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Differentiation syndrome (DS) is the second leading cause of death in acute promyelocytic leukaemia (APL) patients. Few studies have tested predictors of DS events. This study aimed to identify optimized predictors of DS events related to APL. The data of 298 consecutive patients who were newly diagnosed with APL between December 2012 and June 2023 were retrospectively investigated. A systematic review of computer-based patient medical records was conducted to obtain clinical data, including baseline characteristics, routine blood examination findings, biochemical indices and clinical manifestations of DS. Among the 298 patients, 158 were classified into the no-DS group, while 140 had DS. Compared with those of patients without DS, the peripheral blast count, age, and WBC count at each time point were significantly different in patients with DS (P < 0.05 for all time points). Generalized linear mixed models (GLMMs) revealed that WBC Double (Coeff. 0.442, P = 0.000) and WBC Peak (Coeff. 0.879, P = 0.000) were independent risk factors for DS. The frequencies of clinical manifestations of unexplained fever (P = 0.003), dyspnoea (P = 0.002), weight gain of more than 5 kg (P = 0.006), pleural effusion (P = 0.001), pulmonary infiltrates (P < 0.001), pericardial effusion (P = 0.002) and renal failure (P = 0.006) were considerably lower in moderate DS patients than in severe DS patients. The WBC Double occurs earlier than the WBC peak occurrence, so WBC  Double might be a new indicator of DS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To analyze the correlation between serum fibronectin 3 (Ficolin-3) levels and early severe bleeding in newly diagnosed acute promyelocytic leukemia (APL) patients., Methods: A total of 125 patients with newly diagnosed APL admitted to Shanxi Bethune Hospital from January 2020 to August 2023 were selected. All patients were given all-trans retinoic acid+arsenic for induction therapy. The severe bleeding events within 30 days of induction therapy (assessed by WHO bleeding score, grade 0, grade 1 and grade 2 were no bleeding or mild bleeding, grade 3 and grade 4 were severe or fatal bleeding) were used as observation endpoints. The serum Ficolin-3 levels was dected by ELISA method, baseline data and other laboratory indicators were counted, and the correlation between serum Ficolin-3 levels and early severe bleeding in newly diagnosed APL patients was analyzed., Results: 23 out of 125 APL patients experienced early severe bleeding during induction therapy, including 13 cases of grade 3 bleeding and 10 cases of grade 4 bleeding. There were 102 cases of non-serious bleeding, including 30 cases of grade 0, 24 cases of grade 1 bleeding, and 48 cases of grade 2 bleeding. The proportion of serum promyelocytes, white blood cell count, and D-D level in the severe bleeding group were significantly higher than those in the non severe bleeding group ( P < 0.05), while the levels of PLT and FIB were significantly lower than those in the non-serious bleeding group ( P < 0.05). The serum Ficolin-3 levels in the severe bleeding group were significantly lower than those in the non severe bleeding group before treatment, days of treatment, 14 days of treatment, and 30 days of treatment ( P < 0.05). Confirmed by point two column correlation, serum Ficolin-3 levels were negatively correlated with early severe bleeding in newly diagnosed APL patients before treatment, 7 days, 14 days, and 30 days after treatment ( r values were -0.485, -0.397, -0.304, and -0.183, respectively). The receiver operating characteristic curve (ROC) graph of the subjects was drawn, and the results showed that the area under the curve (AUC) of serum Ficolin-3 levels before treatment and at 7 and 14 days after treatment for predicting early severe bleeding in newly diagnosed APL patients was greater than 0.7, all of which had certain predictive efficacy, and the serum Ficolin-3 level before treatment had the best predictive efficacy., Conclusion: The serum Ficolin-3 levels in newly diagnosed APL patients are associated with early severe bleeding, and the serum Ficolin-3 levels before treatment have a significant advantage in predicting early severe bleeding in newly diagnosed APL patients.

