LEUKOCYTOSIS AND RETINOIC ACID SYNDROME IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA TREATED WITH ARSENIC TRIOXIDE

Objective To study the incidence of leukocytosis and retinoic acid （RA） syndrome in newly diagnosed and relapsed acute promyelocytic leukemia （APL） patients treated with arsenic trioxide （ATO）. Methods Thirty patients with newly diagnosed or relapsed APL received ATO for remission induction at the dose of 10 mg/d. RA syndrome was defined when patient was with one or more of the following signs or symptoms： fever, dyspnea, serous cavity effusion, muscular pain, pulmonary infiltration, weight gain, or pulmonary infiltration on chest X-ray. Results Twenty-three （77%） patients achieved complete remission, mean time to remission was 37. 1 days. Leukocytosis was observed in 14 （47%） patients, mean time to leukocytosis was 12. 7 days, median baseline leukocyte count for patients with leukocytosis was 3.1 x 109/L, which was higher than that for patients who did not de,.＇elop leukocytosis （2.6 × 10^9/L, z = - 2. 635, P = 0. 008）. No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in 9 （30%） patients, mean time to diagnose of RA syndrome was 13.9 days, median baseline leukocyte count for patients with RA syndrome was 3.6 × 10^9/L, which was higher than that for patients who did not develop RA syndrome （2. 6 × 10^9/L, z = - 1. 909, P =0. 046）. No patient died of RA syndrome. Conclusion Leukocytosis and RA syndrome are associated with ATO and baseline leukocyte count respectively, and there is distinct link between leukocytosis and RA syndrome.

All-trans Retinoic Acid,Arsenic Trioxide,and Anthracycline-based Chemotherapy Improves Outcome in Newly Diagnosed Acute Promyelocytic Leukemia Regardless of FLT3-ITD Mutation Status

All-trans retinoic acid(ATRA)and pre-upfront arsenic trioxide(ATO)have revolutionized the therapy of acute promyelocytic leukemia(APL).However,internal tandem duplication of FMS-like tyrosine kinase 3(FLT3-ITD)mutations is associated with increased risk of relapse.The aim of this study was to analyze the prognostic impact of FLT3-ITD on APL patients who received remission induction with ATRA,idarubicin(IDA)and/or ATO,followed by ATRA plus ATO along with anthracycline,as consolidation therapy.A total of 72 patients newly diagnosed with APL were included in this study.83.3%of the patients achieved complete remission(CR)after induction therapy.FLT3-ITD mutations were detected in 16(22.2%)patients and closely related to bcr-3 PML-RARa transcript(P<0.001).The 5-year overall survival(OS)rate was 100%in both FLT3-ITDposltlve and FLT3-ITD^(negatlve)groups,and there was no significant difference in 5-year event-free survival(EFS)between the two groups(78.3%vs.83.3%,P=0.85).ATRA plus ATO and anthracycline-based chemotherapy achieved great outcome in newly diagnosed APL regardless of the FLT3-ITD mutation status.

Successful treatment of relapsed acute promyelocytic leukemia with arsenic trioxide in a hemodialysis-dependent patient: A case report

BACKGROUND Arsenic trioxide(ATO)is recommended for patients who do not achieve molecular remission or who have molecular or morphologic relapse.However,there are no guidelines for adjusting ATO dosage in patients with severe renal failure or on dialysis.Herein,we report the successful treatment of relapsed acute promyelocytic leukemia(APL)in a patient on hemodialysis with ATO single agent and review the cases in literature.CASE SUMMARY A 46-year-old woman who has been on hemodialysis to chronic glomerulonephritis for 15 years visited our hospital for pancytopenia.She had been seen for pancytopenia 3 years ago and had been diagnosed with APL.She also received chemotherapy for APL but unfortunately was lost to follow-up after her second consolidation chemotherapy.She was noted to have pancytopenia by her nephrologist during hemodialysis 1 mo ago.Bone marrow biopsy and reverse transcriptase-polymerase chain reaction(RT-PCR)tests revealed a diagnosis of relapsed APL.Treatment for relapsed APL with ATO single agent was started and she achieved molecular remission after administering 24 doses of ATO.Thus far,four consolidation therapies have been performed with the ATO single agent,and,to date,the molecular remission has been maintained as negative promyelocytic leukemia/retinoic acid receptor-αfusion gene as confirmed by RTPCR testing for two years.CONCLUSION This is a rare case of relapsed APL successfully treated with the single agent ATO in a patient on hemodialysis.

