Time-limited,Combined Regimen in Chronic Lymphocytic Leukemia:A Promising Strategy to Achieve a Drug Holiday

Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.

Percutaneous coronary intervention for acute myocardial infarction with mitral regurgitation

Ischemic 僧帽形的流回(国际互联网每月报告) 是尖锐心肌的梗塞(AMI ) 的普通复杂并发症。当前的证据建议有经皮的冠的动脉干预(一种总线标准) 或冠的动脉的犯人容器的 revascularization 绕过 grafting 能为减轻国际互联网每月报告有益。有与国际互联网每月报告复杂的圣片断举起 AMI 的一个 61 岁的男病人的一个 2.5 年的后续数据证明那个僧帽形的流回区域在一种总线标准以后增加了五天，并且减少了降低稳定的水平在一种总线标准以后的三个月。这发现建议在一种总线标准以后的三个月可能是为为 AMI 评估国际互联网每月报告恢复的可能性和僧帽形的阀门的外科的干预的必要性的一个合适的时间点病人。

Clinical Manifestation of Calreticulin Gene Mutations in Essential Thrombocythemia without Janus Kinase 2 and MPL Mutations： A Chinese Cohort Clinical Study

Background： Recently, calreticulin （CALR） gene mutations have been identified in patients with essential thrombocythemia （ET）. A high-frequency of ET cases without Janus kinase 2 （JAK2） mutations contain CALR mutations and exhibit clinical characteristics different from those with mutant JAK2. Thus, we investigated the frequency and clinical features of Chinese patients of Han ethnicity with CALR mutations in ET. Methods： We recruited 310 Chinese patients of Han ethnicity with ET to analyze states of CALR, JAK2 V617F, and MPLW5 15 mutations by polymerase chain reaction and direct sequencing. We analyzed the relationship between the mutations and clinical features. Results： CALR, JAK2V617E and MPLW515 mutations were detected in 30% （n = 92）, 48% （n = 149）, and 1% （n = 4） of patients with ET, respectively. The mutation types of CALR involved deletion and insertion of base pairs. Most of them were Type 1 （52-bp deletion） and Type 2 （5-bp insertion, TTGTC） mutations, leading to de1367fs46 and ins385fs47, respectively. The three mutations were exclusive. Clinically, patients with mutated CALR had a lower hemoglobin level, lower white blood cell （WBC） count, and higher platelet count compared to those with mutated JAK2 （P 〈 0.05）. Furthermore, a significant difference was found in WBCs between wild-type patients （triple negative for JAK2, MPL, and CALR mutations） and patients with JAK2 mutations. Patients with CA LR mutations predominantly clustered into low or intermediate groups according to the International Prognostic Score of thrombosis for ET （P 〈 0.05）. Conclusions： CALR mutations were frequent in Chinese patients with ET, especially in those without JAK2 or MPL mutations. Compared withJAK2 mutant ET, CALR mutant ET showed a different clinical manifestation and an unfavorable prognosis. Thus, C4LR is a potentially valuable diagnostic marker and therapeutic target in ET.

A report on Lineage switch at relapse of CD19 CAR-T therapy for Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia

To the Editor:This study reported that a case of Philadelphia chromosome-positive B-acute lymphoblastic leukemia(Ph+B-ALL)underwent a lineage switch to acute myeloid leukemia(AML)following CD19 chimeric antigen receptor(CAR)-modified T(CAR-T)cells therapy.The study was reviewed and approved by the ethics committee of the first affiliated hospital of Nanjing Medical Universit(No.2020-QT-06).A 46-year-old woman with a 1-month history of chest painwas admitted to our hospital on January 24,2014.The results of her laboratory examinations were as follows:(i)White blood cell count 12.01109/L;hemoglobin 92 g/L;platelet count 47109/L;(ii)Bone marrow(BM)smears showed a massive infiltrate(95.2%)of blast cells;(iii)Immunophenotypic analysis by flow cytometry(FCM)revealed that blast cells accounted for 66.3%,which were positive for CD34,CD10,CD19,CD20,CD22,CD38,and human leukocyte antigen DR;(iv)Karyotype analysis showed no mitotic phase;(v)Fluorescence in situ hybridization demonstrated a positive Philadelphia chromosome(BCR-ABL fusion gene);(vi)BM quantitative real-time polymerase chain reaction(qRT-PCR)detected a positive BCR-ABL p190 transcript(BCR-ABL,184.1%).She was thus diagnosed with Ph+B-ALL.

基于个体化机器学习的原发性免疫性血小板减少症危重出血预测模型:一项全国前瞻性队列研究

原发性免疫性血小板减少症(ITP)中少见但至关重要的危重出血事件,给患者的预后、生活质量和治疗决策带来严重影响。尽管有一些研究探讨了ITP中与危重出血相关的风险因素,但目前尚缺乏大样本数据、大规模多中心研究结果以及针对ITP患者致命出血事件的预测模型。本研究首次采用国际血栓与止血学会新提出的ITP致命出血标准,利用大样本数据开发了首个基于机器学习的在线应用,用于预测ITP患者的致命出血.研究中,我们使用中国各地大型多中心数据进行开发,并对全国39家医疗中心进行为期一年的外部测试,得到了较好的训练、验证和测试数据集预测能力该基于新算法的便捷网络工具能够快速识别ITP患者的出血风险,辅助临床决策,有望未来降低不良事件的发生。

