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Diffuse large B cell lymphoma (DLBCL) is the most common aggressive lymphoid malignancy, with an immunosuppressive microenvironment affecting clinical outcome. Interleukin (IL)-13 overexpression is observed in multiple solid tumors and contributes to tumor progression. This study aims to investigate pretreatment serum IL-13 levels and their relationship with the prognosis of DLBCL patients. One hundred and sixty-six patients with newly diagnosed DLBCL from June 2015 to July 2017 were included. Patients with elevated pretreatment serum IL-13 levels (IL-13≥1.63 pg/ml) were classified into the high IL-13 group and they had significantly lower complete remission rate (60% vs. 74%, p = 0.0059), higher progression rate (43% vs. 23%, p = 0.0051), and poor progression-free survival (2-year PFS, 63% vs. 78%, p = 0.0078) and overall survival (2-year OS, 75% vs. 92%, p = 0.0027), when compared to those in the low IL-13 group (IL-131.63 pg/ml). Meanwhile, increased Treg cell ratio in peripheral blood (p = 0.0147) and elevated serum IL-2 levels (p = 0.0272) were observed in the high IL-13 group. Moreover, RNA sequencing data showed that patients in the high IL-13 group had significantly elevated expression of chemokines and chemokine receptors (CCR4, CCL19, CCL21, CXCL2) related to Treg activation and recruitment. Consistent with the chemokine profile, tumor immunophenotyping analysis revealed that higher Treg cells recruitment in the high IL-13 group than the low IL-13 group (p = 0.0116). In vitro, when lymphoma cells co-cultured with peripheral blood monocytes of healthy controls, metformin down-regulated both IL-13 level and Treg cell ratio, in consistent with the decreased serum IL-13 levels of patients after 6 months of metformin maintenance therapy in the high IL-13 group. Taken together, pretreatment serum IL-13 level is related to the immunosuppressive microenvironment and poor clinical outcome of DLBCL patients and could be targeted by metformin, thus providing a new therapeutic strategy in treating DLBCL with high serum IL-13 levels.

Chidamide has demonstrated significant clinical benefits for patients with relapsed/refractory (R/R) PTCL in previous studies. This multi-center observational study was aimed to evaluate the objective response rate (ORR), overall survival (OS), and safety of chidamide. From February 2015 to December 2017, 548 patients with R/R PTCL from 186 research centers in China were included in the study. Among the 261 patients treated with chidamide monotherapy, ORR was 58.6% and 55 patients (21.1%) achieved complete response (CR). Among the 287 patients receiving chidamide-containing combination therapies, ORR was 73.2% and 73 patients (25.4%) achieved CR. The median OS of all patients was 15.1 months. The median OS of patients receiving chidamide monotherapy and combination therapies was 433 and 463 days, respectively. These results demonstrate a significant survival advantage of chidamide treatments as compared with international historical records. Common adverse effects (AEs) were hematological toxicities. Most AEs in both monotherapy and combined treatments were grade 1–2. No unanticipated AEs occurred. In conclusion, chidamide-based therapy led to a favorable efficacy and survival benefit for R/R PTCL. Future studies should explore the potential advantage of chidamide treatment combined with chemotherapy.

Dasatinib is a highly effective second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML). In 2007, a pivotal phase-2 study of dasatinib as second-line treatment was initiated in 140 Chinese CML patients. This report from the 4-year follow-up revealed that 73% of 59 patients in chronic phase (CML-CP) and 32% of 25 patients in accelerated phase (CML-AP) remained under treatment. The initial dosage of dasatinib for CML-CP and CML-AP patients were 100 mg once daily and 70 mg twice daily (total = 140 mg/ day), respectively. The cumulative major cytogenetic response (MCyR) rate among patients with CML-CP was 66.1% (versus 50.8% at 18 months), and the median time to MCyR was 12.7 weeks. All CML-CP patients who achieved MCyR after a 4-year follow-up also achieved a complete cytogenetic response. The cumulative complete hematological response (CHR) rate among patients with CML-AP was 64% (16/25), with three CML-AP patients achieving CHR between 18 months and 4 years of follow-up; the median time to CHR was 16.4 weeks. The adverse event (AE) profile of dasatinib at 4 years was similar to that at 6 and 18 months. The most frequently reported AEs (any grade) included pleural effusion, headache, and myelosuppression. These long-term follow-up data continue to support dasatinib as a second-line treatment for Chinese patients with CML.

Background Patients with relapsed/refractory B-cell lymphomas have limited treatment options. GERSHWIN is an open-label, single-arm, phase Ib study of obinutuzumab monotherapy in Chinese patients with histologically documented CD20+ relapsed/refractory chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), or follicular lymphoma (FL). The primary outcome measure of pharmacokinetics has been previously reported. We now present data on the secondary endpoint measures (e.g., safety, and efficacy and pharmacodynamics). Methods Patients received 1000 mg obinutuzumab intravenously on days 1, 8, and 15 of cycle 1 (CLL patients; first dose split over 2 days), and on day 1 of cycles 2–8. Each cycle lasted for 21 days; the treatment period was 24 weeks. All subjects receiving at least one dose of obinutuzumab were included in the analysis of safety, efficacy, as well as pharmacodynamics. Results A total of 48 patients (> 18 years of age) were enrolled (CLL: 12; DLBCL: 23; FL: 13). The subjects received a median of two lines of anticancer treatment prior to the enrollment. Thirty-five patients (72.9%) had at least one adverse event (AE). The most frequent AE was infusion-related reactions (15 patients; 31.3%), followed by pyrexia (11 patients; 22.9%). Treatment-related AEs were reported in 28 patients (58.3%), and included one death (interstitial lung disease). End-of-treatment (EoT) response rate was 33.3%. Best overall response rate was 47.9%. Most CLL patients achieved a partial response at EoT (58.3%). CD19+ depletion occurred in 75.0% of the patients with CLL, and all patients with FL and DLBCL. Conclusions The safety and efficacy of obinutuzumab monotherapy in Chinese patients with B-cell lymphomas were similar to that observed in previous studies in non-Chinese patients; no new safety signals were observed. Clinical trial registration ID NCT01680991