Experimental study on the inhibitory effect of arsenic trioxide combined with phorbol ester on the proliferation of acute promyelocytic leukemia cell line Kasumi-1

Objective:To study the effect of arsenic trioxide (As2O3) combined with phorbol ester (PMA) on the proliferation of acute promyelocytic leukemia cell line Kasumi-1.Methods:Acute promyelocytic leukemia cell lines Kasumi-1 were cultured and randomly divided into control group (treated with the RPMI1640 medium without drugs or serum), As2O3 group (treated with serum-free RPMI1640 medium containing 20 μmol/L As2O3), PMA group (treated with serum-free RPMI1640 medium containing 160 nmol/L PMA) and As2O3+ PMA group (treated with serum-free RPMI1640 medium containing 20 μmol/L As2O3 and 160 nmol/L PMA). After treatment, the cell proliferation activity, cell cycle ratio and the protein expression of related genes were measured.Results: 12 h, 24 h and 48 h after treatment, the cell proliferation activity of As2O3 group, PMA group and As2O3+PMA group were significantly lower than that of control group, and the cell proliferation activity of As2O3+PMA group was significantly lower than that of As2O3 group and PMA group;48 h after treatment, the G1 phase and S phase ratio as well as CDK1 and CyclinB1 expression of As2O3 group, PMA group and As2O3+PMA group were significantly lower than those of control group while the G2 phase ratio as well as Bax, Caspase-3, Caspase-9, p-Chk1 and p-Cdc25C9 expression were significantly higher than those of control group;the G1 phase and S phase ratio as well as CDK1 and CyclinB1 expression of As2O3+PMA group were significantly lower than those of As2O3 group and PMA group while the G2 phase ratio as well as Bax, Caspase-3, Caspase-9, p-Chk1 and p-Cdc25C9 expression was significantly higher than those of As2O3 group and PMA group.Conclusion:As2O3 combined with PMA can inhibit the proliferation of acute promyelocytic leukemia cell line Kasumi-1 by inducing apoptosis and blocking cell cycle.

CD71-mediated liposomal arsenic-nickel complex combined with all-trans retinoic acid for the efficacy of acute promyelocytic leukemia

Clinically,arsenic trioxide(ATO)was applied to the treatment of acute promyelocytic leukemia(APL)as a reliable and effective frontline drug.However,the administration regimen of AsⅢwas limited due to its fast clearance,short therapeutic window and toxicity as well.Based on CD71 overexpressed on APL cells,in present study,a transferrin(Tf)-modified liposome(LP)was established firstly to encapsulate AsⅢin arsenic-nickel complex by nickel acetate gradient method.The AsⅢ-loaded liposomes(AsLP)exhibited the feature of acid-sensitive release in vitro.Tf-modified AsLP(Tf-AsLP)were specifically taken up by APL cells and the acidic intracellular environment triggered liposome to release AsⅢwhich stimulated reactive oxygen species level and caspase-3 activity.Tf-AsLP prolonged half-life of AsⅢin blood circulation,lowered systemic toxicity,and promoted apoptosis and induced cell differentiation at lesion site in vivo.Considering that ATO combined with RA is usually applied as the first choice in clinic for APL treatment to improve the therapeutic effect,accordingly,a Tf-modified RA liposome(Tf-RALP)was designed to reduce the severe side effects of free RA and assist Tf-AsLP for better efficacy.As expected,the tumor inhibition rate of Tf-AsLP was improved significantly with the combination of Tf-RALP on subcutaneous tumor model.Furthermore,APL orthotopic NOD/SCID mice model was established by 60CO irradiation and HL-60 cells intravenously injection.The effect of co-administration(Tf-AsLP+Tf-RALP)was also confirmed to conspicuous decrease the number of leukemia cells in the circulatory system and prolong the survival time of APL mice by promoting the APL cells’apoptosis and differentiation in peripheral blood and bone marrow.Collectively,Tf-modified acid-sensitive AsLP could greatly reduce the systemic toxicity of free drug.Moreover,Tf-AsLP combined with Tf-RALP could achieve better efficacy.Thus,transferrinmodified AsⅢliposome would be a novel clinical strategy to improve patient compliance,with promising translation prospects.

