Immunomodulation with rabbit anti-thymocyte globulin in solid organ transplantation

Rabbit anti-thymocyte globulin's manifold mechanisms of action may be attribuited to its polyclonal nature. Its T-cell depleting effect on lymphoid cells is well established: Occurring in the blood and secondary lymphoid tissues, depletion proceeds through complement-dependent lysis, opsonization and apoptotic pathways. Clinical studies have shown that rabbit antithymocyte globulin's immunomodulatory effect extends beyond the initial T-cell depletion and up to the period during which lymphocyte populations begin to recover. The drug is able to mediate immunomodulation and graft tolerance by functionally inactivating cell surface receptors involved in antigen recognition, leukocyte trafficking and leukocyte endothelium adhesion. The complex and prolonged immunomodulation induced by this drug contributes to its efficacy in solid organ transplantation, mainly by reducing the incidence of acute graft rejection.

An investigation of long-term outcome of rabbit anti-thymocyte globulin and cyclosporine therapy for pediatric severe aplastic anemia

Children with severe aplastic anemia(SAA)face heterogeneous prognoses after immunosuppressive therapy(IST).There are few models that can predict the long-term outcomes of IST for these patients.The objective of this paper is to develop a more effective prediction model for SAA prognosis based on clinical electronic medical records from 203 children with newly diagnosed SAA.In the early stage,a novel model for long-term outcomes of SAA patients with IST was developed using machine-learning techniques.Among the indicators related to long-term efficacy,white blood cell count,lymphocyte count,absolute reticulocyte count,lymphocyte ratio in bone-marrow smears,C-reactive protein,and the level of IL-6,IL-8 and vitamin B12 in the early stage are strongly correlated with long-term efficacy(P<.05).Taken together,we analyzed the long-term outcomes of rabbit antithymocyte globulin and cyclosporine therapy for children with SAA through machine-learning techniques,which may shorten the observation period of therapeutic effects and reduce treatment costs and time.

Anti-thymocyte globulin for treatment of T-cell-mediated allograft rejection

Anti-thymocyte globulin(ATG)is a pivotal immunosuppressive therapy utilized in the management of T-cell-mediated rejection and steroid-resistant rejection among renal transplant recipients.Commercially available as Thymoglobulin(rabbit-derived,Sanofi,United States),ATG-Fresenius S(rabbit-derived),and ATGAM(equine-derived,Pfizer,United States),these formulations share a common mechanism of action centered on their interaction with cell surface markers of immune cells,imparting immunosuppressive effects.Although the prevailing mechanism predominantly involves T-cell depletion via the complement-mediated pathway,alternate mechanisms have been elucidated.Optimal dosing and treatment duration of ATG have exhibited variance across randomised trials and clinical reports,rendering the establishment of standardized guidelines a challenge.The spectrum of risks associated with ATG administration spans from transient adverse effects such as fever,chills,and skin rash in the acute phase to long-term concerns related to immunosuppression,including susceptibility to infections and malignancies.This comprehensive review aims to provide a thorough exploration of the current understanding of ATG,encompassing its mechanism of action,clinical utility in the treatment of acute renal graft rejections,specifically steroid-resistant cases,efficacy in rejection episode reversal,and a synthesis of findings from different eras of maintenance immunosuppression.Additionally,it delves into the adverse effects associated with ATG therapy and its impact on long-term graft function.Furthermore,the review underscores the existing gaps in evidence,particularly in the context of the Banff classification of rejections,and highlights the challenges faced by clinicians when navigating the available literature to strike the optimal balance between the risks and benefits of ATG utilization in renal transplantation.

Analysis of the Prognostic Factors of Very Severe Aplastic Anemia Treated with Chinese Kidney-Invigorating Drugs in Combination with Anti-lymphocyte Globulin or Anti-thymocyte Globulin

