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Global Metabolomics in Allogeneic Hematopoietic Cell Transplantation Recipients Discordant for Chronic Graft-versus-Host Disease 慢性移植物抗宿主病的异基因造血细胞移植受体的整体代谢组学不一致
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.06.014
Debra Lynch Kelly , Nosha Farhadfar , Angela Starkweather , Timothy J Garrett , Yingwei Yao , John R. Wingard , Iqbal Mahmud , Victoria Menzies , Param Patel , Karima M. Alabasi , Debra Lyon

Chronic graft-versus-host disease (cGVHD) remains a significant late effect issue for allogeneic hematopoietic cell transplantation (allo-HCT) survivors, contributing to morbidity and mortality. The etiology of cGVHD is not well elucidated. Owing to a lack of early diagnostic tests and pathophysiology ambiguity, targeted treatments remain limited. Biomarkers for prediction, control response, or prognostication have not yet been identified. Metabolomics, the quantification of metabolites, is a potential biomarker of cGVHD but has not been evaluated in this population. In this study, we examined global metabolites of stored plasma to identify differentially expressed metabolites of individuals discordant for cGVHD following allo-HCT. A descriptive, comparative, cross-sectional study design was used to examine differentially expressed metabolites of plasma samples obtained from 40 adult allo-HCT recipients (20 with cGVHD and 20 without cGVHD) from 2 parent studies. Metabolomics profiling was conducted at the University of Florida's Southeast Center for Integrative Metabolomics. Full experimental methods followed a previously published method. All statistical analyses were performed by a PhD-prepared, trained bioinformatics statistician. There were 10 differentially expressed metabolites between participants with cGVHD and those without cGVHD. Differential metabolites included those related to energy metabolism (n = 3), amino acid metabolism (n = 3), lipid metabolism (n = 2), caffeine metabolism (n = 1), and neurotransmission (n = 1). Serotonin had the greatest fold change (21.01). This study suggests that cGVHD may be associated with expanded cellular energy and potentially mitochondrial dysfunction. The differential metabolic profile between patients with and without cGVHD indicates metabolic perturbations that merit further exploration as potential biomarkers of cGVHD. These findings support the need for further examination using a larger, prospective study design to identify metabolomic risk factors that may signal the need for earlier preventive measures and earlier treatment to reduce cGVHD.

慢性移植物抗宿主病(cGVHD)仍然是异基因造血细胞移植(同种异体造血细胞移植)幸存者的一个重要的晚期效应问题,导致发病率和死亡率。cGVHD的病因尚不清楚。由于缺乏早期诊断测试和病理生理学的模糊性,有针对性的治疗仍然有限。预测、控制反应或预测的生物标志物尚未确定。代谢组学,即代谢物的量化,是cGVHD的潜在生物标志物,但尚未在该人群中进行评估。在这项研究中,我们检测了储存血浆的整体代谢物,以鉴定同种异体hct后cGVHD不一致个体的差异表达代谢物。采用描述性、对比性、横断面研究设计,对来自两项亲本研究的40名成人同种异体hct受体(20名cGVHD患者和20名非cGVHD患者)血浆样本中代谢物的差异表达进行了检测。代谢组学分析在佛罗里达大学东南综合代谢组学中心进行。完整的实验方法遵循先前发表的方法。所有统计分析均由博士学位准备,训练有素的生物信息学统计学家进行。在cGVHD患者和非cGVHD患者之间有10种代谢物表达差异。差异代谢物包括与能量代谢(n = 3)、氨基酸代谢(n = 3)、脂质代谢(n = 2)、咖啡因代谢(n = 1)和神经传递(n = 1)相关的代谢物,其中血清素的倍数变化最大(21.01)。这项研究表明,cGVHD可能与细胞能量扩大和潜在的线粒体功能障碍有关。cGVHD患者和非cGVHD患者之间的代谢谱差异表明,代谢扰动值得进一步探索,作为cGVHD的潜在生物标志物。这些发现支持了进一步研究的需要,通过更大的前瞻性研究设计来确定代谢组学危险因素,这些因素可能表明需要早期预防措施和早期治疗来降低cGVHD。
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引用次数: 7
Splenomegaly May Increase the Risk of Rejection in Low-Risk Matched Related Donor Transplant for Thalassemia, This Risk Can Be Partially Overcome by Additional Immunosuppression during Conditioning 脾大可能增加地中海贫血低风险匹配相关供体移植的排斥风险,这种风险可以通过调节期间额外的免疫抑制部分克服
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.06.013
Stalin Ramprakash , C.P. Raghuram , Priya Marwah , Rajpreet Soni , Deepa Trivedi , Sadaf Khalid , Naila Yaqub , Fatima Itrat , Sarah Khan Gilani , Tatheer Zahra , Rakesh Dhanya , Rajat Kumar Agarwal , Lawrence Faulkner

