Treatment of acute myeloid leukemia (AML) is still a challenge because of common relapses or resistance to treatment. Therefore, the development of new therapeutic approaches is necessary. Various studies have shown that certain cancers, including some chemoresistant AML subsets, have upregulated oxidative phosphorylation. In this study, we aimed to assess treatment‐resistant AML patients’ cell modulation using oxidative phosphorylation inhibitors metformin and atovaquone alone and in various combinations with cytosine analog cytarabine and apoptosis inducer venetoclax. Metabolic activity analysis using Agilent Seahorse XF Extracellular Flux Analyzer revealed that peripheral blood mononuclear cells’ metabolic state was different among treatment‐resistant AML patients. We demonstrated that metformin decreased therapy‐resistant–AML cell oxidative phosphorylation ex vivo, cotreatment with cytarabine and venetoclax slightly increased the effect. However, treatment with atovaquone did not have a marked effect in our experiment. Cell treatment had a slight effect on cell proliferation inhibition; combination of metformin, cytarabine, and venetoclax had the strongest effect. Moreover, a slightly higher effect on cell proliferation and cell cycle regulation was demonstrated in the cells with higher initial oxidative phosphorylation rate as demonstrated by gene expression analysis using reverse transcription quantitative polymerase chain reaction (RT‐qPCR). Proteomic analysis by liquid chromatography–mass spectrometry demonstrated that chemoresistant AML cell treatment with metformin modulated metabolic pathways, while metformin combination with cytarabine and venetoclax boosted the effect. We suggest that oxidative phosphorylation inhibition is effective but not sufficient for chemoresistant AML treatment. Indeed, it causes anticancerous changes that might have an important additive role in combinatory treatment.
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.
Background: Hydroxychloroquine and Azithromycin use is associated with QT interval prolongation and arrhythmias. Despite ongoing multiple clinical trials for treatment of COVID19 infection, no definite cardiac safety protocols were proposed. The aim of our study was to assess cardiac safety in COVID-19 patients treated with the combination of Hydroxychloroquine and Azithromycin using close monitoring and arrhythmia risk management plan.Methods and results: We retrospectively examined arrhythmia safety of treatment with Hydroxychloroquine and Azithromycin in the setting of pre-defined cardiac arrhythmia risk management plan. 81 patients were included from March 23rd to May 10th 2020. The median age was 59 years, 58.0% were female. The majority of the study population (82.7%) had comorbidities, 98.8% had radiological signs of pneumonia. 7 patients (8.6%) had QTc prolongation of ≥500 ms. The treatment was discontinued in 4 patients (4.9%). 14 patients (17.3%) experienced QTc≥480 ms and 16 patients (19.8%) had an increase of QTc≥60 ms. None of the patients developed ventricular tachycardia. The risk factors significantly associated with QTc≥500 ms were hypokalemia (p = 0.032) and use of diuretics during the treatment (p = 0.020). Three patients had a lethal outcome; none of them associated with ventricular arrhythmias.Conclusion: We recorded a low incidence of QTc prolongation ≥500 ms and no ventricular tachycardia events in COVID-19 patients treated with Hydroxychloroquine and Azithromycin using cardiac arrhythmia risk management plan.
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