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  • Laboratory and clinical evidence strongly suggests that muta

    2018-10-30

    Laboratory and clinical evidence strongly suggests that mutations of LBD of RARα and B box2 of PML in PML–RARα are responsible for resistance to ATRA and ATO, respectively (Jeanne et al., 2010; Zhang et al., 2010; Goto et al., 2011). However, these mutations generally occur at the time of relapse. Previously we and others observed that at disease presentation, some other molecular events could co-exist with PML–RARα such as mutations of NRAS, KRAS, FMS-like tyrosine kinase 3 [with internal tandem lgk974 cost (FLT3-ITD) or FLT3 point mutations (FLT3-TKD)] and JAK1. In APL patients treated with ATRA and chemotherapy, these mutations might exert potential impact on the biological behavior, clinical manifestation and treatment outcome (Chan et al., 2006; Rampal and Levine, 2011; Shen et al., 2011). More recently, when new genetic markers such as DNMT3A and IDH1/2 were used for mutation screening in APL and genomic data of some APL cases were available (Shen et al., 2011; Wang et al., 2013), it was revealed that still other gene mutations could exist and be related to disease outcome. In this study, we have investigated the gene mutational status of APL in addition to PML–RARα to clarify their potential biological and clinical impact among patients treated with ATRA/ATO based protocol in an attempt to further improve the stratification system of APL.
    Methods
    Results
    Discussion ATRA plus chemotherapy (anthracyclines alone or with Ara-C) has been used as routine practice for treatment of APL in hematology/oncology centers worldwide (Degos et al., 1995; Avvisati et al., 1996; De Botton et al., 1998; Estey et al., 2005; Lo-Coco et al., 2013; Sanz et al., 2000). ATO was tested in re-induction in relapsed patients with a CR rate more than 80% (Tallman and Altman, 2009; Shen et al., 2004, 2001). We initially proposed simultaneous use of ATRA and ATO in newly diagnosed patients based on several lines of evidence. First, ATO and ATRA target, respectively, the N- and C-terminals of PML–RARα and modulate key pathways involved in apoptosis/differentiation. Hence a combined use of the two agents may bring synergistic effect (Wang et al., 2010; Zhang et al., 2010). Second, evidence from pre-clinical study showed that ATRA/ATO combination could significantly reduce the tumor burden or even eliminate the disease in experimental APL animal models (Lallemand-Breitenbach et al., 1999). Third, transcriptome/proteome analysis of APL cells upon the joint effect of the two agents showed enhanced induction of differentiation/apoptosis associated pathways in the absence of obvious induction of pathways related to cell toxicity (Zheng et al., 2005). Fourth, the ATO-induced second or third CR in patients relapsed after treatment with ATRA/chemotherapy usually didn\'t last long. Indeed, with the ATRA/ATO combination therapy, the clinical outcome of APL has dramatically changed and the disease has been transformed from highly fatal to highly curable in a great majority of patients (Chen et al., 1994; Fenaux et al., 1994; Huang et al., 1988; Niu et al., 1999; Tallman and Altman, 2009; Hu et al., 2009; Shen et al., 2004; Zhang et al., 2010; Zhu et al., 2013, 1997; Ito et al., 2008; Zhou et al., 2010; Lo-Coco et al., 2013; Shen et al., 2001). Recent evidence from Huang et al. also proved that ATRA in combination of an oral arsenic compound, As4S4, is as effective as ATRA/ATO (Zhu et al., 2013). A comparison of the results between a historic control group of 97 cases treated with ATO as rescue for relapse after ATRA/chemotherapy regimen (ATRA→ATO group) yielded an outcome significantly inferior to that achieved by simultaneous use of the two medicines in 535 cases in this series (ATRA/ATO group). With a median follow-up time of 60months, the 5year OS and DFS rates were respectively 68.3±4.8% and 76.4±5.4% in ATRA→ATO group as compared to 89.9%±1.4% and 92.9±1.3% in ATRA/ATO group (P<0.001 for both OS and DFS, Supplementary Fig. 4A, B). However, APL is not a homogenous disease and can be stratified into low-, intermediate- and high-risk groups according to clinical parameters, such as WBC and platelet (Sanz and Lo-Coco, 2011; Sanz et al., 2000). Even with ATRA/ATO treatment, a sizable portion of high-risk patients (17.6% in this study) still experienced difficult induction intercourse, disease recurrence and short survival. A low percentage of cases in low- and intermediate-risk groups still got relapse (3.2% and 5.2%, respectively). Therefore, it is important to identify more sensitive markers to have a better stratification system for APL (Sanz and Lo-Coco, 2011).