Pub Date : 2020-10-01DOI: 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.
{"title":"Volume of Gadolinium Enhancement and Successful Repair of the Blood-Brain Barrier in Cerebral Adrenoleukodystrophy","authors":"Troy C. Lund , Michelle Ng , Paul J. Orchard , Daniel J. Loes , Gerald V. Raymond , Ashish Gupta , Dan Kenny-Jung , David R. Nascene","doi":"10.1016/j.bbmt.2020.06.019","DOIUrl":"10.1016/j.bbmt.2020.06.019","url":null,"abstract":"<div><p>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 (cm<sup>3</sup>) on pre-HCT MRI strongly positively correlated to day 30 Gd resolution (<em>P</em> = .0003) with smaller volume correlating to higher proportion resolved, as was the baseline gadolinium intensity score (<em>P</em> = .04), plasma chitotriosidase activity (<em>P</em> = .04), and faster absolute neutrophil count recovery (<em>P</em> = .03). In multivariate analysis, log Gd volume remained superior in determining which patients would have Gd signal resolution by 30 days post-HCT (<em>P</em> = .016). A final analysis indicated that early Gd resolution also correlated with less neurologic progression from baseline to 1 year following HCT (<em>P</em> = .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.</p></div>","PeriodicalId":9165,"journal":{"name":"Biology of Blood and Marrow Transplantation","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.bbmt.2020.06.019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38098459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 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.
{"title":"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","authors":"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","doi":"10.1016/j.bbmt.2020.06.021","DOIUrl":"10.1016/j.bbmt.2020.06.021","url":null,"abstract":"<div><p>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 × 10<sup>8</sup>/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 × 10<sup>3</sup>/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%; <em>P</em> = .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.</p></div>","PeriodicalId":9165,"journal":{"name":"Biology of Blood and Marrow Transplantation","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.bbmt.2020.06.021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38128914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 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。
{"title":"Suppression of Hematopoietic Primitive Cells in Patients with Secondary Failure of Platelet Recovery after Acute Graft-versus-Host Disease","authors":"Aijie Huang, Xiaoming Zhao, Meizhang Li, Gusheng Tang, Yang Fei, Roujia Wang, Lei Gao, Xiong Ni, Weiping Zhang, Jianmin Yang, Xiaoxia Hu, Jianmin Wang","doi":"10.1016/j.bbmt.2020.06.003","DOIUrl":"10.1016/j.bbmt.2020.06.003","url":null,"abstract":"<div><p>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%; <em>P <</em> .0001). Grade II-IV aGVHD was identified as an independent risk factor for SFPR in multivariate analysis (hazard ratio, 9.512; <em>P <</em> .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 (<em>P</em> = .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<sup>+</sup> 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.</p></div>","PeriodicalId":9165,"journal":{"name":"Biology of Blood and Marrow Transplantation","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.bbmt.2020.06.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38045682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 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.
