Pharmacokinetic study of anti-human T-cell porcine immunoglobulin combined with cyclosporine A immunosuppressive therapy in patients with severe aplastic anemia / 中华血液学杂志

Objective: To study the metabolic characteristics of anti-human T-cell porcine immunoglobulin (p-ATG) in patients with severe aplastic anemia (SAA) . Methods: For patients with SAA treated with p-ATG combined cyclosporine A (CsA) immunosuppressants between February 2017 and December 2017, the p-ATG dose was 20 mg·kg(-1)·d(-1) over 12 h of intravenous administration for 5 consecutive days. The blood concentration of p-ATG was detected by the three-antibody sandwich ELISA method, the pharmacokinetic analysis software was fitted, and the second-chamber model method was used to calculate the pharmacokinetic parameters and plot the pharmacokinetic curve. Adverse events were recorded and the hematologic reactions were determined at 6 months after treatment. Results: Sixteen patients with SAA treated with p-ATG were enrolled, including 8 females and 8 males, with a median age of 22 years (range, 12 to 49 years) and a median weight of 62.5 kg (range, 37.5 to 82.0 kg) . The pharmacokinetics of p-ATG could be evaluated in 14 cases. p-ATG is distributed in vivo as a two-chamber model, with an average drug concentration peak (T(max)) of (5.786±2.486) days, a peak concentration (C(max)) of (616±452) mg/L, and a half-life of (10.479±8.242) days. The area under the drug time curve (AUC) was (5.807±3.236) mg/L·d. Six months after treatment, 8 of 14 patients received a hematologic response; the AUC (0-t) of the effective group and ineffective groups was (7.50±3.26) mg/L·d vs (4.50±2.18) mg/L·d, and the C(max) was (627±476) mg/L vs (584±382) mg/L, respectively. Conclusion: The plasma concentration of p-ATG reached a peak after 5 days of continuous infusion, and then decreased slowly, with a half-life of 10.479 days, and the residual drug concentration was detected in the body 60 days after administration. A relationship between drug metabolism and efficacy and adverse reactions could not be determined.

Reassessing the six months prognosis of patients with severe or very severe aplastic anemia without hematological responses at three months after immunosuppressive therapy / 中华血液学杂志

Objective: To reassess the predictors for response at 6 months in patients with severe or very severe aplastic anemia (SAA/VSAA) who failed to respond to immunosuppressive therapy (IST) at 3 months. Methods: We retrospectively analyzed the clinical data of 173 patients with SAA/VSAA from 2017 to 2018 who received IST and were classified as nonresponders at 3 months. Univariate and multivariate logistic regression analysis were used to evaluate factors that could predict the response at 6 months. Results: Univariate analysis showed that the 3-month hemoglobin (HGB) level (P=0.017) , platelet (PLT) level (P=0.005) , absolute reticulocyte count (ARC) (P<0.001) , trough cyclosporine concentration (CsA-C0) (P=0.042) , soluble transferrin receptor (sTfR) level (P=0.003) , improved value of reticulocyte count (ARC(△)) (P<0.001) , and improved value of soluble transferrin receptor (sTfR(△)) level (P<0.001) were related to the 6-month response. The results of the multivariate analysis showed that the PLT level (P=0.020) and ARC(△) (P<0.001) were independent prognostic factors for response at 6 months. If the ARC(△) was less than 6.9×10(9)/L, the 6-month hematological response rate was low, regardless of the patient's PLT count. Survival analysis showed that both the 3-year overall survival (OS) [ (80.1±3.9) % vs (97.6±2.6) %, P=0.002] and 3-year event-free survival (EFS) [ (31.4±4.5) % vs (86.5±5.3) %, P<0.001] of the nonresponders at 6 months were significantly lower than those of the response group. Conclusion: Residual hematopoietic indicators at 3 months after IST are prognostic parameters. The improved value of the reticulocyte count could reflect whether the bone marrow hematopoiesis is recovering and the degree of recovery. A second treatment could be performed sooner for patients with a very low ARC(△).

The current diagnosis and therapy status of aplastic anemia / 中国医师杂志

Aplastic anemia(AA) is characterized by severe pancytopenia. The clinical features of bone marrow failure syndrome are closely related to viral infection, environment toxin, genetic and acquired gene mutation. Aplastic anemia is a historic disease that often occurred in young people, which was fatal to patients. However, here are many methods can treat and cure this fatal disease. Pathological and physiological studies have important guiding significance for the treatment of aplastic anemia. The diagnosis and treatment of current situation and prospect of aplastic anemia are reviewed in this article.

Analysis of five cases of hepatitis associated aplastic anemia presenting with hemophagocytic lymphohistiocytosis at onset / 中华儿科杂志

