Current status of diagnosis and treatment of chronic lymphocytic leukemia in China: A national multicenter survey research / 中华血液学杂志

Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.

Progress in the Treatment of Adult Langerhans Cell Histiocytosis --Review / 中国实验血液学杂志

Langerhans cell histiocytosis (LCH) is a rare proliferative disease dominated by the proliferation of Langerhans cells, which is inflammatory myeloid neoplasms. Its clinical manifestations are variable, occurring at any age and at any site, and it is rarer in adults than in children. The gold standard for diagnosis is histopathological biopsy. Due to the rarity of adult LCH and the heterogeneity of this disease, treatment of adult LCH should be developed according to the extent of the disease and risk stratification. With the discovery of MAPK, PI3K and c-KIT signaling pathway activation, especially BRAF V600E and MAP2K1 mutations, targeted therapy has become a hot spot for therapeutic research. Meanwhile, the discovery of high expression of M2-polarized macrophages and Foxp3+ regulatory T cells (Treg) in LCH has provided an important basis for the immunotherapy. In this article, we will focus on reviewing the latest research progress in the treatment of adult LCH in recent years, and provide a reference for clinical research on the treatment of adult LCH patients.

Clinical Features of Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm / 中国实验血液学杂志

OBJECTIVE@#To analyze the clinical characteristics, pathological features, treatment response and prognosis of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), so as to provide reference for reducing clinical misdiagnosis and treatment regimens.@*METHODS@#The clinical, pathological features, treatment regimens and treatment response of 9 patients with BPDCN diagnosed and treated from January 1, 2013 to June 30,2019 in Xiangya Second Hospital of Central South University were analyzed respectively.@*RESULTS@#The most common site of involvement in 9 patients with BPDCN was skin; the pathological features were involvement of dermis, and the highest positive immunohistochemical indexes rate were CD4, CD43, LCA, CD123, and VIM (all 100%), followed by CD56 and CD68, TDT, CD5, PAX-5, CD3, CD8, CD20; MPO and EBER of 9 patients were negative. However, Ki-67 of the 9 patients showed a medican of 77. 5% (40%-90%), which suggests that CD4, CD43, LCA, CD123, and VIM were the most sensitive antigens for diagnosing BPDCN. Of the 9 patients, 2 cases were lost to follow-up, 2 cases were untreated, and 5 cases were treated, in which 2 cases received treatment of regiment for acute lymphoblastic leukemia and 3 cases received treatment of regimen for lymphoma. The PR of clinical symptoms in the first cycle in 5 patients were 100%, and 1 patient has survived for 6 years since the disease was diagnosed.@*CONCLUSION@#BPDCN is a rare and highly invasive lymphoid hematopoietic malignancy. The most common initial symptom of the patients is skin lesions. The most sensitive pathological indicators are CD4, CD43, LCA, VIM, and the BPDCN patients received treatment of regimens for lymphoid tumor show a better response rate.

Analysis of Clinical Characteristics in 31 Acute Myeloid Leukemia Patients with Chromosome 21 Aberrations / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the clinical characteristics of 31 acute myeloid leukemia (AML) patients with chromosome 21 aberrations.</p><p><b>METHODS</b>Karyotypes of 168 newly diagnosed AML patients in Second Xiangya Hospital from Jan 2014 to July 2016 were reviewed for the presence of chromosome 21 aberrations (accounting for 18.45%). Clinical manifestation, as well as prognostic gene mutations distribution and immune classification were analyzed.</p><p><b>RESULTS</b>Out of 168 AML newly diagnosed patients, 31 cases with chromosome 21 aberrations including t(8;21) accounting for 67.74% (21/31), and trisomy 21 (16.13%,5/31), 2 variants were found as t(1; 21) and t(1; 21; 8); 77 cases had normal karyotype, and 60 cases possessed other chromosomes aberrations. Statistically significant differences did not exist among age, sex and white blood cell count (P>0.05). However, the 21 cases in chromosome aberrations group were predisposed to lower hemoglobin and platelet count(P<0.05). 5 cases of Trisomy 21 were characterized by M5 2 cases, M1 one case, M2 one case M4 one case. And the rate of C-kit/D816V mutation was higher in t(8;21) aberrations group when 7 prognostic genes including FLT3/ITD, C-kit/D816V, NPM1, DNMT3A, TET2 were analyzed, and the immune classification of t(8; 21) aberration group inclined to CD19, CD34but CD33, CD64. And trisomy 21 displayed a trend to CD34and CD7.</p><p><b>CONCLUSION</b>Chromosome 21 is easily involved in acute myeloid leukemia. The patients with involvement of this aberration have characteristic clinic changes.</p>

