Carrimycin in the treatment of acute promyelocytic leukemia combined with pulmonary tuberculosis: A case report

BACKGROUND Pulmonary tuberculosis(PTB)is prevalent in immunocompromised populations,including patients with hematologic malignancies,human immunodeficiency virus infections,and chronic diseases.Effective treatment for acute promyelocytic leukemia(APL)combined with PTB is lacking.These patients show an extremely poor prognosis.Therefore,studies should establish efficient treatment options to improve patient survival and prognosis.CASE SUMMARY A 60-year-old male with pain in the right side of his chest and a fever for 4 d visited the outpatient department of our hospital.Peripheral blood smear revealed 54%blasts.Following bone marrow examinations,variant APL with TNRC18-RARA fusion gene was diagnosed.Chest computed tomography scan showed bilateral pneumonitis with bilateral pleural effusions,partial atelectasis in the lower lobes of both lungs,and the bronchoalveolar lavage fluid gene X-Pert test was positive,indicative of PTB.Carrimycin,ethambutol(EMB),and isoniazid(INH)were administered since he could not receive chemotherapy as the WBC count decreased continuously.After one week of treatment with carrimycin,the patient recovered from fever and received chemotherapy.Chemotherapy was very effective and his white blood cells counts got back to normal.After being given five months with rifampin,EMB and INH and chemotherapy,the patient showed complete remission from pneumonia and APL.CONCLUSION We report a case of PTB treated successfully with carrimycin with APL that requires chemotherapy.

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.

Atypical Hemolytic Uremic Syndrome in a Patient with Acute Promyelocytic Leukemia: A Case Report

Introduction: Acute Promyelocytic Leukemia (APL) is highly associated with hemostasis alterations. The atypical hemolytic uremic syndrome (aHUS) is a rare type of Thrombotic Microangiopathy (TMA) due to an overactivation of the alternative complement pathway. Case Presentation: A 48-years-old woman was diagnosed with APL and achieved molecular remission after induction therapy. During the second consolidation cycle she presented with TMA. She began treatment with plasma exchange plus corticotherapy but due to aggravation of symptoms Eculizumab was initiated. Thrombotic thrombocytopenic purpura, infections and drug toxicity causes were ruled out. There was no evidence of relapse of the APL. Genetic studies of the hereditary anomalies of the alternative complement pathway were negative and the decision of stopping Eculizumab was made. During maintenance therapy for the APL she presented a severe relapse of the aHUS, requiring dialysis. She re-started treatment with Eculizumab with a progressive hematologic recovery and improvement of renal function. She completed APL treatment without relapse of the leukemia for the moment and continues to be treated with Eculizumab. Conclusion: This is the first published case of coexisting aHUS and APL successfully treated with Eculizumab.

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.

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.

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.

Pediatric acute myeloid leukemia patients with i(17)(q10)mimicking acute promyelocytic leukemia:Two case reports

BACKGROUND Chromosome i(17)(q10)abnormality is mainly associated with chronic myeloid leukemia(CML),myelodysplastic syndrome/myeloproliferative tumors(MDS/MPD),and acute myeloid leukemia(AML).The role of i(17)(q10)in AML is still unknown,the differences between AML and acute promyelocytic leukemia(APL)-like AML with i(17)(q10)need more research.This study aimed to investigate the clinical characteristics and laboratory evidence of 2 AML cases with i(17)(q10),similar to APL phenotype.CASE SUMMARY Both pediatric patients were males;case 1 had newly diagnosed AML,and case 2 showed relapsed tumor after 1 year of drug withdrawal.Bone marrow cell morphology,chromosome karyotype analysis,Fully-instrumented submersible housing test,immunological assays,molecular biological methods,and blood tumor panoramic gene test were performed.All-trans retinoic acid(ATRA)combined with arsenic acid(As2O3)were used in the first course of treatment.Bone marrow was dominated by abnormal promyelocytic granulocytes.Karyotype test revealed i(17)(q10)isochromosome.Immunological phenotype mainly included positive expressions of CD9,CD13,CD33,and CD38.Case 1 suffered intracranial hemorrhage after re-chemotherapy and died on D162.For case 2,on D145 and D265,bone marrow promyelocytic granulocytes accounted for 2%.Flow cytometric residual lesion detection showed no abnormal immunophenotype cells.The copy number of WT1 gene in two cases were 1087 and 1010,respectively,and the expression rates were 55.29% and 59.5%,respectively.CONCLUSION ATRA,As2O3,and chemotherapy may be ineffective in treating APL-like AML with i(17)(q10)but without t(15;17)and PML-RARA fusion gene.