Objective@#To discuss the clinical characteristics and management approaches to hepatitis associated aplastic anemia (HAAA) presenting as hemophagocytic lymphohistiocytosis (HLH) at onset.@*Methods@#The clinical data and laboratory results of hospitalized 5 HAAA patients presenting as HLH at onset in Beijing Children′s Hospital from January 2017 to May 2019 were analyzed retrospectively.@*Results@#Among 5 cases, there were 4 males and 1 female. The age of onset was 6.0 (2.7-12.7) years. All patients presented with high fever, hepatomegaly, hepatic dysfunction (aspartate aminotransferase 1 716 (1 409-2 570) U/L, alanine aminotransferase 1 699 (937-2 540) U/L) at onset. After admission, the laboratory results showed pancytopenia (white blood cell 1.2 (0.6-6.7) ×109/L, haemoglobin 94 (65-111) g/L, blood platelet 29 (10-41) ×109/L), decreased fibrinogen (1.3 (1.1-2.5) g/L), significantly elevated triglyceride (4.0 (2.8-5.1) mmol/L), ferritin (1 766 (399-5 253) μg/L) and soluble CD25 (27 457 (9 625-44 000) ng/L). Hemophagocytosis was found in the bone marrow smears of all 5 patients. The diagnosis of acute hepatitis and HLH was confirmed. During the treatment of HLH, the blood cells remain below normal level and the further biopsy of bone marrow (iliac bone) indicated low myeloproliferation. After exclusion of congenital bone marrow failure syndromes and other pancytopenic diseases, HAAA was confirmed. After the diagnosis of HAAA, 1 patient received antithymocyte globulin (ATG) and cyclosporin treatment in our hospital, 1 patient received allogeneic stem cell transplantation (HSCT) in other hospital, 2 patients received ATG in other hospitals. Only 1 patient died of severe infection.@*Conclusions@#HAAA can present as HLH at onset. It is mainly manifested by high fever, acute severe hepatitis, pancytopenia, elevated ferritin and hemophagocytosis in the bone marrow. The diagnosis of HAAA should be considered whenever cytopenia could not completely corrected while apparent improvement of HLH and hepatitis related complications were improved after immunosuppressive therapy. ATG or HSCT treatment should be performed as soon as the diagnosis of severe or transfusion dependent aplastic anemia is confirmed.

Abnormal expression of b10 cell frequencies: possible relation to pathogenesis and disease severity of aplastic anemia

SUMMARY OBJECTIVE: Aplastic anemia (AA) is an immune-mediated disease that destroys hematopoietic cells through activated T lymphocytes. B lymphocyte-mediated humoral immunity also plays an important role in the pathogenesis of AA. Regulatory B cell (Breg) subpopulation, which is defined as "B10", secretes interleukin 10 (IL-10). The objective of our experiment was to investigate whether the scale-down proportion of B10 cells in AA patients may play a key role in the pathogenesis. METHODS: A total of 38 AA patients (14 SAA patients and 24 NSAA patients) and 20 healthy control subjects were included. All subjects did not suffer from autoimmune diseases or any other diseases affecting the immune system, such as infectious diseases. Bone marrow mononuclear cells (PBMCs) were isolated and analyzed by Flow cytometry (FCM) and Immunofluorescence double-labeling assay. The relationship between the relative proportions of B10 and ProB10 and their associations to AA, as well as disease severity, were assessed by common clinical indicators and then examined. RESULTS: Our analyses revealed AA patients had significantly lower proportions of peripheral B10 and B10pro compared to healthy controls. SAA patients had a substantially lower percentage of B10 cells and B10pro cells compared to NSAA patients. In addition, B10 cells and B10pro cells were negatively correlated with absolute neutrophil counts, hemoglobin levels and platelet, and absolute reticulocyte counts in AA patients. CONCLUSIONS: The present study attempted to elucidate the potential role of the scale-down proportion of B10 cells in the pathogenesis of AA.

RESUMO OBJETIVO: A anemia aplástica (AA) é uma doença imunomediada que destrói células hematopoiéticas por meio dos linfócitos T ativados. A imunidade humoral mediada por linfócitos B também desempenha um papel importante na patogênese da AA. A subpopulação de células B reguladoras (Breg), que é definida como "B10", secreta interleucina 10 (IL-10). No experimento, investigou-se se a proporção reduzida de células B10 nos pacientes de AA pode desempenhar um papel-chave na patogênese. MÉTODOS: Um total de 38 pacientes de AA (14 pacientes de anemia aplástica grave e 24 pacientes de anemia aplástica não grave) e 20 indivíduos de controle saudáveis foram incluídos. Todos os indivíduos não sofriam de doenças autoimunes ou de quaisquer outras doenças que afetam o sistema imunológico, tais como doenças contagiosas. As células mononucleares da medula óssea (PBMCs) eram isoladas e analisadas por citometria de fluxo (FCM) e ensaio de dupla marcação por imunofluorescência. A relação entre as proporções relativas de células B10 e as células ProB10 e as suas associações à AA, assim como a gravidade da doença avaliada por indicadores clínicos comuns, foram examinadas. RESULTADOS: Nossas análises revelaram que os pacientes de AA têm proporções significativamente menores de células B10 e células ProB10 periféricas em comparação com indivíduos de controle saudáveis. Os pacientes de anemia aplástica grave tiveram uma percentagem substancialmente menor de células B10 e células B10pro em comparação com pacientes de anemia aplástica não grave. Além disso, as células B10 e B10pro foram negativamente correlacionadas com contagens absolutas de neutrófilos, níveis de hemoglobina e plaquetas e contagem de reticulócitos absolutos nos pacientes de AA. CONCLUSÕES: Além disso, o estudo presente tentou elucidar o papel imunorregulatório potencial das células B10 na patogênese da AA e fornecer uma nova estratégia para a aplicação de imunoterapia baseada na célula B para tratar a AA no futuro.

