Pub Date : 2024-08-01DOI: 10.1016/j.jtct.2024.06.013
CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR-T therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). Considering the limited published data for the utility of post CAR-T therapy consolidative alloHCT in r/r B-ALL, especially data related to patients receiving a second alloHCT, we sought to describe outcomes of patients with r/r B-ALL at our institution who received their first or second alloHCT following response to CAR-T therapy. We performed a retrospective analysis of adult patients with r/r B-ALL who responded to either investigational or standard of care (SOC) CD19-targeted CAR-T therapy and underwent consolidation with alloHCT while in CR without interim therapy. We identified 45 patients, of whom 26 (58%) and 19 (42%) received their first and second alloHCT as consolidation post CAR-T therapy, respectively. The median age was 31 years (range: 19-67) and 31 (69%) patients were Hispanic. Ph-like was the most common genetic subtype and comprised over half of cases (53%; n = 24). The median number of prior therapies pre-transplant was 5 (range: 2-7), and disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 7 (16%), 22 (49%) and 16 (35%) patients, respectively. The median time from CAR-T therapy until alloHCT was 93 (range: 42-262) days. The conditioning regimen was radiation-based myeloablative (MAC) in 22 (49%) patients. With a median follow-up of 2.47 years (range: 0.13-6.93), 2-year overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 57.3% (95% CI: 0.432-0.760), 56.2% (95% CI: 0.562-0.745), 23.3% (95% CI: 0.13-0.42), and 20.4% (95% CI: 0.109-0.384), respectively. Two-year OS (52% vs. 68%, P = .641), RFS (54% vs. 59%, P = .820), CIR (33.5% vs. 8.5%, P = .104), and NRM (12.5% vs. 32.2%, P = .120) were not significantly different between patients who underwent their first vs. second transplant, respectively. In univariate analysis, only Ph-like genotype was associated with inferior RFS (P = .03). AlloHCT post CAR-T response is associated with a relatively low early mortality rate and encouraging survival results in high-risk adults with r/r B-ALL, extending to the second alloHCT for fit and eligible patients.
背景：CD19靶向嵌合抗原受体T细胞（CAR-T）疗法使儿童和成人复发/难治性（r/r）B细胞急性淋巴细胞白血病（B-ALL）患者的完全缓解（CR）率达到了前所未有的水平，但大多数成人患者在初次应答后复发。为延长成人患者对CAR-T疗法反应后缓解的持久性，一种建议的方法是通过异基因造血细胞移植（alloHCT）进行巩固治疗：考虑到已发表的CAR-T治疗后异体造血细胞移植在r/r B-ALL中的应用数据有限，尤其是与接受第二次异体造血细胞移植的患者相关的数据，我们试图描述本院r/r B-ALL患者在对CAR-T疗法产生反应后接受第一次或第二次异体造血细胞移植的疗效：我们对对研究性或标准治疗（SOC）CD19靶向CAR-T疗法有反应的r/r B-ALL成人患者进行了回顾性分析，这些患者在CR期接受了alloHCT巩固治疗，没有接受中期治疗：我们确定了 45 名患者，其中 26 人（58%）和 19 人（42%）分别接受了第一次和第二次异体肝移植，作为 CAR-T 疗法后的巩固治疗。中位年龄为31岁（范围：19-67岁），31名（69%）患者为西班牙裔。Ph-like是最常见的基因亚型，占半数以上（53%；n=24）。移植前既往治疗次数的中位数为5次（范围：2-7次），异体HCT时疾病状态为CR1、CR2或≥CR3的患者分别为7人（16%）、22人（49%）和16人（35%）。从CAR-T治疗到alloHCT的中位时间为93天（42-262天）。22例（49%）患者的调理方案为基于辐射的髓鞘消融（MAC）。中位随访时间为2.47年（范围：0.13-6.93），两年总生存期（OS）、无复发生存期（RFS）、累积复发率（CIR）和非复发死亡率（NRM）分别为57.3%（95%CI：0.432-0.760）、56.2%（95%CI：0.562-0.745）、23.3%（95%CI：0.13-0.42）和20.4%（95%CI：0.109-0.384）。首次移植与第二次移植患者的两年OS（52% vs. 68%，P=0.641）、RFS（54% vs. 59%，P=0.820）、CIR（33.5%% vs. 8.5%，P=0.104）和NRM（12.5% vs. 32.2%，P=0.120）分别无显著差异。在单变量分析中，只有Ph-like基因型与较差的RFS相关（P=0.03）：CAR-T反应后的alloHCT与r/r B-ALL高风险成人患者相对较低的早期死亡率和令人鼓舞的生存结果有关，适合且符合条件的患者可进行第二次alloHCT。