Objective： To explore the prognostic factors for very severe aplastic anemia （VSAA） patients treated mainly with Chinese Kidney （Shen）-invigorating drugs （CKID） combined with anti-lymphocyte globulin （ALG） or anti-thymocyte globulin （ATG）. Methods： Twenty-seven VSAh. patients were treated with CSID＋ALG/ ATG therapy in conjunction with cyclosporine A, androgen, hemopoietic growth factor, etc. The relationship of the effectiveness and some factors （age of patients, course of illness, blood and bone marrow figures, etc.） were analyzed. Results： In the 25 evaluated VSAA patients who had been followed up for over 1 year, 9 patients （36.0%） were basically cured, 5 （20.0%） remitted, 6 （24.0%） were markedly improved, and 5 （20.0%） were treated in vain, with the total effective rate of treatment being 80.0% （20/25）. Better clinical therapeutic effects were shown in patients newly diagnosed with VSAA, of male sex （P=0.037）, 〉20 years old （P=0.045）, with an illness course ≤ 1 month （,P=0.048）, with peripheral neutrophil count 〉0.1 × 10^9/L （P=0.023）, and with reticulocyte count 〉10 × 10^9/L （P=0.002）. Platelet count （P=0.620） and bone marrow lymphocyte percentage （P=0.736） showed no correlation with the therapeutic effectiveness. Multi-factor analysis by the Kaplan-Meier procedure on the factors influencing survival showed that rather longer survival times occurred in patients 〉 20 years old, with peripheral neutrophil count ≤〈0.1 × 10^9/L, reticulocyte count ≤10 × 10^9/L, and platelet count 〉 10 × 10^9/L （allP=0.0001）. Bone marrow lymphocyte percentage and the initiation time of ALG/ATG application （from onset of the illness） showed no significant influence on patients＇ survival time （P=0.085 and P=0.935, respectively）. Conclusions： CSKD＋ALG/ATG therapy for treatment of VSAA could enhance the current clinical therapeutic effects and elevate patients＇ survival rate. Conditions including male sex, age 〉20 years, illness course ≤1 month, neutrophil count 〉0.1× 10^9/L, and reticulocyte count 〉10 × 10^9/L are the likely effective indices for predicting favorable therapeutic effectiveness in newly diagnosed VSAA patients.

A retrospective comparison of the efficacy and safety in kidney transplant recipients with basiliximab and anti-thymocyte globulin

Background Induction therapy are utilized to achieve an adequate immunosuppression at the time of transplantation. The use of basiliximab or anti-thymocyte globulin （ATG） for induction therapy has significantly reduced the incidence of acute rejection episodes post-transplantation. The purpose of this study was to compare the efficacy and safety of the basiliximab in patients with immuno-induction therapy after kidney transplantation with the ATG. Methods A retrospective analysis was carried out in kidney transplant recipients including 146 patients with the basiliximab and 116 cases with the ATG and the acute rejection, graft function, infective complications and 1-year and 5-year actuarial patient and graft survival after renal transplantation were compared between the two treatment groups. Results There were no statistically significant difference between groups regarding age, sex, cold ischemic time, warm ischemic time, human leukocyte antigen （HLA） matching type between the donor and recipient, lymphotoxin test and the use of immunosuppressive agents. There was no statistical significance regarding the incidence of the acute rejection （9.59% vs. 8.62%, P=0.481） and delayed graft function （10.27% vs. 9.48%, P=0.501） between groups. There were significantly lower lung infection incidence （5.48% vs. 12.93%, P=0.029） in the basiliximab-treated group in comparison with the ATG-treated group. One-year patient and graft survival rates were 98%, 97% for the basiliximab-treated group, and 95%, 73% for the ATG-treated group, respectively. Five-year patient and graft survival rates were 92%, 86% for the basiliximab-treated group and 93%, 72% for the ATG-treated group, respectively. Log rank test showed statistically significant difference with P=0.038 for patients and P=-0.033 for grafts, respectively. There were significantly lower the incidence of granulocytopenia （8.22% vs. 17.24%, P=0.022） and thrombocytopenia （4.11% vs. 19.83%, P=0.000） after transplantation in the basiliximab-treated group in comparison with the ATG-treated group. There was no statistical significance regarding the incidence of the heart dysfunction after transplantation between the two groups （6.16% vs. 6.90%, P=0.502）. Conclusion The immuno-induction therapy with the basiliximab in kidney transplant recipients is efficient and safe with less complication compared with the ATG.

Haploidentical hematopoietic cell transplantation for severe acquired aplastic anemia: a case-control study of post-transplant cyclophosphamide included regimen vs. anti-thymocyte globulin & colony-stimulating factor-based regimen

Dear Editor,Haploidentical allogeneic hematopoietic stem cell transplantation(haplo-HSCT),a curative therapy for severe aplastic anemia(SAA)patients,has been used clinically for decades.Two models,not involving ex vitro T-cell depletion,have been adopted for haplo-HSCT in patients with SAA.The first is referred to as the"Beijing protocol"(Xu et al.,2017),and comprises a conditioning regimen using busulfex(BU),cyclophosphamide(CY).

Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia

Chronic graft-versus-host disease(cGVHD)is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation(haplo-HSCT).We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia(n=280).The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria.A total of 169 patients suffered from cGVHD.The patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD(total,66.0%vs.53.7%,P=0.031;moderate to severe,42.4%vs.30.1%,P=0.036)than the patients who had 1 to 2 loci mismatched.The patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD(49.2%vs.32.9%,P=0.024)compared with the patients who had other donors.The patients who had grades III to IV acute GVHD(aGVHD)had higher 8-year incidence of cGVHD(total,88.0%vs.50.4%,P<0.001;moderate to severe,68.0%vs.27.0%,P<0.001)compared with the patients without aGVHD.In multivariate analysis,grades III to IV aGVHD was the only independent risk factor for cGVHD.Thus,further interventions should be considered in patients with severe aGVHD to prevent cGVHD.

猪抗人淋巴细胞球蛋白与兔抗人胸腺细胞球蛋白治疗重型再生障碍性贫血的疗效比较

目的比较猪抗人淋巴细胞球蛋白（ALG）与兔抗人胸腺细胞球蛋白（ATG）治疗重型再生障碍性贫血（再障）的疗效。方法回顾分析2004~2013年接受免疫抑制治疗的重型再障患者（猪ALG组43例,兔ATG组32例）6个月有效率,χ2检验比较组间差异。Kaplan-Meier法绘制生存曲线,log-rank检验比较组间差异。结果猪ALG组6个月有效率为79.07%,高于兔ATG组（56.25%）且差异显著（P=0.034）;5年总生存率为86.047%,高于兔ATG组（72.878%）,但差异不显著（P=0.190）。结论猪ALG血液学应答优于兔ATG,预后和安全性相似。

兔抗人胸腺细胞球蛋白联合环孢素A治疗儿童再生障碍性贫血10例分析

目的观察10例应用兔抗人胸腺细胞球蛋白(r-ATG)联合环孢素A(CsA)治疗儿童再生障碍性贫血的疗效及安全性。方法回顾性分析我院血液科应用r-ATG联合CsA治疗10例患儿的临床资料。结果 10例患儿的中位年龄为7岁,男女比例为2∶3。6例患儿3个月内获得治疗反应,总反应率80%;目前总有效率为70%。不良反应可耐受。结论 r-ATG联合CsA治疗儿童再生障碍性贫血是可耐受且有效的方法。

硼替佐米联合利妥昔单抗和血浆置换治疗高致敏等待肾移植患者

背景:高致敏是肾移植成功的障碍,目前肾移植脱敏治疗方法有静注免疫球蛋白、血浆置换、兔抗人淋巴细胞球蛋白等,但治疗效果常不满意。目的:通过利妥昔单抗和硼替佐米进行肾移植后脱敏治疗,寻求效果满意的治疗方案。方法:1例高致敏等待肾移植患者接受脱敏治疗,接受血浆置换2次后,立即给予利妥昔单抗500mg静滴,2d后开始分别在第1,4,8,11天给予硼替佐米1.3mg/m2,随访观察群体反应性抗体等变化。结果与结论:随访的9个月中,患者群体反应性抗体从92%下降到17%,患者对利妥昔单抗和硼替佐米有良好的耐受性。初步经验表明:硼替佐米联合利妥昔单抗和血浆置换三联脱敏治疗方案可快速持久降低循环抗体水平,硼替佐米可能成为脱敏治疗方案中的重要要素。

CTA制剂对兔耳痒螨的治疗效果和作用机理研究

本文评价“蜱螨类寄生虫抗原注射液”（下简称ＣＴＡ）制剂对兔耳痒螨病的治疗效果。结果表明：对自然感染兔耳痒螨试验组，第１天和第１４天分别使用ＣＴＡ制剂，３周后螨虫消失，且直至试验结束无复发。试验组兔Ｂ淋巴细胞数量和ｒ－球蛋白含量分别比对照组增高４９．９３％和１２４．１３％；比自然感染兔耳痒螨的螨虫对照组分别增高３３．５４％和４４．１０％。本文还对ＣＴＡ制剂杀灭螨虫的免疫机制进行了探讨。