Central nervous system recurrence in a patient treated for acute promyelocytic leukemia,resulting in sideroblastic anemia:A case report

BACKGROUND Previous cases that have been stated in this article have displayed that around 1%to 7%of patients that have been treated with chemotherapy for acute promyelocytic leukemia developed myelodysplastic syndrome or acute myeloid leukemia.One can see that’s why this case presentation of a 60-year-old man that had a good response to acute promyelocytic leukemia treatment,that later presented with a central nervous system recurrence of acute promyelocytic leukemia and acquired sideroblastic anemia(a form of myelodysplasia)from treatment is a unique case report.CASE SUMMARY The presence of central nervous system relapse in acute promyelocytic leukemia patients is very unlikely compared to recurring mainly in the bone marrow.It is also uncommon to be diagnosed with sideroblastic anemia(form of myelodysplastic syndrome)as a result from treatment for acute promyelocytic leukemia.This case report highlights the detection,treatment/maintenance with idarubicin,all-trans-retinoic-acid,arsenic trioxide,methotrexate,6-mercaptopurine,and ommaya reservoir intrathecal methotrexate administration in a patient that had central nervous system relapse of acute promyelocytic leukemia and acquired sideroblastic anemia.CONCLUSION In essence,first time relapse concerning the central nervous system in treated acute promyelocytic leukemia patients who had a good response to therapy is very uncommon.The acquirement of a myelodysplastic syndrome such as ringed sideroblastic anemia is also rare regarding this patient population.Although such cases are infrequent,this case report represents a unique insight of the detection,treatment,and maintenance of a 60-year-old man diagnosed with acute promyelocytic leukemia,resulting in the acquirement of sideroblastic anemia and central nervous system relapse.

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.

Blockade of deubiquitinase YOD1 degrades oncogenic PML/RARα and eradicates acute promyelocytic leukemia cells

In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable oncoprotein for degradation in APL.Elucidating the mechanism regulating the stability of PML/RARαmay help to degrade PML/RARαand eradicate APL cells.Here,we describe a deubiquitinase(DUB)-involved regulatory mechanism for the maintenance of PML/RARαstability and develop a novel pharmacological approach to degrading PML/RARαby inhibiting DUB.We utilized a DUB siRNA library to identify the ovarian tumor protease(OTU)family member deubiquitinase YOD1 as a critical DUB of PML/RARα.Suppression of YOD1 promoted the degradation of PML/RARα,thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice.Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I(G5)as the first YOD1 pharmacological inhibitor.As expected,G5 notably degraded PML/RARαprotein and eradicated APL,particularly drug-resistant APL cells.Importantly,G5 also showed a strong killing effect on primary patient-derived APL blasts.Overall,our study not only reveals the DUB-involved regulatory mechanism on PML/RARαstability and validates YOD1 as a potential therapeutic target for APL,but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL,particularly drug-resistant APL treatment.

Treatment of STAT5b-RARA positive acute promyelocytic leukemia by Venetoclax combining with homoharringtonine, cytarabine: A case report and literature review

Introduction:Acute promyelocytic leukemia(APL)is mostly due to the chromosome translocation t(15;17)(q22;q12),leading to the formation of PML-RARA fusion protein.Some patients carried rare translocation involving RARA gene,who were called variant APL caused by RAR family(RARA,RARB,and RARG)and partner genes.STAT5b-RARA was a rare type of molecular genetic abnormality with unfavorable prognosis which have been reported in only 18 cases in variant APL.Knowledge of STAT5b-RARA(+)APL treatment is still limited.Case report:We presented a 38-year-old female variant APL case,who was STAT5b-RARA positive detected by reverse transcription polymerase chain reaction.The patient failed to respond after four-drug combined induction chemotherapy:idarubicin,cytarabine,all trans retinoic acid,and arsenic trioxide(As 2 O 3).Then,the patient was re-induced with azacytidine,but still failed to achieve complete remission(CR).Next,she was treated with Venetoclax combining with homoharringtonine and cytarabine as the salvage therapy and achieved CR.Later,the patient received hematopoietic stem cell transplantation after 4 cycles of consolidation therapy.Conclusion:Venetoclax combining with homoharringtonine and cytarabine has been used as the salvage therapy in the STAT5b-RARA positive APL successfully.

Predictive values of plasma TNFαand IL-8 for intracranial hemorrhage in patients with acute promyelocytic leukemia

In patients with acute promyelocytic leukemia(APL),intracranial hemorrhage(ICH),if not identified promptly,could be fatal.It is the leading cause of failure of induction and early death.Thus,biomarkers that could promptly predict severe complications are critical.Here,cytokine differences between patients with APL with and without ICH were investigated to develop predictive models for this complication.The initial cytokine profiling using plasma samples from 39 patients and 18 healthy donors found a series of cytokines that were remarkedly different between patients with APL and healthy controls.The APL patients were subsequently divided into high and low white blood cell count groups.Results showed that tumor necrosis factor a and interleukin 8(IL-8)were vital in distinguishing patients with APL who did or did not develop ICH.In addition,verification in 81 patients with APL demonstrated that the two cytokines were positively correlated with the cumulative incidence of ICH.Finally,in-vitro and in-vivo experimental evidence were provided to show that IL-8 influenced the migration of APL-derived NB4 cells and impaired the blood-brain barrier in PML/RARαpositive blast-transplanted FVB/NJ mice.These assessments may facilitate the early warning of ICH and reduce future mortality levels in 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.

