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The prognostic factors to stratify acute myeloid leukaemia (AML) with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm) into different risk groups remains to be determined. In this retrospective study, we evaluated 171 consecutive patients with newly diagnosed AML with CEBPAdm by a Cox proportional hazards regression model. In univariate analyses, colony stimulating factor 3 receptor (CSF3R) and Wilms tumour 1 (WT1) mutations were associated with poor relapse-free survival (RFS). The induction regimens including homoharringtonine (omacetaxine mepesuccinate) or intermediate-dose cytarabine was associated with favourable RFS and overall survival (OS). The induction regimen including both homoharringtonine and intermediate-dose cytarabine was associated with the most favourable RFS (3-year RFS 84.7%) and OS (3-year OS 92.8%) compared to the conventional cytarabine and daunorubicin regimen (3-year RFS 27.7%, hazard ratio [HR] 0.126, 95% confidence interval [CI] 0.051-0.313, Wald p 0.001; and 3-year OS 56.4%, HR 0.179, 95% CI 0.055-0.586, Wald p = 0.005). In multivariate analyses, the induction regimen including intermediate-dose cytarabine (HR 0.364, 95% CI 0.205-0.646, Wald p 0.001) and CSF3R mutations (HR 2.667, 95% CI 1.276-5.572, Wald p = 0.009) were independently associated with RFS. Taken together, we found that induction regimen and CSF3R mutations were independent prognostic factors for AML with CEBPAdm.

Figure S5. Outcomes after consolidation when censoring transplant recipients

Supplementary Tables S1-S5

Chromosome translocations in the 5q31-33 region are associated with a range of hematologic malignancies, some of which involve the platelet derived growth factor receptor beta (PDGFRB) gene. We report a case of acute myeloid leukemia (AML) with a mutation in the NPM1 gene (NPM1-mut AML) and a subclonal gene rearrangement involving the PDGFRB gene. We identified a novel fusion gene, STRN3::PDGFRB, resulting from t(5;14) (q32;q12) chromosomal rearrangement. Sequential FISH confirmed that approximately 15% of leukemic cells carried the PDGFRB gene rearrangement, which suggests that STRN3::PDGFRB is a previously unreported fusion gene in a subclone. Reverse transcription PCR (RT-PCR) and Sanger sequencing confirmed that the fusion gene consisted of STRN3 exon 7 fused to PDGFRB exon 11, resulting in a chimeric protein containing the coiled-coil domain of striatin-3 and the transmembrane and intracellular tyrosine kinase domains of the PDGFRB. The new protein exhibited distinct cytoplasmic localization and had leukemogenic effects, as demonstrated by its ability to transform Ba/F3 cells to growth factor independence and cause a fatal myelodysplastic/myeloproliferative neoplasms (MDS/MPN)-like disease in mice, which then transformant to T-cell lymphoblastic lymphoma in secondary recipients. Ba/F3 cells expressing STRN3::PDGFRB or ETV6::PDGFRB were sensitive to tyrosine kinase inhibitors (TKIs) and selinexor, but in virto experiments showed that the combination of imatinib and selinexor had a marked synergistic effect, although only the imatinib alone group could prolong the survival of T-cell blast transformation recipient mice. Our findings demonstrate the leukemogenic effects of the novel fusion gene and provide insights into the clone evolution of AML, which can be influenced by therapy selection. Furthermore, our results provide insight into the potential therapeutic options for patients with this type of mutation, as well as the need for careful consideration of treatment selection to prevent undesirable side effects.

Acute leukemias of ambiguous lineage, not otherwise specified (ALAL-NOS) is a rare type of acute leukemia. Management of relapse/refractory (R/R) patients is still challenging.traditional chemotherapy treatment is not effective. In this paper, we reported 6 R/R patients diagnosed as ALAL-NOS in our hospital, who were treated with venetoclax based treatment (venetoclax combining with azacitidine or chemotherapy). All 6 patients achieved CR. Five of the six patients received allo-HSCT, four patients were still alive in CR until the follow-up day. Our data provide preliminary evidence and show that venetoclax based regimens are effective and safety in patients with R/R ALAL-NOS. Supplementary Information The online version contains supplementary material available at 10.1186/s40164-021-00239-w.

