Clinical Indicators of Hepatotoxicity in Newly Diagnosed Acute Promyelocytic Leukemia Patients Undergoing Arsenic Trioxide Treatment.

Arsenic trioxide (ATO)-induced hepatotoxicity is often observed in acute promyelocytic leukemia (APL) patients and decreases therapeutic effect of ATO. Thus, concerns over hepatotoxicity have been raised. The aim of this study was to explore some noninvasive clinical indicators that can be used to guide the individualized application of ATO in the future. APL patients treated with ATO were identified retrospectively via electronic health records at our hospital from August 2014 through August 2019. APL patients without hepatotoxicity were selected as controls. The association between putative risk factors and ATO-induced hepatotoxicity was estimated with ORs and 95% CIs, which were calculated using the chi-square test. The subsequent multivariate analysis was performed using logistic regression analysis. In total, 58.04% of patients experienced ATO-induced hepatotoxicity during the first week. Elevated hemoglobin (OR 8.653, 95% CI, 1.339-55.921), administration of nonprophylactic hepatoprotective agents (OR 36.455, 95% CI, 7.409-179.364), non-single-agent ATO to combat leukocytosis (OR 20.108, 95% CI, 1.357-297.893) and decreased fibrinogen (OR 3.496, 95% CI, 1.127-10.846) were found to be statistically significant risk factors for ATO-induced hepatotoxicity. The area under the ROC curve values were 0.846 for "overall ATO-induced hepatotoxicity" and 0.819 for "early ATO-induced hepatotoxicity." The results revealed that hemoglobin ≥ 80 g/L, nonprophylactic hepatoprotective agents, and non-single-agent ATO and fibrinogen < 1 g/L are risk factors for ATO-induced hepatotoxicity in newly diagnosed APL patients. These findings can enhance the clinical diagnosis of hepatotoxicity. Prospective studies should be performed in the future to validate these findings.

Sulfhydryl compound levels are associated with ATO-induced side effects in acute promyelocytic leukemia patients.

OBJECTIVE: The remarkable effect of arsenic trioxide (ATO) was verified, but side effects are generally observed in acute promyelocytic leukemia (APL) patients, especially leukocytosis and hepatotoxicity. Our aims are to study predictors and reduce ATO-induced side effects without inhibiting efficacy. METHODS: Sulfhydryl in ATO-treated APL patients was detected by the Spectra Max M5 microplate reader. And patients were divided into high and low sulfhydryl groups according to median sulfhydryl concentration. The onset time of leukocytosis and the peak value of WBC were compared . Correlations between hepatotoxicity indicators and sulfhydryl concentrations were analysed. RESULTS: The concentration of sulfhydryl before treatment was significantly higher in the high sulfhydryl group. Leukocytosis ((7.0 ± 5.5) vs. (14.6 ± 8.5) day) and the peak value of WBC occurred earlier in the low sulfhydryl group ((10.8 ± 5.9) vs. (19.3 ± 5.5) day) than in the high group, and the peak value was significantly lower in the low sulfhydryl group ((24.04 ± 15.05) × 109/L) than in the high group ((42.95 ± 25.57) × 109/L). The elevated liver enzymes were smaller in the higher sulfhydryl group between time points before treatment and the treatment one week later (ΔALT 66.57 vs. 9.85 U/L, ΔAST 59.52 vs. 17.76 U/L), as between time points before treatment and peak value. There was a negative correlation between sulfhydryl and elevated liver enzymes. CONCLUSIONS: Higher sulfhydryl compounds contribute to ameliorating ATO-induced leukocytosis and hepatotoxicity in APL patients. The low sulfhydryl before treatment can advance the onset of leukocytosis. For patients with higher sulfhydryl in the early stage, close monitoring of liver enzymes is warranted instead of prophylactic applying any hepatoprotective intervention, to maintain ATO efficacy.

A novel stemness classification in acute myeloid leukemia by the stemness index and the identification of cancer stem cell-related biomarkers.

Background: Stem cells play an important role in acute myeloid leukemia (AML). However, their precise effect on AML tumorigenesis and progression remains unclear. Methods: The present study aimed to characterize stem cell-related gene expression and identify stemness biomarker genes in AML. We calculated the stemness index (mRNAsi) based on transcription data using the one-class logistic regression (OCLR) algorithm for patients in the training set. According to the mRNAsi score, we performed consensus clustering and identified two stemness subgroups. Eight stemness-related genes were identified as stemness biomarkers through gene selection by three machine learning methods. Results: We found that patients in stemness subgroup I had a poor prognosis and benefited from nilotinib, MK-2206 and axitinib treatment. In addition, the mutation profiles of these two stemness subgroups were different, which suggested that patients in different subgroups had different biological processes. There was a strong significant negative correlation between mRNAsi and the immune score (r= -0.43, p<0.001). Furthermore, we identified eight stemness-related genes that have potential to be biomarkers, including SLC43A2, CYBB, CFP, GRN, CST3, TIMP1, CFD and IGLL1. These genes, except IGLL1, had a negative correlation with mRNAsi. SLC43A2 is expected to be a potential stemness-related biomarker in AML. Conclusion: Overall, we established a novel stemness classification using the mRNAsi score and eight stemness-related genes that may be biomarkers. Clinical decision-making should be guided by this new signature in prospective studies.

Combined immune and DDR pathway classifier: A novel pathway-based classification aimed at tailoring personalized therapies for acute myeloid leukemia patients.