兔免疫球蛋白液相悬浮芯片的制备及制备条件的优化

目的:制备兔的免疫球蛋白液相悬浮芯片并对其制备条件进行优化,为进一步建立兔免疫球蛋白液相悬浮芯片检测技术提供基础。方法:分别将亲和纯化的兔IgG、IgM和IgA偶联至荧光编码微球,然后优化捕获抗体的偶联量、检测抗体、Streptavidin-PE抗体的最佳工作浓度以及微球-血清反应时间、检测抗体反应时间和Streptavidin-PE抗体反应时间等因素,建立兔IgG、IgM和IgA液相悬浮芯片。结果:1.25×106个荧光微球的最佳偶联抗体浓度分别为10μg IgG、20μg IgM和15μg IgA;biotin标记的IgG、IgM和IgA检测抗体最佳工作浓度分别为2、2和5μg/ml;IgG、IgM和IgA的最佳Streptavidin-PE抗体浓度均为2μg/ml;微球-血清、血清-检测抗体及Streptavidin-PE抗体最佳反应时间分别为60、60和30分钟。结论:制备荧光编码微球兔免疫球蛋白悬浮芯片是可行的方法。

兔免疫球蛋白液相芯片的制备及其检测方法的建立

目的制备实验兔的免疫球蛋白液相芯片，建立液相芯片技术（xMAP）检测方法。方法分别将兔IgG、IgM和IgA亲和纯化的捕获抗体耦联至荧光编码微球，对蛋白耦联量进行优化，制备兔IgG、IgM和IgA液相芯片，同步检测白毛黑眼兔（WHBE兔）和日本大耳白兔（JW兔）血清中IgG、IgM和IgA相对含量，建立可应用于实验兔免疫球蛋白半定量检测的xMAP方法，并对其结果用ELISA方法进行验证。结果（1）IgG、IgM和IgA的最佳蛋白耦联量分别为10、20和15№。（2）xMAP检测结果显示，WHBE兔血清中IgG、IgM蛋白含量显著低于删兔（P〈0．05），IgA蛋白含量显著高于Jw兔（P〈O．01）；ELISA检测结果表明，WHBE兔血清中IgG、IgM蛋白含量显著低于Jw兔（P〈0．05，P〈0．01），其中IgM蛋白含量变化达到极显著水平，IgA蛋白含量显著高于Jw兔（P〈0．01）。结论应用制备的兔IgG、IgM和IgA液相芯片建立的xMAP方法，对实验兔血清进行检测，检测结果与ELISA结果一致，提示该方法可应用于实验兔血清的IgG、IgM和IgA半定量检测。

兔抗胸腺细胞球蛋白联合环孢素对重型再生障碍性贫血患者VEGF、IL-17及IL-6表达的影响

目的:探讨兔抗胸腺细胞球蛋白联合环孢素对重型再生障碍性贫血患者疗效及血管内皮生长因子(vascular endothelial growth factor,VEGF)、白细胞介素(IL)-17及IL-6表达的影响。方法:选取2015年1月-2020年5月本院收治的60例重型再生障碍性贫血患者的临床资料进行回顾性分析。根据治疗方法将患者分为对照组(n=30)和研究组(n=30)。对照组进行环孢素治疗,观察组在对照组基础上联合兔抗胸腺细胞球蛋白治疗。比较两组临床疗效、VEGF、IL-17、IL-6水平、血象指标水平和不良反应。结果:研究组治疗总有效率高于对照组(P<0.05)。治疗后,观察组血清IL-17与IL-6水均低于对照组,而VEGF水平高于对照组(P<0.05)。治疗后,两组血红蛋白(Hb)、血小板计数(BPC)及白细胞计数(WBC)水平均高于治疗前,且研究组均高于对照组(P<0.05)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:兔抗胸腺细胞球蛋白联合环孢素治疗重型再生障碍性贫血患者的效果显著,可明显改善VEGF、IL-17、IL-6水平和血象指标,且安全性较高,值得应用。

Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment

Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell(CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH(familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of(signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome(XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis(e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease(especially EBVHLH).

Pancreas transplantation: The Wake Forest experience in the new millennium

AIM: To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression. METHODS: A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant(SKPT) and solitary pancreas transplant(SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with my-cophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide. RESULTS: Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186(92%) were primary and 16(8%) pancreas retransplants; portalenteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American(AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/m L. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit antithymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient(86% SKPT vs 87% SPT) and kidney(74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates(both 65%) were similar(P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively(P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients(P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a "type 2 diabetes" phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels.CONCLUSION: In the new millennium, acceptablemedium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.