Realgar-indigo naturalis formula for the treatment of patients with relapsed and arsenic trioxide-resistant acute promyelocytic leukemia:A case series

Introduction There is currently no standard treatment for relapsed and arsenic trioxide(ATO)-resistant acute promyelocytic leukemia(APL).Here,we report a case series of realgar-indigo naturalis formula(RIF)for the successful treatment of patients with relapsed and ATO-resistant APL.Case presentation Two patients in the first relapse and one in the second relapse failed to achieve hematologic complete remission(HCR)when reinduced by ATO;the other five patients progressed to relapse during ATO-based regimens for post-remission therapy.These eight patients received RIF in three doses per day totaling 130 mg/kg(≤30 pills)as induction therapy and achieved HCR at a median time of 46.5 days.They received 5 years of post-remission therapy,which consisted of combined chemotherapy followed by RIF.During this period,the patients did not experience renal dysfunction or QT interval prolongation.At the last follow-up,three patients survived without relapse,two patients survived with a second or third relapse and third or fourth remission,and the other three patients relapsed for a third or fourth time and died.The 5-year overall survival and event-free survival rates were 75.0%(95%confidence interval[CI]:31.5–93.1)and 37.5%(95%CI:5.6–71.7),respectively.Conclusion RIF for induction therapy and RIF combined with chemotherapy for post-remission therapy may represent an effective and safe protocol for the treatment of patients with relapsed and ATO-resistant APL.

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.

A drug from poison:how the therapeutic effect of arsenic trioxide on acute promyelocytic leukemia was discovered

It is surprising that,while arsenic trioxide(ATO) is now considered as "the single most active agent in patients with acute promyelocytic leukemia(APL)",the most important discoverer remains obscure and his original papers have not been cited by a single English paper.The discovery was made during the Cultural Revolution when most Chinese scientists and doctors struggled to survive.Beginning with recipes from a countryside practitioner that were vague in applicable diseases,Zhang TingDong and colleagues proposed in the 1970s that a single chemical in the recipe is most effective and that its target is APL.More than 20 years of work by Zhang and colleagues eliminated the confusions about whether and how ATO can be used effectively.Other researchers,first in China and then in the West,followed his lead.Retrospective analysis of data from his own group proved that APL was indeed the most sensitive target.Removal of a trace amount of mercury chloride from the recipe by another group in his hospital proved that only ATO was required.Publication of Western replication in 1998 made the therapy widely accepted,though neither Western,nor Chinese authors of English papers on ATO cited Zhang's papers in the 1970s.This article focuses on the early papers of Zhang,but also suggests it worth further work to validate Chinese reports of ATO treatment of other cancers,and infers that some findings published in Chinese journals are of considerable value to patients and that doctors from other countries can benefit from the clinical experience of Chinese doctors with the largest population of patients.