Introduction The current framework for risk stratification is still insufficient for highly heterogeneous intermediate-risk acute myeloid leukemia (IRC-AML), which lacks specific genomic abnormalities. Methods In order to incorporate novel biomarkers to refine current risk stratification strategies for patients with this subtype, we investigated pretreatment telomere length (TL), which is essential for maintaining genomic stability, in 204 adults with de novo AML (non-acute promyelocytic leukemia). Results We found that TL measured at diagnosis did not decrease with advancing age in 204 patients with AML (R2 = 0.001, P = .695). A multivariate analysis demonstrated that short TL was independently associated with an inferior relapse-free survival (hazard ratio [HR] 3.08, 95% confidence interval [CI] 1.48-6.41, P = .003); event-free survival (HR 2.14, 95% CI 1.12-4.08, P = .021); and overall survival (HR 2.26, 95% CI 1.09-4.67, P = .028) in IRC-AML patients. In addition, IRC-AML patients with short TL also exhibited an increased cumulative incidence of hematologic relapse (HR 2.32, 95% CI 1.08-5.26, P = .032). Conclusion Short TL is an independent prognostic factor for poor prognosis in patients with IRC-AML and may represent a novel mechanism that links genomic stability and disease progression.

Although pediatric-like treatment regimen has remarkably improved the survival rates of adults with acute lymphoblastic leukemia (ALL), the outcome of some adult patients is still poor owing to adverse genetic features. These molecular abnormalities, especially gene deletions, may be considered for the prognosis assessment for adult patients with ALL. In this study, using multiplex ligation-dependent probe amplification (MLPA) method, gene deletions were analyzed in from 211 adult B-ALL patients treated in our center. The data showed that 68.2% (144/211) adult B-ALL patients carried gene deletions, and the frequency is much higher in Ph+B-ALL patients. IKZF1 gene deletion is the most common gene deletion in adult B-ALL, followed by CDKN2A/B deletion. In Ph-B-ALL patients, the overall survival of patients with gene deletions is inferior to that of patients without any gene deletions. More obviously, patients with IKZF1 or CDKN2A/B deletion had a worse prognosis, whereas, allogeneic hematopoietic stem cell transplantation could improve OS in patients with IKZF1 deletion, but not in patients with CDKN2A/B deletion. Moreover, the outcome of Ph-B-ALL patients with double deletion of IKZF1and CDKN2A/B may be much worse than that of patients with IKZF1 or CDKN2A/B alone. Minimal residual disease (MRD) was also analyzed together with gene deletions and demonstrated that gene deletions have a negative impact on survival only in MRD positive Ph-B-ALL patients. In conclusion, gene deletions are closely related with the prognosis of adult Ph-B-ALL patients.

Mutation-based taint inference (MTI) is a novel technique for taint analysis. Compared with traditional techniques that track propagations of taint tags, MTI infers a variable is tainted if its values change due to input mutations, which is lightweight and conceptually sound. However, there are 3 challenges to its efficiency and scalability: (1) it cannot efficiently record variable values to monitor their changes; (2) it consumes a large amount of memory monitoring variable values, especially on complex programs; and (3) its excessive memory overhead leads to a low hit ratio of CPU cache, which slows down the speed of taint inference. This paper presents an efficient and scalable solution named HashMTI. We first explain the above challenges based on 4 observations. Motivated by these challenges, we propose a hash record scheme to efficiently monitor changes in variable values and significantly reduce the memory overhead. The scheme is based on our specially selected and optimized hash functions that possess 3 crucial properties. Moreover, we propose the DoubleMutation strategy, which applies additional mutations to mitigate the limitation of the hash record and detect more taint information. We implemented a prototype of HashMTI and evaluated it on 18 real-world programs and 4 LAVA-M programs. Compared with the baseline OrigMTI, HashMTI significantly reduces the overhead while having similar accuracy. It achieves a speedup of 2.5X to 23.5X and consumes little memory which is on average 70.4 times less than that of OrigMTI.

