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.

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.

COMPARISON OF CLINICAL OBSERVATIONS BETWEEN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA TREATED WITH ALL-TRANS RETINOIC ACID AND CHEMOTHERAPY

Clinical observations were retrospectively compared between 2 matched groups of patients with acute promyelocytic leukemia (APL) each 20. The first group were treated with chemotherapy, the other with all-tram retinoic acid (ATRA) alone at a dose of 45-60mg/M^2/d. The complete remission (CR) rate of ATRA group was significantly higher than that of chemotherapy (90% vs 55%). The time for obtaining CR as well as the duration of fever and hospitalization were shorter and the amount of blood transfused was less in the former than in the latter group. Seven cases were complicated by DIC and 4 died in the group of chemotherapy, while no case was by of DIC or death in the ATRA group. The mechanism was discussed. ATRA is an alternative effective drug for remission induction therapy in APL with high rate of CR.

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 3.1×10 9/L, which was higher than that for patients who did not develop 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.

CYTOKINE SECRETION IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA AFTER TREATMENT WITH ALLTRANS RETINOIC ACID

ABSRTACT Objective: To detect the modulation of cytokines production by acute promyelocytic leukemia (APL) cells before or after exposure to all-trans retinoic acid (ATRA). 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 microfuge tube. Primary APL cells were separated and purified by traditional Ficoll-Hypaque density centrifugation and enriched after adherence to plastic surfaces. IL-1b, IL-6, IL-8, TNFa and G-CSF levels in the supernatants of cultured leukemia cells were estimated by ELISA method. NBT method was used to detect the differentiation of APL cells at the same time. Results: 96 h after exposure to ATRA at 10-6 M in vitro or 60 mg/day in vivo, APL cells showed a significant increase of IL-1b (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 TNFa. On the other hand, the proliferation of APL cells in vitro was statistically correlated to the IL-1b secretion or G-CSF secretion. And the cell number ratio in patients with detectable IL-1b or G-CSF was higher than that without detectable IL-1b or G-CSF. Conclusion: IL-1b and G-CSF secretion may play an important role in the proliferation of APL cells after exposure to ATRA.

Pathophysiology, clinical features and radiological findings of differentiation syndrome/all-trans-retinoic acid syndrome

In acute promyelocytic leukemia, differentiation thera-py based on all-trans-retinoic acid can be complicated by the development of a differentiation syndrome(DS). DS is a life-threatening complication, characterized by respiratory distress, unexplained fever, weight gain, interstitial lung infiltrates, pleural or pericardial effusions, hypotension and acute renal failure. The diagnosis of DS is made on clinical grounds and has proven to be difficult, because none of the symptoms is pathognomonic for the syndrome without any definitive diagnostic criteria. As DS can have subtle signs and symptoms at presentation but progress rapidly, end-stage DS clinical picture resembles the acute respiratory distress syndrome with extremely poor prognosis; so it is of absolute importance to be conscious of these complications and initiate therapy as soon as it was suspected. The radiologic appearance resembles the typical features of cardiogenic pulmonary edema. Diagnosis of DS remains a great skill for radiologists and haematologist but it is of an utmost importance the cooperation in suspect DS, detect the early signs of DS, examine the patients' behaviour and rapidly detect the complications.

Sweet syndrome and differentiation syndrome in a patient with acute promyelocytic leukemia

The differentiation syndrome is an inflammatory reaction with increased capillary permeability that occurs in up to 25% of patients with acute promyelocytic leukemia treated with all-trans retinoic acid. A 50-year-old man with acute promyelocytic leukemia underwent chemotherapy with idarubicin and all-trans retinoic acid. On day +21 the patient developed pruritic prepatelar papules as well as several 10 mm subcutaneous nodules in both thighs accompanied by persistent fever. On the day +25 the patient presented with bilateral pulmonary crackles, infiltrates in the right lower lobe and severe hypotension which required dopamine infusion. Biopsy of one of the thighs nodules was performed. A Sweet syndrome associated to a differentiation syndrome was suspected. All-trans retinoic acid therapy was discontinued and dexamethasone was administered. In 48 h the patient showed remission of the fever and the infiltrates and the skin lesions acquired a residual aspect. It is debatable whether these two syndromes are distinct entities with common mechanisms or whether they are poles of the same spectrum. Dermatologists and hematologists must be aware of these two syndromes and its pathophysiologic association.