Aim The Phase Ib GERSHWIN study (NCT01680991) assessed the pharmacokinetic (PK) profile of obinutuzumab following multiple intravenous (i.v.) doses to Chinese patients with B-cell lymphomas, and compared findings with previous obinutuzumab PK studies in mainly Caucasian (non-Chinese) patients. Methods GERSHWIN was an open-label, single-arm intervention study. Patients aged >18 years with CD20+ relapsed/refractory chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) were enrolled from four centres in China. The treatment period was 24 weeks; patients received obinutuzumab 1000 mg i.v. on Days (D)1, 8 and 15 of Cycle (C)1 (CLL patients: first infusion split over 2 days) and on D1 of C2–8 (all cycles: 21 days). PK parameters were estimated using non-compartmental analysis (NCA), and a population PK analysis was used to determine whether observed GERSHWIN PK data were in accordance with previous obinutuzumab PK studies in non-Chinese patients. Results The PK analysis population included 48 patients: 28 patients completed all treatment cycles. NCA showed a similar PK profile in Chinese patients with FL, DLBCL and CLL. Steady-state concentrations of obinutuzumab appeared to be reached at the start of C2 irrespective of histology. There was no apparent relationship between body weight and systemic exposure. Most PK profiles observed in GERSHWIN lay within the 90% prediction interval of simulated profiles. Conclusions Obinutuzumab exposure was comparable in CLL, DLBCL and FL patients. NCA and population PK analysis indicate that PK characteristics of Chinese patients with B-cell lymphomas are similar to those in non-Chinese patients.

Objectives The arsenic trioxide (ATO) plus all-trans retinoic acid (ATRA) therapy has demonstrated a tremendous success in the first-line treatment of acute promyelocytic leukemia (APL). Actually, early death (ED) is currently thought as a major challenge in APL. ATO has been reported to inhibit platelet function in vitro, and whether it increases the ED rate by exacerbating the hemorrhagic symptoms remains to be investigated. Methods Effects of ATO on platelet aggregation and adhesion were evaluated in vitro and in thirty-two complete remission (CR) and four newly diagnosed APL patients. Furthermore, concentrations of plasma total arsenic were monitored in APL patients via ICP-MS. Results The inhibition of platelet function, either aggregation or adhesion, did occur in vitro when the concentration of ATO reached 2 μmol/L. However, in CR APL patients receiving ATO with normal platelet count, the platelets responded normally when being activated and so did those in the newly diagnosed patients with thrombocytopenia. Our data further showed that the conventional dosage of ATO reached a plasma concentration substantially below the required concentration to inhibit platelets. Conclusions In the first-line treatment of APL, the use of ATO is safe and effective and does not compromise the hemostatic potential that may eventually increase ED rate.

To analyze the clinical features and prognostic factors of patients with mantle cell lymphoma(MCL).The clinical data of 66 MCL patients were collected from the Department of Hematology of Shanghai Ruijin Hospital, Shanghai Jiaotong University Medical School from January 2000 to December 2014. The clinical characteristics, treatment efficiency and survival rate were analyzed retrospectively.The sex ratio of male to female in these 66 MCL patients was 3.71:1, the nosopoietic median age was 59 years old, and most cases were diagnosed as MCL in Ann Arbor stage III-IV(90.9%). "R-HperCVAD" regimen had the highest CR-rate reached to 55.6%, and CR rate of "R-CHOP" reached to 44.4%. The total prospective 5-year overall survival and progress-free survival rates were 35.5%±11.5% and 8.8%±5.6%, respectively. Leukocyte count abnormality(10×10The prognosis of MCL patients is poor, and the incidence is higher in men. The extranodal sites of bone marrow and gastrointestinal tract are involved more easily. The treatment combined with rituximab can increase survival rate for these patients.

Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment., Highlights • The genomic landscapes of adult and pediatric B-ALL were defined by next-generation sequencing of patient samples. • MEF2D and ZNF384 fusions could perturb B-cell differentiation or induce leukemia in mice and exhibited clinical relevance. • Adult patients showed greater enrichment for alterations of genes linked to epigenetic modification and B-cell development. This study comprehensively addressed the genomic signatures of adult versus pediatric B-ALL. The identification of distinct MEF2D and ZNF384 fusions expands the existing knowledge about molecular subtypes of B-ALL in both age groups. RNA-seq data allowed most of the B-ALL cases to be clustered into 8 subgroups related to genetic abnormalities. Notably, adult patients have more cooperative sequence variation mutations than pediatric patients, especially in genes involved in epigenetic regulation and B-cell development. These findings may improve our understanding of leukemogenesis in B-ALL, leading to a more precise genetic classification and the further development of targeted therapy in this disease.