Effect of all-trans retinoic acid and arsenic trioxide on tissue factor expression in acute promyelocytic leukemia cells

OBJECTIVE: To study the effect of all-trans retinoic acid (ATRA) and arsenic troxide (As2O3) on tissue factor (TF) expression and procoagulant activity (PCA) of acute promyelocytic leukemia (APL) cells in vivo and in vitro. METHODS: PCA from freshly isolated APL blasts from APL patients treated with ATRA or As2O3 was detected using a one-stage clotting assay. TF antigen was detected by ELISA and TF mRNA by RT-PCR. The maturation sensitive (NB4) or resistant subclones (NB4-R1) of the promyelocytic NB4 cell line, as well as U937 cells infected with pMSCV-PML-RARa treated with or without ATRA or As2O3, were also examined. RESULTS: Both ATRA and As2O3 can down-regulate the TF antigen, its mRNA transcription and membrane PCA of APL cells in vivo and in vitro, in a time-dependent manner. The TF antigen level in PML-RARa + U937 cells was significantly higher than that in U937 cells infected with retrovirus vector. Both ATRA and As2O3 can also down-regulate the TF antigen in U937 cells transfected with or without PML-RARa. CONCLUSION: Tissue factor expression and PCA in APL cells may be down-regulated by ATRA and As2O3. By down-regulating TF expression, As2O3 might also be used to improve the DIC-related hemorrhage in APL. Our data indicate that elevated TF antigen in PML-RARa + U937 may be related to the fusion protein PML-RARa. The down-regulating effect of ATRA and As2O3 on TF expression in U937 cells might not involve this fusion protein.

Hemostatic abnormalities associated with acute promyelocytic leukemia and corrective effects of all-trans-retinoic acid or arsenic trioxide treatment

Objective To study in vivo effect of all trans retinoic acid (ATRA) or arsenic trioxide (As 2O 3) on the expression of tissue factor (TF) and the hemostatic disorders, a series of parameters were measured in bone marrow blasts and plasma from acute promyelocytic leukemia (APL) patients Methods The plasma variables were measured by ELISA or chromogenic study The TF transcription was assessed using reverse transcription polymerase chain reaction technique (RT PCR) Results The blast cell procoagulant activity (PCA), TF antigen of APL cell lysates, as well as the transcription of APL TF mRNA elevated at diagnosis, were reduced after ATRA or As 2O 3 therapy The plasma level of platelet α granular membrane protein 140, soluble fibrinomonomer complex, thrombomo^dulin, tissue plasminogen activator and D dimer significantly increased, fibrinogen, antigen level of protein C, plasminogen, α2 plasminogen inhibitor and plasminogen activator inhibitor decreased at diagnosis, were restored to normal after complete remission but protein C activity and protein S remained elevated in ATRA group Conclusions There existed activation of platelets and consumption of anticoagulants as well as activation of coagulation and fibrinolytic system before treatment Both ATRA and As 2O 3 therapy down regulated the expression of TF mRNA, decreased the PCA and TF level in APL cells, inhibited coagulation activation, secondary hyperfibrinolysis and recorrected other hemostatic abnormalities, thus greatly improved the bleeding symptom in early stage of the treatment

Advances in Management of Acute Promyelocytic Leukemia with Arsenic Trioxide

Acute promyelocytic leukemia （APL）, with specific features in cell morphology, is classified as M3 by French-American-British （FAB）. Among M3, 95% of patients show specific chromosome translocation t（15;17）q（22;21） with PML-RAR fusion gene, and 5% of patients show other subtypes. According to the statistical analysis of 2 540 adult acute myeloid leukemia （AML） cases in Harbin institute of Hematology ＆ Oncology, APL accounted for 23%.

Effect of arsenic trioxide on cytokine expression by acute promyelocytic leukemia cells

Objective To detect the expression of cytokines by acute promyelocytic leukemia (APL) cells before and after exposure to arsenic trioxide.Methods Diagnoses were performed according to the FAB cytological classification criteria and cytogenetic criteria. Bone marrow or blood samples from APL patients were collected in heparinized tubes,then primary APL cells were separated by traditional Ficoll-Hypaque density centrifugation and purified after adherence to plastic surfaces. IL-1β, IL-6, IL-8, TNFα and G-CSF levels in the leukemia cell culture supernatants were detected by ELISA. At the same time, nitro blue tetrazolium (NBT) reduction test was used to detect the differentiation of APL cells.Results After 96 hours exposure to arsenic trioxide, 10-6 mol/L in vitro or 10 mg/d in vivo, APL cells showed a significant increase of IL-1β ( P < 0. 05) and G-CSF ( P < 0. 05) production, and a significant decrease of IL-6 (P<0. 05) and IL-8 (P<0. 05). However, there was no obvious variation of TNFα when compared with APL cells without exposure to arsenic trioxide. On the other hand, the proliferation ratio of APL cells in vitro was statistically correlated to the IL-1β secretion ratio or G-CSF secretion ratio. The cell number ratio in patients with detectable IL-1βor G-CSF was higher than that without detectable IL-1β or G-CSF.Conclusion IL-1β and G-CSF secretion may play an important role in the proliferation of APL cells after exposure to arsenic trioxide.