Myeloid sarcoma of the colon as initial presentation in acute promyelocytic leukemia:A case report and review of the literature

BACKGROUND Myeloid sarcoma(MS)rarely occurs in acute promyelocytic leukemia(APL)at onset,but it can develop in relapse cases,especially after APL treated with alltrans retinoic acid(ATRA).Therefore little is known about the clinical features and suitable treatment for APL related MS due to the rarity of the disease,although this may be different from the treatment and prognosis of MS in the relapse stage.To our best knowledge,this is the second case report of APL initial presentation as colon MS.CASE SUMMARY A 77-year-old woman complained of intermittent right lower abdominal pain,black stool,and difficult defecation for 2 mo.Physical examination showed diffuse tenderness during deep palpation and an anemic appearance.Laboratory findings showed positivity for fecal occult blood testing;white blood cell count:3.84×109/L;hemoglobin:105 g/L;platelet count:174×109/L;and negativity for tumor markers.Abdominal enhanced computed tomography showed a space occupying lesion in the colon(1.9 cm).Fibrocolonoscopy revealed a polypoid and ulcerated mass measuring 2.5 cm.The tumor was removed.To our surprise,MS was confirmed by immunohistochemistry.PML/RARαfusion gene was detected in colon specimens by fluorescent in situ hybridization and real-time reverse transcription polymerase chain reaction,which was consistent with the bone marrow.She was diagnosed as having APL related MS.A smooth and unobstructed intestinal wall was found by fibrocolonoscopy,and continuous molecular remission was confirmed in both the bone marrow and colon after four courses of ATRA+arsenic trioxide(ATO).ATRA+ATO showed a favorable therapeutic response for both APL and MS.CONCLUSION Early use of ATRA can benefit APL patients,regardless of whether MS is the first or recurrent manifestation.

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.

Effects of varied interferons in combination with all-trans retinoic acid ( ATRA ) on proliferation and differentiation of ATRA-resistent APL cell

Objective: To investigate the effects and mechanisms of interferon in combination with all-trans retinoic acid (ATRA) on proliferation and differentiation of ATRA-resistent APL cell. Methods:After MR2 cells (ATRA-resistance cell line) were treated with IFN-α, IFN-γand ATRA alone or IFN-αand IFN-γin combination with ATRA respectively. The cell proliferation was tested by MTT test and the cell differentiation was tested through light microscope by NBT test and flow cytometry (FCM). The expression of promyelocytic leukemia ( PML) protein was observed by indirect immune fluorescent method. Results: Both IFN-αand IFN-γcould inhibit the proliferation and induce the differentiation of MR2 cells to some extent. The effects were more obvious after both interferons in combination with ATRA respectively (P<0. 05). Moreover, the maturation of MR2 cells induced by IFN-γ+ ATRA group was more higher than that by IFN-α+ ATRA group (P<0. 05). Both interferons could induce the expressions of PML protein. Conclusion:Both interferons can inhibit MR2 cells proliferation, which may be related to the expression of PML protein induced by both interferons. The inducing differentiation effects of IFN-γ+ ATRA group on MR2 cells are more powerful than those of IFN-α+ATRA group, which may be related to the different signal transduction pathway of both interferons.

Safety and efficacy of Compound Huangdai Tablets combined with all-trans retinoic acid for treatment of acute promyelocytic leukemia:Clinical evidence and potential mechanisms

Objective:To evaluate the safety and efficacy of Compound Huangdai Tablets(Realgar-Indigo Naturalis formula,RIF)combined with all-trans retinoic acid(ATRA)to treat acute promyelocytic leukemia(APL).Methods:This study was registered in PROSPERO(CRD42018108118).The relevant literatures on RIF treatment of APL were systematically searched in the following databases:China National Knowledge Infrastructure,Wanfang,VIP Medical Information System,Chinese Biomedical Database,EMBASE,Cochrane Library,and PubMed.The quality of the included studies was evaluated and Review Manager 5.3 software and Stata 13.0 software were used to perform the Meta-analysis.In addition,this study used the method of network pharmacology to conduct a preliminary exploration of the mechanism of RIF on APL.Results:The study included 12 studies involving 775 APL patients.The Meta-analysis showed that there was no significant difference(P>0.05)between the RIF group and the arsenic trioxide(ATO)group for primary outcomes,secondary outcomes apart from liver dysfunction.The incidence of liver dysfunction(P=0.006)in the RIF group were significantly lower than those in the ATO group.In addition,the cost of maintenance therapy in the RIF group was significantly lower(P<0.05)than the ATO group.Besides,the active ingredients in RIF mainly act on targets proteins such as ACHE,NCOA2,RXRA,and then play a role in the treatment of APL through regulating multiple molecular mechanisms,such as TP53 regulates transcription of cell cycle genes,nuclear receptor transcription pathway.Conclusion:There was no significant difference in efficacy of oral RIF combined with ATRA compared with intravenous ATO combined with ATRA for the treatment of APL.The oral RIF exposed patients to less risk,offered more convenience and had lower prices.RIF can treat APL by multi-target and multipathway interventions that inducing apoptosis of APL cells and inhibiting the proliferation of APL cells,and so on.Therefore,oral RIF in the treatment of APL is worthy of further research and development.