Aim: Although numerous pro-inflammatory cytokines promote signaling via intracellular pathways involving Janus kinases, it remains unclear if ruxolitinib, a Janus kinase1/2 inhibitor, provides control of cytokine-release syndrome (CRS) without toxicity against therapeutic T cells. Materials & methods: We report successful clinical experience using ruxolitinib as adjuvant therapy to treat steroid-refractory CRS, which was related to CD22/CD19 chimeric antigen receptor-modified T cell sequential infusion, in a patient with Philadelphia chromosome-like acute lymphoblastic leukemia. Results: His symptoms improved rapidly after first dose of ruxolitinib; this was associated with reduced levels of circulating pro-inflammatory indicators. He eventually achieved minimal residual disease negative remission. Discussion: This is the first case in which ruxolitinib was used to treat steroid-refractory CRS; furthermore, this intervention had no apparent impact on the antileukemic actions of the chimeric antigen receptor-modified T cells. Our results suggest that adjuvant ruxolitinib therapy may be an alternative therapeutic approach for the management of CRS.

Background: The incidence of B-cell ALL follows a bimodal distribution, with the first peak occurring in childhood and a second peak occurring around the age of 50. While the prognosis for pediatric patientshas improved over the past decades, prognosis for the elderly remains very poor. Despite a high rate of response to induction chemotherapy, only 30-40% of adult patients with ALL will achieve long-term remission. Patients with primary refractory and chemo-refractory B-cell ALL have an extremely poor prognosis. A chimeric antigen receptor (CAR) specific for the CD19 B lymphocyte molecule has provide an option of treating B-cell malignancies. Although these CAR-modified T cell products target the same antigen, the designs of CD19-targeted CAR T-cells vary significantly. CNCT19 is autologous CD19-directed genetically modified T cell immunotherapy. The structure of chimeric antigen receptor (CAR) includes CD19scFv-hCD8α hinge-CD8α TM-4-1BB-CD3ζ in tandem. The patent protected CD19scFv sequence is derived from CD19 monoclonal antibody HI19a featured with high specificity and affinity to CD19. This strong binding capability to CD19 leads to killing of the CD19 positive malignant B-cells. Use of 4-1BB co-stimulatory domain is expected to reduce the severity of treatment-associated cytokine release syndrome (CRS) and neurologic toxicities (NT) while maintaining a stronger and longer-term anti-tumor effect. Methods: CNCT19 has been investigated in an open-label, phase 1/2 clinical trial for adult and pediatric patients with r/r ALL who have failed ≥ 2 lines prior therapies. Leukapheresis to obtain T cells was performed following the SOP of the local hospitals. CNCT19 was infused 2 to 14 days after lymphodepletion. All the patients were hospitalized up to 2 weeks. All the PIs have been trained for the management of CNCT19-treatment related CRS and neurotoxicities. A PI committee was involved in the management of CRS and neurologic toxicity. The primary objectives of the study were to determine the safety and the clinical outcomes, including ORR within 3 months, PFS, and overall survival (OS). Results: As of October 2020, 63 patients (adults: n=32 >18 years, children: n=31 < 18 years) have received CNCD19 treatment and all subjects have been followed at least for one year. All grade adverse events occurred in 54 patients (54/63 = 85.7%). Grade ≥3 CRS and NEs occurred in 12 (12/63 = 19%) and 13 (13/63 = 20%), respectively. Out of 63 patients, 59 (59/63= 93.6%) have had overall responder rate (ORR) defined as complete remission (CR) and complete remission with incomplete hematologic recovery (CRi). Among the 59 responded patients, the minimal residual disease (MRD) was negative in 56 patients (56/69 = 94.9%) and 23 patients (38.9%) received allogeneic-HSCT treatment. The relapse-free survival (RFS) and overall survival (OS) were summarized in adult and pediatric groups separately in the following table. Conclusions: CNCT19 treatment of patients with r/r ALL demonstrates improved ORR, PFS, and OS both in children and adults. A pivotal clinical trial is going on in China to evaluate the ORR, PFS, and OS with a clinical plan to decrease the severity of treatment-related adverse events (CRS/NE). Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