Background: Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated., Objectives: To evaluate the associations between biomarker levels and bleeding and DVT in acute leukemia patients., Methods: We examined plasma levels of activators, inhibitors, and biomarkers of the coagulation and fibrinolytic pathways in patients aged ≥18 years with newly diagnosed acute leukemia compared with those of normal controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and DVT in acute leukemia patients. The study included 358 patients with acute leukemia (29 with acute promyelocytic leukemia [APL], 253 with non-APL acute myeloid leukemia, and 76 with acute lymphoblastic leukemia) and 30 normal controls., Results: Patients with acute leukemia had higher levels of extracellular vesicle tissue factor (EVTF) activity, phosphatidylserine-positive extracellular vesicles, plasminogen activator inhibitor-1, plasmin-antiplasmin complexes, and cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared with normal controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among acute leukemia patients. There were 41 bleeding and 23 DVT events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (subdistribution hazard ratio, 2.30; 95% CI, 0.99-5.31), whereas high levels of plasminogen activator inhibitor-1 were associated with increased risk of DVT (subdistribution hazard ratio, 3.00; 95% CI, 0.95-9.47) in these patients., Conclusion: Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and DVT., Competing Interests: Declaration of competing interests R.G. has served as a consultant for Advisory Boards for Alexion, Takeda, and Sanofi and received an honorarium for presenting a webinar from Sanofi. The other authors declare no competing financial interests., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Cell-free DNA (cfDNA) is free DNA found in circulating blood that originates from apoptosis or necrosis, and elevated cfDNA concentrations have been reported in cancers and other diseases., Methods: In this study, the concentrations and fragment distributions of plasma cfDNA were preliminary investigated in elderly ( n = 1) and paediatric ( n = 1) patients with acute promyelocytic leukaemia (APL) treated with arsenic trioxide (ATO)., Results: A slight increase in cfDNA concentrations was observed in the APL patients compared with healthy controls. The change in plasma cfDNA concentrations corresponded to the change in plasma arsenic concentrations during ATO treatment. The fragment distribution pattern did not differ before and during treatment. Three ladder fragments were observed in part of the cfDNA in the second consolidation therapy in an elderly APL patient and the first consolidation therapy of a paediatric APL patient, while two fragments were observed in all other treatment periods. Moreover, APL-related gene mutations were successfully genotyped from plasma cfDNA by using polymerase chain reaction-based methods and these results are consistent with those from leukocytes., Conclusion: This study is the first to report the concentrations and fragment patterns of cfDNA from APL patients treated with ATO. The results suggested that plasma cfDNA concentration in APL patients increased with ATO treatment and that cfDNA is released mainly via neutrophil extracellular traps (and/or necrosis) in addition to apoptosis. To confirm whether cfDNA concentrations and fragment patterns can be used as a biomarker for APL treated with ATO, further accumulative data are needed., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acute promyelocytic leukemia (APL) stands out as a distinctive form of acute leukemia, exhibiting a higher occurrence of thrombotic events when contrasted with other leukemia subtypes. Since thrombosis is a relatively rare but unfavorable condition with poor prognostic implications, it is crucial to determine the risk factors for thrombotic events in APL(thrombosis in large venous or arterial from onset to differentiation therapy in 30d). We performed a retrospective study involving 950 APL patients between January 2000 and October 2022, from which 123 were excluded by younger than 16 years of age, 95 were excluded by incomplete data, and 6 were excluded by thrombosis related to CVC or PICC. A total of 23 APL patients with thrombosis for inclusion in our analysis were performed a 1:5 ratio matching based on sex (perfect match) and age (within 5 years) to patients without thrombosis. These patients were continuously monitored in the outpatient department over a period of 5 years. We meticulously examined clinical and laboratory data to pinpoint the risk factors related to thrombotic events in APL. Our primary clinical endpoints were all-cause mortality and achieving complete remission, while secondary clinical outcomes included APL relapse. Thrombotic events were observed in 2.4% (23/950) of APL patients. Compared to patients without thrombosis, patients with thrombosis had higher lactate dehydrogenase (LDH) [313 (223, 486) vs. 233 (188, 367) U/L, p = 0.020], higher indirect bilirubin [11.2 (7.4, 18.6) vs.8.3 (6.0, 10.7) umol/L, p = 0.004], higher creatinine [72 (62, 85) vs. 63 (54, 74) umol/L, p = 0.026], higher CD2 expression (65.2 vs. 15.2%, p < 0.001), higher CD15 expression (60.9 vs. 24.3%, p = 0.001), and PML/RARαisoforms (p < 0.001). Multivariate-logistic-regression analysis revealed several factors that were markedly related to thrombosis, including LDH (OR≈1.003, CIs≈1.000-1.006, p = 0.021), indirect bilirubin (OR≈1.084, CIs≈1.000-1.188, p = 0.043), CD2 expression positive (OR≈16.629, CIs≈4.001-62.832, p < 0.001), and CD15 expression positive (OR≈7.747, CIs≈2.005-29.941, p = 0.003). The S-type (OR≈0.012, CIs≈0.000-0.310, p = 0.008) and L-type (OR≈0.033, CIs≈0.002-0.609, p = 0.022) PML/RARα isoforms were negatively associated with thrombosis. Kaplan-Meier curves indicated that the survival rates were remarkably varied between APL patients with and without thrombosis (HR:21.34, p < 0.001). LDH and indirect bilirubin are variables significantly associated with thrombosis in APL, S-type and L-type PML/RARαisoforms exhibit a negative association with thrombotic events. The thrombotic events of APL can predict the subsequent survival of thrombosis. The findings of our study have the potential to facilitate early detection of thrombosis and enhance the prognosis for individuals with APL who develop thrombosis. Further validation of our findings will be essential through future prospective or multicenter studies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Acute promyelocytic leukemia (APL) is a specific type of acute myeloid leukemia [1,2], the onset of the disease is insidious and the disease progresses rapidly, and failure to detect it in time or missing the best time to seek medical treatment is likely to cause secondary cerebral hemorrhage and lead to early death (ED: deaths occur in the first 30 days post diagnosis) [3-5]., Methods: A patient with APL was rapidly identified by peripheral blood image, fibrinogen (FIB), and D-dimer within 24 hours. Finally, APL was confirmed by bone marrow cell morphology, molecular biology, and cytogenetics., Results: The presence of faggot cells with Auer rods in the peripheral blood image and the coagulation function changes abnormally at the same time. Once the above abnormal results are found, APL should be highly suspected and timely reported to the clinic for corresponding treatment., Conclusions: APL is a critical disease, the time limit for definitive diagnosis should be calculated in hours rather than days. Peripheral blood smear microscopic examination can effectively screen out rare promyelocytes and combine with abnormal FIB and D-dimer results that are highly suspicious of APL. These methods have important clinical significance in the initial screening, early diagnosis, and reduction of early mortality due to APL.

Acute promyelocytic leukemia (APL) is associated with a high incidence of early death, which occurs within 30 days of diagnosis. The major cause of early death in APL is severe bleeding, particularly intracranial bleeding. Although APL is known to be associated with activation of coagulation, hyperfibrinolysis, and thrombocytopenia, the precise mechanisms that cause bleeding have not yet been elucidated. I propose that a combination of four pathways may contribute to bleeding in APL: (1) tissue factor, (2) the urokinase plasminogen activator/urokinase plasminogen activator receptor, (3) the annexin A2/S100A100/tissue plasminogen activator, and (4) the podoplanin/C-type lectin-like receptor 2. A better understanding of these pathways will identify new biomarkers to determine which APL patients are at high risk of bleeding and allow the development of new treatments for APL-associated bleeding., (© 2024. Japanese Society of Hematology.)

The treatment of PML/RARA+ acute promyelocytic leukemia (APL) with all-trans-retinoic acid and arsenic trioxide (ATRA/ATO) has been recognized as a model for translational medicine research. Though an altered microenvironment is a general cancer hallmark, how APL blasts shape their plasma composition is poorly understood. Here, we reported a cross-sectional correlation network to interpret multilayered datasets on clinical parameters, proteomes, and metabolomes of paired plasma samples from patients with APL before or after ATRA/ATO induction therapy. Our study revealed the two prominent features of the APL plasma, suggesting a possible involvement of APL blasts in modulating plasma composition. One was characterized by altered secretory protein and metabolite profiles correlating with heightened proliferation and energy consumption in APL blasts, and the other featured APL plasma-enriched proteins or enzymes catalyzing plasma-altered metabolites that were potential trans-regulatory targets of PML/RARA. Furthermore, results indicated heightened interferon-gamma signaling characterizing a tumor-suppressing function of the immune system at the first hematological complete remission stage, which likely resulted from therapy-induced cell death or senescence and ensuing supraphysiological levels of intracellular proteins. Overall, our work sheds new light on the pathophysiology and treatment of APL and provides an information-rich reference data cohort for the exploratory and translational study of leukemia microenvironment., (© 2023. Higher Education Press.)