{"title":"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","authors":"Nina Salooja , Hildegaard Greinix , Tapani Ruutu , Steffie van der Werf , Anja van Biezen , Anita Lawitschka , Grzegorz Basak , Rafael Duarte","doi":"10.1016/j.bbmt.2020.06.022","DOIUrl":"10.1016/j.bbmt.2020.06.022","url":null,"abstract":"<div><p>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.</p></div>","PeriodicalId":9165,"journal":{"name":"Biology of Blood and Marrow Transplantation","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1083879120303979/pdfft?md5=92314f167250d6ea920712c0b5fe8f40&pid=1-s2.0-S1083879120303979-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38123520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 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。
{"title":"Predicting Mortality after Autologous Transplant: Development of a Novel Risk Score","authors":"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","doi":"10.1016/j.bbmt.2020.06.028","DOIUrl":"10.1016/j.bbmt.2020.06.028","url":null,"abstract":"<div><p>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; <em>P</em>< .0001) and OS (1 to 5 years; 94% to 73% versus 89% to 75% versus 76% to 47% versus 65% to 52% respectively; <em>P</em> < .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.</p></div>","PeriodicalId":9165,"journal":{"name":"Biology of Blood and Marrow Transplantation","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.bbmt.2020.06.028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38138135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 10.1016/j.bbmt.2020.08.007
Mitchell S. Cairo
{"title":"Black Lives and Black Donors Matter Post-Hematopoietic Stem Cell Transplantation","authors":"Mitchell S. Cairo","doi":"10.1016/j.bbmt.2020.08.007","DOIUrl":"10.1016/j.bbmt.2020.08.007","url":null,"abstract":"","PeriodicalId":9165,"journal":{"name":"Biology of Blood and Marrow Transplantation","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.bbmt.2020.08.007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38255032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 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。
{"title":"Ixazomib for Chronic Graft-versus-Host Disease Prophylaxis following Allogeneic Hematopoietic Cell Transplantation","authors":"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","doi":"10.1016/j.bbmt.2020.07.005","DOIUrl":"10.1016/j.bbmt.2020.07.005","url":null,"abstract":"<div><p>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, <em>P</em> = .64) or MUD cohorts (HR = 0.68, <em>P</em> = .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 <span>www.clinicaltrials.gov</span><svg><path></path></svg> as NCT02250300.</p></div>","PeriodicalId":9165,"journal":{"name":"Biology of Blood and Marrow Transplantation","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.bbmt.2020.07.005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38143804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 10.1016/j.bbmt.2020.07.004
Kathryn L. Bradford , Siyu Liu , Maja Krajinovic , Marc Ansari , Elizabeth Garabedian , John Tse , Xiaoyan Wang , Kit L. Shaw , H. Bobby Gaspar , Fabio Candotti , Donald B. Kohn
The pharmacokinetics of low-dose busulfan (BU) were investigated as a nonmyeloablative conditioning regimen for autologous gene therapy (GT) in pediatric subjects with adenosine deaminase-deficient severe combined immunodeficiency disease (ADA SCID). In 3 successive clinical trials, which included either γ-retroviral (γ-RV) or lentiviral (LV) vectors, subjects were conditioned with BU using different dosing nomograms. The first cohort received BU doses based on body surface area (BSA), the second cohort received doses based on actual body weight (ABW), and in the third cohort, therapeutic drug monitoring (TDM) was used to target a specific area under the concentration-time curve (AUC). Neither BSA-based nor ABW-based dosing achieved a consistent cumulative BU AUC; in contrast, TDM-based dosing led to more consistent AUC. BU clearance increased as subject age increased from birth to 18 months. However, weight and age alone were insufficient to accurately predict the dose that would consistently achieve a target AUC. Furthermore, various clinical, laboratory, and genetic factors (eg, genotypes for glutathione-S-transferase isozymes known to participate in BU metabolism) were analyzed, but no single finding predicted subjects with rapid versus slow clearance. Analysis of BU AUC and the postengraftment vector copy number (VCN) in granulocytes, a surrogate marker of the level of engrafted gene-modified hematopoietic stem and progenitor cells (HSPCs), demonstrated gene marking at levels sufficient for therapeutic benefit in the subjects who had achieved the target BU AUC. Although many factors determine the ultimate engraftment following GT, this work demonstrates that the BU AUC correlated with the eventual level of engrafted gene-modified HSPCs within a vector group (γ-RV versus LV), with significantly higher levels of granulocyte VCN in the recipients of LV-modified grafts compared to recipients of γ-RV-transduced grafts. Taken together, these findings provide insight into low-dose BU pharmacokinetics in the unique setting of autologous GT for ADA SCID, and these dosing principles may be applied to future GT trials using low-dose BU to open the bone marrow niche.