Introduction Major resources of our current knowledge on acute leukemia epidemiology and prognosis are based on data from clinical trials. Due to the selective bias of clinical trials, data might differ from the general leukemia population in real-life setting. National Clinical Research Center for Blood Disease established a comprehensive database through the electronic health records (EHR) to facilitate research of the hematologic cancers i.e. acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and acute promyelocytic leukemia (APL). The aim of the database is to gain insight into the epidemiology of these cancers, to evaluate treatment responses, to compare results between geographical regions of China. Furthermore, with the privilege of national research center, the database expects to identify prognostic and predictive factors for outcome to improve the quality of treatment and patients care. Methods The database development was initiated in 2001. Standard data elements were established to capture the key clinical variables. For individual patients, data from EHRs were extracted, integrated and quality checked. The implement of database facilitated the clinical professions to identify eligible patients, establish research projects, conduct retrospective analysis and follow-up patient outcomes. Continued efforts were made for improving the construction and quality of the database over two decades. We performed a 10-year real-world data review in the database to evaluate the quality of the recorded data and, moreover to describe the clinical, cytogenetic characteristics and survival of acute leukemia patients. The completeness for collected variables was acceptable for statistical analysis. In total, 3,404 patients (1,895 males and 1,509 females) who were diagnosed and treated between Jan. 1, 2010 and Dec. 31, 2020 were enrolled. A substantial proportion (>60%) of patients were residents of the northern and northeast region of China. Demographic and baseline characteristics also included age, age class, baseline blood test, transplantation and research participation. Molecular mutations such as nucleophosmin-1 (NPM1), FMS-related tyrosine kinase 3 (FLT3), and CCAAT/enhancer-binding protein alpha (CEBPA) et al were included in the screening panels. We explored the treatment remission rate and prognosis of different chromosomal karyotype groups among AML patients. Results The patient numbers of the AML, ALL and APL subgroups were 2,345, 769 and 290 respectively. Blood routine results well demonstrated the clinical characteristics of each subgroup (Tbl. 1). In AML group, the frequencies of NPM1, FLT3-ITD, KIT and CEBPA double mutations were 17.9%, 13.2%, 8.7% and 10.1%, respectively (Tbl. 2). In term of ALL, 640 cases (83.2%) were B-ALL and 129 (16.8%) were T-ALL. Among B-ALL, 256 cases (33.3%) were Ph positive. 10-year analysis for overall survival shown that AML patients had better outcomes as compared with ALL group (Fig. 1). In this database, 1,780 AML cases (excluding APL) were enrolled in cytogenetic analysis. The survival rates of different cytogenetic risk groups from our real-world data were separated by the ELN2017 and MRC risk stratification respectively (Fig. 2A-B). Remarkably, we found two rare but recurrent abnormalities, 16 cases with t(7;11) (p15;p15) and 12 cases with t(16;21)(p11;q22/q24;q22). Cases showed high relapse and mortality rate. Compared with the normal karyotype group, the survival of both subentities was worse and transplantation might be recommended in CR1 phase (Fig. 2C), therefore, we recommend that these two subtypes might be regarded as the worse risk group, although neither is mentioned in the current guidelines. The incidence of t(8;21) in our database was 17.9% (Fig. 3). To explore the impact of additional chromosomal abnormalities on the prognosis of t(8;21), we found that the overall survival of patients with additional trisomy 4 was worse than those without trisomy 4 (Fig. 2D), which was rarely mentioned in previous reports. Conclusion The real-world database is of great importance for defining the comprehensive features of AML, APL and ALL in clinical setting. The results offered a remarkable contribution to our knowledge on acute leukemia and identified the prognosis of rare chromosomal karyotype in AML. Figure 1 Figure 1. Disclosures Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