Circularly permuted TRAIL (CPT) has exhibited promising efficacy as a mono-therapy or in combination with thalidomide for patients with multiple myeloma (MM). In this phase 2 study, the safety and efficacy of CPT in combination with thalidomide and dexamethasone (CPT + TD) was evaluated in patients with pretreated relapsed/refractory MM (RRMM). Patients who received at least two previous therapies for MM were randomly assigned at a 2:1 ratio to receive treatment with CPT + TD or thalidomide and dexamethasone (TD). The primary endpoint was the overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), duration of response (DOR) and safety. Overall, 47 patients were assigned to the CPT + TD group, and 24 patients were recruited to the TD group. The ORR in the CPT + TD group was 38.3 vs. 25.0% in the TD group. The median PFS time was 6.7 months for the CPT + TD group and 3.1 months for the TD group. The median DORs for the CPT + TD and TD groups were 7.1 and 3.2 months, respectively. Most of the adverse effects (AEs) were grade 1 or 2. Serious AEs were reported in 19.7% of the patients. No treatment-related deaths were reported. CPT plus TD could serve as a new therapeutic strategy for patients with RRMM. A randomized, double-blind, placebo-controlled confirmatory study is currently under way.

Introduction Bortezomib, a novel proteasome inhibitor, is approved for the treatment of relapsed multiple myeloma (MM). Efficacy and safety of bortezomib is well known; however, it was necessary to validate the data in patients with different ethnic backgrounds. The efficacy and safety of bortezomib was assessed in patients from China with relapsed/refractory MM in a real-world scenario. Methods This prospective, non-interventional, observational study enrolled both male and female Chinese patients, aged ≥18 years and diagnosed with relapsed or refractory MM. Administration of intravenous bortezomib at 1.3 mg/m2 was recommended twice a week for 2 weeks (days 1, 4, 8 and 11), followed by a 10-day rest period (maximum of 8 cycles) and a follow-up every 12 weeks for 3 years. Efficacy assessments included best response, objective response rate (ORR), time to response, duration of response, and overall survival. Safety was also assessed. Results A total of 517 patients were enrolled with a median age of 58.7 years. Patients predominantly had immunoglobulin G type (46.2%) and stage III (47.8%) myeloma. Overall, 202 (42.3%) patients had partial response as best response, ORR was 88.9% and the proportion of patients exhibiting complete response was 24.7%. The median time to response observed was 27 (21–40) days. Median time to progression was 415 days and median overall survival was 475 days. Thrombocytopenia (14.4%) was the most common adverse event. Conclusion Bortezomib demonstrated clinical response in majority of patients and was well tolerated in this observational study in Chinese patients with relapsed/refractory MM. Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0159-z) contains supplementary material, which is available to authorized users.

The Glasgow Prognostic Score (GPS) incorporates C-reactive protein and albumin as clinically useful markers of tumor behavior and shows significant prognostic value in several types of solid tumors. The accuracy of the GPS in predicting outcomes in diffuse large B cell lymphoma (DLBCL) remains unknown. We performed this study to evaluate the prognostic significance of the GPS in DLBCL in China. We retrospectively analyzed 160 patients with newly diagnosed DLBCL at the Shanghai Ruijin Hospital (China). The prognostic value of the GPS was evaluated and compared with that of the International Prognostic Index (IPI) and immunohistochemical subtyping. The GPS was defined as follows: GPS-0, C-reactive protein (CRP) ≤10 mg/L and albumin ≥35 g/L; GPS-1, CRP10 mg/L or albumin35 g/L; and GPS-2, CRP10 mg/L and albumin35 g/L. Patients with lower GPS tended to have better outcomes including progression-free survival (PFS, P 0.001) and overall survival (OS, P 0.001). Multivariate analysis demonstrated that high GPS and high IPI score were independent adverse predictors of OS. Similar to several other tumors, GPS is a reliable predictor of survival outcomes in DLBCL patients treated with R-CHOP therapy. Inflammatory responses are implicated in the progression and survival of patients with DLBCL.

This paper deals with maximum-likelihood (ML) detection of symbol sequence in the absence of synchronization information. A novel iterative scheme is proposed to obtain the ML estimates of the symbols without an estimation of synchronization parameters. Instead of the optimal sampling point recovery and explicit carrier phase compensation, the detection of symbols employs the direct calculation of the matched filter output, eliminating the need for a separate synchronizer. The detection problem is treated as ML estimation from incomplete data, which is solved by means of an iterative scheme based on the expectation-maximization algorithm. The proposed scheme is compared with conventional non-data-aided and iterative ML synchronizers. Accordingly, the simulation results indicate that the proposed detector enables improvements on both the bit error rate and convergence property.

Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML. http://ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00261846","term_id":"NCT00261846"}}NCT00261846. Am. J. Hematol. 89:732–742, 2014. © 2014 The Authors American Journal of Hematology Published by Wiley Periodicals, Inc.

In the signal combining system of deep space network, the estimation error of time-delay between signals will reduce the effectiveness. The time-delay alignment technique based on combined output signal as the reference (CC-SUMPLE algorithm) makes use of the mutual information offered by multi-antenna and improves the alignment performance. However, it only takes ordinary cross-correlation into consideration rather than the cyclostationary of digital communication signal during calculating time-delay in the iterative process. As to this problem, this paper proposes multi-antenna signal time-delay alignment algorithm based on cyclostationary of communication signal (MCCC-SUMPLE algorithm) which reconstructs the combined reference signal and takes advantage of multi-cycle frequencies. The simulation results show that the proposed algorithm will improve the estimation accuracy and time-delay alignment performance compared with CC-SUMPLE algorithm.