Severe thalassemia syndromes (ST) are highly curable by bone marrow transplant (BMT), but rejection may still occur. We retrospectively analyzed our fully matched related donor transplants to establish if isolated splenomegaly is an independent risk factor for rejection and if this risk can be reduced by modifying the conditioning protocol. In this study, we compared rejection rates between patients with and without splenomegaly in 189 consecutive low-risk ST transplants across 2 sequential conditioning regimens: regimen A (August 2013 to December 2016): busulfan (14 mg/kg oral, not adjusted to serum levels), cyclophosphamide (200 mg/kg), and anti-thymocyte globulin (ATG) (Genzyme (Sanofi, Paris, France) 4 mg/kg or Fresenius (Grafalon, Neovii Biotech GmbH, Gräfelfing Germany) 16 mg/kg on days –12 to –10), and regimen B: same backbone as regimen A except fludarabine total dose of 150 mg was added upfront and ATG dose was increased to 7 mg/kg in case of splenomegaly and/or sex-mismatched transplants (January 2017 to September 2018). Compared with regimen A, in regimen B, both overall rejection rates (RRs) (16% versus 6.5%, P = .023) and treatment-related mortality (TRM) (9.9% versus 2.8%, P = .038) improved significantly. By Cox regression analysis, the improvement in RR between the 2 protocols was particularly significant in patients with splenomegaly (RR 54.5% versus 6.5%, P = .00015; TRM 18.2% versus 6.5%, P = .25) (hazard ratio, 4.13; confidence interval, 1.61 to 10.6; P = .003). The increased risk of rejection related to splenomegaly can be overcome by adding fludarabine to the standard ATG-Busulfan- Cyclophosphamide (ATG-Bu-Cy) protocol without significantly increasing transplant-related morbidity and mortality or resorting to splenectomy pre-BMT.

严重地中海贫血综合征(ST)可通过骨髓移植(BMT)高度治愈,但仍可能发生排斥反应。我们回顾性分析了完全匹配的相关供体移植,以确定孤立性脾肿大是否是排斥反应的独立危险因素,以及是否可以通过修改条件方案来降低这种风险。在这项研究中,我们比较了189例连续低风险ST移植患者的脾肿大和非脾肿大患者在2个顺序调节方案中的排异率:方案A(2013年8月至2016年12月):busulfan(口服14mg /kg,未调整到血清水平)、环磷酰胺(200mg /kg)和抗胸腺细胞球蛋白(ATG) (Genzyme (Sanofi, Paris, France) 4mg /kg或Fresenius (Grafalon, Neovii Biotech GmbH, Gräfelfing德国)16mg /kg,第12天至第10天),方案B。2017年1月至2018年9月,在脾大和/或性别不匹配移植的情况下,前期增加氟达拉滨总剂量150 mg, ATG剂量增加至7 mg/kg,与方案A相同。与方案A相比,方案B的总排斥率(RRs)(16%对6.5%,P = 0.023)和治疗相关死亡率(TRM)(9.9%对2.8%,P = 0.038)均显著改善。Cox回归分析显示,两种治疗方案在脾肿大患者中的RR改善尤为显著(RR分别为54.5%和6.5%,P = 0.00015;TRM为18.2%对6.5%,P = 0.25)(风险比4.13;置信区间为1.61 ~ 10.6;p = .003)。通过在标准ATG-Busulfan- Cyclophosphamide (ATG-Bu-Cy)方案中加入氟达拉滨,可以克服脾大相关排斥反应风险的增加,而不会显著增加移植相关的发病率和死亡率,也不会在bmt前进行脾切除术。
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引用次数: 2
Chimeric Antigen Receptor Therapy: How Are We Driving in Solid Tumors? 嵌合抗原受体治疗:我们如何在实体肿瘤中驱动?
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.06.020
Uri Greenbaum , Fevzi F. Yalniz , Samer A. Srour , Katayoun Rezvani , Harjeet Singh , Amanda Olson , George Blumenschein Jr , David S. Hong , Elizabeth J. Shpall , Partow Kebriaei