低剂量兔抗人胸腺细胞免疫球蛋白用于儿童肾移植诱导治疗的临床研究

目的探讨低剂量兔抗人胸腺细胞免疫球蛋白(rabbit anti-human thymocyte globulin,rATG)用于儿童肾移植诱导治疗的有效性与安全性。方法回顾性分析2018年10月至2021年5月郑州大学第一附属医院肾移植科应用低剂量rATG诱导方案的儿童肾移植受者临床资料。观察术后1年受者/移植肾存活率、肾功能恢复情况、AR及不良反应。采用Friedman检验分析术后肾功能变化;根据术前基线资料分层,采用Pearson卡方检验或Fisher精确检验分析术后AR及不良反应影响因素。结果共纳入77例儿童肾移植受者,术后1年内共有16例(20.78%)受者出现AR,且均发生在术后前6个月;移植肾功能延迟恢复(delayed graft function,DGF)的发生率为14.29%(11/77)。移植术后严重感染的发生率为18.18%(14/77),BK病毒感染发生率为25.97%(20/77),中性粒细胞减少症发生率为32.47%(25/77)。术后1年受者/移植肾存活率分别为97.40%(75/77)和94.81%(73/77)。卡方检验结果显示,体重≤30 kg、身高≤138 cm儿童受者的术后感染发生率分别为28.95%(11/38)和27.50%(11/40),均高于体重>30 kg、身高>138 cm儿童受者的7.69%(3/39)和8.11%(3/37),组间比较,差异均有统计学意义(P=0.016和0.028)。结论低剂量rATG预防儿童肾移植受者发生AR的总体疗效良好,且出现相关不良反应的风险可能更低;本方案下术前发育较好儿童受者的术后感染发生率较低。

Machine learning algorithm as a prognostic tool for Epstein-Barr virus reactivation after haploidentical hematopoietic stem cell transplantation

Epstein-Barr virus(EBV)reactivation is one of the most important infections after hematopoietic stem cell transplantation(HSCT)using haplo-identical related donors(HID).We aimed to establish a comprehensive model with machine learning,which could predict EBV reactivation after HID HSCT with anti-thymocyte globulin(ATG)for graft-versus-host disease(GVHD)prophylaxis.We enrolled 470 consecutive acute leukemia patients,60%of them(n=282)randomly selected as a training cohort,the remaining 40%(n=188)as a validation cohort.The equation was as follows:Probability(EBV reactivation)=1/1+exp(−Y),where Y=0.0250×(age)–0.3614×(gender)+0.0668×(underlying disease)–0.6297×(disease status before HSCT)–0.0726×(disease risk index)–0.0118×(hematopoietic cell transplantation-specific comorbidity index[HCT-CI]score)+1.2037×(human leukocyte antigen disparity)+0.5347×(EBV serostatus)+0.1605×(conditioning regimen)–0.2270×(donor/recipient gender matched)+0.2304×(donor/recipient relation)–0.0170×(mononuclear cell counts in graft)+0.0395×(CD34+cell count in graft)–2.4510.The threshold of probability was 0.4623,which separated patients into low-and high-risk groups.The 1-year cumulative incidence of EBV reactivation in the low-and high-risk groups was 11.0%versus 24.5%(P<.001),10.7%versus 19.3%(P=.046),and 11.4%versus 31.6%(P=.001),respectively,in total,training and validation cohorts.The model could also predict relapse and survival after HID HSCT.We established a comprehensive model that could predict EBV reactivation in HID HSCT recipients using ATG for GVHD prophylaxis.