Background: Imatinib is the first TKI that was officially approved by the Food and Drug Administration (FDA) for the treatment of patients (pts) with CP-CML and it is the most commonly used treatment in CML pts on the international scene. Generic imatinib was offered and accessible as frontline treatment of CML in china in June 2013, which predictably lowered the cost of CML therapy. However the statistics regarding their effectiveness and tolerability in greater proportion of the population of CML pts are not available. (ClinicalTrials. gov number, NCT02317159.) Aim: To evaluate the efficacy and safety of generic imatinib in the treatment of pts that were newly diagnosed with CP-CML. Methods: In this multi-center, prospective open-label study, 75 pts with CP-CML were enrolled to receive generic imatinib mesylate capsules at a dose of 400 mg once daily. The primary end point was major molecular response (MMR) by 12 months. Imatinib plasma level and adverse events (AEs) were assessed. Results: The Median age at diagnosis was 46 years (range 19-75 years), and 50 pts (66.7%) were male. The median follow-up was 22.1 (range0.5-24) months. 35 pts (44%), 26 pts (34.7%) and 12 pts (16%) were in low, intermediate and high risk group, respectively, according to Sokal prognostic score (Not available in 2 pts). By 12 months, the cumulative rate of MMR (BCR-ABL1IS ≤0.1%) was 42.7% (32/75), and the cumulative rate of complete cytogenic response (CCyR) was74.7% (56/75). Complete hematologic response (CHR), CCyR, MMR rate at 3 months,6 months and 12 months were shown in Table 1. For pts who presented with BCR-ABL1 IS≤ 10% at 3 months, had better response as compared with those with BCR/ABL1IS> 10% (Table 2). The estimated progression-free survival at 12 months was 94.7%. Imatinib plasma levels at 29 days on imatinib were variable in individual, with 1522.9±775.3 ng/mL for median level (rang 394.4 to3891 ng/mL). Although those numerical values showed difference, no statistically significant correlations were found between imatinib plasma level and CCyR or MMR(P=0.902;P=0.349). The incidents and profile of AEs were similar to those reported previously. Conclusion: This study confirmed that generic imatinib produced in China is effective and well-tolerated in Chinese CP-CML pts. The outcome of generic imatinib in the treatment of CP-CML is similar to brand imatinib reported in the literatures. The introduction of generic imatinib at a reduced and affordable cost may strikingly impact the cost of care for CML and improve the clinical outcomes of CML in China. Disclosures No relevant conflicts of interest to declare.

SUMMARY Objective To assess the efficacy and safety of deferasirox in Chinese thalassaemia major (TM) patients Background EPIC (Evaluation of Patients' Iron Chelation with Exjade®) was a large multi-national study and, notably, the first clinical trial of an iron chelator registered with the Chinese State Food and Drug Administration. Methods Efficacy and safety of deferasirox were compared in Chinese (n = 117) and non-Chinese (n = 998) TM patients. Deferasirox was initiated at 20 mg kg−1 day−1, with titration increments of 5−10 mg kg−1day−1, based on serum ferritin trends and safety parameters. Results At baseline, Chinese patients were younger than non-Chinese (mean age 6·8 versus 19·5 years), with higher median serum ferritin (4519 vs 3058 ng mL−1). Over 1 year, mean actual deferasirox dose was similar for Chinese and non-Chinese patients (24·6 and 24·0 mg kg−1 day−1, respectively); median serum ferritin did not change significantly from baseline in Chinese patients (+340 ng mL−1, P = 0·102) and significantly decreased in non-Chinese patients (−220 ng mL−1; P

Despite advances in the treatment of T‑cell acute lymphoblastic leukemia (T‑ALL), the outcome of T‑ALL treatment remains unsatisfactory, therefore, more effective treatment is urgently required. The present study examined the cytotoxicities of bortezomib in combination with daunorubicin against human Jurkat and Molt‑4 T‑ALL cells and primary T‑ALL cells. Compared with treatment alone, co‑exposure of cells to bortezomib and daunorubicin resulted in a significant increase in cell death in the Jurkat cells, as evidenced by the increased percentage of Annexin V‑positive cells, the formation of apoptotic bodies. In addition, the administration sequence of bortezomib and daunorubicin had an effect on cell viability. Treatment with bortezomib followed by daunorubicin treatment was more effective, compared with treatment with daunorubicin followed by bortezomib. Co-treatment with bortezomib and daunorubicin markedly enhanced the activation of caspase‑3, ‑8 and ‑9, which was reversed by the pan‑caspase inhibitor, Z‑VAD‑FMK. In addition, cotreatment with bortezomib and daunorubicin enhanced the collapse of mitochondrial transmembrane potential and upregulated the proapoptotic protein, B‑cell lymphoma 2 (Bcl‑2)‑interacting mediator of cell death (Bim), but not Bcl‑2 or Bcl‑extra large. Consistent with this, it was demonstrated that cotreatment of bortezomib and daunorubicin efficiently induced apoptosis in primary T‑ALL cells, and cell death was associated with the collapse of mitochondrial transmembrane potential and the upregulation of Bim. Taken together, these findings indicated that the combination of bortezomib and daunorubicin significantly enhanced their apoptosis‑inducing effect in T‑ALL cells, which may warrant further investigation in preclinical and clinical investigations.