Immune effector cell (IEC) therapy is emerging as a promising approach in the field of cancer immunotherapy. Clinical IEC trials, predominantly using chimeric antigen receptor (CAR) T cells, have shown excellent responses in CD19+ B cell malignancies and multiple myeloma. In solid tumors, preclinical data are encouraging, but clinical data are in their infancy, and there are challenges in using CAR T therapy in this setting, including (1) on-target off-tumor toxicity, (2) optimal target identification, (3) effective trafficking into bulky tumor tissue, and (4) resistance to tumor immune evasion mechanisms.

Novel techniques and modifications are being explored in both the preclinical and clinical settings, aiming to improve treatment efficacy and address the aforementioned obstacles to successful CAR T therapy in solid tumors. Here we review these challenges in a clinically oriented approach and summarize published clinical trials using CAR T therapy in a variety of solid tumors.

免疫效应细胞(IEC)治疗是肿瘤免疫治疗领域的一种很有前途的方法。临床IEC试验主要使用嵌合抗原受体(CAR) T细胞,在CD19+ B细胞恶性肿瘤和多发性骨髓瘤中显示出良好的应答。在实体瘤中,临床前数据令人鼓舞,但临床数据尚处于起步阶段,在这种情况下使用CAR - T疗法存在挑战,包括(1)靶外肿瘤毒性,(2)最佳靶点识别,(3)有效运输到庞大的肿瘤组织,以及(4)抵抗肿瘤免疫逃避机制。新的技术和改进正在临床前和临床环境中进行探索,旨在提高治疗效果并解决上述阻碍CAR - T治疗实体瘤成功的障碍。在这里,我们以临床为导向的方法回顾了这些挑战,并总结了在各种实体瘤中使用CAR - T疗法的已发表的临床试验。
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引用次数: 7
Volume of Gadolinium Enhancement and Successful Repair of the Blood-Brain Barrier in Cerebral Adrenoleukodystrophy 脑肾上腺白质营养不良患者的钆增强体积和血脑屏障的成功修复
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.06.019
Troy C. Lund , Michelle Ng , Paul J. Orchard , Daniel J. Loes , Gerald V. Raymond , Ashish Gupta , Dan Kenny-Jung , David R. Nascene

Up to 40% of boys with adrenoleukodystrophy develop a severe central nervous system demyelinating form (cALD) characterized by white matter changes and gadolinium enhancement on magnetic resonance imaging (MRI). Hematopoietic cell transplant (HCT) is the only proven means to attenuate cALD progression. The elimination of active neuroinflammation is indicated radiographically by the resolution of gadolinium (Gd) enhancement and correlates to speed of donor neutrophil recovery. We analyzed 66 boys with cALD undergoing HCT for biomarkers correlating with early (30 days post-HCT) Gd signal resolution. We found that log Gd volume (cm3) on pre-HCT MRI strongly positively correlated to day 30 Gd resolution (P = .0003) with smaller volume correlating to higher proportion resolved, as was the baseline gadolinium intensity score (P = .04), plasma chitotriosidase activity (P = .04), and faster absolute neutrophil count recovery (P = .03). In multivariate analysis, log Gd volume remained superior in determining which patients would have Gd signal resolution by 30 days post-HCT (P = .016). A final analysis indicated that early Gd resolution also correlated with less neurologic progression from baseline to 1 year following HCT (P = .006). MRI Gd volume may serve as a contributing biomarker to better delineate outcomes and an important metric in comparing therapies in the treatment of cALD.

