Kirchhoff Hanna, Karsli Uemran, Schoenherr Caroline, Battmer Karin, Erschow Sergej, Talbot Steven R, Steinemann Doris, Heuser Michael, Heidenreich Olaf, Hilfiker-Kleiner Denise, Ganser Arnold, Eder Matthias, Scherr Michaela
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation.
Department of Cardiology and Angiology.
Blood. 2021 May 13;137(19):2657-2661. doi: 10.1182/blood.2020008544.
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.
复发的B细胞前体急性淋巴细胞白血病（BCP-ALL）成年患者预后不佳。为改善药物治疗，我们从细胞毒性和作用方式方面分析了维奈托克和奥英妥珠单抗诱导细胞凋亡的情况。基于流式细胞术的线粒体外膜通透性（MOMP）分析以及共济失调毛细血管扩张症突变激活分析表明，维奈托克可快速诱导MOMP，而奥英妥珠单抗可分别诱导DNA损伤信号传导。在原发性ALL样本和患者来源的异种移植（PDX）模型中，在所有测试的ALL样本中，维奈托克和奥英妥珠单抗与地塞米松联合使用时在体外具有协同作用。在小鼠PDX模型中，奥英妥珠单抗而非维奈托克以剂量依赖性方式诱导完全缓解，但始终未能实现无复发生存。相比之下，维奈托克、地塞米松和奥英妥珠单抗联合治疗在所有测试的3种ALL-PDX模型中均诱导了长期无白血病生存和无需治疗的生存。这些数据表明，在临床前模型中，联合治疗具有协同作用且高效，有资格在临床试验中进行评估。