Gene Analysis of A Chinese Family with Hereditary Hemorrhagic Telangiectasia and its Curative Effect of Thalidomide / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analyze a hereditary hemorrhagic telangiectasia(HHT) family Activin receptor-like kinase 1(ACVRL1), Endoglin (ENG) and Mothers against decapentaplegic homolog 4 (MADH4, SMAD4) gene mutation, meanwhile, to observe the curative effect of thalidomide in treatment of HHT patients.</p><p><b>METHODS</b>The clinical feature of the HHT family was analyzed, the polymerase chain reaction (PCR) combined with Sanger sequencing of ACVRL1, ENG and SMAD4 were used to investigate the proband. The suspicious mutations were further detected in the other 7 family members. Proband was treated with thalidomide (100 mg/day) for 6 months, and the frequency and quantity of bleeding and blood transfusion frequency were assayed to evaluate the curative efficacy.</p><p><b>RESULTS</b>One ACVRL1 mutation (c.1231C>T) was identified in proband(II-1) and the other 4 family members(II-2, III-1, III-2, III-3), which was reported as a pathogenic gene and revealed cosegregation with HHT clinical phenotype. One ENG mutation (c.1096G>C) was previously reported as gene polymorphism, which was identified in some family members(II-1, II-3, III-1, III-2) without cosegregation with clinical phenotype. No gene mutation was found in SMAD4. After thalidomide treatment, the frequency and quantity of bleeding and blood transfusion frequncy in the proband were reduced, hemoglobin concentration and serum iron level were increased.</p><p><b>CONCLUSION</b>There is phenotypic heterogeneity in hereditary hemorrhagic telangiectasia and the features are age-dependent, the pathogenic gene of this pedigree is ACVRL1 mutation (c.1231C>T;p. R 411 W). Thalidomide is effective for the treatment of hemorrhage in hereditary hemorrhagic telangiectasia.</p>

Thalidomide Effects in Patients with Hereditary Hemorrhagic Telangiectasia During Therapeutic Treatment and in Fli-EGFP Transgenic Zebrafish Model / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasia, and arteriovenous malformations. The efficacy of traditional treatments for HHT is very limited. The aim of this study was to investigate the therapeutic role of thalidomide in HHT patients and the effect in FLI-EGFP transgenic zebrafish model.</p><p><b>METHODS</b>HHT was diagnosed according to Shovlin criteria. Five HHT patients were treated with thalidomide (100 mg/d). The Epistaxis Severity Score (ESS), telangiectasia spots, and hepatic computed tomography angiography (CTA) were used to assess the clinical efficacy of thalidomide. The Fli-EGFP zebrafish model was investigated for the effect of thalidomide on angiogenesis. Dynamic real-time polymerase chain reaction assay, ELISA and Western blotting from patient's peripheral blood mononuclear cells and plasma were used to detect the expression of transforming growth factor beta 3 (TGF-β3) messenger RNA (mRNA) and vascular endothelial growth factor (VEGF) protein before and after 6 months of thalidomide treatment.</p><p><b>RESULTS</b>The average ESS before and after thalidomide were 6.966 ± 3.093 and 1.799 ± 0.627, respectively (P = 0.009). The "telangiectatic spot" on the tongue almost vanished; CTA examination of case 2 indicated a smaller proximal hepatic artery and decreased or ceased hepatic artery collateral circulation. The Fli-EGFP zebrafish model manifested discontinuous vessel development and vascular occlusion (7 of 10 fishes), and the TGF-β3 mRNA expression of five patients was lower after thalidomide therapy. The plasma VEGF protein expression was down-regulated in HHT patients.</p><p><b>CONCLUSIONS</b>Thalidomide reverses telangiectasia and controls nosebleeds by down-regulating the expression of TGF-β3 and VEGF in HHT patients. It also leads to vascular remodeling in the zebrafish model.</p>

Screen of phosphopeptide specific for acute leukemia / 中华血液学杂志

<p><b>OBJECTIVE</b>To screen phosphopeptide specific for acute leukemia.</p><p><b>METHODS</b>Mononuclear cells from bone marrow were collected from 16 newly diagnosed acute lymphoblastic leukemia (ALL) and 20 acute myeloid leukemia (AML) patients. Peptides were extracted and purified, analyzed by immunoprecipitation and liquid chromatography coupled with tandem mass spectrometry (LC-MS).</p><p><b>RESULTS</b>(1) Non-receptor tyrosine kinase family members Fyn, Yes, Src widely expressed in acute leukemia; (2) Some phosphopeptides, including non-receptor tyrosine kinase family members Abl/iso1 and Abl, non-receptor Ser/Thr protein kinase family members Bcr, JNK2, JNK2 iso2, Adaptor/scaffold members Cas-L, Cbl, CrkL CENTD1 (Centaurin delta1) ZO2, transcriptor GFR-1 and phosphatase SHIP-2 were detected in Ph positive ALL, but not in other kinds of ALL. (3) Hck, Lyn and Fgr selectively expressed in AML (except AML-M(3)).</p><p><b>CONCLUSION</b>Some phosphopeptides were specific for ALL and AML, and may be useful for diagnosis and therapy of acute leukemia.</p>