{"title":"Consolidation with First and Second Allogeneic Transplants in Adults with Relapsed/Refractory B-ALL Following Response to CD19CAR T Cell Therapy","authors":"","doi":"10.1016/j.jtct.2024.06.013","DOIUrl":"10.1016/j.jtct.2024.06.013","url":null,"abstract":"<div><p>CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR-T therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). Considering the limited published data for the utility of post CAR-T therapy consolidative alloHCT in r/r B-ALL, especially data related to patients receiving a second alloHCT, we sought to describe outcomes of patients with r/r B-ALL at our institution who received their first or second alloHCT following response to CAR-T therapy. We performed a retrospective analysis of adult patients with r/r B-ALL who responded to either investigational or standard of care (SOC) CD19-targeted CAR-T therapy and underwent consolidation with alloHCT while in CR without interim therapy. We identified 45 patients, of whom 26 (58%) and 19 (42%) received their first and second alloHCT as consolidation post CAR-T therapy, respectively. The median age was 31 years (range: 19-67) and 31 (69%) patients were Hispanic. Ph-like was the most common genetic subtype and comprised over half of cases (53%; <em>n</em> = 24). The median number of prior therapies pre-transplant was 5 (range: 2-7), and disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 7 (16%), 22 (49%) and 16 (35%) patients, respectively. The median time from CAR-T therapy until alloHCT was 93 (range: 42-262) days. The conditioning regimen was radiation-based myeloablative (MAC) in 22 (49%) patients. With a median follow-up of 2.47 years (range: 0.13-6.93), 2-year overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 57.3% (95% CI: 0.432-0.760), 56.2% (95% CI: 0.562-0.745), 23.3% (95% CI: 0.13-0.42), and 20.4% (95% CI: 0.109-0.384), respectively. Two-year OS (52% vs. 68%, <em>P</em> = .641), RFS (54% vs. 59%, <em>P</em> = .820), CIR (33.5% vs. 8.5%, <em>P</em> = .104), and NRM (12.5% vs. 32.2%, <em>P</em> = .120) were not significantly different between patients who underwent their first vs. second transplant, respectively. In univariate analysis, only Ph-like genotype was associated with inferior RFS (<em>P</em> = .03). AlloHCT post CAR-T response is associated with a relatively low early mortality rate and encouraging survival results in high-risk adults with r/r B-ALL, extending to the second alloHCT for fit and eligible patients.</p></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/j.jtct.2024.05.015
In αβ T-cell/CD19 B-cell depleted hematopoietic stem cell transplantation (αβhaplo-HSCT) recipients, antithymocyte globulin (ATG; Thymoglobulin) is used for preventing graft rejection and graft-versus-host disease (GVHD). The optimal dosing remains to be established, however. Here we present the first comparative analysis of 3 different ATG dosing strategies and their impact on immune reconstitution and GVHD. Our study aimed to evaluate the effects of 3 distinct dosing strategies of ATG on engraftment success, αβ+ and γδ+ T cell immune reconstitution, and the incidence and severity of acute GVHD in recipients of αβhaplo-HSCT. This comparative analysis included 3 cohorts of pediatric patients with malignant (n = 36) or nonmalignant (n = 8) disease. Cohorts 1 and 2 were given fixed ATG doses, whereas cohort 3 received doses via a new nomogram, based on absolute lymphocyte count (ALC) and body weight (BW). Cohort 3 showed a 0% incidence of day 100 grade II-IV acute GVHD, compared to 48% in cohort 1 and 27% in cohort 2. Furthermore, cohort 3 (the ALC/BW-based cohort) had a significant increase in CD4+ and CD8+ naïve T cells by day 90 (P = .04 and .03, respectively). Additionally, we found that the reconstitution and maturation of γδ+ T cells post-HSCT was not impacted across all 3 cohorts. Cumulative ATG exposure in all cohorts was lower than previously reported in T cell-replete settings, with a lower pre-HSCT exposure (<40 AU*day/mL) correlating with