Purpose: APL patients have recurrent alterations in FLT3, WT1, NRAS and KRAS. Gene mutations have a strong potential for involvement in pathogenesis and may have potential effects on the clinical manifestations. Gene mutations may even be associated with early death (ED) in APL patients. However, there is little published information on mutations in APL patients and whether they are attributed to early death., Methods: In this study, we retrospectively analyzed the clinical data and gene mutations of 134 de novo APL patients. We detected the gene mutations by next-generation sequencing (NGS) to investigate the genetic predictors of early death in APL patients. According to the number of gene mutations per patient, the 134 APL patients were divided into three groups. All patients received arsenic trioxide (ATO) alone as induction therapy. The clinical data and gene mutations were compared and analyzed., Results: A total of 134 APL patients were involved in the study. The clinical data of sex, WBC, PT, and DD, UA, and LDH level were significantly different between the three groups (P = 0.000, P = 0.000, P = 0.009, P = 0.020, P = 0.030, P = 0.001 and P = 0.014, respectively). Meanwhile, among them, the Sanz risk stratification and early death rate were significantly different (P = 0.001). The early death rate was 10.4%, and the median time to early death was 6.6 days (range 2-15 days). For the next-generation sequencing, a mean of 1.28 ± 1.06 mutations per patient was detected (range: 0-5). The univariate and the multivariate regression analysis showed that age > 50[HR = 1.666, CI (1.027-2.702), P = 0.039], high WBC count [HR = 4.702, CI (1.026-21.543), P = 0.046] and low ALB levels [HR = 4.547, CI (1.088-18.995), P = 0.038] were independent risk factors for early death in APL patients. Furthermore, Kaplan-Meier survival analysis, univariate analysis, and the multivariate regression analysis showed that patients with multiple gene mutations [HR = 2.258, CI (1.115-4.571), P = 0.024], KRAS [HR = 5.136, CI (1.356-19.455), P = 0.016] and/or GATA2 [HR = 4.070, CI (1.287-12.877), P = 0.017] have a significantly higher early death rate., Conclusion: The results of this investigation show that both molecular markers and clinical variables should be used as potential predictors for early death in APL patients. Our results suggested that age > 50, high WBC count, low ALB levels, and the presence of multiple gene mutations, KRAS and/or GATA2 at the time of diagnosis were independent risk factors for early death in APL patients. For these patients, clinicians should be more cautious during the course of induction treatment., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Background: Arsenic trioxide (ATO) has been successfully applied in the treatment of acute promyelocytic leukemia (APL). Arsenic metabolites including inorganic arsenic and methylated arsenic could lead to different toxicity and curative effect. This study aims to establish a method to determine arsenic species in red blood cells (RBCs), clarify the distribution characteristics of arsenic species in RBCs., Methods: Steady state blood samples were collected from 97 APL patients. H 2 O 2 and HClO 4 were used to release the hemoglobin bounding arsenic and precipitate protein. Arsenite (iAs III ), arsenate (iAs V ), monomethylarsonic acid (MMA V ) and dimethylarsinic acid (DMA V ) in plasma and RBCs were detected by HPLC-HG-AFS. Free and bound arsenic species in RBCs were separated by 30 kDa molecular mass cutoff filters and determined to evaluate hemoglobin binding capacity of different arsenic species., Results: The method was validated with accuracy ranged from 84.75% to 104.13%. Arsenic species in RBCs followed the trend iAs > MMA > DMA (p < 0.01), while the concentration of DMA was significantly higher than iAs and MMA in plasma (p < 0.01). The correlation between iAs concentration in plasma and corresponding RBCs arsenic level was weak. And the concentrations of DMA and MMA in plasma were moderately positive correlated with those in RBCs. Hemoglobin-binding ratios of iAs, MMA and DMA were all over 70 %., Conclusions: In this study, we provided a reliable method to determine arsenic species in RBCs of APL patients treated with ATO by HPLC-HG-AFS. It was confirmed that the concentration of DMA is the highest in plasma, while MMA is the most predominant methylated arsenic in RBCs. High affinity of MMA with human Hb was responsible for the accumulation of arsenic in RBCs of APL patients., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Early hemorrhagic death remains a major cause of treatment failure in acute promyelocytic leukemia (APL). This study investigated the role of fibrinogen concentrations in early hemorrhage and overall survival (OS) of APL patients. Laboratory and clinical data, including fibrinogen concentrations and other coagulation indexes, bleeding events, and survival data, of 198 patients newly diagnosed with APL from February 2012 to December 2017 were extracted from patient records and retrospectively investigated. Patients with moderate/severe bleeding had significantly lower median fibrinogen concentrations ( p = .023), higher Chinese disseminated intravascular coagulation scoring system (CDSS) ( p < .001), and were more often female ( p = .034) than patients with no such bleeding. Additionally, patients with fibrinogen <1.0 g/L and 1.0-1.6 g/L had significantly higher moderate/severe bleeding rates than those with fibrinogen >1.6 g/L ( p = .015; p = .023). However, moderate/severe ( p = .088) and severe bleeding rates ( p = .063) were comparable for patients with fibrinogen <1.0 g/L and 1.0-1.6 g/L. Multivariate analysis showed that fibrinogen ≤1.6 g/L ( p = .036), platelet counts ≤10 × 10 9 /L ( p = .037), and CDSS scores ≥5 ( p = .023) were independent risk factors for moderate/severe bleeding. Survival analysis indicated that moderate/severe bleeding ( p = .018), fibrinogen ≤1.6 g/L combined with prothrombin time >12.8 s ( p = .005), age ≥60 years ( p = .001), and CDSS ≥5 ( p = .044) were independent predictors of 1-year OS. Fibrinogen ≤1.6 g/L may be an independent risk factor for early bleeding in newly treated patients with APL and is associated with a worse 1-year OS. Increasing fibrinogen to >1.6 g/L may help to prevent bleeding.

Retinoic acid inducible gene G ( RIG-G ) is an inducible gene produced during the treatment of acute promyelocytic leukemia with all-trans retinoic acid (ATRA). However, it is unclear the expression level of RIG-G gene in the peripheral blood of healthy subjects and patients with acute promyelocytic leukemia (APL or AML-M3). In the present study, we established the TaqMan-MGB fluorescent probe qPCR (real-time polymerase chain reaction) method for the first time to detect the expression of RIG-G gene in APL. Twenty APL patients were selected, and their RIG-G expression levels were quantified to assess the correlation between the expression of peripheral blood and bone marrow samples. U test was used to analyze the expression level of RIG-G in the peripheral blood of 40 normal specimens and 20 APL patients to observe the prognostic monitoring effect of RIG-G gene in the ATRA treatment process. ROC (receiver operating characteristic curve) was used to analyze and test the diagnostic efficiency of RIG-G gene for APL patients. There is a strong positive correlation between the expression of RIG-G in peripheral blood and bone marrow of APL patients. The expression level of RIG-G in peripheral blood of APL patients is significantly lower than that in healthy controls ( p < 0.001). The changes in the expression level of RIG-G in peripheral blood changed indicates the remission and recurrence of APL patients after ATRA treatment, and the ROC curve shows that it has a better diagnostic power for APL. In summary, the TaqMan-MGB real-time PCR method we have established has successfully run. The detection of RIG-G gene expression in peripheral blood can effectively monitor the disease changes of APL patients and avoid harmful bone marrow puncture injury.