Clinical characteristics of myeloid sarcoma:analyses of 12 cases / 白血病·淋巴瘤

Objective To investigate the clinical characteristics, curative effect and prognosis of myeloid sarcoma. Methods The clinical data of 12 patients with MS diagnosed at Xijing Hospital of Air Force Medical University from August 2008 to May 2018 were retrospectively analyzed. Their clinical manifestations, diagnosis, treatment and survival were analyzed. Results Twelve patients were 17 to 62 years old. The initial site included lymph node, external auditory canal, eye, buttock, lung, liver, pancreas, breast,skin, vertebra and its surroundings,and cervix. Among 11 patients with peripheral blood classification, bone marrow aspiration and bone marrow biopsy, 6 cases were isolated MS [one of which developed acute myeloid leukemia (AML)], 1 case was chronic myeloid leukemia in chronic phase, 2 cases were AML-M2, and 1 case was myelodysplastic syndrome (MDS), and 1 case was after aplastic anemia (AA) with no infiltration of bone marrow. Immunohistochemical results showed that LCA(+) (7/7), MPO(+) (12/12), CD43(+) (9/9), lysozyme(+) (5/7), CD3(-) (8/8), CD20(-) (9/9), CD34(+) (5/6), CD117(+) (7/7), and Ki-67(+) 30%-90%. Four patients were examined for bone marrow chromosomes, 2 patients with AML had t (8;21), 1 patient with MDS was 47, XX, +8, del(11)(q21), and 1 patient with CML was t(9;22). Two of the 12 patients were lost to follow-up. Among the 10 patients who were followed up, 6 died and 4 survived, and the median survival time was 21 months (2-27 months). Conclusions AA in stable phase with MS and CML in chronic phase with MS are rarely reported. The clinical manifestations of MS patients are varied, of which the common incidence sites are superficial lymph nodes, the infrequent sites are vertebra and its surrounding areas, and the rare sites are eye, pancreas, lung, liver, etc. The median survival time of MS patient is short and the curative effect is poor.

Maternal and fetal outcomes and related risk factors of 85 cases with aplastic anemia in pregnancy: a retrospective case control study / 中华围产医学杂志

Objective@#To analyze the maternal and fetal outcomes of pregnancies complicated by aplastic anemia (AA) and to investigate the underlying risk factors.@*Methods@#In this retrospective case control study, we retrieved medical records of 85 singleton gravidas with AA (AA group) who were admitted to Peking University People's Hospital from January 2003 to January 2016, and another 340 singleton gravidas (case∶control=1∶4) without blood system or immune system diseases who gave birth at the same period were selected as the control group. Differences in general condition and the incidence of maternal and neonatal complications were compared between the two groups. AA group were further divided into adverse outcome subgroup (n=33) and non-adverse outcome subgroup (n=52), and relevant factors were also analyzed. Statistical analysis was performed using t-test, Chi-square test and logistic regression.@*Results@#No maternal deaths occurred in all 85 cases of AA group, 81 of them gave live birth [one neonate died and the others survived with a mean gestational age of 36+5 weeks (30+2-40+5 weeks)], and 45 developed maternal or fetal adverse outcomes. Compared with the control group, AA group had higher incidences of hypertensive disorders of pregnancy [20.0% (17/85) vs 6.2% (21/340)], acute heart failure [7.1% (6/85) vs 0.0% (0/340)], postpartum hemorrhage [5.9% (5/85) vs 0.9% (3/340)], puerperal infection [2.4% (2/85) vs 0.0% (0/340)], preterm birth [22.3% (19/85) vs 5.6% (19/340)], small for gestational age [11.7% (10/85) vs 0.9% (3/340)], fetal growth restriction [8.2% (7/85) vs 1.2% (4/340)], intrauterine fetal death [4.7% (4/85) vs 0.0% (0/340)] and neonatal death [1.2% (1/85) vs 0.0% (0/340)] (all P<0.05). After adjusting for age, pregnancy history and the time of diagnosis, we found that low median (OR=0.88, 95%CI: 0.83-0.95), mean (OR=0.85, 95%CI: 0.79-0.93) and minimal (OR=0.87, 95%CI: 0.82-0.93) values of hemoglobin concentration during pregnancy, and low median (OR=0.96, 95%CI: 0.92-1.00), mean (OR=0.96, 95%CI: 0.92-1.00) and minimal (OR=0.95, 95%CI: 0.90-0.99) values of platelet counts during pregnancy were risk factors for adverse maternal and fetal outcomes of gravidas with AA (all P<0.05).@*Conclusions@#Maternal and fetal complications are more common in pregnant women with AA and maintain hemoglobin and platelet counts at a certain level may improve the outcomes.

Caracterização epidemiológica de pacientes submetidos ao transplante de células-tronco hematopoéticas em um centro de referência de Curitiba, Paraná, Brasil, 2011-2015 / Epidemiological characterization of patients submitted to hematopoietic stem cell transplantation at a reference center in Curitiba, Paraná, Brazil, 2011-2015

INTRODUÇÃO: O transplante de células-tronco hematopoéticas (TCTH) é a única alternativa para o tratamento de algumas doenças. Entretanto, identifica-se escassez de estudos na população brasileira. OBJETIVO: Caracterizar o perfil dos pacientes submetidos ao TCTH no Hospital de Clínicas da Universidade Federal do Paraná (HC/UFPR), entre 2011 e 2015, com base em variáveis demográficas, diagnóstico, duração da internação, e a taxa de mortalidade na instituição. MÉTODOS: Pesquisa de séries temporais baseada em dados do Sistema de Informações Hospitalares. Avaliou-se a tendência na distribuição das proporções ao longo dos anos por meio do teste de Cochran­Armitage e da regressão binomial negativa. A presença de Autocorrelação seriada foi testada pelo teste de Durbin-Watson. RESULTADOS: De 2011-2015 o Paraná foi responsável por 9,2% dos TCTH realizados no Brasil. O HC/UFPR foi responsável por 46,0% destes procedimentos realizados no Paraná. Não foram observadas variações significativas na distribuição das variáveis sexo (p=0,788) e número de TCTH (p=0,213). 59,5% dos pacientes residiam no PR, 49,4% tinham entre 0 e 17 anos, 79,9% eram brancos, e 63,5% do sexo masculino. O TCTH alogênico foi o mais realizado (88,5%). 58,5% permaneceram internados de 31 a 60 dias (média=37,6 dias). 9,1% foram a óbito. A anemia aplástica adquirida foi a doença base mais frequente (31,9%). CONCLUSÃO: O TCTH é um procedimento de alto custo e complexidade. O estudo e a compreensão dos fatores determinantes para o seu sucesso são de extrema importância para o melhor planejamento, estimativa de risco e elaboração de políticas públicas de saúde.

