karsli, Uemran
AU - Schoenherr, Caroline
AU - Battmer, Karin
AU - Erschow, Sergej
AU - Talbot, Steven R
AU - Steinemann, Doris
AU - Heuser, Michael
AU - Heidenreich, Olaf
AU - Hilfiker-Kleiner, Denise
AU - Ganser, Arnold
AU - Eder, Matthias
AU - Scherr, Michaela
N1 - © 2021 by The American Society of Hematology.
PY - 2021/5/13
Y1 - 2021/5/13
N2 - 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.
AB - 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.
KW - Adolescent
KW - Adult
KW - Aged
KW - Animals
KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology
KW - Apoptosis/drug effects
KW - Bridged Bicyclo Compounds, Heterocyclic/administration & dosage
KW - Calicheamicins/pharmacology
KW - DNA Breaks, Double-Stranded
KW - DNA Damage
KW - DNA, Neoplasm/drug effects
KW - Dexamethasone/administration & dosage
KW - Drug Synergism
KW - Female
KW - Humans
KW - Inotuzumab Ozogamicin/administration & dosage
KW - Male
KW - Mice
KW - Mice, Inbred NOD
KW - Mice, SCID
KW - Middle Aged
KW - Mitochondrial Membranes/drug effects
KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Recurrence
KW - Sulfonamides/administration & dosage
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=85105603526&partnerID=8YFLogxK
U2 - 10.1182/blood.2020008544
DO - 10.1182/blood.2020008544
M3 - Article
C2 - 33512436
SN - 0006-4971
VL - 137
SP - 2657
EP - 2661
JO - Blood
JF - Blood
IS - 19
ER -