engraftment failure (P = .007). Conversely, a post-HSCT ATG exposure of 10 to 15 AU*day/mL was optimal for improving day 100 CD4+ (P = .058) and CD8+ (P = .03) immune reconstitution without increasing the risk of relapse or nonrelapse mortality. This study represents the first comparative analysis of ATG exposure in αβhaplo-HSCT recipients. Our findings indicate that (1) a 1- to 2-fold ATG to ATLG bioequivalence is more effective than previously established standards, and (2) ATG exposure post-HSCT does not adversely affect γδ+ T cell immune reconstitution. Furthermore, a model-based ATG dosing strategy effectively reduces graft rejection and day 100 acute GVHD while also promoting early CD4+/CD8+ immune reconstitution. These insights suggest that further optimization, including more distal administration of higher ATG doses within an ALC/BW-based strategy, will yield even greater improvements in outcomes.
{"title":"Model-Based Antithymocyte Globulin in αβhaplo-Hematopoietic Stem Cell Transplantation Facilitates Engraftment, Expedites T Cell Recovery, and Mitigates the Risk of Acute Graft-versus-Host Disease","authors":"","doi":"10.1016/j.jtct.2024.05.015","DOIUrl":"10.1016/j.jtct.2024.05.015","url":null,"abstract":"<div><p><span><span>In αβ T-cell/CD19 B-cell depleted hematopoietic stem cell transplantation (αβhaplo-HSCT) recipients, antithymocyte globulin (ATG; Thymoglobulin) is used for preventing graft rejection<span> and graft-versus-host disease (GVHD). The optimal dosing remains to be established, however. Here we present the first comparative analysis of 3 different ATG dosing strategies and their impact on immune reconstitution and </span></span>GVHD. Our study aimed to evaluate the effects of 3 distinct dosing strategies of ATG on engraftment success, αβ</span><sup>+</sup> and γδ<sup>+</sup><span> T cell immune reconstitution, and the incidence and severity of acute GVHD in recipients of αβhaplo-HSCT. This comparative analysis included 3 cohorts of pediatric patients with malignant (n = 36) or nonmalignant (n = 8) disease. Cohorts 1 and 2 were given fixed ATG doses, whereas cohort 3 received doses via a new nomogram, based on absolute lymphocyte count (ALC) and body weight (BW). Cohort 3 showed a 0% incidence of day 100 grade II-IV acute GVHD, compared to 48% in cohort 1 and 27% in cohort 2. Furthermore, cohort 3 (the ALC/BW-based cohort) had a significant increase in CD4</span><sup>+</sup><span> and CD8</span><sup>+</sup> naïve T cells by day 90 (<em>P</em> = .04 and .03, respectively). Additionally, we found that the reconstitution and maturation of γδ<sup>+</sup> T cells post-HSCT was not impacted across all 3 cohorts. Cumulative ATG exposure in all cohorts was lower than previously reported in T cell-replete settings, with a lower pre-HSCT exposure (<40 AU*day/mL) correlating with engraftment failure (<em>P</em> = .007). Conversely, a post-HSCT ATG exposure of 10 to 15 AU*day/mL was optimal for improving day 100 CD4<sup>+</sup> (<em>P</em><span> = .058) and CD8</span><sup>+</sup> (<em>P</em><span> = .03) immune reconstitution without increasing the risk of relapse or nonrelapse mortality. This study represents the first comparative analysis of ATG exposure in αβhaplo-HSCT recipients. Our findings indicate that (1) a 1- to 2-fold ATG to ATLG<span> bioequivalence is more effective than previously established standards, and (2) ATG exposure post-HSCT does not adversely affect γδ</span></span><sup>+</sup> T cell immune reconstitution. Furthermore, a model-based ATG dosing strategy effectively reduces graft rejection and day 100 acute GVHD while also promoting early CD4<sup>+</sup>/CD8<sup>+</sup> immune reconstitution. These insights suggest that further optimization, including more distal administration of higher ATG doses within an ALC/BW-based strategy, will yield even greater improvements in outcomes.</p></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1016/j.jtct.2024.07.022
