Predictive Value of Dynamic Peri-Transplantation MRD Assessed By MFC Either Alone or in Combination with Other Variables for Outcomes of Patients with T-Cell Acute Lymphoblastic Leukemia

We performed a retrospective analysis to investigate dynamic peri-hematopoieticstem cell transplantation(HSCT)minimal/measurable residual disease(MRD)on outcomes inpatients with T-cell acute lymphoblastic leukemia(T-ALL).A total of 271 patients were enrolledand classified into three groups:unchanged ncgative MRD pre-and post-HSCT group(group A),post-MRD non-increase group(group B),and post-MRD increase group(group C).The patientsin group B and group C experienced a higher cumulative incidence of relapse(CIR)(42%vs.71%vs.16%,P<0.001)and lower leukemia-free survival(LFS)(46%vs.21%vs.70%,P<0.001)andoverall survival(OS)(50%vs.28%vs.72%,P<0.001)than in group A,but there was no significantdifference in non-relapse mortality(NRM)among three groups(14%vs.12%vs.8%,P=0.752).Multivariate analysis showed that dynamic peri-HSCT MRD was associated with CIR(HR=2.392,95%CI,1.816-3.151,P<0.001),LFS(HR=1.964,95%CI,1.546-2.496,P<0.001)and os(HR=1.731,95%CI,1.348-2.222,P<0.001).We also established a risk scoring system based ondynamic peri-HSCT MRD combined with remission status pre-HSCT and onsct of chronic graft-versus-host disease(GVHD).This risk scoring system could better distinguish ClR(c=0.730)thanthat for pre-HSCT MRD(c=0.562),post-HSCT MRD(c=0.616)and pre-and post-MRD dynamics(c=0.648).Our results confirm the outcome predictive value of dynamic peri-HSCT MRD eitheralone or in combination with other variables for patients with T-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。

Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation

Haploidentical stem cell transplantation(haplo-SCT)achieves superior or at least comparable clinical outcomes to HLA-matched sibling donor transplantation(MSDT)in treating hematological malignancies.To define the underlying regulatory dynamics,we analyzed time courses of leukemia burden and immune abundance of haplo-SCT or MSDT from multiple dimension.First,we employed two nonirradiated leukemia mouse models which carried human AML-ETO or MLL-AF9 fusion gene to establish haplo-identical and major histocompatibility(MHC)-matched transplantation models and investigated the immune cell dynamic response during leukemia development in vivo.We found that haplo-matching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mice survival and reduced leukemia burden.The stronger graft-versus-leukemia activity in haplo-SCT group mainly induced by decreased apoptosis and increased cytotoxic cytokine secretion including tumor necrosis factor–α,interferon-γ,pore-forming proteins and CD107a secreted by T cells or natural killer cells.Furthermore,we conducted a prospective clinical trial which enrolled 135 patients with t(8;21)acute myeloid leukemia that displayed minimal residual disease before transplantation and underwent either haplo-SCT or MSDT.The results showed that the haplo-SCT slowed the kinetics of the leukemia burden in vivo and reduced the cumulative incidence of relapse compared with MSDT.Ex vivo experiments showed that,1 year after transplantation,cytotoxic T lymphocytes from the haplo-SCT group had higher cytotoxicity than those from the MSDT group during the same period.Our results unraveled the role of immune cells in superior antileukemia effects of haplo-SCT compared with MSDT.

The role of collateral related donors in haploidentical hematopoietic stem cell transplantation

A key issue in the haploiedntical hematopoietic stem cell transplantation(haplo-HSCT) setting is the search for the best donor, because donor selection can significantly impact the clinical outcomes. We aimed to identify the role of collateral related donors(CRDs) in donor selection for haplo-HSCT through comparing the clinical outcomes between CRDs(n = 60) and maternal donors(MDs, n = 296), which were the last choice of donor selection in immediate related donors(IRDs). The cumulative incidence of graft-versus-host disease was comparable between CRDs and MDs. The 5-year cumulative incidence of relapse and non-relapse mortality was 22.0%(95% CI, 11.3%–32.7%) versus 17.4%(95% CI, 13.0%–21.8%)(P = 0.455) and 25.0%(95% CI, 13.9%–36.1%) versus 23.1%(95% CI, 18.2%–28.0%)(P = 0.721) for the CRDs and MDs, respectively. The 5-year probabilities of disease-free survival and overall survival was 53.2%(95% CI, 40.4%–66.0%) versus 59.5%(95% CI, 53.8%–65.2%)(P = 0.406) and 56.5%(95% CI,43.8%–69.2%) versus 61.8%(95% CI, 56.1%–67.5%)(P = 0.458) for the CRDs and MDs, respectively.Female donor/male recipient(FDMR) CRDs were associated with the poorest clinical outcomes, and the clinical outcomes of non-FDMR CRDs were comparable to those of MDs. In summary, our results showed that CRDs did not showed superiority over MDs. Thus, IRDs should be the first choice of donor selection, and CRDs could only be the donors for those without IRDs.