The present case report describes a 46-year-old female patient diagnosed with M4 acute myeloid leukemia (AML), accompanied with a t(1;9)(p22;q34) chromosomal abnormality. Transcriptome sequencing identified a DEK proto-oncogene (DEK)/nucleoporin (NUP)214 fusion gene, which results from the t(6;9)(p23;q34) chromosomal translocation. Polymerase chain reaction analysis and fluorescence in situ hybridization were used to verify the existence of the DEK/NUP214 fusion gene. Few patients with AML with the t(6;9)(p23;q34) chromosomal translocation have been reported to have other chromosomal or karyotype changes. To our knowledge, no AML patient with the DEK/NUP214fusion gene but without the classic t(6;9)(p23;q34) translocations had been reported until now. The prognosis of AML cases with the DEK/NUP214 fusion gene is poor. The rate of complete remission is ~65% (71% in children, 58% in adult patients), while the estimated 5-year survival rate is 28% for children and 9% for adults. The 2008 revision of World Health Organization classification have defined the DEK/NUP214 mutation as a recurrent genetic abnormality of AML. The overall survival of the patient in the current report was ~29 months, and they relapsed twice. To the best of our knowledge, this is the first report of at(1;9)(p22;q34) variant translocation that results in expression of the DEK/NUP214 fusion gene.

Background: Acute myeloid leukemia (AML) is a heterogeneous disease in which 20-50% patients are resistant to chemotherapy. Relapsed/refractory (R/R) AML has a poor long-term prognosis resulting from chemotherapeutic drug resistance. However, the specific gene-drug pairs have been rarely reported. The purpose of our study was to explore an accurate algorithm for screening gene profiles classifier associated with chemotherapy drug sensitivity. Method: 43 AML patients from the Institute of Hematology and Blood Diseases Hospital were enrolled, including newly diagnosis (n=23) and R/R (n=20) AML between March 2019 to January 2020. We separated bone marrow cells (BMCs) of the 43 patients. Additionally, 24 therapeutic drugs panel (Figure 1) were selected and 7-concentration gradient were used to test drug sensitivity in vitro by HDS (High-throuphput Drug Sensitivity Analysis Strategy). Paired molecular data of RNA-seq and DNA methylation 850K CHIP implemented simultaneously. K-Means, an unsupervised algorithm, was applied to cluster all samples into two groups (Resistance/Sensitive group) according to IC50 and 100% PPC inhibition rate of each drug. We used a combination of different algorithms to build a proper gene classifier. The whole process was shown as Figure 2. The major objectives of the evaluating algorithm included F1 score, precision rate, recall rate and AUC. "pRRophetic", a R package, was modified to specify target type as "AML" in aim to estimate IC50 of samples based on GDSC database. Furthermore, we cultured Ara-C resistant cell line of HL-60 in purpose of comparing relative gene expression with wide type (wt) by quantitative Real-time PCR (qPCR) to prove the selected gene signature. Result: The HDS data suggested that sensitivities of newly diagnosis AML to chemotherapeutic-drugs were highly variable. However, Newly Diagnosis Group was more sensitive to majority chemotherapeutic drugs in contrast to R/R AML (P As heterogeneous drug response in vitro, we found K-means (k=2) was more reasonable algorithm, as compared to K-means (k=3) for grouping all samples. SVM of transcription data for each drug showed a significantly advantage over other algorithms (P Compared to newly diagnosis AML, R/R Group possessed 2134 upregulated genes and 1210 down-regulated genes in the aspect of RNA-seq data. Crosslinking analysis of RNA-seq and methylation data of the two group, 1 gene were described as up-regulated expression with hypo-methylation, and 39 genes was down-regulated expression with hyper-methylation. 8/39 genes are corresponded with SVM algorithm. Moreover, 4-gene-drug pairs, including FOXC1 for anthracyclines drug, IGFBP5 for Ara-C, VTRNA1-1 and TKTL1 for pan-drug, were investigated by overlapping TOP 5 genes for each drug of SVM algorithm and DEGs between R/R and newly diagnosis AML. High expression of four genes was identified as a risk factor for AML prognosis. The result of qPCR revealed that IGFBP5 is overexpression in Ara-C-resistant HL-60 than wt. Conclusion: We construct a model of K-Means and RFE-DEG/DMP-SVM, a validated and precise computational approach, for predicting drug sensitivity related genes in AML patients. Up-regulated expression with hypo-methylation genes may be signature genes for drug resistance. 4-gene-based classifier may make contributions to chemotherapeutic-drug resistance prediction and AML treatment decision-making. Disclosures No relevant conflicts of interest to declare.