Clinical features and prognostic analysis of high-risk acute promyelocytic leukemia patients

<正>Objective To investigate the clinical features and outcomes of high-risk acute promyelocytic leukemia(APL)patients.Methods A retrospective analysis was conducted to compare the clinical characteristics and prognosis of 118 high-risk APL patients(WBC≥10×10~9/L)and 234 low and intermedia-risk patients(WBC<10×10~9/L)from January 2003 to April 2015。

Establishment and assessment of a nomogram for predicting the differentiation syndrome of acute promyelocytic leukemia

Objective By analyzing the risk factors for occurrence of differentiation syndrome(DS)during induction therapy in newly-diagnosed acute promyelocytic leukemia(APL)patients,a prediction nomogram for DS was established and the accuracy of this nomogram was validated.Methods The modeling group was made up of 130classical APL patients during the period of 1st。

Cross-sectional network analysis of plasma proteins/metabolites correlated with pathogenesis and therapeutic response in acute promyelocytic leukemia

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.

EFFECTS OF ANTI-PML/RARα OR ANTI-PML ANTISENCE ON THE GROWTH, DIFFERENTIATION AND APOPTOSISOF NB4 CELL LINES

Objectire To investigate the ellects of anti - PML/RARx or anti - PML antisence on the growth,dtherentiation and apoptosis of NB4 cell lines. Methods Wright’s stain for cell morphology, flow cytometry andDNA gel electronphoresis for cell apoptosis, methylcellulose assays for leukemic colony forming unit andtrypan - blue exclusion for cell counts. Results Both the start cordon region of the PML or PML - RARx mRNA(STAS) and the fusion point region of the long type PML - RARx mRNA (FUAS) could inhibit cell growth. Cellsbecame partially differentiated at 5d of treatment, and FUAS - treated cells showed more significant differentiationthan STAS- treated cells. Morphology of typical apoptosis could be seen at 7, 9d incubation with antisenceoligodeoxynucleotides (AS). In contrast, no cell growth inhibition, no morphology changes were seen in Sen or Rantreated cells compared with untreated cells. The number of acute myelocytic leukemia colony forming unit(AML - CFU) markedly decreased in STAS and FUAS treated cells. Cell DNA content analyzed by flow cytometryshowed the typical profile of apoptotic cells, in which pre - G1 peak appear before G1 peak at 7,9d of treatment withSTAS or FUAS. Conclusion Anti - PML/RARx or anti- PML antisence inhibit the cell growth, inducedifferentiation and differentiated cell apoptosis of NB4 cells.

Using sound Clinical Paths and Diagnosis-related Groups(DRGs)-based payment reform to bring benefits to patientcare: A case study of leukemia therapy

China has been undertaking a profound reform on health care.Although more than 1.16 billion people have been covered by rural and urban medical insurance to date,the level of reimbursement from insurance is very limited,especially for critical diseases such as leukemia.This places heavy economic burdens on patients.Under these circumstances,systems innovation is imperative for the efficient utilization of limited funding.In this respect,certain valuable experience from other countries may prove helpful.The prospective payment system of Diagnosis-related Groups(DRGs),Clinical Paths,and the Comparative Effectiveness Analysis adopted by the National Institute of Health and Clinical Excellence(NICE,UK),can befine tools to reduce medical costs and improve quality of services.Treatments of acute promyelocytic leukemia at Rui-Jin Hospital,and childhood acute lymphoblastic leukemia at Shanghai Children’s Medical Center,can be taken as suitable models to illustrate the crucial role of Clinical Paths in guaranteeing clinical and cost effectiveness of medical services for critical diseases,and to satisfactorily justify the feasibility of DRGs in China.

Dynamic and Temporal Transcriptomic Analysis Reveals Ferroptosis-Mediated Antileukemia Activity of S-DimethylarsinoGlutathione:Insights into Novel Therapeutic Strategy

S-dimethylarsino-glutathione(ZIO-101,darinaparsin®)exhibits broader antitumor activity and less toxicity than arsenic trioxide(ATO),a clinically used drug for acute promyelocytic leukemia(APL)treatment.However,the mechanisms of action underlying antileukemia activities of ZIO-101 remain largely unknown.Herein,by integrating dynamic transcriptomic analysis and biochemical characterizations,we for the first time delineated that ZIO-101 exerted antiproliferative effects against leukemia cells via activating ferroptosis pathway,a newly discovered iron-dependent programmed cell death,at the early stage,as evidenced by abnormally elevated intracellular iron contents and lipid peroxidation.We further demonstrated that silencing heme oxygenase 1(HMOX1),an important iron homeostasis-related gene,effectively attenuated ferroptosis induced by ZIO-101,with iron accumulation and lipid peroxidation being significantly alleviated.Significantly,we discovered that ZIO-101 and kinase inhibitors(Dasatinib/Dactolisib)could synergistically kill leukemia cells,with a combination index of<1.0 under all the tested drug concentrations.Our findings regarding the ferroptosis-mediated antileukemia activity of ZIO-101,based on the dynamic and temporal transcriptomic analysis,provide promising approaches to combat drug-resistant leukemia by combining ZIO-101 with kinase inhibitors.The methodology may be further exploited for uncovering the modes of action of other drugs.