<div><div>Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary toxicity that can arise after hematopoietic cell transplantation (HCT). Risk factors and outcomes are not well understood owing to a sparsity of cases spread across multiple centers. The objectives of this epidemiologic study were to characterize the incidence, outcomes, transplantation-related risk factors and comorbid critical care diagnoses associated with post-HCT DAH. Retrospective analysis was performed in a multicenter cohort of 6995 patients age ≤21 years who underwent allogeneic HCT between 2008 and 2014 identified through the Center for International Blood and Marrow Transplant Research registry and cross-matched with the Virtual Pediatric Systems database to obtain critical care characteristics. A multivariable Cox proportional hazard model was used to determine risk factors for DAH. Logistic regression models were used to determine critical care diagnoses associated with DAH. Survival outcomes were analyzed using both a landmark approach and Cox regression, with DAH as a time-varying covariate. DAH occurred in 81 patients at a median of 54 days post-HCT (interquartile range, 23 to 160 days), with a 1-year post-transplantation cumulative incidence probability of 1.0% (95% confidence interval [CI], .81% to 1.3%) and was noted in 7.6% of all pediatric intensive care unit patients. Risk factors included receipt of transplantation for nonmalignant hematologic disease (reference: malignant hematologic disease; hazard ratio [HR], 1.98; 95% CI, 1.22 to 3.22; <em>P</em> = .006), use of a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis (referent: CNI plus methotrexate; HR, 1.89; 95% CI, 1.07 to 3.34; <em>P</em> = .029), and grade III-IV acute GVHD (HR, 2.67; 95% CI, 1.53-4.66; <em>P</em> < .001). Critical care admitted patients with DAH had significantly higher rates of systemic hypertension, pulmonary hypertension, pericardial disease, renal failure, and bacterial/viral/fungal infections (<em>P</em> < .05) than those without DAH. From the time of DAH, median survival was 2.2 months, and 1-year overall survival was 26% (95% CI, 17% to 36%). Among all HCT recipients, the development of DAH when considered was associated with a 7-fold increase in unadjusted all-cause post-HCT mortality (HR, 6.96; 95% CI, 5.42 to 8.94; <em>P</em> < .001). In a landmark analysis of patients alive at 2 months post-HCT, patients who developed DAH had a 1-year overall survival of 33% (95% CI, 18% to 49%), compared to 82% (95% CI, 81% to 83%) for patients without DAH (<em>P</em> < .001). Although DAH is rare, it is associated with high mortality in the post-HCT setting. Our data suggest that clinicians should have a heightened index of suspicion of DAH in patients with pulmonary symptoms in the context of nonmalignant hematologic indication for HCT, use of CNI + MMF as GVHD prophylaxis, and severe acute GVHD. Further inves
背景：弥漫性肺泡出血（DAH弥漫性肺泡出血（DAH）是造血细胞移植（HCT）后可能出现的一种危及生命的肺部毒性反应。由于分散在多个中心的病例稀少，人们对其风险因素和预后还不甚了解：这项流行病学研究的目的是描述与造血干细胞移植后DAH相关的发病率、结局、移植相关风险因素和合并重症监护诊断：研究设计：研究人员对国际血液和骨髓移植研究中心（Center for International Blood and Marrow Transplant Research）登记在册的6995名年龄≤21岁、在2008-2014年间接受异基因HCT的患者进行了多中心队列回顾性分析，并与虚拟儿科系统数据库进行交叉匹配，以获得重症监护特征。采用多变量 Cox 比例危险模型确定 DAH 的风险因素。逻辑回归模型用于确定与 DAH 相关的重症监护诊断。使用地标法和将DAH作为时变协变量的Cox回归法分析了生存结果：81名患者的DAH发生在HCT后中位54天（IQR 23-160天），移植后1年的累积发生率为1.0%（95% CI 0.81-1.3%），占所有PICU患者的7.6%。风险因素包括非恶性血液病移植（参考：恶性血液病，HR=1.98，95% CI 1.22-3.22，P=0.006）、使用钙神经蛋白抑制剂加霉酚酸酯（CNI + MMF）作为预防GvHD（参考：钙神经蛋白抑制剂加甲氨蝶呤，HR=1.89，95% CI 1.07-3.34，P=0.029）、III-IV级急性GvHD（HR=2.67，95% CI 1.53-4.66，P结论：虽然DAH很罕见，但它与HCT后的高死亡率有关。我们的数据表明，临床医生在非恶性血液学移植适应症、使用 CNI + MMF 作为 GvHD 预防措施以及严重急性 GvHD 的情况下，应提高对肺部症状患者 DAH 的怀疑指数。鉴于疗效不佳，有必要对可改变的风险因素进行进一步调查和验证。