Purpose: Cytarabine, 100–200 mg/mE+2/day, is commonly used in induction therapy of acute myelogenous leukemia (AML). Whether a higher dose of cytarabine would be more effective is unknown. Also, there is controversy whether high-dose cytarabine is better than an intermediate-dose combined with other drugs for post-remission therapy. In this open-label, randomized controlled, parallel group study, roles of intermediate-dose cytarabine were investigated. Patients and Methods: Subjects with AML age 15–55 years were randomized to receive daunorubicin, omacetaxine mepesuccinate, and conventional- or intermediate-dose cytarabine. Subjects achieving complete remission were randomized to receive 3 courses of high-dose cytarabine or 2 courses of intermediate-dose cytarabine with daunorubicin in the 1st and mitoxantrone in the 2nd course. The primary endpoint was disease-free survival (DFS). Results: 591 subjects were randomized to intermediate- (N = 295) or conventional-dose (N = 296) cytarabine group. Three-year DFSs were 67% [95% confidence interval (CI), 61–73] in the intermediate-dose cohort compared with 54% (95% CI, 48–61) in the conventional-dose cohort [Hazard Ratio (HR), 0.67; 95%CI, 0.51–0.89; P = 0.005). Three-year survivals were 68% (95%CI, 63–74) and 59% (95%CI, 53–65; HR, 0.720; 95%CI, 0.56–0.94; P = 0.014). Two courses of intermediate-dose cytarabine with daunorubicin or mitoxantrone resulted in similar DFS and survival as three courses of high-dose cytarabine when used for post-remission therapy. Conclusions: Induction therapy with intermediate-dose cytarabine with daunorubicin and omacetaxine mepesuccinate increases DFS and survival in persons with AML ages 15–55 years compared with conventional-dose cytarabine. See related commentary by Watts and Bradley, p. 3073

The study of candidemia in Chinese leukemia patients has been limited. This retrospective study aims to investigate the characteristics and prognostic factors of candidemia among leukemia patients. From 2009 to 2015, 30 isolates of candidemia were detected in 19 patients with acute leukemia after chemotherapy. The overall incidence of candidemia was 2.12 episodes per 1000 admissions. Candida tropicalis was the most common Candida species (n = 17; 89.5%). The vast majority of candidal infections are endogeneous. The overall 30-day crude mortality rate was 31.6%. Neutrophil recovery (P = 0.000) and initiation of empiric antifugal treatment before first positive blood culture (P = 0.041) were associated with a significant improvement in overall survival. Early diagnosis, followed by rapid antifungal treatment remains the cornerstone of successful management. The widespread use of newer antifungal agents as prophylaxis among patients with acute leukemia may result in a decreased candidemia incidence.