研究了低剂量丁硫丹(BU)作为一种非清髓调节方案用于小儿腺苷脱氨酶缺陷严重联合免疫缺陷病(ADA SCID)的自体基因治疗(GT)的药代动力学。在3个连续的临床试验中,包括γ-逆转录病毒(γ-RV)或慢病毒(LV)载体,受试者使用不同的剂量图接受BU治疗。第一组采用基于体表面积(BSA)给药,第二组采用基于实际体重(ABW)给药,第三组采用治疗药物监测(TDM)在浓度-时间曲线(AUC)下针对特定区域给药。基于bsa和abw的给药均未达到一致的累积BU AUC;相比之下,基于tdm的剂量导致更一致的AUC。从出生到18个月,BU清除率随着受试者年龄的增加而增加。然而,仅凭体重和年龄不足以准确预测持续达到目标AUC的剂量。此外,我们分析了各种临床、实验室和遗传因素(例如,已知参与布鲁里溃疡代谢的谷胱甘肽- s -转移酶同工酶的基因型),但没有一个单一的发现预测受试者的清除速度是快还是慢。分析BU AUC和移植后粒细胞的载体拷贝数(VCN),这是移植基因修饰的造血干细胞和祖细胞(HSPCs)水平的替代标志物,表明基因标记水平足以使达到目标BU AUC的受试者获得治疗益处。尽管许多因素决定了GT后的最终移植,但本研究表明,在载体组(γ-RV vs . LV)中,BU AUC与移植基因修饰的HSPCs的最终水平相关,与γ-RV转导的移植物受体相比,LV修饰的移植物受体的粒细胞VCN水平明显更高。综上所述,这些发现为ADA SCID自体GT治疗中低剂量BU的药代动力学提供了见解,这些给药原则可能适用于未来使用低剂量BU打开骨髓生态位的GT试验。
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Pub Date : 2020-10-01DOI: 10.1016/j.bbmt.2020.06.005
Go-Un Woo , Junshik Hong , Hyangseon Kim , Ja Min Byun , Youngil Koh , Dong-Yeop Shin , Inho Kim , Sung-Soo Yoon
The integration of antithymocyte globulin (ATG) into therapy has significantly reduced the incidence of graft-versus-host disease (GVHD) and is being actively used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The ATG dosage is determined by the recipient's body weight, but some insist that this approach does not reflect the actual target of ATG. In this respect, weight-based dosing may lead to ATG overdose, particularly in recipients with a relatively low absolute lymphocyte count (ALC). We retrospectively analyzed 84 patients with acute leukemia or myelodysplastic syndrome who underwent matched related donor (MRD) allo-HSCT with reduced-intensity conditioning (RIC) at a single institution. Patients were dichotomized according to the ALC measured on the first day of conditioning (day -7) to investigate the associations of the ALC with GVHD and survival outcomes. The median duration of follow-up was 29 months. The preconditioning ALC was closely correlated with the ALC at the first ATG administration (day -3). The cumulative incidences of both acute GVHD and chronic GVHD were significantly lower in the preconditioning ALC <500/μL group compared with the ALC ≥500/μL group. There was no significant difference in disease relapse incidence between the 2 groups; however, mortality was significantly higher in the ALC <500/μL group. Multivariate analysis including disease status, modified European Blood and Marrow Transplantation score, and preconditioning ALC (≥500/μL versus <500/μL) identified disease status and ALC as being independently associated with overall survival (OS). In particular, infection was the most common cause of death in the ALC <500/μL group. Our data suggest that uniform weight-based ATG dosing in MRD allo-HSCT with RIC is associated with an increase in nonrelapse mortality and a relatively inferior OS in patients with a significantly low preconditioning ALC. Therefore, alternative strategies for the integration of ATG should be considered in allo-HSCT, at least for patients with a substantially low preconditioning ALC.