INTRODUCTION: Hematopoietic stem cell transplantation (HSCT) is the only alternative for the treatment of some diseases. However, there is a shortage of studies in Brazilian population. OBJECTIVE: To identify the profile of patients submitted to HSCT at the Hospital de Clínicas da Universidade Federal do Paraná (HC/UFPR), between 2011 and 2015, based on demographic variables, diagnosis, duration of hospitalization and the mortality ration in the institution. METHODS: Time Series Studies research based on data from the Hospital Information System. The trend in the distribution of proportions over the years was evaluated through Cochran­Armitage test and negative binomial regression. The presence of serial autocorrelation was tested by the Durbin­Watson test. RESULTS: From 2011-2015 Paraná was responsible for 9.2% of HSCT performed in Brazil. HC/UFPR accounted for 46.0% of these procedures performed in Paraná. There were no significant variations in the sex distribution (p=0.788) and number of HSCT (p=0.213). 59.5% of the patients were from PR, 49.4% were between 0 and 17 years old, 79.9% were white, and 63.5% were male. The allogeneic HSCT was the most performed procedure (88.5%). 58.5% were hospitalized from 31 to 60 days (mean=37.6 days). 9.1% died. Acquired aplastic anemia was the most common underlying disease (31.9%). CONCLUSION: HSCT is a procedure of high cost and complexity. The study and the understanding of the determinants of its success are of extreme importance for the best planning, risk estimation and elaboration of public health policies.

Haploidentical hematopoietic stem cell transplantation in the treatment of acquired aplastic anemia in children: a single center retrospective analysis / 中华儿科杂志

Objective@#To investigate the safety and efficacy of haploidentical hematopoietic stem cell transplantation with different intensity conditioning regimen in the treatment of childhood aplastic anemia (AA) .@*Methods@#Thirty-seven AA patients who underwent haploidentical transplantation in BaYi Children's Hospital Affiliated to PLA Army General Hospital from January 2013 to January 2017 were enrolled. According to the dosage of conditioning regimen, 34 patients excluding 3 other conditioning regimens were divided into high-dosage group (regimen 2, 22 cases) and low-dosage group (regimen 3, 12 cases). The data of Engraftment, graft-vs-host disease (GVHD), hematopoietic reconstitution, relapse, infection, overall survival (OS) were analyzed. The comparison between the two groups was tested by χ2 test.@*Results@#A total of 35 of 37 patients achieved primary engraftment; 2 cases died of regimen-related toxicity and severe infection before the infusing of the grafts. The activation rate of CMV and EBV was 60% (21/35) . Post-transplant lymphocyte disease (PTLD) of lung occurred in one case. The cumulative incidences of acute GVHD grade Ⅰ-Ⅳ and chronic GVHD were 29% (10/35) and 34% (12/35) respectively and the incidence of extensive chronic GVHD was 6% (2/35) . The median follow-up time was 18.8 (2.9-44.1) months, the OS was 92% (34/37) .All survived patients were no longer dependent on blood transfusion and none of them had recurrence. Comparing the rates of overall survival(86%(19/22) vs.100%(12/12)) and rates of chronic GVHD(40%(8/20) vs. 17%(2/12)) in regimen 2 and regimen 3 group, there were no significant difference (χ2=1.742, 1.841, all P>0.05) . Significant difference was found at the incidence of Ⅰ-Ⅳ acute GVHD (10% (2/20) vs. 50% (6/12) ,χ2=6.200, P=0.013).@*Conclusions@#Haploidentical hematopoietic stem cell transplantation is effective and safe. It is suitable for patients who are not eligible for matched donor transplantation. Application of reduced dose preconditioning in haploid transplantation is worth exploring.

Impact on platelet recovery of recombinant human thrombopoietin in severe aplastic anemia patients with allogeneic hematopoietic stem cell transplantation / 中华血液学杂志

Objective@#To investigate and analyze the impact on PLT recovery of recombinant human thrombopoietin (rhTPO) in severe aplastic anemia (SAA) patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT).@*Methods@#A retrospective analysis of Hematology Division of General Hospital of Jinan Military Command was conducted in the 85 SAA cases who treated with allo-HSCT from January 2010 to March 2017. According to the administration of medicines for platelets, 85 patients were divided into rhTPO group (n=29), rhIL-11 group (n=27) and blank group (n=29), respectively. The median time of PLT ≥20×109/L, PLT ≥50×109/L, and PLT ≥100×109/L, the numbers of megakaryocytes in marrow smear (25±5) days after transplantation and the quantities of platelet transfusion were analyzed retrospectively. The adverse events of rhTPO and rhIL-11 groups were observed.@*Results@#There were no significant differences in the recovery of granulocytes and PLT ≥20×109/L among the three groups (P>0.05). The time of PLT ≥50×109/L in rhTPO group was shorter than that in blank group [16.5 (11-39) d vs 22 (14-66) d, P<0.05], as well as the time of PLT ≥100×109/L [rhTPO: 23 (12-51) d; rhIL-11: 28 (12-80) d; blank group: 35 (18-86) d, P<0.05]. Platelet transfusions were also less in rhTPO group than in rhIL-11 and blank groups [20 (10-30) U, 30 (10-50) U, 35 (10-70) U, P<0.05]. The counts of megakaryocyte in rhTPO group, rhIL-11 group and blank group were 31.5 (0-200), 12 (0-142) and 11(0-187) (P<0.05), respectively. The difference between rhTPO group and rhIL-11 group was statistically significant (P<0.05), but no difference between rhIL-11 group and blank group (P>0.05). Multivariate analysis showed that rhTPO was an independent factor for platelet recovery [HR=4.01 (95%CI 1.81-9.97), P=0.010]. The rhTPO group had no obvious adverse events.@*Conclusion@#rhTPO can promote platelet recovery of SAA patients after allo-HSCT, reduce platelet transfusion with safety.