Purpose Dasatinib is a second-generation tyrosine kinase inhibitor with higher central nervous system (CNS) penetration compared with imatinib and nilotinib in in vitro studies. However, limited clinical data are available regarding the dosage and CNS penetration of dasatinib. The purpose of this study was to investigate the actual ability of dasatinib to cross the blood–brain barrier in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). Methods Plasma and cerebrospinal fluid (CSF) samples collected from Ph+ ALL patients treated with dasatinib were analyzed by using an LC-MS/MS assay. Findings Orally administered dasatinib 100 mg once daily was well absorbed by the patient but penetrated poorly into the CSF. The use of a higher drug dosage (140 mg/d) may increase systemic drug exposure and enhance the penetration of dasatinib into the CSF. Implications Based on this study, the use of a higher dosage of dasatinib (140 mg/d) is recommended in patients at high risk of CNS relapse or patients who need treatment for CNS leukemia. ClinicalTrials.gov identifier: NCT02523976.

Minimal residual disease (MRD) levels monitored by polymerase chain reaction are associated with outcomes in acute myeloid leukemia with RUNX1–RUNX1T1. The objectives of our study were to quantitatively compare the predictive value of MRD reduction and absolute copies and assess the influence of other prognostic factors on MRD. A total of 224 consecutive patients with RUNX1–RUNX1T1 aged ≤55 years were included in the MRD study. Patients received different induction regimens including conventional- or intermediate-dose cytarabine plus low-dose daunorubicin and omacetaxine mepesuccinate or daunorubicin at 60 mg/m2/day on days 1–3. As continuous variables, both MRD reduction and absolute MRD level were significantly associated with cumulative incidence of relapse (CIR; hazard ratio [HR] = 1.610, 95% confidence interval [CI]: 1.370–1.890, p

Background BCOR gene is a transcription repressor that may influence normal hematopoiesis and is associated with poor prognosis in acute myeloid leukemia (AML) with normal karyotype. However, due to the rare mutation frequency in AML (3.8%-5%), clinical characteristics and prognosis of AML patients with BCOR mutation including abnormal karyotype are still unknown. In addition, the clonal evolution of AML patients with BCOR mutation has not been fully investigated. Methods By means of next generation of sequencing, we performed sequencing of 114 genes related to hematological diseases including BCOR on 509 newly diagnosed AML patients (except for acute promyelocytic leukemia) from March 2017 to April 2019. The 2017 European Leukemia Net (ELN) genetic risk stratification was used to evaluate prognosis. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Relapse-free survival (RFS) was measured from remission to relapse or death. Clonal evolution was investigated through analyzing bone marrow samples at diagnosis, complete remission (CR) and relapse from the same patient. Result Among 509 AML patients, we found BCOR mutations in 23 patients (4.5%). BCOR mutations were enriched in patients with mutations of RUNX1 (p = 0.008) and BCORL1 (p = 0.0003). Patients with BCOR mutation were more at adverse ELN risk category compared to patients without BCOR mutation (p = 0.007). Besides, there was a larger proportion of patients with normal karyotype in BCOR mutation group but it had not reached statistical difference (62.5% vs 45.5%, p = 0.064). The abnormal karyotype in patients with BCOR mutations included trisomy 8, t(9;11), inv(3), -7 and complex karyotype.There were no significant differences in age, sex, white blood cell count, hemoglobin or platelet count between the two groups. More patients died during induction (13.0% vs 3.5%, p = 0.56) and fewer patients achieved CR after 2 cycles of chemotherapy when patients had BCOR mutations (69.6% vs 82.5%, p = 0.115) but the difference had not reached statistical difference . Patients with BCOR mutations had inferior 2-year OS (52.1% vs 70.7%, p = 0.0094) and 2-year RFS (29.8% vs 61.1%, p = 0.0090). After adjustment for ELN risk stratification, BCOR mutation was still remain a poor prognostic factor. However, the adverse prognostic impact of BCOR mutation is overcome by hematopoietic stem cell transplantation (HSCT), in which there was no difference between BCOR mutation group and wild type group (p = 0.474) (Figure 1). Through analysis of paired bone marrow sample at diagnosis, remission and relapse, we revealed the clonal evolution that BCOR mutation was only detected at diagnosis sample as a subclone and diminished at CR and relapse while TP53 mutation was only detected at relapse with a variant allele frequency (VAF) of 25.5%. We also found BCOR mutation at another patient's diagnosis and relapse sample while TP53 mutation was detected at relapse with VAF of 11.8%. Conclusion BCOR is associated with RUNX1 mutation and higher ELN risk. AML patients with BCOR mutation including normal and abnormal karyotype conferred a worse impact on OS that can be overcome by HSCT. BCOR mutation is a subclone at diagnosis or relapse in some patients, in which TP53 mutation clone occurred at relapse. Disclosures No relevant conflicts of interest to declare.