{"title":"Epidemiology of Diffuse Alveolar Hemorrhage in Pediatric Allogeneic Hematopoietic Cell Transplantation Recipients","authors":"","doi":"10.1016/j.jtct.2024.07.022","DOIUrl":"10.1016/j.jtct.2024.07.022","url":null,"abstract":"<div><div>Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary toxicity that can arise after hematopoietic cell transplantation (HCT). Risk factors and outcomes are not well understood owing to a sparsity of cases spread across multiple centers. The objectives of this epidemiologic study were to characterize the incidence, outcomes, transplantation-related risk factors and comorbid critical care diagnoses associated with post-HCT DAH. Retrospective analysis was performed in a multicenter cohort of 6995 patients age ≤21 years who underwent allogeneic HCT between 2008 and 2014 identified through the Center for International Blood and Marrow Transplant Research registry and cross-matched with the Virtual Pediatric Systems database to obtain critical care characteristics. A multivariable Cox proportional hazard model was used to determine risk factors for DAH. Logistic regression models were used to determine critical care diagnoses associated with DAH. Survival outcomes were analyzed using both a landmark approach and Cox regression, with DAH as a time-varying covariate. DAH occurred in 81 patients at a median of 54 days post-HCT (interquartile range, 23 to 160 days), with a 1-year post-transplantation cumulative incidence probability of 1.0% (95% confidence interval [CI], .81% to 1.3%) and was noted in 7.6% of all pediatric intensive care unit patients. Risk factors included receipt of transplantation for nonmalignant hematologic disease (reference: malignant hematologic disease; hazard ratio [HR], 1.98; 95% CI, 1.22 to 3.22; <em>P</em> = .006), use of a calcineurin inhibitor (CNI) plus mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis (referent: CNI plus methotrexate; HR, 1.89; 95% CI, 1.07 to 3.34; <em>P</em> = .029), and grade III-IV acute GVHD (HR, 2.67; 95% CI, 1.53-4.66; <em>P</em> < .001). Critical care admitted patients with DAH had significantly higher rates of systemic hypertension, pulmonary hypertension, pericardial disease, renal failure, and bacterial/viral/fungal infections (<em>P</em> < .05) than those without DAH. From the time of DAH, median survival was 2.2 months, and 1-year overall survival was 26% (95% CI, 17% to 36%). Among all HCT recipients, the development of DAH when considered was associated with a 7-fold increase in unadjusted all-cause post-HCT mortality (HR, 6.96; 95% CI, 5.42 to 8.94; <em>P</em> < .001). In a landmark analysis of patients alive at 2 months post-HCT, patients who developed DAH had a 1-year overall survival of 33% (95% CI, 18% to 49%), compared to 82% (95% CI, 81% to 83%) for patients without DAH (<em>P</em> < .001). Although DAH is rare, it is associated with high mortality in the post-HCT setting. Our data suggest that clinicians should have a heightened index of suspicion of DAH in patients with pulmonary symptoms in the context of nonmalignant hematologic indication for HCT, use of CNI + MMF as GVHD prophylaxis, and severe acute GVHD. Further inves","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1016/j.jtct.2024.07.019
Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potentially curative treatment for many hematologic malignancies (HM). We previously developed a two-step approach that separates the lymphoid and myeloid portions of the graft, allowing a consistent T cell dosing and sparing the stem cells from the effect of post-transplant cyclophosphamide (CY). The two-step approach demonstrated safety and efficacy in patients treated with myeloablative and reduced-intensity conditioning. Here, we extended our two-step platform to older and less fit patients and explored the effects of using a high dose of T cells on disease relapse and transplant outcomes. Thirty-four patients with HM were treated. Median age was 68 years old and included a minority population constituting 32%. Eighty-two percent had a hematopoietic cell transplantation comorbidity index score ≥3. Ninety-one percent were haploidentical, and the rest were matched-related donor HSCT. Following administration of fludarabine and 2 Gy total body irradiation (TBI) (13 patients) or 4 Gy TBI (21 patients) conditioning regimen, a fixed dose of 2 × 108/kg CD3+ T cells was given, followed 2 days later by CY, then infusion of CD34-selected stem cells. Overall survival (OS) was 70% at 1 year and 48% at 3 years. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were 22% and 33% at 3 years. However, the CI of relapse was much lower for patients treated with 4 Gy TBI versus those treated with 2 Gy TBI (11% versus 54%, P = .045), while NRM was similar (23% versus 15%, P = .399). This contributed to a high OS of 64% in patients who received 4 Gy TBI-based conditioning at 3 years, with median OS not reached, although this was not statistically significant (P = .68). The median time to neutrophil and platelet recovery was 12 and 17 days, respectively. The CI of grade II acute graft-versus-host-disease (aGVHD) was 22% and 26% at 100 days and 6 months, respectively. The CI of chronic GVHD (cGVHD) was 7.5% at 3 years. There was no grade III or IV aGVHD, no severe cGVHD, and no deaths attributable to GVHD. In conclusion, the two-step approach HSCT demonstrated a low disease relapse rate and high survival in patients treated with 4 Gy TBI-based conditioning, despite a generally older and more medically compromised patient population.
异基因造血干细胞移植（HSCT）仍然是许多血液系统恶性肿瘤（HM）唯一可能治愈的治疗方法。我们之前开发了一种两步法，将移植物的淋巴细胞和髓细胞部分分开，使T细胞剂量保持一致，并使干细胞免受移植后环磷酰胺（PTCY）的影响。两步法在接受髓内消融和降低强度调理治疗的患者中显示出安全性和有效性。在这里，我们将两步法平台扩展到年龄较大、体质较差的患者，并探索了使用高剂量T细胞对疾病复发和移植结果的影响。34名HM患者接受了治疗。中位年龄为68岁，少数民族占32%。82%的患者造血细胞移植综合指数（HCT-CI）评分≥3。91%为单倍体（HI），其余为匹配的亲缘供者造血干细胞移植。在使用氟达拉滨和2 Gy全身照射（13名患者）或4 Gy全身照射（21名患者）调理方案后，给予固定剂量的2×108/kg CD3+ T细胞，2天后使用环磷酰胺，然后输注CD34筛选干细胞。1年总生存率为70%，3年总生存率为48%。3年后，非复发死亡率（NRM）和复发的累积发生率（CI）分别为22%和33%。然而，接受 4 Gy TBI 治疗的患者的复发 CI 远低于接受 2 Gy TBI 治疗的患者（11% vs 54%，p = 0.045），而非复发死亡率则相似（23% vs 15%，p = 0.399）。这使得接受基于 4 Gy TBI 治疗的患者在 3 年后的总生存率（OS）高达 64%，中位 OS 未达到，但无统计学意义（p = 0.68）。中性粒细胞和血小板恢复的中位时间分别为 12 天和 17 天。在100天和6个月时，II级急性移植物抗宿主病（aGVHD）的CI分别为22%和26%。3年后，慢性移植物抗宿主疾病（cGVHD）的CI为7.5%。没有III级或IV级aGVHD，没有严重的cGVHD，也没有因GVHD导致的死亡。总之，两步法造血干细胞移植显示，尽管患者年龄普遍较大、病情较重，但采用基于4 Gy TBI的调理方法治疗的患者疾病复发率低、存活率高。
{"title":"A Tender Reduced-Intensity Conditioning for the Unfit: A Novel 4 Gy Total Body Irradiation-Based Conditioning Followed by Two-Step Haploidentical Stem Cell Transplant, Results of a Prospective Trial","authors":"","doi":"10.1016/j.jtct.2024.07.019","DOIUrl":"10.1016/j.jtct.2024.07.019","url":null,"abstract":"<div><div>Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potentially curative treatment for many hematologic malignancies (HM). We previously developed a two-step approach that separates the lymphoid and myeloid portions of the graft, allowing a consistent T cell dosing and sparing the stem cells from