A novel algorithm aligning the time-delay of each signal received by a uniform antenna array is presented. In order to solve the problem that time-delay alignment performance is poor at the low signal-to-noise ratio (SNR) value, the proposed algorithm makes use of iterative estimation. Then we analyze and compare the performance between the proposed method and the time-delay alignment algorithm based on quasi synthesis reference (TAQSR), indicating that the new algorithm has better performance. Simulation results show that the new algorithm not only improves the time-delay alignment performance in the multi-antenna signal synthesis system, especially in low SNR, but is also free from the actual value of the time-delay difference, compared with TAQSR.

Summary Background Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. Methods We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0–2. Before enrolment, all patients had received 3–18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). Findings Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40–61) and 40 of 95 in the imatinib group (42%, 32–53%; difference 7·9% in favour of nilotinib; 95% CI −6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3–4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. Interpretation While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. Funding Novartis Pharmaceuticals.

This multicenter, randomized trial assessed the efficacy and safety of a recombinant human thrombopoietin (rhTPO) in patients with persistent primary immune thrombocytopenia (ITP) who had failed glucocorticosteroid treatment. A total of 140 eligible patients were randomized to receive rhTPO + danazol (rhTPO group, 73 patients) or danazol (control group, 67 patients) alone. During the first phase, the increase in the mean maximal platelet counts (101.2 × 10(9)/L) and the area under curve (749.6) in the rhTPO group were significantly higher compared to control (33.3 × 10(9)/L and 316.2; P = 0.0060 and 0.0000, respectively). The major response rate (MRR) and total response rate (TRR) in the rhTPO group were 38.4 and 60.3 %, respectively, significantly higher than in control (MRR 7.9 %, P = 0.0003; TRR 36.5 %, P = 0.0104). In the control group, 45 patients with platelet counts

Gastrointestinal diffuse large B cell lymphoma (DLBCL) is a common subtype of extranodal lymphoma. There has been uncertainty about the clinical efficacy of combination therapy (surgery and chemotherapy) for gastrointestinal DLBCL. We retrospectively analyzed 114 patients with newly diagnosed gastrointestinal DLBCL from six medical centers. We evaluated four groups based on whether they were treated with or without surgery as the initial treatment for DLBCL, followed by either a regimen with cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) or CHOP with rituximab (R-CHOP). For all patients, treatment with R-CHOP resulted in significantly greater overall survival (OS; 93.2 vs 74.5 %, p = 0.008) and progression-free survival (89.8 % vs 72.7, p = 0.029). Tumor resection did not improve OS (84.0 vs 85.0 %, for surgery and chemotherapy alone, respectively, p = 0.980). However, for younger patients, overall survival was greater (p = 0.005) for patients treated with surgery plus chemotherapy (83.9 %) than for patients treated with chemotherapy alone (40.0 %). Elevated serum lactate dehydrogenase level (p = 0.004) and performance status (Eastern Cooperative Oncology Group; p = 0.003) were independent predictors of survival in patients with gastrointestinal DLBCL. Stage-modified IPI was recognized as the best prognostic tool. There were significant differences among patients with low-risk, intermediate-risk, and high-risk groups in 50-month OS (94.2 vs 84.0 vs 66.7 %, p = 0.008). The results of this large-scale study suggest that R-CHOP regimen is the first-line treatment for gastrointestinal DLBCL. The benefit of surgery for these patients remains controversial. Further prospective analyses are warranted.

It has been generally acknowledged that the diagnosis, treatment and prognosis evaluation of leukemia largely rely on an adequate identification of genetic abnormalities. A systemic analysis of genetic aberrations was performed in a cohort of 1346 patients with newly diagnosed acute lymphoblastic leukemia (ALL) in China. The pediatric patients had higher incidence of hyperdiploidy and t(12;21) (p13;q22)/ETV6–RUNX1 than adults (P

Results: The expression rates of leptin and OB-R in esophageal carcinoma were 78.8% (41/52) and 82.7% (43/52), respectively, and the rates in normal esophagus samples were 58.3% (28/49) and 59.2% (29/49), respectively. The expression rates of leptin and OB-R have statistically significant differences between esophageal carcinoma and normal esophagus tissue (P =0.027, P=0.009, P

Nilotinib has shown favorable safety in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic (CML-CP) or accelerated phase (CML-AP) who failed prior imatinib, and superior efficacy over imatinib in newly diagnosed Ph+ patients with CML-CP. Reported here are the efficacy and safety data for patients in CML-AP (n = 181) or blast crisis (CML-BC) (n = 190; myeloid BC, 133; lymphoid BC, 50; unknown, seven) enrolled in an expanded access phase IIIb study. Non-hematologic adverse events were mostly mild to moderate. Drug-related myelosuppression was generally manageable with dose reductions or interruptions and infrequently led to discontinuation of nilotinib. Drug-related grade 3/4 elevations in serum bilirubin and lipase were infrequent. While an analysis of efficacy was not the primary objective of this study, significant hematologic and cytogenetic responses were observed. These results support the safety and efficacy of nilotinib in patients with advanced CML in AP and BC.

Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

BACKGROUND: Nilotinib is a selective, potent BCR-ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic phase (CML-CP) or accelerated phase who failed prior imatinib. METHODS: This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML-CP (N = 1422). RESULTS: In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression-free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re-escalation, 87% successfully achieved re-escalation to the full dose. CONCLUSIONS: This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. Cancer 2012;. © 2011 American Cancer Society.