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

study the effect of all trans retinoic acid (ATRA) and arsenic trioxide (As 2O 3) 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 As 2O 3 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 As 2O 3, were also examined Results Both ATRA and As 2O 3 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 As 2O 3 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 As 2O 3 By down regulating TF expression, As 2O 3 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 As 2O 3 on TF expression in U937 cells might not involve this fusion

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

Combination of al-trans retinoic acid with butyric acid and its prodrugs markedly enhancing differentiation of human acute promyelocytic leukemia NB_4 cells

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Detecting PML-RARα transcript in acute promyelocytic leukemia using real-time quantitative RT-PCR

Background Real-time quantitative RT-PCR （RQ-PCR） assay has become a vital tool to monitor residual disease of leukemia, However, the complexity and standardization of RQ-PCR should never be overlooked and the results should be interpreted cautiously in clinical conditions. We aimed to assess the methodology of RQ-PCR and its clinical applications in monitoring molecular kinetics of 36 newly diagnosed cases of acute promyelocytic leukemia patients with t （15;17） from October 2004 to December 2005.Methods All the TaqMan probe-based RQ-PCR reactions and analysis were performed on an ABI-PRISM 7500 platform, The quantitation of PML-RARα transcripts was represented by the normalized quotient, that is, PML-RARα transcript copies divided by ABL transcript copies, According to induction therapy, the patients were classed into two groups： group 1 （n=23）, three-drug combination including arsenics, all-trans retinoic acid and mitoxantrone; and group 2 （n=13）.two-drug combination from all-trans retinoic acid, arsenics and mitoxantrone.Results The sensitivity of RQ-PCR was 1 per 105 cells and 5 copies of the PML-RARα transcript could be reproducibly detected, No false positive results occurred in 40 non-acute promyelocytic leukemia samples, Optimal amplification efficiency could be attained, which was determined by the slope of the standard curves （slope： -3.2 -- -3.7）. The inter-assay and intra-assay variation coefficients of the method were 1.01% and 0.56% respectively. Although the time to attain hematological complete remission was similar in both groups, the time to achieve molecular remission of group 1 was significantly shorter than that of group 2 （61 days vs 75 days, P=0.034）. The rate of molecular remission within 70 days was higher in group 1 than in group 2 （75.00% vs 38.46%, P=0.036）, Compared with pretreatment, median reduction of the PML-RARα transcript before first consolidation therapy differed significantly between group 1 and group 2 （log scale, 3.15 vs 2.31, P=0.024）, Interestingly, we found that PML-RARα transcript levels temporarily increased in bone marrow （7 patients） and peripheral blood （22 patients） samples of patients during induction therapy in both groups.Conclusions The RQ-PCR assay is reliable for the detection of PML-RARα transcripts. Arsenics, all-trans retinoic acid and mitoxantrone triad induction treatment of acute promyelocytic leukemia is superior to two-drug combination induction therapy in terms of the molecular response.

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

Arsenic in the treatment of newly diagnosed acute promyelocytic leukemia:current status and future research direction

Acute promyelocytic leukemia(APL)is a subtype of acute myeloid leukemia.In past decades,intensive studies on the biology and treatment of this disease have resulted in a remarkably thorough understanding of its pathogenesis and improvement of treatment outcomes.In particular,the introduction of all-trans retinoic acid to conventional chemotherapy improved dramatically the remission and survival rates of APL patients and consequently became the major treatment modality for it.In the last decade,the groundbreaking development of arsenic further improved the survival rate of APL patients.As the most active agent in APL,arsenic directly degrades the PML-RARαfusion transcript,leading to the differentiation and apoptosis of leukemia cells and the potential eradication of APL leukemiainitiating cells(LICs),thus making the disease a potentially curable type of leukemia.More notably,the recent development of oral arsenic compounds may further enhance not only clinical outcomes but also the convenience of patients,which may dramatically change the APL clinical scenario in the near future.

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.

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。

转谷氨酰胺酶2通过mTOR通路和自噬调控全反式维甲酸诱导的白血病细胞HL60和U937的髓系分化

全反式维甲酸(ATRA)是具有融合基因PML-RARα的急性早幼粒细胞白血病(APL)特异的靶向治疗药物。此外,ATRA在无PML-RARα融合的急性髓系白血病及其它一些肿瘤中也有一定治疗效果。但ATRA治疗也会引起一些并发症或发生愈后复发。因此,对ATRA诱导分化调控机制的研究非常重要。转谷氨酰胺酶2(TGM2)是一种多功能酶,能调控mTOR信号通路和自噬等。ATRA能诱导APL细胞中TGM2表达上调,TGM2敲低抑制ATRA诱导的细胞分化。但其调控机制及涉及的信号通路尚不明确。本研究发现,在HL60和U937细胞中,ATRA能够上调CD11b和TGM2的表达(P<0.05),抑制mTOR信号通路,并增强自噬;与对照相比,敲低TGM2,mTOR信号通路增强,自噬被抑制,而ATRA诱导的CD11b表达被抑制(P<0.05),分化减弱,被ATRA抑制的mTOR信号通路得到部分恢复,而被ATRA增强的自噬适当减弱。这表明ATRA使HL60和U937细胞发生髓系分化,并诱导TGM2表达升高;而TGM2通过mTOR信号通路和自噬途径调控ATRA诱导的髓系分化。该研究将有利于更深入地了解ATRA诱导白血病细胞分化的过程和机制,也有利于加深对TGM2的多功能性的认识;有助于对APL等白血病及其它癌症的药物诱导疗法的探讨。