Accurate network traffic classification is of fundamental importance to network traffic measurement and analysis. Machine learning based approaches takes use of various characteristics instead of only depending on port numbers and protocol details. This paper proposes a traffic classification approach based on extreme learning machine(ELM), in which a rough set is before ELM algorithms applied in classification. Comparing to the huge time-consuming, low accuracy rates and inefficient capability of the classification of the conventional algorithms, an extreme learning machine proposed for classification model. Comparing hierarchical extreme learning machine (H-ELM) to AR-ELM, the results of experiment shows that AR-ELM algorithm can be used in classification effectively and the classification based on ELM model has many advantages like quite fast training speed and low error rate. H-ELM improves the overall learning performance by removing redundancy of the original inputs with compact features. The proposed AR-ELM conducts the classification in combination with the advantages of both ELM and H-ELM.

The aim of this study is to investigate the efficacy and safety of nilotinib combined with multi-agent chemotherapy in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Thirty patients with Ph+ ALL were recruited. Standard induction chemotherapy was given for 4 weeks. Nilotinib was administered beginning on day 15 of induction. After achieving hematologic complete remission (HCR), patients received either seven courses of consolidation or hematopoietic cell transplantation (HCT). Nilotinib was continued 2 years after achieving HCR or before stem cell transplantation conditioning. HCR and molecular complete response (MCR), overall survival (OS), hematologic relapse-free survival (HRFS), molecular relapse-free survival (MRFS), toxicity, and nilotinib levels in the serum and cerebrospinal fluid were evaluated. All patients achieved HCR, and cumulative MCR rate was 83.3%. The median HRFS and OS were 18 and 47.5 months, respectively. Four-year HRFS and OS rates were 54% and 45%, respectively. The median MRFS and 4-year MRFS for the patients with MCR were 19 months and 45%, respectively. The molecular response of patients after induction cycle had no impact on HRFS, MRFS, or OS. The patients who achieved MCR after 3 and 6 months had superior HRFS. The HCT cohort in the first HCR had significantly lower rates of relapse and longer MRFS, HRFS, and OS. Most adverse events were reversible with dose reduction or transient interruption of nilotinib therapy. Only traces of nilotinib were detected in cerebrospinal fluid. Nilotinib combined with cytotoxic chemotherapy was effective and translated to a high HCR and MCR for patients with Ph+ ALL. It should be noted that nilotinib cannot cross the blood–brain barrier.

This file contains Tables S1â S7, including Table S1. CBF ratios in European, American, and Eastern Asian cohorts; Table S2. NPM1 mutation ratios in European and our cohorts; Table S3. FLT3-ITD mutation ratios in European and our cohorts; Table S4. FLT3-ITD mutation ratios in older patients from Chinese cohort against European and American cohorts; Table S5. CBF leukemia ratios in older patients from Japanese and Chinese cohorts against European and American cohorts; Table S6. NPM1 mutation ratios in older patients from Chinese cohort against European and American cohorts; and Table S7. Outcomes in European, American, and Eastern Asian cohorts. (PDF 568Â kb)