The synergistic effect of proteasome inhibitor bortezomib and valproic acid (VPA), a histone deacetylase inhibitor, were investigated in this study. Co-treatment with VPA and bortezomib on acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cell lines resulted in marked inhibition of proliferation and induction of apoptosis, including a striking increase in mitochondrial injury, caspase cascade activation, and altered expression of Bcl-2 family proteins. Moreover, combination treatment inhibited cyto-protective signaling pathways, including inactivation of nuclear factor κB (NF-κB), the extracellular signal-related kinase (ERK) and Akt pathways, and activated stress-related signaling pathway, including the c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38) pathways. In addition, this regimen significantly caused G2/M phase arrest, while downregulating the expression of phospho-CDC2 and CyclinD1 as well as increasing p21(cip1). Furthermore, combination treatment efficiently induced apoptosis in primary AML/MDS cells, with little effect on normal cells. In summary, these findings indicate that combination treatment with VPA and bortezomib may be a potent therapy for AML/MDS malignancies.

Aim: Chinese adults with relapsed/refractory Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (Ph- ALL) have poor outcomes. Patients & methods: We conducted a nationwide, retrospective, observational study to assess outcomes in this patient population. Results: Of the 270 enrolled patients, 31% of patients at last salvage achieved complete remission (CR) or CR with partial hematologic recovery (CRh), with median time to CR/CRh of 30 days and median CR/CRh duration of 2.7 months. The CR/CRh rate was more favorable with earlier versus later lines of salvage (41, 24 and 17% at first, second and third or later salvages, respectively). Conclusion: This dataset serves as an important reference of real-world outcomes using currently available chemotherapy regimens for high-risk Chinese adults with relapsed/refractory Ph- ALL.

Eriocalyxin B (EriB) is a natural diterpenoid purified from Isodon eriocalyx var. laxiflora and possesses strong antileukemic activity. In this study, we further investigated its effect and mechanism of action in human lymphoma.In vitro, a series of B- and T-lymphoma cells were treated with EriB. Cell apoptosis was analyzed using flow cytometric assay. Expression of proteins related to apoptosis and cell signal transduction were assessed using Western blot. In vivo antitumor activity of EriB was examined in murine xenograft B- and T-lymphoma models, with in situ cell apoptosis detected by terminal deoxytransferase-catalyzed DNA nick-end labeling assay.EriB significantly inhibited lymphoma cell proliferation and induced apoptosis in association with caspase activation. Antiapoptotic Bcl-2 family members Bcl-2 and Bcl-xL were downregulated, with proapoptotic member Bax stable or upregulated, resulting in reduced Bcl-2/Bax and Bcl-xL/Bax ratios. Meanwhile, multiple signal transduction pathways were involved in lymphoma cell apoptosis in response to EriB, including inhibition of nuclear factor (NF)-kappaB and AKT pathways, and the activation of extracellular signal-related kinase (ERK) pathway. AKT inactivation was related to increased expression of cyclin-dependent kinase inhibitor P21, decreased expression of antiapoptotic phosphorylated form of Bad, and NF-kappaB activator IkappaB kinase alpha/beta. ERK activation corresponded to reactive oxygen species production and could be blocked by antioxidant dithiothreitol. In murine xenograft lymphoma models, EriB remarkably inhibited tumor growth and induced in situ tumor cell apoptosis.These findings broaden the value of EriB as a promising candidate targeting apoptosis cascade in treatment of hematological malignancies.

All- trans retinoic acid (ATRA)/arsenic trioxide (ATO) combination-based therapy has benefitted newly diagnosed acute promyelocytic leukemia (APL) in short-term studies, but the long-term efficacy and safety remained unclear. From April 2001, we have followed 85 patients administrated ATRA/ATO with a median follow-up of 70 months. Eighty patients (94.1%) entered complete remission (CR). Kaplan–Meier estimates of the 5-year event-free survival (EFS) and overall survival (OS) for all patients were 89.2% ± 3.4% and 91.7% ± 3.0%, respectively, and the 5-year relapse-free survival (RFS) and OS for patients who achieved CR ( n = 80) were 94.8% ± 2.5% and 97.4% ± 1.8%, respectively. Upon ATRA/ATO, prognosis was not influenced by initial white blood cell count, distinct PML-RAR α types, or FLT3 mutations. The toxicity profile was mild and reversible. No secondary carcinoma was observed, and 24 months after the last dose of ATRA/ATO, patients had urine arsenic concentrations well below the safety limit. These results demonstrate the high efficacy and minimal toxicity of ATRA/ATO treatment for newly diagnosed APL in long-term follow-up, suggesting a potential frontline therapy for de novo APL.

MassARRAY assay: a more accurate method for JAK2V617F mutation detection in Chinese patients with myeloproliferative disorders

Background Diffuse large B cell lymphoma (DLBCL) represents the most common histological subtype of primary gastrointestinal lymphoma and is a heterogeneous group of disease. Prognostic characterization of individual patients is an essential prerequisite for a proper risk-based therapeutic choice. Methods Clinical and pathological prognostic factors were identified, and predictive value of four previously described prognostic systems were assessed in 101 primary gastrointestinal DLBCL (PG-DLBCL) patients with localized disease, including Ann Arbor staging with Musshoff modification, International Prognostic Index (IPI), Lugano classification, and Paris staging system. Results Univariate factors correlated with inferior survival time were clinical parameters [age >60 years old, multiple extranodal/gastrointestinal involvement, elevated serum lactate dehydrogenase and β2-microglobulin, and decreased serum albumin], as well as pathological parameters (invasion depth beyond serosa, involvement of regional lymph node or adjacent tissue, Ki-67 index, and Bcl-2 expression). Major independent variables of adverse outcome indicated by multivariate analysis were multiple gastrointestinal involvement. In patients unfit for Rituximab but received surgery, radical surgery significantly prolonged the survival time, comparing with alleviative surgery. Addition of Rituximab could overcome the negative prognostic effect of alleviative surgery. Among the four prognostic systems, IPI and Lugano classification clearly separated patients into different risk groups. IPI was able to further stratify the early-stage patients of Lugano classification into groups with distinct prognosis. Conclusions Radical surgery might be proposed for the patients unfit for Rituximab treatment, and a combination of clinical and pathological staging systems was more helpful to predict the disease outcome of PG-DLBCL patients. Electronic supplementary material The online version of this article (doi:10.1186/s12957-015-0668-5) contains supplementary material, which is available to authorized users.