高达40%的肾上腺脑白质营养不良男孩发展为严重的中枢神经系统脱髓鞘形式(cALD),其特征是白质改变和磁共振成像(MRI)的钆增强。造血细胞移植(HCT)是唯一被证实的减轻cALD进展的方法。活动性神经炎症的消除是通过钆(Gd)增强的分辨率来指示的,并与供体中性粒细胞恢复的速度相关。我们分析了66名接受HCT的cALD男孩,以寻找与早期(HCT后30天)Gd信号分辨率相关的生物标志物。我们发现,hct前MRI上的Gd体积(cm3)与第30天的Gd分辨率呈强正相关(P = 0.0003),体积越小,分辨率越高,基线钆强度评分(P = .04)、血浆壳三酸苷酶活性(P = .04)和绝对中性粒细胞计数恢复速度越快(P = .03)也是如此。在多变量分析中,对数Gd体积在确定hct后30天Gd信号分辨率方面仍然优于其他患者(P = .016)。最终分析表明,早期Gd消退也与HCT后基线至1年的神经系统进展较少相关(P = .006)。MRI Gd体积可以作为一种有贡献的生物标志物,以更好地描述结果,并作为比较cALD治疗方法的重要指标。
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引用次数: 4
Low Nonrelapse Mortality after HLA-Matched Related 2-Step Hematopoietic Stem Cell Transplantation Using Cyclophosphamide for Graft-versus-Host Disease Prophylaxis and the Potential Impact of Non- Cyclophosphamide-Exposed T Cells on Outcomes 使用环磷酰胺进行hla匹配相关2步造血干细胞移植预防移植物抗宿主病后的低非复发死亡率和非环磷酰胺暴露的T细胞对结果的潜在影响
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.06.021
Dolores Grosso , Matthew Carabasi , Joanne Filicko-O'Hara , John L. Wagner , William O'Hara , Michael Sun , Beth Colombe , W. Shi , Maria Werner-Wasik , Shannon Rudolph , Onder Alpdogan , Adam Binder , Margaret Kasner , Thomas Klumpp , Ubaldo Martinez-Outschoorn , Neil Palmisiano , Lindsay Wilde , Pierluigi Porcu , Usama Gergis , Neal Flomenberg

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

环磷酰胺(CY)用于受体和供体T细胞的双向耐受与hla匹配的造血干细胞移植(HSCT)后移植物抗宿主病(GVHD)和非复发死亡率(NRM)的降低有关。然而,复发性疾病仍然是长期生存的主要障碍。我们将两步方法扩展到hla匹配的相关HSCT,使用基于放射的清髓调节方案结合高剂量T细胞,试图降低复发率,同时保持CY耐受性的有益效果。经调节后,患者接受2组移植物:(1)固定剂量2 × 108/kg T细胞,2天后接受CY, (2) cd34选择的移植物含有少量未CY暴露的T细胞,中位剂量为2.98 × 103/kg。对46例恶性血液病患者进行了治疗。尽管采用了清髓调节方案和使用高剂量的T细胞,但1年和5年II-IV级急性GVHD、慢性GVHD和NRM的累积发病率非常低,分别为13%、9%和4.3%。这使得1年和5年的总生存率分别达到89.1%和65.8%。复发是死亡的主要原因,1年和5年的累计发病率分别为23.9%和45.7%。在一项事后分析中,接受CD34产品中非cy暴露残余T细胞大于或小于组中位数的患者的复发率显著低于接受CD34产品中位数的患者(19.3%对58.1%;P = 0.009), NRM未同时升高。在目前的形式下,这种两步治疗方案是高度耐受的,但需要减少复发的策略,可能需要添加未暴露于CY的T细胞。
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引用次数: 1
Suppression of Hematopoietic Primitive Cells in Patients with Secondary Failure of Platelet Recovery after Acute Graft-versus-Host Disease 急性移植物抗宿主病后继发性血小板恢复失败患者的造血原始细胞抑制
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.06.003
Aijie Huang, Xiaoming Zhao, Meizhang Li, Gusheng Tang, Yang Fei, Roujia Wang, Lei Gao, Xiong Ni, Weiping Zhang, Jianmin Yang, Xiaoxia Hu, Jianmin Wang