the effect of post-transplant cyclophosphamide (CY). The two-step approach demonstrated safety and efficacy in patients treated with myeloablative and reduced-intensity conditioning. Here, we extended our two-step platform to older and less fit patients and explored the effects of using a high dose of T cells on disease relapse and transplant outcomes. Thirty-four patients with HM were treated. Median age was 68 years old and included a minority population constituting 32%. Eighty-two percent had a hematopoietic cell transplantation comorbidity index score ≥3. Ninety-one percent were haploidentical, and the rest were matched-related donor HSCT. Following administration of fludarabine and 2 Gy total body irradiation (TBI) (13 patients) or 4 Gy TBI (21 patients) conditioning regimen, a fixed dose of 2 × 10<sup>8</sup>/kg CD3+ T cells was given, followed 2 days later by CY, then infusion of CD34-selected stem cells. Overall survival (OS) was 70% at 1 year and 48% at 3 years. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were 22% and 33% at 3 years. However, the CI of relapse was much lower for patients treated with 4 Gy TBI versus those treated with 2 Gy TBI (11% versus 54%, <em>P</em> = .045), while NRM was similar (23% versus 15%, <em>P</em> = .399). This contributed to a high OS of 64% in patients who received 4 Gy TBI-based conditioning at 3 years, with median OS not reached, although this was not statistically significant (<em>P</em> = .68). The median time to neutrophil and platelet recovery was 12 and 17 days, respectively. The CI of grade II acute graft-versus-host-disease (aGVHD) was 22% and 26% at 100 days and 6 months, respectively. The CI of chronic GVHD (cGVHD) was 7.5% at 3 years. There was no grade III or IV aGVHD, no severe cGVHD, and no deaths attributable to GVHD. In conclusion, the two-step approach HSCT demonstrated a low disease relapse rate and high survival in patients treated with 4 Gy TBI-based conditioning, despite a generally older and more medically compromised patient population.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1016/j.jtct.2024.07.018
Chimeric antigen receptor (CAR) T-cell therapy is rapidly advancing, offering promising treatments for patients with hematological malignancy. However, associated infectious complications remain a significant concern because of their contribution to patient morbidity and non-relapse mortality. Recent epidemiological insights shed light on risk factors for infections after CAR T-cell therapy. However, the available evidence is predominantly retrospective, highlighting a need for further prospective studies. Institutions are challenged with managing infections after CAR T-cell therapy but variations in the approaches taken underscore the importance of standardizing infection prevention and management protocols across different healthcare settings. Therefore, the Infectious Diseases Special Interest Group of the American Society of Transplantation and Cellular Therapy assembled an expert panel to develop best practice considerations. The aim was to guide healthcare professionals in optimizing infection prevention and management for CAR T-cell therapy recipients and advocates for early consultation of Infectious Diseases during treatment planning phases given the complexities involved. By synthesizing current evidence and expert opinion these best practice considerations provide the basis for understanding infection risk after CAR T-cell therapies and propose risk-mitigating strategies in children, adolescents, and adults. Continued research and collaboration will be essential to refining and effectively implementing these recommendations.