亚砷酸诱导的老年急性早幼粒细胞白血病早期死亡分析

目的分析经单药亚砷酸(arsenic trioxide,ATO)诱导治疗的老年(年龄≥60岁)初发急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)的早期死亡(early death,ED)发生情况及预测因素。方法收集连续收治的71例老年APL患者和456例年轻APL患者的临床资料。选取临床上可以快速获取的10个临床及实验室检测参数,采用χ^(2)检验及Logistic回归模型进行统计学分析。结果老年患者的ED率(22.5%,16/71)高于年轻患者(15.1%,69/456),但差异无统计学意义(P=0.115)。老年感染相关ED(8.5%)和血栓相关ED(2.3%)的发生率均显著高于年轻患者(分别为2.0%和0.3%),差异有统计学意义(P<0.01)。男性和白细胞计数>10×10^(9)/L是两组患者ED的共同独立风险因素,低白蛋白血症(P<0.001)和血清纤维蛋白原<1g/L(P=0.001)还是年轻患者ED的独立风险因素。结论单药ATO诱导治疗的老年APL患者的入院临床特征、ED发生情况及风险因素与年轻患者明显不同。因此,有必要对APL患者的ED情况进行年龄分层研究。

三氧化二砷在肿瘤治疗中临床应用及相关分子机制研究进展

三氧化二砷(ATO)具有广泛抗肿瘤作用,用于治疗疾病已有2000多年的历史。自20世纪70年代以来,ATO被用于治疗急性早幼粒细胞白血病(APL)。越来越多的证据表明,ATO在其他癌种中同样发挥抗肿瘤效果,如多发性骨髓瘤、肝癌和胰腺癌等。现对ATO在肿瘤治疗中的临床应用及相关分子机制进行综述。

Long term survey of outcome in acute promyelocytic leukemia

Objective To investigate all trans retinoic acid (ATRA) and As 2O 3 which were found to be able to selectively induce differentiation and apoptosis in acute promyelocytic leukemia (APL) and recently became standard treatment for de novo or relapsed APL The results of long term follow up in 72 APL patients were presented and prognostic factors discussed Methods Seventy two newly diagnosed patients with APL entering CR with ATRA were consolidated with chemotherapy alone (31 patients), ATRA+chemotherapy (30 patients) and ATRA alone (11 patients) Univariate analysis was done to identify the potential prognostic factors A total of 40 cases of patients relapsed after their first complete remission, including 3 groups of patients: group A, patients treated with ATRA and chemotherapy after relapse (8 patients); group B patients treated with As 2O 3 alone for 2 nd CR and consolidation (21 patients); group C patients treated with As 2O 3 for 2 nd CR and both As 2O 3 and chemotherapy for consolidation (11 patients) Univariate analysis was also done to identify the potential prognostic factors Results With a median follow up of 45 months (5 75 months), the median event free survival was 21 months and median overall survival was not achieved The estimated 3 and 5 year event free survival (EFS) and over all survival (OS) were 32 5±10 5%, 18 4±7 5% and 73 8±17 5%, 58 5±15 2% In denovo patients, the combination of ATRA and chemotherapy in both induction and post remission treatment was found to be statistically significant for EFS ( P =0 023), and initial peripheral leukocyte count was significantly related to OS In relapsed patients, only the treatment of As 2O 3 with or without chemotherapy in consolidation after relapse was statistically significant for CR and both EFS ( P =0 0061) and OS ( P =0 0013) Conclusion ATRA is an effective induction therapy and can be considered as first choice of treatment in denovo APL Addition of chemotherapy in both induction and post remission therapy can delay or decrease the possibility of relapse compared to ATRA alone As 2O 3 is an effective agent for relapsed APL and remains an important prognostic factor for relapsed APL