Background: Acute myeloid leukemia (AML) is a common, challenging hematologic malignancy worldwide. Thai data on its characteristics and outcomes have never been systematically reported, to our knowledge. The objective of this study was to determine the clinical features and outcomes of Thai patients with AML., Patients and Methods: This was a prospective observational study of nine academic hospitals. Patients with newly diagnosed AML were invited to register online., Results: A total of 679 patients with AML were included. The presence of circulating peripheral blood blasts was correlated with a high white blood cell count. Acute promyelocytic leukemia (APL) had predominantly lower white blood cell counts and higher proportions without peripheral blood blasts compared with non-APL AML. Disseminated intravascular coagulation was commonly presented in APL (37.7%). Splenomegaly and normal platelet count were more frequently seen in patients with Philadelphia chromosome-positive AML. The median follow-up time for those who survived more than 1 year was 28.0 months. One-year overall survival rates for non-APL AML and APL were 31.9% and 88.2%, respectively; 2-year overall survival rates were 29.6% and 88.2%, respectively. Hematopoietic stem cell transplantation could improve survival in non-APL AML., Conclusion: APL should be considered despite absence of peripheral blood blast. This study demonstrates poor outcome of Thai AML and more research to improve outcomes are underway. Expanding access to hematopoietic stem cell transplantation should be considered in Thailand., (Copyright © 2021. Published by Elsevier Inc.)

Acute promyelocytic leukemia (APL) cells constitutively express a large amount of tissue factor (TF) antigen, most of which is present in the cytoplasm. Coagulopathy may persist after induction therapy. We evaluated the overall role of circulating microparticles (MPs) in coagulation activation in APL-associated coagulopathy before and during induction therapy. Eleven adult patients with ≥ World Health Organization's (WHO) grade 2 bleeding events and 11 sex- and age-matched healthy controls were selected. All patients received arsenic trioxide alone as induction therapy. MP-associated TF (MP-TF) activity and MP procoagulant activity (MP-PCA) and 12 coagulation- and anticoagulation-associated indexes were measured before, during, and after induction therapy. Correlation between MP-associated indexes and the other 12 indexes was analyzed in patients. The MP-TF activity was negligible in controls, whereas it markedly increased in patients, dropped rapidly after treatment, and returned to normal at the end of induction therapy. The MP-PCA was similar between patients and controls. The correlation analysis revealed that TF-bearing MPs in patients mainly originated from APL cells. Partially differentiated APL cells could also release TF-bearing MPs, and the higher the degree of APL cell differentiation, the lower the ability of APL cells to release TF-bearing MPs. MP-TF was the main source of active TF in plasma and an important contributor for the coagulation activation in APL-associated coagulopathy. It was MPs released by APL cells/partially differentiated APL cells that served as the vehicle to transfer the large amount of TF to plasma to activate coagulation.

Acute promyelocytic leukaemia (APL) represents a modern success of precision medicine. However, fatalities occurring within the first 30 days of induction treatment, in particular intracranial haemorrhage (ICH), remain the main causes of death. We studied the clinico-biological characteristics of 13 patients with APL who experienced ICH. Compared to 85 patients without this complication, patients with ICH were older and more frequently had high-risk APL. Moreover, positivity for the 'swirl' sign at neuroradiological imaging and hydrocephalus were predictors of a fatal outcome, together with lower fibrinogen, prolonged international normalized ratio (INR) and higher lactate dehydrogenase levels., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

A transgenic acute promyelocytic leukemia (APL) murine model established by Michael Bishop by cloning a human PML-RARα cDNA into the hMRP8 expression cassette has been widely used in the all-trans retinoid acid and arsenic preparations for the research of APL. However, in the existing literature, the data of regularity and characteristics of the pathogenesis of this model were still missing, which hinder the development of many studies, especially application of new technologies such as single-cell sequencing. Therefore, in this article, we have made up this part of the missing data using an improved APL murine model. We clarified the effects of different inoculation doses on the onset time, latency, morbidity, life span, and proportion of APL cells in peripheral blood (PB), spleen, bone marrow, and so on. The relationship between the proportion of APL cells in the bone marrow, spleen, and PB and organ histological changes was also revealed. These results were a supplement and refinement of this APL model. It would add to the knowledge base of the field and aid in ensuring that accurate models are used for directed interventions. It also provides a great convenience for the researchers who will carry out similar research.

Background: Differentiation syndrome (DS) is the main life-threatening adverse event that occurs in acute promyelocytic leukemia (APL) patients treated with all-trans retinoic acid (ATRA). Cytokine imbalances have been reported to play role during the developing of acute promyelocytic leukemia differentiation syndrome (APL-DS). However, the relationship between the plasma cytokine levels and their prognostic value for the prediction of DS developing in patients with APL during the treatment with ATRA and anthracyclines has not been previously reported., Methods: In this study, we followed an APL cohort (n = 17) over 7 days of ATRA therapy in DS (n = 6) and non-DS groups (n = 11). Interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12p70 and TNF-α were measured in the peripheral blood plasma from 17 patients with APL and 11 healthy adult controls by using the cytometric bead array method., Results: In non-DS patients, IL-8 plasma levels were significantly reduced in the seventh day of ATRA treatment (34.16; 6.99 to 147.11 pg mL - 1 in D0 vs. 10.9; 0 to 26.81 pg mL - 1 in D7; p = 0.02) whereas their levels did not discriminate between DS and non-DS development during the entire induction period (all p > 0.05 in D0, D3, and D7). No significant differences were found in IL-6 levels between groups (p > 0.05 in D0-D7). Other cytokines tested were all undetectable in patients with APL or healthy controls., Conclusions: We demonstrated that the modulation of IL-8 following ATRA treatment may occur regardless of the development of DS and, therefore, does not appear to be a predictive biomarker to monitor the APL-DS.