To explore the genetic abnormalities that cooperate with AML1-ETO ( AE ) fusion gene to cause acute myeloid leukemia (AML) with t(8;21), we screened a number of candidate genes and identified 11 types of mutations in C-KIT gene ( mC-KIT ), including 6 previously undescribed ones among 26 of 54 (48.1%) cases with t(8;21). To address a possible chronological order between AE and mC-KIT, we showed that, among patients with AE and mC-KIT , most leukemic cells at disease presentation harbored both genetic alteration, whereas in three such cases investigated during complete remission, only AE , but not mC-KIT , could be detected by allele-specific PCR. Therefore, mC-KIT should be a subsequent event on the basis of t(8;21). Furthermore, induced expression of AE in U937-A/E cells significantly up-regulated mRNA and protein levels of C-KIT. This may lead to an alternative way of C-KIT activation and may explain the significantly higher C-KIT expression in 81.3% of patients with t(8;21) than in patients with other leukemias. These data strongly suggest that t(8;21) AML follows a stepwise model in leukemogenesis, i.e., AE represents the first, fundamental genetic hit to initiate the disease, whereas activation of the C-KIT pathway may be a second but also crucial hit for the development of a full-blown leukemia. Additionally, Gleevec suppressed the C-KIT activity and induced proliferation inhibition and apoptosis in cells bearing C-KIT N822K mutation or overexpression, but not in cells with D816 mC-KIT . Gleevec also exerted a synergic effect in apoptosis induction with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia.

Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous subtype of non-Hodgkin’s lymphoma. This study aims to better define the prognostic factors and compare the predictive value of the prognostic scores in Chinese patients with PTCL-NOS. One hundred and five patients diagnosed as PTCL-NOS from our institution were retrospectively studied and grouped according to four previously described prognostic scores [International Prognostic Index (IPI), Prognostic Index for PTCL-NOS (PIT), modified PIT (m-PIT), and International PTCL Project (IPTCLP)]. In addition to clinical parameters, peripheral lymphopenia and thrombocytopenia, serum Epstein-Barr virus positivity, and tumor Ki-67 were significantly associated with poor disease outcome. Multivariate analysis revealed that age >60 years, poor performance status, elevated lactic dehydrogenase, and bone marrow involvement were independent adverse variables for survival. All prognostic scores were successful for survival estimation. Risk subgroups in IPI and PIT could be further discriminated by platelet count (IPTCLP factor) and Ki-67 (m-PIT factor), respectively. Together, patient- and tumor-specific characteristics may be incorporated in risk stratification of PTCL-NOS patients. The prognostic scores could be mutually active to improve their predictive value of disease outcome.

Introduction: Outcomes are poor among Chinese adults with r/r ALL. Current recommendations in China for the treatment of adults with Ph- ALL include induction therapy with vincristine or vindesine, anthracyclines/anthraquinones, and corticosteroids; intensive consolidation therapy following complete remission (CR); and hematopoietic stem cell transplantation (HSCT). Currently, there is a lack of studies assessing treatment status and outcomes in Chinese adults with r/r ALL. The objective of this study was to assess the efficacy of currently available treatments for adults with r/r Ph- ALL in China. Methods: Between January 2009 and December 2014, adults with r/r B-precursor ALL and defined Philadelphia chromosome status were identified and enrolled from 14 hematology centers in China. All patients were ≥ 15 years of age at time of de novo (initial) diagnosis of ALL, had no central nervous system involvement at time of relapse, and had no isolated extramedullary relapse. Clinical data were retrospectively collected by chart review. The primary analysis set included only patients with r/r Ph- ALL, defined as meeting 1 of the following criteria: primary refractory, had relapsed within 12 months of first CR, relapsed after first or later salvage, or relapsed within 12 months of HSCT. The primary endpoint was rate of overall response (CR or CR with partial hematologic recovery [CRh]) after last salvage treatment. Key secondary endpoints included rate of CR with incomplete hematologic recovery (CR/CRh/CRi), duration of CR/CRh, rate of allogeneic hematopoietic stem cell transplantation (alloHSCT) realization after CR/CRh, and overall survival (OS). Results: Of 458 eligible patients, 304 (66%) had Ph- ALL, 270 (89%) of whom were in the primary analysis set (female, 46%; median [range] age at diagnosis, 29 (15-73) years). Of these, 45 (17%) had primary refractory disease, 159 (59%) had relapsed within 12 months of first CR, 49 (18%) had relapsed twice or more, and 17 (6%) had relapsed within 12 months post-HSCT. Baseline characteristics at the time of last salvage therapy among patients without prior HSCT included 195 (72%) with no prior salvage, 45 (17%) with 1 prior salvage, and 6 (2%) with ≥ 2 prior salvage treatments. Prior HSCT (n = 24; 9%) included both autologous (n = 8) and allogeneic (n = 16). Among those with prior HSCT, 18 (7%) had prior salvage, 6 (2%) had 1 prior salvage, and none had ≥ 2 prior salvages. Efficacy data at last salvage are presented in the table. Overall, 31% (84/270; 95% confidence interval [CI], 26%-37%) of patients achieved CR/CRh at last salvage. The median time to CR/CRh was 30 days. Median (range) number of therapies to CR/CRh was 1 (1-3). The occurrence of CR/CRh by line of salvage was 104/254 (41%) for 1st line, 13/55 (24%) for 2nd line, and 1/6 (17%) for 3rd line or later. Median (95% CI) duration of CR/CRh at last salvage was 2.7 (2.0-3.8) months with 57% events among 84 patients who achieved CR/CRh. Among CR/CRh responders, 13 of 16 evaluable patients (81%) achieved a minimal residual disease response. Median (95% CI) OS was 4.4 (3.6-5.1) months, with 54 (20%) deaths among 270 patients. At last salvage, 24/84 (29%) responders subsequently received alloHSCT. Conclusions: In this population of Chinese adults with r/r Ph- ALL treated with currently available salvage chemotherapies, CR/CRh responses were low (31%) and prognosis was poor. The median duration of CR/CRh was short (2.7 months), and the alloHSCT realization rate was low among responders. Thus, new therapies are needed to improve treatment outcomes in Chinese adults with primary refractory or relapsed Ph- ALL. Disclosures Meng: Amgen: Employment, Equity Ownership.

