APR-246 is a promising new therapeutic agent that targets p53 mutated proteins in myelodysplastic syndromes and in acute myeloid leukemia (AML). APR-246 reactivates the transcriptional activity of ...p53 mutants by facilitating their binding to DNA target sites. Recent studies in solid cancers have found that APR-246 can also induce p53-independent cell death. In this study, we demonstrate that AML cell death occurring early after APR-246 exposure is suppressed by iron chelators, lipophilic antioxidants and inhibitors of lipid peroxidation, and correlates with the accumulation of markers of lipid peroxidation, thus fulfilling the definition of ferroptosis, a recently described cell death process. The capacity of AML cells to detoxify lipid peroxides by increasing their cystine uptake to maintain major antioxidant molecule glutathione biosynthesis after exposure to APR-246 may be a key determinant of sensitivity to this compound. The association of APR-246 with induction of ferroptosis (either by pharmacological compounds, or genetic inactivation of SLC7A11 or GPX4) had a synergistic effect on the promotion of cell death, both in vivo and ex vivo.
Despite its crucial importance in numerous physiological processes, iron also causes oxidative stress and damage which can promote the growth and proliferation of leukemic cells. Iron metabolism is ...strictly regulated and the related therapeutic approaches to date have been to restrict iron availability to tumor cells. However, since a new form of iron-catalyzed cell death has been described, termed ferroptosis, and subsequently better understood, iron excess is thought to represent an opportunity to selectively kill leukemic cells and spare normal hematopoietic cells, based on their differential iron needs. This review summarizes the physiology of iron metabolism and its deregulation in leukemia, the known ferrotoposis pathways, and therapeutic strategies to target the altered iron metabolism in leukemia for the purposes of initiating ferroptosis in these cancer cells.
Metabolic reprogramming is a common cancer cell phenotype as it sustains growth and proliferation. Targeting metabolic activities offers a wide range of therapeutic possibilities which are applicable ...to acute myeloid leukemia (AML). Indeed, in addition to the IDH1/2-mutated AML model which established the proof-of-concept for specifically targeting metabolic adaptations in AML, several recent reports have expanded the scope of such strategies in these diseases. This review highlights recent findings on metabolic deregulation in AML and summarizes their implications in leukemogenesis.
Patients with hematological malignancies are at greater risk of severe COVID-19 and have been prioritized for COVID-19 vaccination. A significant proportion of them have an impaired vaccine response, ...both due to the underlying disease and to the treatments.
We conducted a prospective observational study to identify the specific risks of the outpatient population with hematological diseases.
Between 22 December 2021 to 12 February 2022, we followed 338 patients of which 16.9% (
= 57) developed SARS-CoV-2 infection despite previous vaccination (94.7%). COVID-19 patients were more likely to have received immunotherapy (85.5% vs. 41%,
< 10
), and particularly anti-CD20 monoclonal antibodies (40% vs. 14.9%,
< 10
) and Bruton's tyrosine kinase inhibitors (BTKi) (7.3% vs. 0.7%,
< 10
). There was no significant difference in demographic characteristics or hematological malignancies between COVID-19-positive and non-positive patients. Patients hospitalized for COVID-19 had more frequently received immunotherapy than patients with asymptomatic or benign forms (100% vs. 77.3%,
< 0.05). Hospitalized COVID-19 patients had a higher proportion of negative or weakly positive serologies than non-hospitalized patients (92.3% vs. 61%,
< 0.05). Patients who received tixagevimab/cilgavimab prophylaxis (
= 102) were less likely to be COVID-19-positive (4.9 vs. 22%,
< 0.05) without significant difference in hospitalization rates.
In the immunocompromised population of patients with hematological malignancies, the underlying treatment of blood cancer by immunotherapy appears to be a risk factor for SARS-CoV-2 infection and for developing a severe form.
Despite recent advances in acute myeloid leukemia (AML) molecular characterization and targeted therapies, a majority of AML cases still lack therapeutically actionable targets. In 127 AML cases with ...unmet therapeutic needs, as defined by the exclusion of ELN favorable cases and of FLT3-ITD mutations, we identified 51 (40%) cases with alterations in RAS pathway genes (RAS+, mostly NF1, NRAS, KRAS, and PTPN11 genes). In 79 homogeneously treated AML patients from this cohort, RAS+ status were associated with higher white blood cell count, higher LDH, and reduced survival. In AML models of oncogenic addiction to RAS-MEK signaling, the MEK inhibitor trametinib demonstrated antileukemic activity in vitro and in vivo. However, the efficacy of trametinib was heterogeneous in ex vivo cultures of primary RAS+ AML patient specimens. From repurposing drug screens in RAS-activated AML cells, we identified pyrvinium pamoate, an anti-helminthic agent efficiently inhibiting the growth of RAS+ primary AML cells ex vivo, preferentially in trametinib-resistant PTPN11- or KRAS-mutated samples. Metabolic and genetic complementarity between trametinib and pyrvinium pamoate translated into anti-AML synergy in vitro. Moreover, this combination inhibited the propagation of RA+ AML cells in vivo in mice, indicating a potential for future clinical development of this strategy in AML.
Data on octogenarian patients with MM are scarce, and optimal management remains controversial. We report a retrospective cohort of unselected octogenarian patients with NDMM treated with bortezomib ...dexamethasone (Vd). Seventy-four patients were treated with an initial doublet therapy (Vd regimen, 2−3 cycles, induction). A dose escalation with an adjunction of melphalan or cyclophosphamide was proposed for patients who had an insufficient response after induction and who could tolerate it. In responders, the treatment was continued until progression or a plateau response for 6 months (consolidation). The overall response rate was 73%. After a median follow-up of 31.4 months, median progression-free survival (PFS) and overall survival (OS) were 13.2 and 26.9 months, respectively. PFS and OS of patients with ECOG PS < 3 (25.4 and 54.9 months, respectively) were better in comparison to PFS and OS of patients with ECOG PS ≥ 3 (9.3 and 11.3 months, respectively). Thirteen patients (17.6%) died during induction. Twelve patients (16.2%) died during consolidation. In conclusion, a conservative therapeutic strategy based on Vd resulted in a good response rate. However, the survival remains poor in the population of patients with an ECOG PS ≥ 3, mainly because of early mortality not related to progressive disease.
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