Secondary failure of platelet recovery (SFPR) can occur after allogeneic hematopoietic stem cell transplantation (alloHSCT), and 20% of cases are related to acute graft-versus-host disease (aGVHD). The underlying mechanisms of this association are unclear, however. The aim of the present study was to investigate the potential mechanisms of SFPR secondary to aGVHD, which may provide a new therapeutic strategy for these patients. A total of 468 patients with malignant hematologic disease who underwent alloHSCT were included. Sixty-six patients developed SFPR after alloHSCT, and in 45 of these 66 patients (68.2%), SFPR was secondary to grade II-IV aGVHD (SFPR/aGVHD). Compared with patients with good graft function (GGF), patients with SFPR had poor overall survival (20.72% versus 88.01%; P < .0001). Grade II-IV aGVHD was identified as an independent risk factor for SFPR in multivariate analysis (hazard ratio, 9.512; P < .0001). We observed reduced erythroid and megakaryocyte colony formation in bone marrow (BM) samples isolated from SFPR/aGVHD patients, consistent with the lower frequency of megakaryocyte and erythrocyte progenitors in BM. Levels of the inflammatory cytokines IL-2R and TNF-R1 were significantly higher in the SFPR/aGVHD group compared with the GGF group (P = .002 and .001, respectively), as were the frequencies of proinflammatory T helper subsets. Furthermore, the pathways that regulate hematopoiesis and immune responses were universally underexpressed in CD34+ cells isolated from SFPR/aGVHD patients. Differentially expressed genes were significantly enriched in the hematopoietic cell lineage pathway and other pathways involved in both immune responses and megakaryopoiesis. In summary, we found that both the immune microenvironment and compromised proliferation of hematopoietic primitive cells contribute to the development of SFPR secondary to aGVHD, and our data provide new insight into the mechanisms of SFPR in the context of aGVHD.

同种异体造血干细胞移植(alloHSCT)后可发生继发性血小板恢复失败(SFPR), 20%的病例与急性移植物抗宿主病(aGVHD)有关。然而,这种关联的潜在机制尚不清楚。本研究旨在探讨aGVHD继发SFPR的潜在机制,为这些患者提供新的治疗策略。共纳入468例接受同种异体造血干细胞移植的恶性血液病患者。66例患者在同种异体移植后发生SFPR,其中45例(68.2%)SFPR继发于II-IV级aGVHD (SFPR/aGVHD)。与移植物功能良好的患者(GGF)相比,SFPR患者的总生存率较差(20.72% vs 88.01%;P & lt;。)。在多因素分析中,II-IV级aGVHD被确定为SFPR的独立危险因素(风险比,9.512;P & lt;。)。我们观察到SFPR/aGVHD患者骨髓(BM)样品中红细胞和巨核细胞集落形成减少,与BM中巨核细胞和红细胞祖细胞频率降低一致。与GGF组相比,SFPR/aGVHD组的炎症细胞因子IL-2R和TNF-R1水平显著升高(P分别为0.002和0.001),促炎T辅助亚群的频率也显著升高。此外,从SFPR/aGVHD患者分离的CD34+细胞中,调节造血和免疫反应的途径普遍表达不足。差异表达基因在造血细胞谱系途径和其他涉及免疫反应和巨核生成的途径中显著富集。综上所述,我们发现免疫微环境和造血原始细胞增殖受损都有助于aGVHD继发性SFPR的发展,我们的数据为aGVHD背景下SFPR的机制提供了新的见解。
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引用次数: 4
Investigation and Management of Bone Mineral Density Following Hematopoietic Cell Transplantation: A Survey of Current Practice by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation 造血细胞移植后骨密度的调查和管理:欧洲血液和骨髓移植学会移植并发症工作组对当前实践的调查
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.06.022
Nina Salooja , Hildegaard Greinix , Tapani Ruutu , Steffie van der Werf , Anja van Biezen , Anita Lawitschka , Grzegorz Basak , Rafael Duarte

Reduced bone mineral density (BMD) is a well-recognized complication of hematopoietic cell transplantation (HCT), with significant drops in BMD occurring within the first 12 months after HCT. Guidance on identifying and managing this complication is available in several published guidelines. In this study, we investigated current practices in the investigation and management of low BMD in centers registered with the European Society for Blood and Marrow Transplantation (EBMT). A questionnaire about bone health was sent to all registered centers, and responses were received from 99 centers in 25 countries (52%) currently registered with the EBMT. Our data highlight considerable heterogeneity in practices across European centers in relation to investigations, management, and use of guidelines. Our data demonstrate the need for better dissemination and implementation of existing guidelines and also for the development of multidisciplinary guidelines with input from all relevant stakeholders.

