Venetoclax and dexamethasone synergize with inotuzumab ozogamicin–induced DNA damage signaling in B-lineage ALL

Abstract

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.

Acute lymphoblastic leukemia in older adults: curtain call for conventional chemotherapy?

“…MDACC has added blinatumomab con sol i da tion to their IO plus mini-hyper-CVD pro to col. Venetoclax plus IO will also soon be tested in R/R B-ALL due to non over lap ping toxicities and pre clin i cal evi dence for syn ergy. 30 If shown to be safe, it may be use ful as a front line reg i men. For T-cell ALL, a che mo ther apy-free option does not yet exist.…”

Chemotherapy-Free Targeted Anti-BCR-ABL+ Acute Lymphoblastic Leukemia Therapy May Benefit the Heart

“…This induces activation of the effector proteins, BCL2-associated X (BAX) and BCL2-antagonist/Killer (BAK) and culminates in mitochondrial outer-membrane permeabilization (MOMP), the point of no return in intrinsic apoptosis induction [ 7 ]. Its efficacy can be potentiated by suitable combination therapy approaches [ 9 , 10 , 11 ].…”

“…Current targeted therapies combining the specific inhibition of the BCR-ABL oncoprotein by TKIs such as DAS with conventional polychemotherapy are currently considered the best treatment for BCR-ABL+ ALL. Accordingly, the curative potential of DAS, VEN and dexamethasone (DEX) combination therapy has been evaluated in preclinical murine xenotransplantation models for high-risk BCR-ABL+ ALL with regard to clinically relevant endpoints [ 9 , 10 ]. However, targeted anti-tumor therapies may exert unexpected on- and off-target side effects in organ systems that are not affected by malignant transformation or malignant cells.…”

Targeted anti-BCR-ABL+ ALL therapy may benefit the heart

“…Targeted therapies are currently considered the best cost-benefit anti-cancer treatment. Accordingly, mechanism-based interventions can rationally be designed and evaluated in murine xenograft models with regard to clinically relevant end points (1,2). However, targeted anti-tumor therapies may exert unexpected on-and off-target side effects in other organ systems not affected by malignant transformation or malignant cells.…”

“…The DAS/VEN/DEX triple combination has been optimized for apoptosis induction in ALL cells based on increased mitochondrial outer membrane permeabilization (MOMP) (1,2). In these cells DEX and DAS enhance BIM loading to BCL2 thereby sensitizing for VEN cytotoxicity (1,2). Surprisingly and in contrast to its effect on ALL cells the DAS/VEN/DEX triple-therapy does not enhance the low level of apoptosis in the heart but rather induces cardiac recovery from ALL induced damage.…”