Expression characteristics of heat shock protein 70 and pim-1 gene in bone marrow mononuclear cells from leukemia patients and their clinical significance / 中国实验血液学杂志

This study was aimed to investigate the expression characteristics of HSP70 protein/mRNA, pim-1 mRNA in bone marrow mononuclear cells from leukemia patients, and to clarify whether these changes are related to leukemia type, tumor burden of leukemia, therapeutic reaction and prognosis. HSP70 mRNA and pim-1 mRNA in BMMNCs were detected with semi-quantitative RT-PCR in 40 leukemia patients and 10 controls. HSP70 protein in BMMNCs was assayed with Western blot in 34 leukemia patients and 10 controls. Relation of HSP70 and pim-1 expression with leukemia classification, the degree of tumor burden and therapeutic reaction were analyzed. The results showed that the BMMNCs from both leukemia patients and controls expressed HSP70 protein/mRNA. The mean ODR value of HSP70 mRNA in BMMNCs from leukemia patients was significantly higher than that of the controls; the mean ODR value of HSP70 protein/mRNA in acute myeloid leukemia and chronic myeloid leukemia patients both were significantly higher than that of acute lymphocytic leukemia patients; the mean ODR value of HSP70 protein/mRNA in acute leukemia patients with high-degree tumor burden was higher than that of the patients with low-degree tumor burden; the mean ODR value of HSP70 protein/mRNA in the patients after chemotherapy was significantly higher than that of the patients before chemotherapy; the BMMNCs from both leukemia patients and controls expressed pim-1 mRNA. The mean ODR value of pim-1 mRNA in BMMNCs from leukemia patients was significantly higher than that of the controls; the mean ODR value of pim-1 mRNA in BMMNCs for Acute lymphocytic leukemia patients was significantly higher than that of the patients suffered from acute myeloid leukemia and chronic granulocytic leukemia; there was a positive relationship between pim-1 mRNA and HSP70 mRNA expressions in leukemia patients (p < 0.05). It is concluded that there are high expressions of HSP70 and pim-1 in leukemia and their positive correlation is shown. The over-expressions of HSP70 and pim-1 protein/mRNA are related to tumor burden in leukemia patients.

Clinical phenotypes, ALK1 gene mutation and level of related plasma proteins in Chinese hereditary hemorrhagic telangiectasia / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>We determined the diagnosis of hereditary hemorrhagic telangiectasis (HHT) in a suspected HHT family, identified ALK1 gene mutation and established a gene diagnosis method of HHT. The level of related plasma proteins (transforming growth factor beta and thrombomodulin) were also analyzed.</p><p><b>METHODS</b>Bleeding history and family history were collected; Dilatant nasal mucosal capillaries in proband were observed under nasal cavity endoscope; exons 3, 7, 8 of ALK1 gene in proband and her family members were amplified with polymerase chain reaction (PCR), and the PCR products were analyzed. Using enzyme-linked immunosorbent assay (ELISA), plasma TGF-beta1 and TGF-beta2 concentrations were measured. Plasma thrombomodulin (TM) level was detected by Western blotting.</p><p><b>RESULTS</b>Of all family members, four had epstaxis, two had evident telangiectases on skin or mucosa. Gene screening results showed that C to T substitution at position 1231 in exon 8 of ALK1 gene (CGG-->TGG) existed in proband, her affected brother and their father. The mutation did not exist in proband's sister-in-law and nephew. Plasma TGF-beta1 concentrations in the affected HHT was 20,538, 17,194, 13,131 pg/ml, while that of normal control and unaffected family members was 15,950, 20,297, 12,836 pg/ml, respectively. Plasma TGF-beta2 in HHT patients was 14,502, 9550, 10,592 and that of normal controls 8579, 20,297, 7680 pg/ml respectively. Level of plasma TM was in HHT subjects significantly lower than in normal subjects.</p><p><b>CONCLUSIONS</b>Chinese HHT individuals have mutant ALK1 gene, a C1231T variation on exon 8 of ALK1 is responsible for HHT clinical phenotypes in this family. ALK1 gene analysis, together with special clinical phenotypes and family history, provides a reliable method in diagnosing HHT. In affected HHT subjects, plasma TGFbeta levels were not obviously different from those of normal subject; while plasma TM concentration was significantly lower than that in normal subjects. The significance and mechanism remain to be elucidated.</p>