128例再生障碍性贫血患儿接受兔源抗胸腺细胞球蛋白联合环孢素治疗的疗效分析

摘要目的观察儿童再生障碍性贫血(AA)接受兔源抗胸腺细胞球蛋白(rATG)联合环孢素进行免疫抑制治疗(IST)的疗效、不良反应及治疗反应率的影响因素,探讨不同临床分型儿童AA的最佳治疗方案。方法选择2006年1月1日至2017年2月1日于中山大学孙逸仙纪念医院儿科通过外周血常规及骨髓形态学和(或)骨髓病理检查确诊为AA,并且接受rATG联合环孢素治疗的128例患儿为研究对象。按照疾病临床分型,将研究对象分为非重型再生障碍性贫血(NSAA)组(n=22)、重型再生障碍性贫血(SAA)组(n=63)、极重型再生障碍性贫血(VSAA)组(n=43)。回顾性分析3组患儿的临床资料,评估治疗后第3、6、9、12个月及截至随访终点的疗效。并且观察3组患儿治疗相关不良反应及预后情况。3组患儿的治疗反应率比较采用χ2检验。不同年龄、中性粒细胞绝对计数、血小板计数、网织红细胞绝对值等治疗反应影响因素的单因素分析采用χ2检验。将单因素分析结果中有统计学意义的影响因素,纳入Cox比例风险回归模型进行多因素分析。采用Kaplan-Meier法进行生存分析。本研究遵循的程序符合2013年修订的《世界医学会赫尔辛基宣言》要求,征得研究对象监护人知情同意,并且签署治疗知情同意书。结果①本研究128例患儿中,可评价疗效患儿为121例,失访患儿为5例,早期死亡患儿为2例。治疗后第3、6、9、12个月及截至随访终点的完全缓解(CR)率分别为5.0%(6/121)、14.9%(18/121)、16.5%(20/121)、28.9%(35/121)及51.2%(62/121),治疗反应率分别为33.9%(41/121)、38.9%(47/121)、49.6%(60/121)、62.8%(76/121)及65.3%(79/121)。NSAA组患儿治疗后第3、6个月治疗反应率分别为63.6%(14/22)和68.2%(15/22),明显高于SAA组的30.5%(18/59)和39.0%(23/59),以及VSAA组的22.5%(9/40)和22.5%(9/40),并且前者分别与后两者相比,差异均有统计学意义(χ^2=11.416、13.297,P=0.001、<0.001;χ^2=6.050、11.991,P=0.014、0.001)。②不良反应及预后方面,本研究128例患儿的血清病发生率为71.1%(91/128)、感染发生率为65.6%(84/128),复发率为5.0%(6/121)、恶性克隆性转变率为1.6%(2/121),病死率为7.0%(9/121)。③单因素分析结果显示,治疗前外周血淋巴细胞计数<1.5×109/L、血小板计数≥20×109/L、CD3+CD4+细胞比例降低者治疗反应率高于淋巴细胞计数≥1.5×109/L、血小板计数<20×109/L及CD3+CD4+细胞比例正常/升高者,并且差异均有统计学意义(χ^2=6.949,P<0.01;χ^2=3.965,P<0.05;χ^2=5.005,P=0.025),而不同年龄、性别、临床分型等患儿的治疗反应率比较,差异无统计学意义(P>0.05)。④将单因素分析结果有统计学意义的治疗前淋巴细胞计数<1.5×109/L、血小板计数≥20×109/L、CD3^+CD4^+细胞比例降低纳入Cox比例风险回归模型进行多因素分析的结果显示,上述因素不是rATG联合环孢素治疗AA患儿疗效的独立影响因素(P>0.05)。结论rATG联合环孢素治疗SAA及VSAA患儿反应率较高、严重并发症发生率低,可作为无合适供者移植时的一线治疗方案。治疗前淋巴细胞计数<1.5×109/L、血小板计数≥20×109/L、CD3^+CD4^+细胞比例降低可能作为rATG联合环孢素治疗儿童AA疗效良好的预测指标。

R-ATG联合环孢素与环孢素联合雄激素一线治疗输血依赖非重型再生障碍性贫血的疗效比较:单中心回顾性研究

目的:评估兔抗人胸腺细胞免疫球蛋白(R-ATG)是否适于输血依赖非重型再生障碍性贫血(TDNSAA)免疫抑制治疗。方法:回顾性分析TD-NSAA患者资料,比较一线采用R-ATG联合环孢素A(CsA)与CsA联合雄激素治疗的血液学反应及生存情况。结果:109例TD-NSAA患者中,31例一线接受R-ATG联合CsA治疗,78例一线接受CsA联合雄激素治疗。2组患者治疗后3个月总体血液学反应率分别为67.7%和46.2%(P=0.042),良好血液学反应率分别为22.6%和11.5%(P=0.142);2组患者治疗后6个月总体血液学反应率分别为83.9%和56.4%(P=0.007),良好血液学反应率分别为41.9%和23.1%(P=0.049)。R-ATG联合CsA组与CsA联合雄激素组患者预期5年总生存率相似(94.1%∶97.4%,P=0.387),而R-ATG联合CsA组无事件生存率明显升高(78.6%∶35.1%,P=0.003)。结论:一线应用R-ATG联合CsA治疗TD-NSAA安全、有效;TD-NSAA一线免疫抑制治疗应采用ATG联合CsA方案。