Postremission therapy with repeated courses of high-dose cytarabine,idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia

Consolidation treatment in acute myeloid leukemia (AML) patients achieving complete remission (CR) is warranted. High-dose cytarabine (HDAC) is considered first choice in favorable risk and an option in intermediate-risk AML. However, its optimal dose and schedule, as well as the benefit of additional chemotherapy agents remain controversial. Herein, we report on the long-term outcome of consecutive unselected AML patients treated with repeated courses of HDAC, with the addition of idarubicin, followed by autologous peripheral blood stem cell (PBSC) support, in order to limit toxicity, according to Northern Italy Leukemia Group (NILG) AML-01/00 study (EUDRACT number 00400673). Among 338 patients consecutively diagnosed from 2001 to 2017 at our center, 148 with high-risk AML (adverse cytogenetic, isolated FLT3-internal tandem duplication mutation, refractory to first induction) were addressed to allogeneic stem cell transplant. All other cases, 186 patients (55%), median age 53 (range 19–75), were considered standard-risk and received the NILG AML-01/00 program. After achieving CR, patients were mobilized with cytarabine 8 g/sqm to collect autologous CD34+-PBSC and received three consolidation cycles with HDAC (20 g/sqm) plus idarubicin (20 mg/sqm) per cycle, followed by reinfusion of limited doses of CD34+ PBSC (1-2x106/kg). The program was completed by 160 (86%) patients. Toxicity was acceptable. Neutrophils recovered a median of 10 days. Treatment-related mortality was 3/160 (1.8%). After a median follow-up of 66.4 months, overall survival (OS) and relapse-free survival (RFS) at 5-years were 61.4% and 52.4%, respectively. Twenty-eight selected patients aged >65 had similar outcomes. According to European leukemia net-2010 classification, the OS and RFS at 5-years were 76.4% and 65% in favorable risk, without differences between molecular subgroups, 52.3% and 47.2% in Intermediate-I, 45.2% and 36.5% in Intermediate-II risk patients, respectively. In conclusion, consolidation including repeated courses of high dose cytarabine and idarubicin, with limited PBSC support, proved feasible and very effective in nonhigh risk patients. The incorporation of novel agents in its backbone may be tested to further improve patient's prognosis.     

Frequency and Correlation of Common Genes Copy Number Alterations in Childhood Acute Lymphoblastic Leukemia with Prognosis

Objective: It was shown by genomic profiling that despite no detectable chromosomal abnormalities a proportion of children with pre-B acute lymphoblastic leukemia harbors copy number alterations (CNA) of genes playing role in B-cell development and function. The aim of the study was to determine the frequency of CNA in pediatric acute lymphoblastic leukemia and correlate these findings with clinical outcome. Methods: DNA extracted from peripheral blood or bone marrow at diagnosis/relapse of fifty newly diagnosed children with precursor B-cell acute lymphoblastic leukemia was analyzed for CNA with multiplex ligation-dependent probe amplification. Results: The analysis revealed 76 CNA in 24 patients most frequently found in PAR1 (17%), CDKN2A/B (15.7%) and PAX5 (14.4%) genes. There were significant CNA co-occurrences between PAX5, CDKN2A/B, BTG1, ETV6, PAR1 or XP22 genes, (p <0.020) and the high-risk group. There was a significant correlation between EBF1, RB1, and IKZF1 alterations and bone marrow relapse. Patients with CNA in screened genes are more likely to succumb to their disease except for those with PAR1 or XP22 genes (p <0.050). Conclusion: The multiplex ligation-dependent probe amplification could be considered as an independent diagnostic tool allowing prompt identification of patients at high risk of treatment failure and, subsequently, a more adequate treatment approach.     

Annual Research Review: Rethinking childhood trauma-new research directions for measurement,study design and analytical strategies

Childhood trauma is a key modifiable risk factor for psychopathology. Despite significant scientific advances, traumatised children still have poorer long-term outcomes than nontraumatised children. New research paradigms are, thus, needed. To this end, the review examines three dominant assumptions about measurement, design and analytical strategies. Current research warns against using prospective and retrospective measures of childhood trauma interchangeably; against interpreting cross-sectional differences in putative mediating mechanisms between adults with or without a history of childhood trauma as evidence of longitudinal changes from pre-trauma conditions; and against directly applying explanatory models of resilience or vulnerability to psychopathology in traumatised children to forecast individual risk in unseen cases. The warnings equally apply to research on broader measures of adverse childhood experiences (ACEs). Further research examining these assumptions can generate new insights on how to prevent childhood trauma and its detrimental effects.     