抗胸腺细胞球蛋白(ATG)整合到治疗中显著降低了移植物抗宿主病(GVHD)的发病率,并被积极用于同种异体造血干细胞移植(alloo - hsct)。ATG的剂量由受体的体重决定,但有人坚持认为这种方法不能反映ATG的实际目标。在这方面,以体重为基础的给药可能导致ATG过量,特别是在绝对淋巴细胞计数(ALC)相对较低的受体中。我们回顾性分析了84例急性白血病或骨髓增生异常综合征患者,他们在同一家机构接受了匹配相关供体(MRD)低强度调节(RIC)的同种异体造血干细胞移植。根据适应第一天(第7天)测量的ALC将患者分为两组,以研究ALC与GVHD和生存结果的关系。中位随访时间为29个月。预处理ALC与第一次ATG给药(第3天)时ALC密切相关。与ALC≥500/μL组相比,预处理ALC≥500/μL组急性GVHD和慢性GVHD的累积发病率均显著降低。两组患者疾病复发率比较,差异无统计学意义;ALC 500/μL组死亡率显著高于ALC 500/μL组。多变量分析包括疾病状态、改良的欧洲血液和骨髓移植评分和预处理ALC(≥500/μL vs <500/μL),发现疾病状态和ALC与总生存(OS)独立相关。其中,感染是ALC 500/μL组最常见的死亡原因。我们的数据表明,在伴有RIC的MRD同种异体造血干细胞移植中,统一的基于体重的ATG剂量与非复发死亡率的增加和预处理ALC明显较低的患者相对较低的OS相关。因此,在同种异体造血干细胞移植中,至少对于预处理ALC相当低的患者,应该考虑ATG整合的替代策略。
{"title":"Preconditioning Absolute Lymphocyte Count and Transplantation Outcomes in Matched Related Donor Allogeneic Hematopoietic Stem Cell Transplantation Recipients with Reduced-Intensity Conditioning and Antithymocyte Globulin Treatment","authors":"Go-Un Woo , Junshik Hong , Hyangseon Kim , Ja Min Byun , Youngil Koh , Dong-Yeop Shin , Inho Kim , Sung-Soo Yoon","doi":"10.1016/j.bbmt.2020.06.005","DOIUrl":"10.1016/j.bbmt.2020.06.005","url":null,"abstract":"<div><p>The integration of antithymocyte globulin (ATG) into therapy has significantly reduced the incidence of graft-versus-host disease (GVHD) and is being actively used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The ATG dosage is determined by the recipient's body weight, but some insist that this approach does not reflect the actual target of ATG. In this respect, weight-based dosing may lead to ATG overdose, particularly in recipients with a relatively low absolute lymphocyte count (ALC). We retrospectively analyzed 84 patients with acute leukemia or myelodysplastic syndrome who underwent matched related donor (MRD) allo-HSCT with reduced-intensity conditioning (RIC) at a single institution. Patients were dichotomized according to the ALC measured on the first day of conditioning (day -7) to investigate the associations of the ALC with GVHD and survival outcomes. The median duration of follow-up was 29 months. The preconditioning ALC was closely correlated with the ALC at the first ATG administration (day -3). The cumulative incidences of both acute GVHD and chronic GVHD were significantly lower in the preconditioning ALC <500/μL group compared with the ALC ≥500/μL group. There was no significant difference in disease relapse incidence between the 2 groups; however, mortality was significantly higher in the ALC <500/μL group. Multivariate analysis including disease status, modified European Blood and Marrow Transplantation score, and preconditioning ALC (≥500/μL versus <500/μL) identified disease status and ALC as being independently associated with overall survival (OS). In particular, infection was the most common cause of death in the ALC <500/μL group. Our data suggest that uniform weight-based ATG dosing in MRD allo-HSCT with RIC is associated with an increase in nonrelapse mortality and a relatively inferior OS in patients with a significantly low preconditioning ALC. Therefore, alternative strategies for the integration of ATG should be considered in allo-HSCT, at least for patients with a substantially low preconditioning ALC.</p></div>","PeriodicalId":9165,"journal":{"name":"Biology of Blood and Marrow Transplantation","volume":null,"pages":null},"PeriodicalIF":4.3,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.bbmt.2020.06.005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38068644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 10.1016/S1083-8791(20)30546-2
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