Rapamycin affect the apoptosis of splenic CD4+CD25+ regulatory T cells of mouse severe aplastic anemia model / 中华血液学杂志

Objective@#To explore the effects and possible mechanism of rapamycin (RAPA) on apoptosis of CD4+CD25+ Tregs from the mouse severe aplastic anemia (SAA) model.@*Methods@#The BALB/c female SAA model mice were induced by interferon-gamma in combination with busulphan. The SAA model mice were intraperitoneal injection with RAPA at daily dose of 0.5 mg/kg for 5 days (the RAPA-treated group, n=15) in the SAA group (n=15) and the un-treated group (n=15) were control. Bone marrow hematopoiesis changes were observed by the patho-morphological examination of femurs. The mononuclear cells of the peripheral blood and spleen were subjected to assess the intracellular Foxp3 expression in CD4+CD25+ Tregs by flow cytometry (FCM). In addition, after being pured by immunomagnetic beads, the splenic CD4+CD25+ Tregs was subjected to assess apoptosis by FCM and the Akt and Stat3 phosphorylation by using of western blot.@*Results@#The patho-morphological examination of femurs showed normal marrow cell proliferation in un-treated group and hypocellularity in both SAA group and RAPA-treat group, with an increase in the number of fat cells. The bone marrow hematopoietic tissue ratio in RAPA-treat group was higher than SAA group [(9.75±1.83)% vs (7.00±2.00)%, Δx=2.15% (95%CI 0.15%-5.35%), P=0.037]. In the SAA group, FCM analysis showed down-expression of Foxp3 in CD4+CD25+ Tregs compared with the un-treated group. However, after treatment with RAPA, the expression of Foxp3 in CD4+CD25+ Tregs was increased (P<0.017). Compared with the un-treated group, increased CD4+CD25+ Tregs apoptosis [(19.84±1.39)% vs (29.85±2.72)%] with increased Akt phosphorylation accompanied by increased Stat3 phosphorylation was found in SAA group (P<0.05, respectively). On the contrary, RAPA-treated group exhibited CD4+ CD25+ Tregs with a reduction in apoptosis rate [(22.39±3.71)%], Akt phosphorylation and Stat3 phosphorylation compared with the SAA group (P<0.05, respectively).@*Conclusion@#These results indicate that RAPA may increase the expression of Foxp3 by down-regulation the levels of Akt and Stat3 phosphorylation and reduce apoptosis in splenic CD4+CD25+ Tregs from the mice model of SAA.

Comparison of different styles of allogeneic hematopoietic stem cell transplantation as first-line treatment treated with severe aplastic anemia in children and adolescents / 中华血液学杂志

Objective@#To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from different donors as first-line treatment for children and adolescents with severe aplastic anemia (SAA) .@*Methods@#The clinical data of 79 children and adolescents with SAA diagnosed from January 2013 to December 2016 in Henan Province were retrospectively analyzed. There were 50 males and 29 females, with a median age of 14(4-18) years. 40 cases received matched sibling transplantation (MSD-HSCT), 17 with unrelated donor transplantation (UD-HSCT), and 22 with haploidentical transplantation (haplo-HSCT).@*Results@#The comparison of MSD-HSCT, UD-HSCT, haplo-HSCT groups was conducted and the median times of neutrophils engraftment were statistically significant [12(9-25) d, 14(10-22) d, 16(11-26) d, respectively (χ2=13.302, P=0.001)], but no difference in+30 d engraftment rate [97.3%(36/37), 100%(15/15), 100%(20/20), χ2=0.959, P=0.619]. The median times of PLT engraftment were not statistically significant [14(6-34)d, 16(7-32)d, 19(10-34)d, respectively, χ2=5.892, P=0.053], and the +30 d engraftment rate had no difference [97.3%(36/37), 100%(15/15), 100%(20/20), χ2=0.959, P=0.619]. The post-transplant infection rate showed no statistically significance [35.0% (14/40), 29.4% (5/17), 45.5% (10/22), χ2=1.158, P=0.560], as well as the incidences of aGVHD, grade III/IV aGVHD and cGVHD(χ2=0.230, P=0.891; χ2=2.628, P=0.269; χ2=3.187, P=0.203). The two-years OS rate was not statistically significant respectively [(77.1±6.7)%, (70.6±11.1)%, (77.3±8.9)%, χ2=0.330, P=0.845]. Severe post-transplant infection (RR=4.617, P=0.009), grade Ⅲ/Ⅳ aGVHD (RR=2.707, P=0.048) were independent risk factors for OS.@*Conclusion@#The overall efficacy of MSD-HSCT, UD-HSCT and haplo-HSCT as first-line therapy for children and adolescents with SAA/VSAA is comparable.