骨矿物质密度(BMD)降低是造血细胞移植(HCT)的一个公认的并发症,骨密度在HCT后的头12个月内显著下降。在一些已出版的指南中提供了关于识别和处理这种并发症的指导。在这项研究中,我们调查了目前在欧洲血液和骨髓移植协会(EBMT)注册的中心调查和管理低骨密度的做法。向所有注册中心发送了一份关于骨骼健康的问卷,并收到了来自25个国家99个中心(52%)目前在EBMT注册的回复。我们的数据突出了欧洲各中心在调查、管理和使用指南方面的实践存在相当大的异质性。我们的数据表明,需要更好地传播和实施现有指南,也需要在所有相关利益相关者的投入下制定多学科指南。
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引用次数: 0
Predicting Mortality after Autologous Transplant: Development of a Novel Risk Score 预测自体移植后的死亡率:一种新的风险评分方法的发展
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.06.028
Mariano Berro , Saurabh Chhabra , José Luis Piñana , Jorge Arbelbide , Maria M. Rivas , Ana Lisa Basquiera , Adriana Vitriu , Alejandro Requejo , Vera Milovic , Sebastian Yantorno , Gonzalo Bentolila , Juan Jose Garcia , Martin Castro , Silvina Palmer , Martin Saslavsky , Patricio Duarte , Amalia Cerutti , Gustavo Jarchum , Matias Tisi Baña , Bicky Thapa , Gustavo Kusminsky

There have been several efforts to predict mortality after autologous stem cell transplantation (ASCT), such as the hematopoietic cell transplant-comorbidity index (HCT-CI), described for allogeneic stem cell transplantation and validated for ASCT, but there is no composite score in the setting of ASCT combining comorbidities with other clinical characteristics. Our aim is to describe a comprehensive score combining comorbidities with other clinical factors and to analyze the impact of this score on nonrelapse mortality (NRM), overall survival (OS), and early morbidity endpoints (mechanical ventilation, shock or dialysis) after ASCT. For the training cohort, we retrospectively reviewed data of 2068 adult patients who received an ASCT in Argentina (October 2002 to June 2017) for multiple myeloma or lymphoma. For the validation cohort, we analyzed 2168 ASCTs performed in the Medical College of Wisconsin and Spanish stem cell transplant group (Grupo Español de Trasplante Hematopoyético (GETH)) (January 2012 to December 2018). We first performed a multivariate analysis for NRM in order to select and assign weight to the risk factors included in the score (male patients, aged 55 to 64 and ≥65 years, HCT-CI ≥3, Hodgkin lymphoma and non-Hodgkin lymphoma). The hazard ratio for NRM increased proportionally with the score. Patients were grouped as low risk (LR) with a score of 0 to 1 (686, 33%), intermediate risk (IR) with a score of 2 to 3 (1109, 53%), high risk (HR) with a score of 4 (198, 10%), and very high risk (VHR) with a score of ≥5 (75, 4%). The score was associated with a progressive increase in all the early morbidity endpoints. Moreover, the score was significantly associated with early NRM (day 100: 1.5% versus 2.4% versus 7.6% versus 17.6%) as well as long term (1 to 3 years; 1.8% to 2.3% versus 3.8% to 4.9% versus 11.7% to 14.5% versus 25.0% to 27.4%, respectively; P< .0001) and OS (1 to 5 years; 94% to 73% versus 89% to 75% versus 76% to 47% versus 65% to 52% respectively; P < .0001). The score was validated in an independent cohort (N = 2168) and was significantly associated with early and late events. In conclusion, we developed and validated a novel score predicting NRM and OS in 2 large cohorts of more than 2000 autologous transplant patients. This tool can be useful for tailoring conditioning regimens or defining risk for transplant program decision making.