EBV-Mir-BART5-5p targets p53 independent pathway in cytoplasm:Potential role in EBV lymphomagenesis

EBV-positive diffuse large B-cell lymphoma(DLBCL),which has a clonal EBV carrying proliferation of B-cells,defines a new DLBCL subtype and predicts a poor prognosis.Further studies are needed to explore the underlying mechanisms in EBV lymphomagenesis.EBV encoded microRNAs(miRNAs)have been proven to contribute to the pathogenesis and oncogenesis of EBV-associated malignancies.^(1)In this study,research has focused on the pathological roles of miRNAs in EBV-positive DLBCL progression and survival,which might provide ideas for therapeutic decision to improve the prognosis.

Xanthophyll Cycle and Inactivation of Photosystem Ⅱ Reaction Centers Alleviating Reducing Pressure to Photosystem Ⅰ in Morning Glory Leaves under Short-term High Irradiance

Under 30-min high irradiance （1500μmol m^-2 s^-1）, the roles of the xanthophyll cycle and D1 protein turnover were investigated through chlorophyll fluorescence parameters in morning glory （Ipomoea setosa） leaves, which were dipped into water, dithiothreitol （DTT） and lincomycin （LM）, respectively. During the stress, both the xanthophyll cycle and D1 protein turnover could protect PSI from photoinhibition. In DTT leaves, non-photochemical quenching （NPQ） was inhibited greatly and the oxidation level of P700 （P700^＋） was the lowest one. However, the maximal photochemical efficiency of PSII （Fv/Fm） in DTT leaves was higher than that of LM leaves and was lower than that of control leaves. These results suggested that PSI was more sensitive to the loss of the xanthophyll cycle than PSII under high irradiance. In LM leaves, NPQ was partly inhibited, Fv/Fm was the lowest one among three treatments under high irradiance and P700^＋ was at a similar level as that of control leaves. These results implied that inactivation of PSII reaction centers could protect PSI from further photoinhibition. Additionally, the lowest of the number of active reaction centers to one inactive reaction center for a PSII cross-section （RC/CSo）, maximal trapping rate in a PSll cross-section （TRo/CSo）, electron transport in a PSll cross-section （ETo/CSo） and the highest of 1-qP in LM leaves further indicated that severe photoinhibition of PSII in LM leaves was mainly induced by inactivation of PSII reaction centers, which limited electrons transporting to PSh However, relative to the LM leaves the higher level of RC/CSo, TRo/CSo, Fv/Fm and the lower level of 1-qP in DTT leaves indicated that PSI photoinhibition was mainly induced by the electron accumulation at the PSI acceptor side, which induced the decrease of P700^＋ under high irradiance.

Efficacy and safety of decitabine combined with low-dose cytarabine, aclarubicin, and granulocyte colony-stimulating factor compared with standard therapy in acute myeloid leukemia patients with TP53 mutation

Tumor suppressor gene P53(TP53)is a critical tumor suppressor gene.The mutant p53 protein enhances the activity,invasion and metastasis of tumor cells.Acute myeloid leukemia(AML)patients with TP53 mutations respond poorly to conventional chemotherapy and have poor clinical outcomes.We previously conducted a multi-center phase II clinical trial(No.ChiCTRONC-11001700)in elderly AML patients with decitabine,low-dose cytarabine,aclarubicin,and granulocyte colony-stimulating factor(G-CSF)(DCAG regimen),which showed an overall response rate(ORR)of 82.4%and a complete remission(CR)rate of 64.7%.[1]Given this satisfactory effect of DCAG regimen,the present study has been designed to compare the efficacy and safety of DCAG regimen with standard therapy in AML patients with TP53 mutations.

Presence of serum antinuclear antibodies correlating unfavorable overall survival in patients with chronic lymphocytic leukemia

Background: Serum antinuclear antibodies (ANAs) are positive in some patients with chronic lymphocytic leukemia (CLL), prognostic value of ANAs remains unknown. The aim of this study was to evaluate the role of ANAs as a prognostic factor in CLL. Methods: This study retrospectively analyzed clinical data from 216 newly diagnosed CLL subjects with ANAs test from 2007 to 2017. Multivariate Cox regression analyses were used to screen the independent prognostic factors related to time to first treatment (TTFT), progression free survival (PFS) and overall survival (OS). Receiver operator characteristic curves and area under the curve (AUC) were utilized to assess the predictive accuracy of ANAs together with other independent factors for OS. Results: The incidence of ANAs abnormality at diagnosis was 13.9%. ANAs positivity and TP53 disruption were independent prognostic indicators for OS. The AUC of positive ANAs together with TP53 disruption was 0.766 (95% confidence interval [CI]: 0.697-0.826), which was significantly larger than that of either TP53 disruption (AUC:0.706, 95% CI:0.634-0.772, P=0.034) or positive ANAs (AUC:0.595, 95% CI:0.520-0.668,P<0.001) in OS prediction. Besides, serum positive ANAs as one additional parameter to CLL-international prognostic index (IPI) obtained superior AUCs in predicting CLL OS than CLL-IPI alone. Conclusion: This study identified ANAs as an independent prognostic factor for CLL, and further investigations are needed to validate this finding.