Outcome of combination of HLA-haploidentical hematopoietic SCT with an unrelated cord blood unit for 127 patients with acquired severe aplastic anemia / 中华血液学杂志

Objective@#To evaluate the outcome of combination of haploidentical donor (HID) hematopoietic stem cell transplantation (HSCT) with an unrelated cord blood unit for severe aplastic anemia (SAA).@*Methods@#The clinical data of 127 SAA patients [including 74 male and 53 female patients, 65 very severe aplastic anemia (vSAA), the median age as 23.5(3-54) years] received HID-HSCT from September 2011 to April 2017 were analyzed retrospectively. The median interval from SAA diagnosis to transplantation was 2 (0.5-180) months. The conditioning was modified Bu/Cy+ATG/ALG-based (Busulfan + cyclophosphamide + antithymocyte immunoglobulin/antilymphocyte immunoglobulin) regimen. Cord blood units were selected based on the results of HLA typing and cell doses evaluated before freezing. Units with at least 4/6 matched HLA loci became the candidates. Prophylaxis for graft-versus host disease (GVHD) was by cyclosporine (CsA), mycophenolate mofetil (MMF) plus short-term methotrexate (MTX).@*Results@#The median values of absolute nucleated cell counts were 10.87 (3.61-24.00)×108/kg in the haploidentical grafts and 2.22 (1.10-7.30)×107/kg in the cord blood units, respectively. The median doses of CD34+ cells infused were 3.49(1.02-8.89) ×106/kg in the haploidentical grafts and 0.56 (0.16-2.27) ×105/kg in the cord blood units, respectively. Of the 127 patients, 5 patients occurred early death, one patient occurred primary graft failure. All 121 surviving patients attained complete haploidentical engraftment. The median durations of myeloid engraftment were 11 (9-28) days and 15 (9-330) days for platelets, with a cumulative platelet engraftment incidence of 96.1%. The incidence of infection was 58.27% (74/127). During a median follow-up of 20.5 (4-60) months, the incidence of grade Ⅱ-Ⅳ acute GVHD was 24.79% (30/121), moderate-severe chronic GVHD was 14.15% (15/106), 4-year estimated overall survival was (78.5±4.3) %, 4-year estimated failure-free survival was (77.4±4.3) %, respectively.@*Conclusion@#Combination of HID-HSCT and an unrelated umbilical cord blood unit was a feasible choice with favorable outcome for SAA patients without matched donors.

The life span of red blood cell in patients with severe/very severe aplastic anemia / 中华血液学杂志

Objective@#To explore the life span of red blood cells (RBC) in patients with severe/very severe aplastic anemia (SAA/VSAA).@*Methods@#Clinical data of 128 SAA/VSAA patients from November 2016 to April 2017 were retrospectively analyzed, and 13 healthy volunteers in the same period was used as normal control. The endogenous Breath Carbon Monoxide (CO) test was used to detect the life span of RBC in SAA/VSAA patients, and the effect of immunosuppressive therapy (IST) on the life span of RBC in these patients was explored.@*Results@#The mean life span of RBC in 51 untreated SAA/VSAA patients was (50.69±21.43) d, which was significantly shorter than that in normal controls[(111.85±31.55) d](t=-6.611, P<0.001). The mean life span of RBC in 77 patients treated with IST was (87.14±39.28) d. The mean life span of RBC in complete responses (CR), hematologic response (HR) and non-response (NR) patients were (106.15±32.12) d, (92.00±38.60) d and (50.44±21.56) d, respectively. The life span of RBC in patients with HR was significantly longer than that in newly diagnosed and NR patients (t=7.430, P<0.001; t=4.846, P=0.002), which was similar to that in the normal controls (t=-1.743,P=0.085). There was no statistical significance between CR patients and the normal controls in the mean life span of RBC (t=-0.558, P=0.579). No factor affecting the RBC life span was found in univariate logistical regression analyses in the newly diagnosed SAA/VSAA patients. The serum levels of IL-2R and IL-6 were much lower in HR patients than NR patients[IL-2R: 4.3×105 U/L vs 6.5×105 U/L, z=-2.733, P=0.006; IL-6: 2.6 (2.0-17.7) ng/L vs 6.1 (2.0-14.4) ng/L, z=-2.968, P=0.003]. Of the 51 newly diagnosed patients, 38 received IST and their 3-month curative effect was evaluated. Receiver operator characteristics (ROC) curve was used to analyze the predictive effect of RBC life span of untreated patients on the efficacy of IST before treatment. The cut-off point was 60 days with sensitivity of 37.5% and specificity of 86.4%. In 9 cases with life span of RBC>60 d before IST, 6 cases acquired HR, while in 29 cases with life span of RBC ≤ 60 d before IST, 10 cases acquired HR, the difference was not statistically significant (P=0.128).@*Conclusion@#The life span of RBC in SAA/VSAA patients was shortened, which can be improved even recovered to the normal after IST. Elevated cytokines might play a role in the pathophysiology of the shortened RBC life span in SAA/VSAA.

Posaconazole as primary prevention of fungal infection in intensive immunosuppressive therapy for severe aplastic anemia / 中华血液学杂志

Objective@#To Evaluate the efficacy and safety of posaconazole as primary prevention of invasive fungal disease (IFD) in patients with severe aplastic anemia (SAA) treated with anti-thymus/lymphocyte immunoglobulin (ATG/ALG) combined with cyclosporine intensive immunosuppressive therapy (IST).@*Methods@#A retrospective analysis of clinical data of 58 SAA patients who received IST of anti-thymocyte immunoglobulin combining cyclosporine and antifungal prophylaxis during April 2013 to May 2017 in Peking Union Medical College Hospital was performed. The patients were divided into posaconazole prophylaxis group and the control group (itraconazole or fluconazole). The disease characteristics, IFD prevention effect and adverse drug reaction, curative effect and prognosis of the two groups were compared.@*Results@#Posaconazole was used to prevent fungal infection in 20 patients. The other 38 patients were used as the control group. Retrospective analysis showed comparable characteristics (gender, age, disease severity, etiology, interval between the onset of disease to treatment, ATG/ALG type) of both groups. The incidence of IFD were 0 and 15.8% in posaconazole prophylaxis group and the control group, respectively (P=0.084). In the control group, there were 6 cases diagnosed as IFD. Of them, 2 were confirmed, 2 suspected and 2 not identified. Five of the 6 cases were pulmonary infection, 1 bloodstream infections. Of the 6 IFD cases, 5 were very severe aplastic anemia (VSAA). There was no obvious adverse reaction in posaconazole prophylaxis group.@*Conclusion@#Posaconazole is safe and effective for primary prevention of fungal infection of SAA patients receiving IST, especially for the VSAA.