Hemorrhagic death is the leading cause of treatment failure in acute promyelocytic leukemia (APL). Our ability to identify patients at greatest risk of hemorrhage, and to actively prevent hemorrhage, remains limited. Nevertheless, some data is available to guide contemporary clinical practice and future investigation. Circulating disease burden, best represented by the peripheral WBC / blast count, is the most consistent predictor of major and fatal bleeding risk. In contrast, laboratory markers of disseminated intravascular coagulation (DIC) appear to be poor predictors. A number of interventions have been posited to reduce bleeding risk. Prompt initiation of all-trans retinoic acid (ATRA), avoidance of invasive procedures, transfusion support, and cytoreduction all have theoretical merit. Though they lack strong evidence to support their benefit with respect to bleeding, they are associated with limited risks, and are therefore advisable. Low-dose therapeutic heparin and antifibrinolytics have not shown the ability to positively modify bleeding risk, and heparin has been associated with harm. Thrombomodulin has shown promise in limited retrospective studies however further prospective data are needed. rFVIIa may have a role in cases of life-threatening bleeding however evidence is largely anecdotal. Additional studies evaluating the above interventions, and investigating other potential interventions are needed., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.

Background: Acute myeloid leukemia (AML) evolves from neoplastic transformation of stem cell disease termed "leukemia stem cells" (LSCs). An unsatisfactory response to AML therapy is determined by the presence of minimal residual disease (MRD). The predominance of LSCs might anticipate sustained MRD results. The present study aimed to demonstrate the effect of LSCs on MRD at induction days 14 and 28 on overall survival (OS) and disease-free survival (DFS) and to compare LSC expression with MRD status., Patients and Methods: A total of 84 patients with de novo adult AML underwent testing using LSC panels for CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33 and different regular MRD panels., Results: At day 14 after induction, the high expression of CD123 and CD133 had adverse effects on both OS and DFS (P = .004 and P ≤ .001 and P ≤ .001 and P ≤ .001, respectively). Greater expression of CD34 + /CD38 - /CD123 + resulted in unfavorable OS and DFS (P ≤ .001 for both). Both CD34 + /CD38 - /CD123 + and CD34 - /CD38 + /CD123 + expression at day 14 after induction had an adverse effect on DFS only (P < .001 and P = .029, respectively). On multivariate analysis, CD133 expression and MRD status were independent prognostic parameters (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.2-4.4; P = .015; and HR, 2.9; 95% CI, 1.0-7.9; P = .041). At day 28 after induction, MRD and increased CD123 + /CD34 - , CD34 + /CD38 - /CD123 + , CD133 + /CD33 - expression were associated with inferior OS (P = .016, P = .0035, P = .0.002, and P = .002, respectively). MRD and high expression of CD34 + CD123 + , CD133 + /CD33 - , CD34 + /CD38 - /CD123 + were associated with inferior DFS (P < .001, P = .002, P < .001, P < .001, respectively). On multivariate analysis, only CD133 + /CD33 - expression was the independent prognostic factor (HR, 3.1; 95% CI, 1.5-6.7; P = .003)., Conclusions: Estimation of LSC expression is a sensitive indicator of the response to therapy in adult patients with AML and might be a better prognosticator than the findings from regular MRD panels., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Overriding the differentiation blockage in acute myeloid leukemia (AML) is the most successful mode-of-action in leukemia therapy - now curing the vast majority of patients with acute promyelocytic leukemia (APL) using all-trans retinoic acid (ATRA)-based regimens. Similar approaches in other leukemia subtypes, such as IDH1/2-mutated AML, are under active investigation. We herein present successful release of the differentiation blockage upon treatment with the natural (-)-Δ 9 -Tetrahydrocannabinol isomer dronabinol in vitro and in vivo., Methods: Cellular maturation and differentiation were followed in two patients employing whole genome methylation profiling, proteome analyses, NGS deep sequencing and multispectral imaging flow cytometry. For functional studies lentiviral OGT knock-down in vitro and ex vivo cell models were created to evaluate proliferative, apoptotic and differentiating effects of OGT in acute leukemia., Findings: In here, we provide molecular evidence that dronbinol is capable to override the differentiation blockage of acute leukemia blasts at the state of the leukemia-initiating clone. We further identify the O-linked β-N-acetyl glucosamine (O-GlcNAc) transferase (OGT) to be crucial in this process. OGT is a master regulator enzyme adding O-GlcNAc to serine or threonine residues in a multitude of target proteins. Aberrant O-GlcNAc modification is implicated in pathologies of metabolic, neurodegenerative and autoimme diseases as well as cancers. We provide evidence that dronabinol induces transcription of OGT via epigenetic hypomethylation of the transcription start site (TSS). A lentiviral OGT-knock out approach proves the central role of OGT exerting antileukemic efficacy via a dual-mechanism of action: High concentrations of dronabinol result in induction of apoptosis, whereas lower concentrations drive cellular maturation. Most intriguingly, overriding of the differentiation blockage of acute leukemia blasts is validated in vivo following two patients treated with dronabinol., Interpretation: In conclusion, we provide evidence for overcoming the differentiation blockage in acute leukemia in subentities beyond promyelocytic and IDH1/2-mutated leukemia and thereby identify O-GlcNAcylation as a novel (drugable) field for future leukemia research., Funding: Unrestricted grant support by the IZKF Program of the Medical Faculty Tübingen (MMS) and Brigitte Schlieben-Lange Program as well as the Margarete von Wrangell Program of the Ministry of Science, Research and the Arts, Baden-Württemberg, Germany (KKS) and Athene Program of the excellence initiative University of Tübingen (KKS)., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Although AML-M3 (APL) and HLA-DR negative non-APL are characterized by negative HLA-DR antigen, they are different entities with similar morphology in some cases. The aim of this study is the precise, differential diagnosis of APL from HLA-DR negative non-APL by flow cytometry to narrow the diagnosis window. Bone marrow or blood samples of 580 AML patients were analyzed, and flow cytometry and molecular analysis were performed for the diagnosis of blood disorders. In 105 HLA-DR negative AML patients, expression of HLA-DR, CD33, CD117, CD11b, CD64, CD34, CD9 and myeloperoxidase staining pattern were evaluated. Fifty-six patients were diagnosed with APL, and 49 patients were diagnosed with HLA-DR negative non-APL. The APL blasts expressed CD33, CD117, CD64, and CD9 in 100%, 80.3%, 94.6%, and 100% of the cases, respectively. HLA-DR negative non-APL blasts expressed CD33, CD117, CD64 and CD9 in 75.5%, 59.1%, 32.6%, and 73.4% of the cases, respectively. APL cells were negative for HLA-DR, CD11b, and CD34 in 96.4%, 94.6%, and 91.0%, respectively. Blasts in HLA-DR negative non M3-AML were negative for CD11b, CD117, and CD34 in 77.5%, 40.9%, and 22.4%, respectively. We also investigated myeloperoxidase (MPO) staining pattern and found strong diffuse reaction in APL cells while HLA-DR negative non-APL cells showed focal positive reaction. In all of the APL patients, except for one, PML/RARA translocation was positive, and in another case with HLA-DR negative non-APL, PML/RARA and other translocations were not detected. The six-panel combination profile rapidly and specifically identifies APL from other HLA-DR negative AML.