Background:The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) has turned chronic myeloid leukemia (CML) from a fatal disease into a controllable chronic condition. Most CML patients, especially those who were in chronic phase (CP), now may require life-long TKIs therapy. Thus, the long-term safety of TKIs is of great importance. Dasatinib is a second-generation TKI that has been approved in China in 2011 as a treatment for imatinib-resistant or -intolerant CML. Previously we have reported safety findings from the Chinese dasatinib registration study after 4 years of follow-up. The results showed that dasatinib was well tolerated, with a low rate of discontinuation and a safety profile that supported previous data from large Phase 3 clinical trials (CA180-034)[1]. Here we present the safety results from the 6-year follow-up of 59 CML-CP patients in this pivotal Chinese study Aims:To evaluate the long-term safety of dasatinib in Chinese CML-CP patients who were resistant to or intolerant of imatinib after 6 years of follow-up. Important endpoints included the incidence and severity of adverse events (AEs) and treatment discontinuation due to drug-related AEs. Methods:This was an open-label, single-arm phase 2 clinical study conducted at 10 centers in China. Adult, Chinese CML patients with imatinib-resistant or -intolerant were recruited. CML-CP patients received oral dasatinib of 100mg/d, until disease progression or intolerable toxicity. Follow-up visits were scheduled at least every 4 weeks until all study-related toxicities returned to baseline or ≤ National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 Grade 1, stabilized or were irreversible. Results:A total of 140 patients were enrolled, 59 of whom had CML-CP. After 6 years of follow-up, 61% (36/59) of patients with CML-CP remained on treatment. Between the 4- and 6-year follow-up, there were no further deaths on the study and no more patients with CML-CP discontinued treatment due to drug-related AEs. Overall, drug-related AEs of any grade were experienced by 74.6% (44/59) of patients with CML-CP, of which 3 patients experienced drug-related AEs after 4-year follow-up (Table). 20.3% (12/59) of patients with CML-CP experienced drug-related, Grade 3-4 AEs and 16.9% (10/59) experienced drug-related serious AEs (Table). 16.9% (10/59) of patients experienced haematological AEs (Grade 3-4, 11.9%, 7/59) and none of the 10 cases happened after 4-year follow-up. The most frequently reported drug-related AEs for CML-CP patients remained pleural effusion (25.4%, 15/59; Grade 3-4, 3.4%, 2/59) and 1.7% (1/59) of the patients discontinued dasatinib treatment due to pleural effusion. Only 1 new case of pleural effusion occurred between 4-year and 6-year follow-up and no more Grade 3-4 pleural effusion has been observed after 4-year follow-up. Pulmonary hypertension were experienced by 8.5% (5/59) patients. Only 1 new case of pulmonary hypertension happened between 4-year and 6-year follow-up and no more Grade 3-4 pulmonary hypertension occurred after 4-year follow-up. Between 4-year and 6-year follow-up, 1 patient (1.7%) experienced Grade 1-2 pulmonary arterial hypertension and this was the only case of pulmonary arterial hypertension observed in the study. Deep vein thrombosis (1.7%, 1/59) occurred to 1 patient in 4-year follow-up and no more cases of deep vein thrombosis occurred between 4-year and 6-year follow-up. Conclusion:The safety profile of dasatinib after 6-year follow-up was consistent with the results from 4-year follow-up, which confirmed the long-term safety of dasatinib in the treatment for Chinese CML-CP patients with imatinib-resistance or -intolerance. Pleural effusion remained the most common adverse event during long-term follow up. As TKI-associated vascular AEs (VAEs) is drawing more and more attention in recent years, we have evaluated their incidence in our study and the results showed that the risk of VAEs remained low with long-term dasatinib treatment. Acknowledgment: BMS funded this research and medical writing support. Reference [1] Huang XJ, Hu JD, Li JY, et al. Four-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukaemia receiving dasatinib: efficacy and safety. Poster (#54229) presented at the 19th European Haematology Association Annual Congress; 12-15 June 2014; Milan, Italy Disclosures No relevant conflicts of interest to declare.