肿瘤坏死因子α增强全反式维甲酸诱导早幼粒白血病细胞凋亡

目的:分析肿瘤坏死因子α增强全反式维甲酸诱导早幼粒白血病细胞凋亡的作用。方法:选择NB4人急性早幼粒白血病细胞，利用全反式维甲酸单独作用，并选择肿瘤坏死因子α联合全反式维甲酸作用，测定细胞增殖以及细胞凋亡情况。结果:随着早幼粒白血病细胞分化的逐渐进行，单一组、联合组的细胞增殖速度均慢慢下降；随着早幼粒白血病细胞分化的逐渐加深，单一组、联合组细胞凋亡率慢慢升高；分化2天，联合组细胞CD11b阳性率明显高于单一组，P<0.05。结论:全反式维甲酸具有诱导早幼粒白血病细胞分化、凋亡的作用，而肿瘤坏死因子α会增强全反式维甲酸的作用效果。     

An evaluation of glasdegib for the treatment of acute myelogenous leukemia

ABSTRACT

Introduction

Despite recent advances in the treatment of adult acute myelogenous leukemia (AML), the overall outcome remains dismal especially in high-risk AML patients, including the elderly and the relapsed/refractory populations. In this setting, various clinical trials have recently explored novel therapeutic agents either used alone or in combination with intensive chemotherapy or low-intensity treatments.     

自然杀伤细胞治疗急性髓系白血病的研究进展

自然杀伤细胞(natural killer cell,NK)为一种存在于天然免疫系统中的淋巴细胞,具有杀伤肿瘤细胞和抗病毒感染的能力,在天然免疫和过继免疫治疗中发挥重要作用。随着NK细胞的特征和功能越来越被熟知,其已被广泛应用于临床抗肿瘤治疗,特别是血液系统恶性肿瘤如急性髓系白血病(acute myeloid leukemia,AML)、淋巴瘤等治疗。目前,基于NK细胞的免疫治疗主要包括自体NK细胞输注、异体NK细胞输注、嵌合抗原修饰NK(chimeric antigen receptor,CAR)细胞输注以及基于NK细胞的其他免疫治疗等。以NK细胞为基础的免疫治疗旨在增强NK细胞的抗肿瘤能力以及克服肿瘤免疫逃逸。随着研究进展,NK细胞将成为治疗AML的有效方法。     

A new era of immuno-oncology in acute myeloid leukemia - antibody-based therapies and immune checkpoint inhibition

Acute myeloid leukemia (AML) remains a therapeutically challenging malignancy with high rate of relapse and poor outcomes. There has been increased understanding of the molecular characteristics of AML and the various roles of the immune system in its pathogenesis, the result of which has led to the study and development of multiple immune-based approaches for this disease. In this review, we aim to provide an overview of the recent advancements made in antibody-based approaches to the treatment of AML including monoclonal antibodies, antibody-drug conjugates, and immune checkpoint inhibition. In addition, we provide insight and discuss the promise of these agents, some of which may soon enter the therapeutic armamentarium we currently employ against this lethal disease.     

青黛作用于急性幼粒细胞白血病的可视化“药靶蛋白模型”分析

目的:目前青黛已是治疗急性幼粒细胞白血病(APL)的临床有效药物,但其分子机制与物质基础仍不明确。基于此本研究构建青黛与APL可视化药靶蛋白模型,以探究青黛作用于APL的分子机制。方法:通过GEO数据库检索APL微阵列芯片分析APL差异表达基因,使用TCMSP数据库筛选青黛活性成分,结合PubChem和SwissTargetPrediction匹配活性成分的靶基因并进行富集分析。String用于挖掘并构建APL可视化蛋白互作数据,将其读入Cytoscape,通过Centiscape实现网络拓扑分析。综合APL差异表达基因,通过Sybyl与青黛活性成分构建药靶蛋白模型。结果:筛选出3张APL微阵列芯片,164个差异表达基因,9种青黛活性成分,541个靶基因,这些靶点较多地参与细胞凋亡、药物结合、癌症途径、慢性粒细胞白血病等,这些都在APL中起重要作用。拓扑分析显示ELANE,CTSS为核心基因,将其与青黛9种活性成分进行药靶蛋白模型预测,显示靛玉红和靛蓝与核心基因结合度最佳。结论:APL是受多基因调控的复杂疾病,而青黛成分中靛玉红和靛蓝可通过结合ELANE,CTSS作用于APL的发生发展。     

Vitamin B6 Addiction in Acute Myeloid Leukemia

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