Introduction: Patients with acute promyelocytic leukemia (APL) are characterized by the highest expression of Wilms' tumor 1 (WT1) gene compared with other subtypes of acute myeloid leukemia, and yet this molecular marker is almost never used for risk stratification and in therapy response monitoring., Methods: Quantitative assessment of Wilms' tumor 1 (WT1) gene transcripts was performed using real-time PCR method. The bone marrow samples were collected at the time of diagnosis for 47 APL patients, and for 31/47 patients during follow-up/relapse of the disease (129 samples in total). We examined how this molecular marker can be used for prognosis and minimal residual disease (MRD) monitoring., Results: Increased WT1 expression was found in 34% of patients. WT1 high status was an independent unfavorable factor for early death occurrence and was associated with shorter overall survival (OS). Assessment of log reduction value of WT1 expression in paired diagnosis/complete remission samples did not reveal its impact on relapse rate, disease-free survival, and OS. Also, measurement of WT1 expression level at different time points during therapy was not a reliable method for MRD monitoring., Conclusion: Increased expression of WT1 gene detected in high proportion of APL patients could be considered as a marker for more precise risk stratification models in an attempt to further improve treatment and outcome of APL patients., (© 2019 John Wiley & Sons Ltd.)

Background: MicroRNA (miRNA) expression has been implicated in leukaemia. In recent years, miRNAs have been under investigation for their potential as non-invasive biomarkers in acute promyelocytic leukaemia (APL). We investigated whether miR-638 in circulating leukaemia cells is a non-invasive biomarker in diagnosis, assessment of the treatment response and minimal residual disease (MRD) surveillance of APL., Methods: Sixty cases of acute myeloid leukaemia (AML), including 30 cases of APL and 30 cases of non-APL AML, were selected. Thirty healthy controls were also selected. Bone marrow (BM) and peripheral blood (PB) samples were collected from APL patients at diagnosis and post-induction. Microarray analysis and quantitative real-time PCR (qRT-PCR) were performed for miRNA profiling and miR-638 expression analysis, respectively. For statistical analysis, Mann-Whitney U test, Wilcoxon Signed Rank test, receiver operating characteristic (ROC) curve analysis and Spearman's rho correlation test were used., Results: Both microarray and qRT-PCR data showed that miR-638 was significantly upregulated in BM after APL patients received induction therapy. Moreover, miR-638, which is specifically downregulated in APL cell lines, was upregulated after all-trans retinoic acid (ATRA)-induced myeloid differentiation. Receiver operating characteristic (ROC) curve analyses revealed that miR-638 could serve as a valuable biomarker for differentiating APL from controls or non-APL AML. Furthermore, miR-638 expression was sharply increased after induction therapy and complete remission (CR). An inverse correlation was observed between miR-638 and PML-RARα transcripts levels in BM samples, while a positive correlation was revealed between PB miR-638 and BM miR-638 levels in APL patients after induction therapy., Conclusions: Our study suggested that miR-638 may serve as a potential APL biomarker for diagnosis and assessment of the response to targeted therapy, and PB miR-638 could be used for non-invasive MRD surveillance in APL.

Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation between chromosomes 15 and 17, t(15;17), resulting in the expression of PML-RARα fusion protein, which disrupts the normal PML nuclear bodies (PML-NBs) to micro-speckled pattern, leading to loss of their original functions. Moreover, reformation of PML-NBs in APL by arsenic is considered as one of the important step for APL treatment. Leptomycin B (LMB), a nuclear export inhibitor, is commonly used to inhibit the proteins exporting from the nucleus to the cytoplasm. In the present study, we found that LMB could induce the reformation of PML-NBs in leukemia NB4 cells as well as in APL blast cells from the patients, implying that nuclear shuttle proteins might be involved in the reformation of PML-NBs. Herein, we further found that LMB totally lost the ability to induce PML-NBs reformation when the endogenous PML gene was knocked out, indicating that endogenous PML protein is probably involved in the reformation of PML-NBs. More interestingly, among all PML isoforms (i.e., seven isoforms), reformation of PML-NBs was only observed when co-transfection of PML-RARα with PML-I after LMB treatment. Similarly, deletion of nuclear export signal (NES) of PML-I could also reform PML-NBs, suggesting that the protein level of endogenous PML-I in nucleus is important for the reformation of PML-NBs that interfered by PML-RARα fusion protein. Additionally, LMB has synergistic effect with iAs III on enhancing PML-RARα fusion protein degradation, and it might provide new insight into APL treatment at clinical level in the near future., (Copyright © 2019. Published by Elsevier Inc.)

We studied the outcomes of children with APL treated by the Beijing Children's Hospital's (BCH) acute promyelocytic leukemia (APL) 2005 protocol (BCH-APL2005). The clinical data of 77 patients enrolled from January 2005 to June 2015 were analyzed retrospectively. The hematologic complete remission (CR) rate and overall survival (OS) rate were evaluated between standard-risk (SR) and high-risk (HR) groups. Prognostic factors and complications were investigated in these two groups. CR in the SR and HR groups was 96.4% (54/56) and 85.7% (18/21), respectively, while the 10-year OS was 94.6% (53/56) and 76.2% (16/21), respectively. The cumulative incidence of early death was 6.5% (5/77), and the SR and HR groups were 1.8% (1/56) and 19.0% (4/21), respectively. Only two patients relapsed, and the relapse rate was 2.6% (2/77). According to Kaplan-Meier analysis, the SR group had a significantly better long-term survival than HR counterparts ( p = .016). Initial leukocyte count was the only prognostic factor ( p = .016) by univariate analysis, while other factors, such as FLT3-ITD and platelet count, had no correlation with prognosis. In addition, early deaths were mainly due to intracranial hemorrhage. Although the combination of all-trans retinoic acid (ATRA) and chemotherapy can improve the outcome of APL patients, the early deaths and anthracycline-related cardiac toxicity were relatively higher in our study. Current efforts focus on reducing or even avoiding chemotherapy in APL children and rest on the frontline regimen of intravenous arsenic trioxide or oral realgar-indigo naturalis formula plus ATRA, which is the direction for APL treatment.

