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.
Targeted therapies are currently considered the best cost-benefit anti-cancer treatment. In hematological malignancies, however, relapse rates and non-hematopoietic side effects including cardiotoxicity remain high. We here describe significant heart damage due to advanced acute lymphoblastic leukemia with t(9;22) encoding the bcr-abl oncogene (BCR-ABL+ ALL) in murine xenotransplantation models. Echocardiography reveals severe cardiac dysfunction with impaired left ventricular function and reduced heart and cardiomyocyte dimensions associated with increased apoptosis. This cardiac damage is fully reversible, but cardiac recovery depends on the therapy used to induce ALL remission. Chemotherapy-free therapy with dasatinib and venetoclax (targeting the BCR-ABL oncoprotein and mitochondrial Bcl2, respectively), as well as dexamethasone can fully revert cardiac defects whereas depletion of otherwise identical ALL in a genetic model using HSV-TK cannot. Mechanistically, dexamethasone induces pro-apoptotic BIM expression and apoptosis in ALL cells but enhances pro-survival BCLXL expression in cardiomyocytes and clinical recovery with reversion of cardiac atrophy. These data demonstrate that therapies designed to optimize apoptosis induction in ALL may circumvent cardiac on-target side effects and may even activate cardiac recovery. In the future, combining careful clinical monitoring of cardiotoxicity in leukemic patients with further characterization of organ-specific side effects and signaling pathways activated by malignancy and/or anti-tumor therapies seems reasonable.
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