Relationship of Cell Compositions in AIIografts with Outcomes after Haploidentical Transplantation for Acquired Severe Aplastic Anemia： Effects of CD34＋ and CD14＋ Cell Doses

Background： The dose of certain cell types in allografts affects engraftment kinetics and clinical outcomes after allogeneic stem cell transplantation （SCT）. Hence, the present study investigated the association of cell compositions in allografts with outcomes after unmanipulated haploidentical SCT （haplo-SCT） for patients with acquired severe aplastic anemia （SAA）. Methods： A total of 131 patients with SAA who underwent haplo-SCT were retrospectively enrolled. Cell subsets in allografts were determined using flow cytometry. To analyze the association of cellular compositions and outcomes, Mann-Whitney U nonparametric tests were conducted for patient age, sex, weight, human leukocyte antigen mismatched loci, ABO-matched status, patient ABO blood type, donor-recipient sex match, donor-recipient relationship, and each graft component. Multivariate analysis was performed using logistic regression to determine independent influence factors involving dichotomous variables selected from the univariate analysis. Results： A total of 126 patients （97.7%） achieved neutrophil engraftment, and 121 patients （95.7%） achieved platelet engraftment. At 100 days after transplantation, the cumulative incidence of II-IV acute graft-versus-host disease （GVHD） was 32.6%. After a median follow-up of 842 （range： 124-4110） days for surviving patients, the cumulative incidence of total chronic GVHD at 3 years after transplantation was 33.7%. The probability of overall survival at 3 years was 83.0%. Multivariate analysis showed that higher total doses of CD14＋ （P = 0.018） and CD34＋ cells （P 〈 0.001） were associated with a successful platelet engraftment. A successthl platelet was associated with superior survival （P 〈 0.001）. No correlation of other cell components with outcomes was observed. Conclusions： These results provide evidence and explain that higher doses ofCD34＋ and CD 14＋ cells in haploidentical allografts positively affect platelet engraftment, contributing to superior survival for patients with SAA.

Association of Persistent Minimal Residual Disease with Poor Outcomes of Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background: Several studies have shown that detection of minimal residual disease (MRD) in acute myeloid leukemia (AML) is an independent prognostic factor. This study aimed to evaluate the significance of dynamic MRD pretransplantation on outcome of AML patients receiving allogeneic hematopoietic stem cell transplantation (allo?HSCT). Methods: We retrospectively analyzed 145 consecutive AML patients undergoing allo?HSCT in complete remission status between June 2013 and June 2016. MRD was determined with multiparameter flow cytometry after the first and second courses of chemotherapy and pre?HSCT. Results: In matched sibling donor transplantation (MSDT) settings, patients with positive MRD had higher cumulative incidence of relapse (CIR) than those without MRD after the first (32.3 ± 9.7% vs. 7.7 ± 3.1%, χ2 = 3.661, P = 0.055) or second course of chemotherapy (57.1 ± 3.6% vs. 12.5 ± 2.7%, χ2 = 8.759, P = 0.003) or pre?HSCT (50.0 ± 9.7% vs. 23.0 ± 3.2%, χ2 = 5.547, P = 0.019). In haploidentical SCT (haplo?SCT) settings, the MRD status at those timepoints had no significant impact on clinical outcomes. However, patients with persistent positive MRD from chemotherapy to pre?HSCT had higher CIR than those without persistent positive MRD both in MSDT and haplo?SCT settings. Patients with persistent positive MRD underwent MSDT had the highest relapse incidence, followed by those with persistent positive MRD underwent haplo?SCT, those without persistent MRD underwent haplo?SCT, and those without persistent MRD underwent MSDT (66.7 ± 9.2% vs. 38.5 ± 6.0% vs. 18.8 ± 8.7% vs. 12.0 ± 1.0%, χ2 = 20.763, P < 0.001). Multivariate analysis showed that persistent positive MRD before transplantation was associated with higher CIR (hazard ratio [HR] = 1.69, 95% confidence interval [CI]: 1.200–2.382, P = 0.003), worse leukemia?free survival (HR = 1.812, 95% CI: 1.168–2.812, P = 0.008), and overall survival (HR = 2.354, 95% CI: 1.528–3.627, P < 0.001). Conclusion: Our results suggest that persistent positive MRD before transplantation, rather than positive MRD at single timepoint, could predict poor outcome both in MSDT and haplo?SCT settings.