Clinical efficacy and safety of porcine antihuman lymphocyte immunoglobulin in alternative donor allogeneic hematopoietic cell transplantation for severe aplastic anemia / 中华血液学杂志

Objective@#To compare eficacy and safety of porcine antihuman lymphocyte immunoglobulin (pALG) and rabbit antithymocyte immunoglobulin (rATG) as a part of alternative donor allogeneic hematopoietic stem cell transplantation (AD allo-HSCT) for severe aplastic anemia (SAA).@*Methods@#The clinical data of 46 SAA patients received AD allo-HSCT from January 2006 to November 2016 were retrospectively analyzed. The cohort of patients were divided into two groups based on rATG or pALG as a part of conditioning regimen to compare implantation rate, transplantation related complications and outcome.@*Results@#In rATG group 30 patients achieved ANC reconstitution, 27 patients achieved PLT reconstitution. In pALG group all 16 patients achieved ANC and PLT reconstitutions. There were no significant differences between the two groups in terms of acute graft-versus-host disease (aGVHD) (P=0.475), Ⅲ-Ⅳ grade aGVHD (P=0.876), chronic GVHD (cGVHD) (P=0.309), extensive cGVHD (P=0.687), graft rejection (GR) (P=0.928), bloodstream infection (P=0.443), invasive fungal disease (P=0.829), cytomegalovirus viremia (P=0.095) respectively. Prospective 5-year overall survival (OS) in rATG and pALG groups were (75.1±8.2)% and (53.6±13.3)% with median follow-up of 14(2-102) and 23(4-63) months, respectively (P=0.190).@*Conclusion@#As a part of conditioning regimen, pALG could achieve similar efficacy as rATG, without increasing the incidences of transplantation complications such as GVHD, GR and infection, in the setting of AD allo-HSCT for SAA patients.

Short stature, optic nerve atrophy and Pelger-Huët anomaly syndrome with antibody immunodeficiency and aplastic anemia: a case report and literature review / 中华儿科杂志

Objective@#To investigate the clinical features and genetic characteristics of cases with NBAS gene defects.@*Method@#Characteristics of clinical materials, immunological data and gene mutation of the first case in China with NBAS gene mutation were retrospectively analyzed. The related literature was searched by using search terms'NBAS’.@*Result@#A 2-year-four-month old girl, was admitted due to 'fever and pallor for one day’. There was an intrauterine growth retardation at her fetal stage. Since her birth, she had suffered from recurrent infections and development delay was accompanied by persistent liver dysfunction. Her head circumference and height were 43.5 cm and 60 cm, respectively. She seemed pale. She had progeroid appearance with loose skin, sparse hair, proptosis and low-set ears. The cranial suture did no close and the anterior fontanel was about 6 cm×5 cm. Abdominal palpation showed that the liver was 2 cm below the right costal margin, and the spleen was 1.5 cm below the left rib. Both alanine aminotransferase(100-1 991 IU/L) and aspartate aminotransferase (191-1 367 IU/L) were persistently abnormal. Visual evoked potentials and fundus examination revealed optic nerve atrophy. Bone mineral density assessment showed osteoporosis. The IgG level was 2.0 g/L (3.41-19.6) and absolute count of CD19+B cells was 231.27/μl (608.8-2 167.7) . Her hemoglobin level was 53 g/L. Bone marrow smear showed serious hypoplasia in erythroid cell. The gene sequencing results showed NBAS gene c.5741C> T, pR1914H and c.6496-6497insA, p.S2166Ffs* 2 compound heterozygous mutations. A total of 8 literatures were collected including 57 cases with NBAS gene homozygous or compound heterozygous mutation. These 57 cases were characterized by short stature(88%, 50/57) , Pelger-Huët anomaly (75%, 43/57) , skeletal dysplasia (74%, 42/57), optic nerve atrophy (72%, 41/57), abnormality of liver enzymes or acute liver failure (42%,24/57), abnormalities of immune system(19%, 11/57), development delay of mental, language or sports(11%, 6/57). Other clinical manifestations such as progeroid appearance, proptosis and hypotonia were also common. NBAS gene c.5741G>A homozygous mutation accounted for 61% (35/57) cases.@*Conclusion@#Cases with NBAS gene defects often manifests as short stature, optic nerve atrophy, Pelger-Huët anomaly, skeletal dysplasia, recurrent infections, abnormality of liver enzymes, progeroid appearance, proptosis, hypotonia and immunodeficiency. Gene sequencing analysis showed NBAS gene homozygous or compound heterozygous mutations, and homozygous mutation of c.5741G>A was most common.

