Outcomes of relapsed or refractory acute myeloid leukemia patients failing venetoclax‐based salvage therapies

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of PML nuclear bodies (NBs), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mtDNA, activating cGAS signaling and boosting ROS production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies. SIGNIFICANCEActinomycin D induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML bodies (NBs).Actinomycin D targets mitochondria, yielding ROS which enforce PML NB-biogenesis and restore senescence. Dual targeting of mitochondria with actinomycin D and venetoclax sharply potentiates their anti-AML activities in vivo.Research.

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“…6). (53). Thus, mechanism-based prospective trials associating ActD and Venetoclax could be envisioned in AML patients.…”

Section: Discussionmentioning

confidence: 99%

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Rérolle

Berthier

et al. 2021

Cancer Discovery

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Glasdegib in combination with low-dose Cytarabine for the outpatient treatment of relapsed or refractory acute myeloid leukemia in unfit patients

et al. 2021

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We retrospectively collected clinical data on 31 relapsed or refractory acute myeloid leukemia (R/R AML) patients who were treated with outpatient glasdegib and low-dose Cytarabine (LDAraC) at our institution. The median age was 67 years (45–86). The median Eastern Cooperative Oncology Group performance status was 2 (1–3). The patients had previously received a median number of 2 (1–4) treatment lines, 61% (19/31) had been treated with intensive chemotherapy, 29% (9/31) had relapsed after allogeneic stem cell transplantation, and 45% (14/31) had had venetoclax exposure. Adverse cytogenetics were identified in 45% (14/31) of the cases. The CR + CRp rate was 21% (6/29) among evaluable patients. The median overall survival was 3.9 months for all patients. Different median overall survival times were observed in responders, patients achieving stable disease and those diagnosed with progressive disease: not reached vs 3.9 months vs 0.8 months, respectively ( p < 0.001). The most common adverse events were pneumonia (29%, 9/31), sepsis (23%, 7/31), and febrile neutropenia (16%, 5/31). Glasdegib + LDAraC is a fairly safe, non-intensive, outpatient regimen inducing complete remission and resulting in prolonged survival in some R/R AML patients.

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Venetoclax-based regimens in combination with trametinib for RAS-mutated relapsed or refractory myeloid malignancies

Kevličius

Cepulyte

Vasilevska

et al. 2022

Bone Marrow Transplant

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Outcomes of relapsed or refractory acute myeloid leukemia patients failing venetoclax‐based salvage therapies

Cited by 9 publications

References 27 publications

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

Glasdegib in combination with low-dose Cytarabine for the outpatient treatment of relapsed or refractory acute myeloid leukemia in unfit patients

Venetoclax-based regimens in combination with trametinib for RAS-mutated relapsed or refractory myeloid malignancies

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