A risk score system for stratifying the risk of relapse in B cell acute lymphocytic leukemia patients after allogenic stem cell transplantation

Background:For patients with B cell acute lymphocytic leukemia(B-ALL)who underwent allogeneic stem cell transplantation(allo-SCT),many variables have been demonstrated to be associated with leukemia relapse.In this study,we attempted to establish a risk score system to predict transplant outcomes more precisely in patients with B-ALL after allo-SCT.Methods:A total of 477 patients with B-ALL who underwent allo-SCT at Peking University People’s Hospital from December 2010 to December 2015 were enrolled in this retrospective study.We aimed to evaluate the factors associated with transplant outcomes after allo-SCT,and establish a risk score to identify patients with different probabilities of relapse.The univariate and multivariate analyses were performed with the Cox proportional hazards model with time-dependent variables.Results:All patients achieved neutrophil engraftment,and 95.4%of patients achieved platelet engraftment.The 5-year cumulative incidence of relapse(CIR),overall survival(OS),leukemia-free survival(LFS),and non-relapse mortality were 20.7%,70.4%,65.6%,and 13.9%,respectively.Multivariate analysis showed that patients with positive post-transplantation minimal residual disease(MRD),transplanted beyond the first complete remission(≥CR2),and without chronic graft-versus-host disease(cGVHD)had higher CIR(P<0.001,P=0.004,and P<0.001,respectively)and worse LFS(P<0.001,P=0.017,and P<0.001,respectively),and OS(P<0.001,P=0.009,and P<0.001,respectively)than patients without MRD after transplantation,transplanted in CR1,and with cGVHD.A risk score for predicting relapse was formulated with the three above variables.The 5-year relapse rates were 6.3%,16.6%,55.9%,and 81.8%for patients with scores of 0,1,2,and 3(P<0.001),respectively,while the 5-year LFS and OS values decreased with increasing risk score.Conclusion:This new risk score system might stratify patients with different risks of relapse,which could guide treatment.

Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation

Adoptive transfer of cytomegalovirus(CMV)-specific cytotoxic T lymphocytes(CMV-CTLs)from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation(allo-SCT),but the antiviral activity of CMV-CTL types has not been compared.To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs,we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models,compared the in vivo recovery of CMV-specific immunity,and analyzed the underlying mechanisms driving sustained antiviral immunity.The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion.The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups.A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups.Our clinical study,which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection,further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity.We observed strong expansion of CD8+tetramer+T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion,which were associated with a reduced or cleared viral load.Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

NK cell reconstitution following unmanipulated HLA-mismatched/ haploidentical transplantation compared with matched sibling transplantation

Dear Editor,NK cells are the first cells reconstituted after Allogeneic haematopoietic stem cell transplantation(allo-HSCT)(Raulet and Vance,2006;Zhao et al.,2007).The roles of alloreactive NK cells are conflicting in allogeneic transplantation,mainly because several factors influence the reconstitution of NK cells,including different transplantation conditioning regimens,disease backgrounds and graft-versus-host disease(GVHD)prophylaxis(Zhao et al.,2011).

Correlation of CD19+CD24hiCD38hl B cells in coronary artery disease with severity of atherosclerosis

To the Editor:Atherosclerosis is a chronic inflammatory disease that involves multiple types of immune cells.Adaptive immunity exerts diverse and profound effects on atherosclerosis.The effector phenotype of lesional T cells may affect lesion growth and stability.Regulatory T cells with anti-inflammatory properties have been reported in atherosclerotic plaques.The targets of suppression of regulatory T cells include naive and effector CD4+and CD8+T cells,dendritic cells,and macrophages.A new subset of B cells,with CD19+CD24h,CD38hl phenotype in humans,is becoming a hot issue in the field of autoimmunity such as systemic lupus erythematosus and arthritis.*11 These regulatory B cells(Bregs)play important roles in immune system by regulating functions of effector and regulatory T cells.Bregs exhibit protective role by attenuating the neointimal formation of atherosclerosis through an interleukin 10(IL-10)mediated mechanism in a experimental study.121 There have been few studies on human Bregs in atherosclerosis disease until now.In this study we aimed to investigate CD 19+CD24hlCD38hl B cells in coronary artery disease(CAD)patients requiring coronary artery bypass graft(CABG)surgery.