Acute myeloid leukemia (AML) constitutes a group of lethal hematological malignancies with high heterogeneity, resulting in widely variable outcomes of targeted therapy and immunotherapy. A better basic understanding of the molecular pathways of AML would help greatly in tailoring treatments to patients. Here, we propose a novel subtyping protocol for AML combination therapy. Three datasets, namely, the TCGA-LAML, BeatAML and Leucegene datasets, were used in this study. Single-sample GSEA (ssGSEA) was performed to calculate the expression scores of 15 pathways, including immune-related, stromal-related, DNA damage repair (DDR)-related and oncogenic pathways. The consensus clustering was used to classify AML based on pathway score data. We identified four phenotypic clusters-IM+DDR-, IM-DDR-, IM-DDR+ and IM+DDR+-representing distinct pathway expression profiles. The IM+DDR- subtype exhibited the most robust immune function, and patients of IM+DDR- subtype were likely to derive the greatest benefit from immunotherapy. Patients in IM+DDR+ subtype had the second highest immune scores and the highest DDR scores, suggesting that combination therapy (immune + DDR-targeted therapy) is the optimal treatment. For patients of IM-DDR- subtype, we recommend the combination of venetoclax and PHA-665752. A-674563 and dovitinib could be combined with DDR inhibitors to treat patients in IM-DDR+ subtype. Moreover, single-cell analysis revealed that there are more immune cells clustered in the IM+DDR- subtype and higher number of monocyte-like cells, which exert immunosuppressive effects, in the IM+DDR+ subtype. These findings can be applied for molecular stratification of patients and might contribute to the development of personalized targeted therapies for AML.

Analysis of gamma-glutamyltransferase in acute promyelocytic leukemia patients undergoing arsenic trioxide treatment.

OBJECTIVES: The remarkable effect of arsenic trioxide (ATO) was verified, but elevated gamma-glutamyltransferase (GGT), aminotransferases (ALT and AST) are generally observed in acute promyelocytic leukemia (APL) patients undergoing ATO treatment. However, utilization of hepatoprotective agents or discontinuation of ATO may inhibit ATO efficacy. In order to maintain ATO effect from hepatoprotective agents' influence so we investigate relationships between single elevation in GGT and hepatocellular injury in this study. METHODS: Correlation of GGT variation and leukocyte counts were analyzed in all 81 APL patients, correlations among liver enzymes (ALT, AST and GGT) were also analyzed in patients without prophylactic hepatoprotective agents. In following study, we take the clinical observation of changes in aminotransferases in patients with single elevation in GGT without hepatoprotective agents. RESULTS: The average elevated GGT in the WBC abnormal group was more than the normal group (53.86U/L vs. 31.03U/L, P = 0.008), a positive Pearson's correlation of GGT variation and changed leukocyte counts in patients without prophylactic hepatoprotective agents. There are no significant correlation between aminotransferases (ALT and AST) and GGT but correlation between ALT and AST was statistically significant (R = 0.649, P = 0.000). For APL patients with single elevation in GGT, ALT and AST levels were normal throughout the ATO treatment without hepatoprotective agents. CONCLUSION: Single elevation in GGT without elevated aminotransferases can't be identified as hepatotoxicity, and the elevated levels of GGT are associated with increasing leukocyte counts. Continue single-agent ATO without prophylactic hepatoprotective agents is recommended in APL patients with single elevation in GGT, in order to maintain ATO effect.

Inhibition factors of arsenic trioxide therapeutic effects in patients with acute promyelocytic leukemia.

OBJECTIVE: To summarize limitations involved in arsenic trioxide therapeutic effects in acute promyelocytic leukemia, because current studies show that some individuals of acute promyelocytic leukemia have relatively poor outcomes during treatment with arsenic trioxide. DATA SOURCES: Most relevant articles were included in the PubMed database between 2000 and 2013 with the keywords "acute promyelocytic leukemia," "arsenic trioxide," "thiol" or "methylation." In addition, a few older articles were also reviewed. STUDY SELECTION: Data and articles related to arsenic trioxide effect in acute promyelocytic leukemia treatment were selected and reviewed. We developed an overview of limitations associated with arsenic trioxide therapeutic effect. RESULTS: This review focuses on the researches about the arsenic trioxide therapeutic effect in acute promyelocytic leukemia and summarizes three mainly limitations which can influence the arsenic trioxide therapeutic effect to different degrees. First, with the combination of arsenic and glutathione the therapeutic effect and cytotoxicity decrease when glutathione concentration increases; second, arsenic methylation, stable arsenic methylation products weaken the apoptosis effect of arsenic trioxide in leukemia cells; third, gene mutations affect the sensitivity of tumor cells to arsenic trioxide and increase the resistance of leukemia cells to arsenic trioxide. CONCLUSIONS: The chief limitations are listed in the review. If we can exclude all of them, we can obtain a better therapeutic effect of arsenic trioxide in patients with acute promyelocytic leukemia.

Determination of arsenic metabolites in patients with newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide.

The efficacy of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL) is widely accepted. It is necessary to determine the concentration of arsenic due to its toxicity. The profiles of arsenic speciation in patients with relapsed or refractory APL have been demonstrated in few reports. Arsenic metabolite concentrations in the plasma of patients with newly diagnosed APL during the first course of arsenic remission induction therapy were determined, and the complicated change pattern of these metabolite concentrations in this phase is described for the first time in this study. We demonstrated that the concentration of trivalent inorganic arsenic (As(III)), which is regarded as the most effective and toxic, was much lower than those of other metabolites. Concentrations of the same arsenic metabolites were obviously distinct among various individuals. We infer that determination of the metabolites separately is necessary, and cannot be replaced by total arsenic determination. In addition, the amount of methylated metabolites of arsenic increased during the first course of ATO therapy, and these metabolites might therefore play an increasingly important role. Further research should be carried out to study the relationship between arsenic metabolite concentrations and efficacy, as well as side effects in patients with APL treated with ATO.