已有一些研究试图预测自体干细胞移植(ASCT)后的死亡率,如造血细胞移植合并症指数(HCT-CI),该指标用于异体干细胞移植,并对ASCT进行了验证,但在ASCT合并合并症和其他临床特征的情况下,没有综合评分。我们的目的是描述一个结合合并症和其他临床因素的综合评分,并分析该评分对ASCT后非复发死亡率(NRM)、总生存期(OS)和早期发病率终点(机械通气、休克或透析)的影响。对于培训队列,我们回顾性回顾了阿根廷(2002年10月至2017年6月)接受多发性骨髓瘤或淋巴瘤ASCT的2068名成年患者的数据。对于验证队列,我们分析了2012年1月至2018年12月在威斯康辛医学院和西班牙干细胞移植组(Grupo Español de Trasplante hematopoy2013.com (GETH))进行的2168例asct。我们首先对NRM进行了多变量分析,以选择和分配评分中包含的危险因素(男性患者,年龄55 - 64岁,≥65岁,HCT-CI≥3,霍奇金淋巴瘤和非霍奇金淋巴瘤)。NRM的风险比随着得分成比例地增加。患者分为低危(LR),评分为0 ~ 1分(686.33%),中危(IR),评分为2 ~ 3分(1109,53%),高危(HR),评分为4分(198,10%),极高危(VHR),评分≥5分(75.4%)。该评分与所有早期发病率终点的进行性增加相关。此外,该评分与早期NRM(第100天:1.5% vs . 2.4% vs . 7.6% vs . 17.6%)以及长期(1至3年;分别是1.8% - 2.3% 3.8% - 4.9% 11.7% - 14.5% 25.0% - 27.4%;术中;0.0001)和OS(1 - 5年;94%对73% 89%对75% 76%对47% 65%对52%P & lt;。)。该评分在独立队列(N = 2168)中得到验证,并与早期和晚期事件显著相关。总之,我们在2000多名自体移植患者的2个大队列中开发并验证了一种预测NRM和OS的新评分。该工具可用于定制调理方案或确定移植计划决策的风险。
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引用次数: 7
Black Lives and Black Donors Matter Post-Hematopoietic Stem Cell Transplantation 黑人生命和黑人供体影响造血干细胞移植
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.08.007
Mitchell S. Cairo
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引用次数: 0
Ixazomib for Chronic Graft-versus-Host Disease Prophylaxis following Allogeneic Hematopoietic Cell Transplantation 伊沙唑米预防异基因造血细胞移植后慢性移植物抗宿主病
IF 4.3 Q1 Medicine Pub Date : 2020-10-01 DOI: 10.1016/j.bbmt.2020.07.005
Saurabh Chhabra , Alexis Visotcky , Marcelo C. Pasquini , Fenlu Zhu , Xiaoying Tang , Mei-Jie Zhang , Robert Thompson , Sameem Abedin , Anita D'Souza , Binod Dhakal , William R. Drobyski , Timothy S. Fenske , James H. Jerkins , J. Douglas Rizzo , Lyndsey Runaas , Wael Saber , Nirav N. Shah , Bronwen E. Shaw , Mary M. Horowitz , Parameswaran N. Hari , Mehdi Hamadani

Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

慢性移植物抗宿主病(cGVHD)是异基因造血细胞移植(HCT)后发病和死亡的主要原因。Ixazomib是一种口服第二代蛋白酶体抑制剂,已在临床前模型中显示可预防GVHD。我们在57名患者中进行了一项I/II期试验,以评估ixazomib在接受同种异体HCT的患者中预防cGVHD的安全性和有效性。一旦在I期(n = 6)确定了推荐的4 mg II期剂量,口服伊沙唑米每周给配相关供体(MRD, n = 25)或匹配非相关供体(MUD, n = 26)异体HCT患者,共4次剂量,从+60天开始到+90天。所有患者接受外周血移植和他克莫司和甲氨蝶呤的标准GVHD预防。Ixazomib给药安全且耐受性良好,血小板减少、白细胞减少、胃肠道不适和疲劳是最常见的不良事件(10%)。在II期(n = 51)中,MRD组1年cGVHD累积发病率为36%(95%可信区间[CI], 19% - 54%), MUD组为39% (95% CI, 21% - 56%)。MRD队列的1年累计非复发死亡率(NRM)和复发率分别为0%和20% (95% CI, 8%至36%)。在MUD队列中,NRM和复发率分别为4%(0%至16%)和34%(17%至52%)。该研究的结果与同期匹配的国际血液和骨髓移植研究中心(CIBMTR)对照进行了比较。事后分析显示,与CIBMTR对照组相比,MRD组(风险比[HR] = 0.85, P = 0.64)或MUD组(风险比[HR] = 0.68, P = 0.26)的cGVHD发生率均无显著改善。与已发生cGVHD的患者相比,未发生cGVHD的患者服用伊沙唑米后血浆B细胞活化因子水平显著升高。这项研究表明,同种异体HCT后短期口服伊沙唑米的新策略是安全的,但与匹配的CIBMTR对照相比,MRD和MUD移植受体的cGVHD发病率没有显着改善。本研究注册于www.clinicaltrials.gov,编号为NCT02250300。
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引用次数: 5
期刊
Biology of Blood and Marrow Transplantation
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