Fatal hemorrhage is the most common cause of induction failure and death among patients with acute promyelocytic leukemia (APL). However, there remains no established means of hemorrhagic risk stratification in APL. In this single center retrospective study of 43 patients treated for APL group-based trajectory modeling was used to identify laboratory trends associated with major bleeding. Bleeding risk was significantly associated with particular trends in white blood cell count (WBC) and lactate dehydrogenase level (LDH). Specifically, patients who presented with high WBC and/or LDH, and whose WBC and/or LDH then proceeded to uptrend during the initial days of induction, were significantly more likely to experience major bleeding ( p  = .0111 and p  = .0143, respectively). Additionally, there appeared to be a temporal association between WBC and LDH trends and major bleeding events. Among nonlaboratory variables, differentiation syndrome (DS) was significantly associated with major bleeding ( p  = .00149).

Molecular measurable residual disease (MRD) monitoring based on real-time quantitative reverse transcription PCR (RT-qPCR) plays an important role in acute promyelocytic leukemia (APL) management, but the performance status of clinical reports is unknown. This study focuses on the specific elements in molecular MRD monitoring report and their impact on clinical decision-making. The participating laboratories were asked to submit real and formal clinical reports for mock samples panel with APL clinical case. The MRD-specific elements were analyzed and summarized. The significance of longitudinal MRD monitoring curve and the missing MRD-specific elements for clinical decision-making were assessed. MRD-specific elements were significantly missing in clinical reports. The element "testing results" existed great inconsistencies in the written form of testing items and data. The longitudinal MRD monitoring curve of false-negative or false-positive MRD result was obviously different from all-correct. It not only identified MRD time point of tissue sampling relative to treatment and ensured the reliability of the negative MRD results, but also gave MRD diagnosis, clinical interpretation, and further recommendation. Clinician-friendly reports with MRD-specific elements can better serve clinical practice. The correctly intuitive results and clinically important MRD-specific elements can provide a good description of the reliability and clinical significance of MRD results.

The clinical outcomes of autologous hematopoietic stem cell transplantation (ASCT) in acute myelogenous leukemia (AML) have improved over time. Indeed, numerous studies have demonstrated that ASCT is associated with a lower relapse rate and acceptable nonrelapse mortality compared with chemotherapy alone in patients with AML. In addition, ASCT is also associated with comparable overall survival outcomes to those of allogeneic hematopoietic stem cell transplantation in some patients with AML. To date, age, cytogenetic and molecular risk stratification, and minimal residual disease (MRD) status have been shown to be closely related to clinical outcomes following ASCT. ASCT is recommended for patients with favorable-risk and intermediate-risk AML in first complete remission and patients with acute promyelocytic leukemia in second complete remission for whom a matched sibling donor is not available. MRD status pre-ASCT is the most important factor to consider when determining whether a patient is eligible for ASCT and can effectively predict clinical outcomes after ASCT. Advanced age is not an absolute contradiction for ASCT. In this review, we describe the literature and clinical trials evaluating the outcomes of ASCT in patients with AML and discuss the indications for ASCT therapy. Because the greatest concern in ASCT recipients is early relapse, important factors that should be monitored before ASCT and future perspectives in this area are also presented., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Acute Promyelocytic Leukemia (APL) is a rare and potentially lethal condition in which risk-based therapy often leads to better outcomes. Because of its rarity and relatively high overall survival rate, prospective randomized trials to investigate alternative APL treatment schedules are challenging. Mathematical models may provide useful information in this regard. We collected clinical data from 38 patients treated for APL under the International Consortium on Acute Leukemia (ICAL) protocol and laboratory data during induction therapy. We propose a mathematical model that represents the dynamics of leukocytes in peripheral blood and the effect of ICAL treatment on the disease's dynamics. We observe that our cohort presents demographic characteristics and clinical outcomes similar to previous clinical trials on APL. Over a follow-up period of 41.8 months, the relapse-free survival and overall survival at two years are both found to be 78.7%. For two selected patients, the model produces a good fit to the clinical data. Information such as the response to treatment and risk of relapse can be derived from the model, and this may assist in clinical practice and the design of clinical trials., Competing Interests: The authors have declared that no competing interests exist.

Acute promyelocytic leukemia (APL) is generally held to have favorable risk, but we have observed a high incidence of early deaths caused by fatal bleeding and differentiation syndrome (DS). We retrospectively analyzed 259 APL patients from 2002 to 2014 who all received all-trans retinoic acid (ATRA) with the support of sufficient transfusions, followed by 4 days of idarubicin. High-risk status was determined as a diagnostic leukocyte count (WBCdx) >10 × 10 9 /L (Sanz criteria). For patients with hyperleukocytosis, we sometimes conducted leukapheresis and also used hydroxyurea and prophylactic dexamethasone. Because we frequently observed patient fatalities from progressive hyperleukocytosis, we also checked the maximum leukocyte count (WBCmax) and stratified patients by their incremental ratios. The 8-week cumulative incidence of early death and DS was 13.5% and 17.8%, respectively. We found that WBCmax correlated better with early death and DS, even in the low-risk group, than WBCdx. Among the patients with WBCdx <10 × 10 9 /L, a WBCmax >43 × 10 9 /L correlated with early death (26.7%) and DS (40.0%). Also, having a WBCdx of 10 to 43 × 10 9 /La that increased to a WBCmax >43 × 10 9 /L correlated with increased early death (33.3%). The multivariate analysis revealed that a WBCmax >43 × 10 9 /L correlated significantly with both early death and DS.

Purpose: Acute promyelocytic leukemia (APL) is the most prognostically favorable subtype of Acute myeloid leukemia (AML). Defining the features that allow identification of APL patients likely to relapse after therapy remains challenging., Experimental Design: Proteomic profiling is performed on 20 newly diagnosed APL, 205 non-APL AML, and 10 normal CD34+ samples using Reverse Phase Protein Arrays probed with 230 antibodies., Results: Comparison between APL and non-APL AML samples identifies 8.3% of the proteins to be differentially expressed. Proteins higher expressed in APL are involved in the pro-apoptotic pathways or are linked to higher proliferation. The "MetaGalaxy" approach that considers proteins in relation to other assayed proteins stratifies the APL patients into two protein signatures. All of the relapse patients (n = 4/4) are in protein signature 2 (S2). Comparison of proteins between the signatures shows significant differences in relative expression for 38 proteins. Protein expression summary plots suggest less translational activity in combination with a less proliferative character for S2 compared to signature 1., Conclusions and Clinical Relevance: This study provides a potential proteomic-based classification of APL patients that may be useful for risk stratification and therapeutic guidance. Validation in a larger independent cohort is required., (© 2019 The Authors. Proteomics - Clinical Application published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To assess plasma fibrinogen levels as a biomarker to predict the prognosis and treatment outcome in acute myeloid leukemia (AML), a retrospective study of 215 patients with AML excluding M3 was conducted in a single center. Patients were divided into low and high group according to the cutoff value of 3.775 g/L obtained by analyzing the receiver operating characteristic (ROC) curve of fibrinogen at diagnosis. Importantly, overall survival (OS) was markedly better in low fibrinogen group ( p =.006) as well as disease-free survival (DFS) ( p = .045). Furthermore, when patients achieved complete remission (CR), the median plasma fibrinogen levels were dramatically decreased in high fibrinogen group but increased in low fibrinogen group. In conclusion, our data suggest that initial plasma FBG levels can be used as an independent prognostic biomarker affecting OS and DFS, as well as a potential parameter reflecting the treatment outcome in patients with non-M3 AML.

