Adult patients with relapsed B- cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy we analyzed apoptosis induction 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 (ATM) activation demonstrates rapid MOMP induction by venetoclax and DNA-damage signalling 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 ALL samples tested. 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- and treatment-free survival in all three ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualifies for evaluation in clinical trials.