ATRA+ATO+蒽环类三联疗法治疗非高危成人APL疗效评估

目的探讨全反式维甲酸(ATRA)+亚砷酸(ATO)+蒽环类三联方案对成人非高危急性早幼粒细胞白血病(APL)的治疗效果。方法选取2018年1月~2022年1月在河南科技大学第一附属医院治疗的成人非高危APL患者88例,采用信封法分为观察组和对照组各44例,观察组给予ATRA+ATO+蒽环类三联方案,对照组给予ATRA+ATO,观察两组治疗效果、凝血功能及生活质量改善情况。结果观察组达到完全缓解(CR)时间快于对照组,凝血反应时间(R)、血凝块形成时间(K)和凝血酶原时间(PT)低于对照组,Angle角(Angle)、最大振幅(MA)和纤维蛋白原(Fib)高于对照组(P<0.05)。观察组治疗后生活质量核心量表(EORTC QLQ-C30)疲劳得分低于对照组,而总体健康状况得分高于对照组(P<0.05)。结论ATRA+ATO+蒽环类三联方案治疗成人非高危APL效果好,可改善凝血功能、提高生活质量。

Current treatment strategy of acute promyelocytic leukemia

Acute promyelocytic leukemia(APL)is a unique subtype of acute myeloid leukemia(AML).The prognosis of APL has changed from the worst among the AMLs to currently the best.The application of all-trans retinoic acid(ATRA)in the induction therapy of APL decreases the high mortality of newly diagnosed patients,thereby significantly improving the response rate.ATRA combined with anthracycline-based chemotherapy is the current standard treatment,and for high-risk patients,high doses cytarabine have a beneficial effect on relapse prevention.In recent years,the indications of arsenic trioxide(ATO)therapy for APL have been extended from the salvage therapy for relapse patients to the first-line treatment of de novo APL.The introduction of both ATRA and ATO represents great achievements in translational medicine.In this review article,we discuss the therapeutic strategies for this disease,including the initial approaches to newly diagnosed patients,prevention,and treatment of side effects and relapse to ensure the best and timely treatment for each newly diagnosed APL patient.

三氧化二砷治疗急性早幼粒细胞白血病的机制研究

细胞形态学和白血病细胞系ＨＬ６０的实验研究表明，三氧化二砷（ＡＳ_２Ｏ_３）对急性早幼粒细白血病（ＡＰＬ）细胞有诱导分化作用；并可能是通过“原浆毒”作用同时诱导细胞凋亡；大剂量时有抑制细胞增殖作用，这三种作用的依次出现与治疗的累积量有关。认为砷剂是目前治疗ＡＰＬ的较理想药物。

亚砷酸和全反式维甲酸对急性早幼粒细胞白血病疗效和副作用的比较

目的比较亚砷酸（ATO）和全反式维甲酸（ATRA）对急性早幼粒细胞白血病（APL）的疗效及副作用。方法回顾性分析了71例APL初治患者的临床资料,根据诱导缓解治疗方案不同分为ATO组（n=41）和ATRA组（n=30）,比较两组患者的完全缓解率（CR）和达CR的时间。结果ATO组和ATRA组患者的CR率分别为97.5%和93.3%,两组相比差异无统计学意义（P〉0.05）。ATO组患者达到CR的中位时间为29 d（21-45 d）,明显短于ATRA组患者的38.5 d（24-63 d）（P〈0.001）。52.9%的ATRA组患者出现维甲酸综合征,常影响进一步治疗。结论ATO和ATRA对APL患者均有很高的诱导缓解率。ATO诱导达到CR的时间短于ATRA,不良反应更易于控制,可作为APL患者诱导缓解治疗的一线药物。