Acute promyelocytic leukemia (APL) is generally characterized by t(15;17)(q24;q21). In some cases, the classic translocation cannot be identified by conventional methods, since the PML-RARA fusion protein results from complex, variant, or cryptic translocation. The diagnostic algorithm of APL starts with screening methods, such as flow cytometry (FC), followed by fluorescence in situ hybridization or polymerase chain reaction to confirm the diagnosis. Our aim was to develop a novel protocol for analyzing APL samples based on multidimensional dot-plots that can provide comprehensive information about several markers at the same time. The protocol included four optimized multidimensional dot-plots, which were tested by retrospective reanalysis of FC results in APL (n = 8) and non-APL (n = 12) acute myeloid leukemia (AML) cases. After predicting the potential position of hypergranular- and microgranular-type aberrant promyelocytes, the percentages of blast populations were examined within the gates in all AML cases. The percentage of blasts in each predefined gate was well above the cut-off value (95%) in APL cases in all tubes. In non-APL AML cases, the percentage of blasts in the same gates never reached the cut-off value in all investigated tubes, and even when it did in a single tube, the pattern was markedly different from that observed in APL cases. In conclusion, multidimensional dot-plots can be used for screening APL even in cryptic APL cases, although reproducibility across several laboratories would require standardization of antibodies and fluorochromes. This easy-to-use and quick method can support the diagnosis of APL and the prompt initiation of the appropriate treatment.

To study the effect of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combination treatment on apoptosis of acute promyelocytic leukemia cells (NB4), inflammation and prognosis. The effect of ATRA - ATO combination on the proliferation of NB4 was determined using MTT assay. Apoptosis of NB4 cells was assessed with TUNEL assay. The effect of ATRA-As2O3 combination on the expressions of IL-6 and TNF-α in NB4 cells was determined using ELISA kits, while its effect on the quality of life of 25 acute promyelocytic leukemia patients admitted to our hospital was scored, as an index of prognosis. The combination treatment with ATRA and ATO significantly inhibited the proliferation of NB4 cells and promoted their apoptosis, relative to the model group. In addition, the combination treatment reduced serum IL-6 and TNF-α levels in patients with acute promyelocytic leukemia, and improve their quality of life and survival. Combination treatment with ATRA and ATO significantly inhibits the proliferation of NB4 cells and promotes their apoptosis, and reduces inflammatory responses in patients with acute promyelocytic leukemia, while improving their quality of life and prognosis.

Objective: To investigate the immunophenotypic characteristics of acute promyelocytic leukemia (APL) and explore the sensitivity and specificity of various antibody combinations for the timely and accurate diagnosis APL., Methods: A retrospective analysis was performed using morphological, immunological, genetic, and molecular biological data from 92 patients diagnosed with APL and 190 controls diagnosed with non-APL acute myeloid leukemia., Results: For APL diagnosis, the CD9/CD11b/human leukocyte antigen (HLA)-DR antibody combination had 85% sensitivity and 95% specificity, AUC = 0.85. However, the sensitivity and specificity were 39% and 92%, AUC = 0.65, respectively, for the HLA-DR/CD34/CD117 combination, and 80% and 80%, AUC = 0.80, respectively for the CD11b/HLA-DR combination. Significant differences were observed between the different antibody combinations., Conclusions: The CD9/CD11b/HLA-DR antibody combination displays high sensitivity and specificity and can be used to diagnose APL., (© 2018 John Wiley & Sons Ltd.)

This study presents outcome and pharmacokinetics of arsenic trioxide (ATO) metabolites in patients on continuous venovenous haemodialysis (CVVHD). Of 3 acute promyelocytic leukaemia patients receiving CVVHD in management of acute kidney injury, only 1 patient was included. The patient presented disseminated intravascular coagulation and acute kidney injury before induction therapy was conducted. CVVHD was performed and ATO was initiated. Species of ATO metabolites in plasma and effluent were analysed using high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry. Plasma concentrations of As III , monomethylarsonic acid and dimethylarsinic acid with CVVHD were lower than those without CVVHD. Area under the concentration-time curve from 0 to the last sample with quantifiable concentration of As III without CVVHD was significantly higher than that with CVVHD (292.10 ng h/mL vs 195.86 ng h/mL, P = .037), which were not observed for monomethylarsonic acid and dimethylarsinic acid. Dialysate saturation of arsenic species was remarkable, especially for As III . Complete remission was achieved and renal function recovered. In this study, ATO can be used safely and effectively to treat acute promyelocytic leukaemia patients undergoing CVVHD without dose adjustment., (© 2019 The British Pharmacological Society.)

The introduction of arsenic trioxide (ATO) in treatment of acute promyelocytic leukemia (APL) has resulted in high clinical complete remission (CR) rates over 90%. On the contrary, the risk for early death (ED) in APL patients treated with ATO continues to have a negative impact for optimization of APL therapeutics. There is an urgent need for precision medicine and biomarkers in clinical monitoring of ATO toxicity in APL, and ED in particular. This retrospective case series cohort proteomics study was conducted as a hypothesis generation effort and provides here several potential molecular leads on serum peptides expressed at different times after treatment with ATO in patients with APL. In 12 patients with a de novo APL diagnosis, and treated with single-agent ATO as frontline remission induction therapy, serum peptides were fractionated by weak cation exchange magnetic beads and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Ten peptides (m/z 2075.5, 2084.2, 2203.0, 2265.2, 2872.8, 2916.6, 3145.2, 3153.4, 3953.4, and 3964.8) were significantly downregulated in serum after ATO treatment. Among them, four peptides were identified as (1) Immunoglobulin heavy chain V-III region BUT, (2) RRP15-like protein, (3) filaggrin, and (4) protein SON isoform F. To the best of our knowledge, this is the first clinical oncology proteomic biomarker study with a view to future rational therapeutic monitoring of patients with APL in the course of single-agent ATO treatment and hematological CR.