Expression mechanism of helper T cells in children with aplastic anemia pathogenesis / 中国基层医药

Objective To investigate the expression mechanism and significane of helper T cells in children with aplastic anemia(AA).Methods 53 children of AA were divided into heavy AA group(SAA group,21 cases),light AA group(MAA group,i7 cases),AA remission group (CR group,15 cases) by the disease,the other taken the non-aplastic anemia blood platelet disorders caused by reduced or anemia in children (AL group) of 16 cases,20 healthy children were selected as the NC group.The peripheral blood CD4+,CD4+ CD225+,CD4+ CD25+ CD127low,CD4+ IFN-γ(Thl cells),CD4+ IL-4 + (Th2 cells) in each group were detected by flow cytometry.ELISA test was used to detect peripheral blood levels of transforming growth factor-β (TGF-β),interferon-γ (IFN-γ) and interleukin-4 (IL-4).Results The peripheral blood CD4+,CD4+ CD25+,CD4+ CD25+ CD127low,TGF-beta 1 levels in the SAA group were (26.59 ± 4.37) ％,(3.44 ± 0.29) ％,(3.13 ± 1.16) ％,(14.59 ± 3.10) ng/mL,respectively,which in the MAA group were (32.67 ± 3.19) ％,(5.42 ± 0.28) ％,(4.29 ± 1.21) ％,(22.98 ± 3.38) ng/mL,respectively,which in the CR group were (33.13 ±3.24)％,(5.23 ±0.26)％,(4.36 ± 1.33)％,(23.19 ± 3.91) ng/mL,respectively,which in the AL group were (37.98 ± 4.01)％,(6.89 ± 0.28)％,(4.99 ± 1.42)％,(34.46 ± 5.23) ng/mL,respectively,which in the NC group were (38.66 ± 3.41) ％,(7.01 ± 0.38) ％,(5.10 ± 1.52) ％,(35.17 ±5.i4) ng/mL,respectively,the differences among the four groups were statistically significant(F =23.72,25.49,15.24,24.52,all P ＜ 0.05).Peripheral blood Th1,Th2 and Th1/Th2 levels in the SAA group were (13.04 ± 3.01)％,(3.44 ±0.29)％,(1.99 ± 1.17),respectively,which in the MAA group were (11.01 ±2.89)％,(6.28 ±2.99)％,(1.75 ± 0.97),respectively,which in the CR group were (10.38 ± 3.27)％,(6.41 ± 3.18)％,(1.62 ±1.03),respectively,which in the AL group were (8.033 ±.42) ％,(6.35 ± 3.08) ％,(1.26 ± 1.11),respectively,which in the NC group were (8.41 ± 3.84) ％,(6.23 ± 3.44) ％,(1.34 ± 1.12),the differences among the four groups were statistically significant (F =35.92,42.43,22.24,all P ＜ 0.05).Peripheral blood IFN-gamma and IL-4levels in SAA group were (13.04 ± 2.58) pg/mL,(17.22 ± 3.88) pg/mL,respectively,which in MAA group were (10.11 ± 2.22) pg/mL,(17.24 ± 4.21) pg/mL,respectively,which in the CR group were (9.88 ± 2.16) pg/mL,(17.01 ±4.00)pg/mL,respectively,which in the AL group were (8.01 ± 1.68)pg/mL,(16.63 ± 3.58)pg/mL,respectively,which in the NC group were (38.66 ± 3.41) pg/mL,(16.743 ±.81) pg/mL,the differences among the four groups were statistically significant (F =24.17,3.39,all P ＜ 0.05).Conclusion Treg cells decreased,the inhibition extent of TGF-β1 on Th1 cells and IFN-γsecretion decreased,which leading to Th1/Th2 shifted to Th1,leading to hematopoietic marrow failure may be one of the pathogenesis of children sufferred from AA.

Risk-factor analysis of poor graft function after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia / 中华血液学杂志

Objective@#To investigate the risk factors of poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe aplastic anemia (SAA) .@*Methods@#Clinical data from 111 SAA patients who received allo-HSCT were analyzed retrospectively. Factors including age, gender, interval to transplantation, the level of serum ferritin before transplantation were analyzed by Cox multivariate regression analysis.@*Results@#Among the 111 patients who underwent allo-HSCT, 16 developed PGF (14.4%) . Multivariate analysis showed donor type (HR=2.656, 95%CI 1.204-5.858, P= 0.016) and the level of serum ferritin before tansplantation (HR=3.170, 95%CI 1.400-7.180, P=0.006) were significant risk factors for PGF.@*Conclusion@#Unrelated donor transplantation and the high level of serum ferritin before transplantation are risk factors for PGF.

Improved outcome by optimized conditioning regimens with an increased dose of cyclophosphamide in allogeneic peripheral blood stem cell transplantation for severe aplastic anemia / 中华血液学杂志

Objective@#To respectively analyze the impact of conditioning regimens with a dose-decreased cyclophosphamide (Cy) on the outcome in fully matched sibling donor (MSD) peripheral blood stem cell transplantation (PBSCT) for severe aplastic anemia (SAA) .@*Methods@#Two conditioning regimens with different doses of Cy (150 mg/kg or 120 mg/kg) in combination with fludarabine (Flu) and antithymocyte globulin (ATG) for MSD-PBSCT were investigated in 51 patients with acquired SAA.@*Results@#Overall survival and failure-free survival in patients received 150 mg/kg of Cy (Cy150 cohort) or 120 mg/kg (Cy120 cohort) were 93.5% vs 90.0% (χ2=0.170, P=0.680) and 90.3% vs 85.0% (χ2=0.285, P= 0.594) respectively. However, either acute or chronic graft-versus-host disease risks were higher in Cy120 cohort than in Cy150 cohort (HR=3.89, 95% CI 1.21-12.53, P=0.023; HR=4.48, 95% CI 1.40-14.32, P= 0.011, respectively) . No difference was found for opportunistic infections or graft failure between two cohorts.@*Conclusion@#Cy at a dose of 150 mg/kg, in combination with Flu and ATG, was more effective than that of 120 mg/kg Cy to produce improved clinical outcome in the setting of acquired SAA patients after MSD-PBSCT.