嵌合抗原受体（CAR）T 细胞疗法发展迅速，为血液恶性肿瘤患者提供了前景广阔的治疗方法。然而，由于相关的感染并发症会导致患者发病率和非复发死亡率，因此仍然是一个值得关注的重大问题。最近的流行病学研究揭示了 CAR T 细胞疗法后感染的风险因素。然而，现有证据主要是回顾性的，因此需要进一步开展前瞻性研究。医疗机构在 CAR T 细胞治疗后的感染管理方面面临挑战，但所采取的方法各不相同，这凸显了在不同医疗机构中统一感染预防和管理方案的重要性。因此，美国移植与细胞治疗学会感染性疾病特别兴趣小组组建了一个专家小组，以制定最佳实践注意事项。其目的是指导医护人员优化 CAR T 细胞疗法受者的感染预防和管理，并倡导在治疗计划阶段尽早咨询传染病科，因为这涉及到复杂的问题。通过综合现有证据和专家意见，这些最佳实践注意事项为了解 CAR T 细胞疗法后的感染风险提供了基础，并提出了儿童、青少年和成人的风险缓解策略。持续的研究与合作对于完善和有效实施这些建议至关重要。
{"title":"Best Practice Considerations by The American Society of Transplant and Cellular Therapy: Infection Prevention and Management After Chimeric Antigen Receptor T Cell Therapy for Hematological Malignancies","authors":"","doi":"10.1016/j.jtct.2024.07.018","DOIUrl":"10.1016/j.jtct.2024.07.018","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T-cell therapy is rapidly advancing, offering promising treatments for patients with hematological malignancy. However, associated infectious complications remain a significant concern because of their contribution to patient morbidity and non-relapse mortality. Recent epidemiological insights shed light on risk factors for infections after CAR T-cell therapy. However, the available evidence is predominantly retrospective, highlighting a need for further prospective studies. Institutions are challenged with managing infections after CAR T-cell therapy but variations in the approaches taken underscore the importance of standardizing infection prevention and management protocols across different healthcare settings. Therefore, the Infectious Diseases Special Interest Group of the American Society of Transplantation and Cellular Therapy assembled an expert panel to develop best practice considerations. The aim was to guide healthcare professionals in optimizing infection prevention and management for CAR T-cell therapy recipients and advocates for early consultation of Infectious Diseases during treatment planning phases given the complexities involved. By synthesizing current evidence and expert opinion these best practice considerations provide the basis for understanding infection risk after CAR T-cell therapies and propose risk-mitigating strategies in children, adolescents, and adults. Continued research and collaboration will be essential to refining and effectively implementing these recommendations.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666636724005499/pdfft?md5=0960826b339264fc9c8c8081f2d2ee72&pid=1-s2.0-S2666636724005499-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for graft-versus-host disease (GVHD) prevention was developed. This study aims to perform a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haploidentical hematopoietic stem cell transplantation. Meta-analysis was conducted with Review Manager version 5.4; pooled risk ratios (RRs) and hazard ratios (HRs) were calculated for dichotomous data and time-to-event data, respectively. A fixed-effects model was used if there was no significant heterogeneity. Literature search and study selection identified 14 eligible studies, including both randomized controlled trial and retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grades II-IV acute GVHD compared with ATG (RR 0.52; 95% CI: 0.41-0.65; P < .00001) and PTCy (RR 0.53; 95% CI: 0.34-0.83; P = .005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly better overall survival and GVHD-free/relapse-free survival than ATG and PTCy. Future research is required to further establish the benefits of ATG/PTCy and determine the optimal dosage adjustment strategies.
Background: Haploidentical stem cell transplantation (haplo-HSCT) is associated with higher incidences of graft-versus-host disease (GVHD). A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for GVHD prevention has been developed, but its benefits and risks remain unclear.
Objective: This study aims to performs a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haplo-HSCT.
Study design: Literature search was performed in databases including Ovid Medline, Embase, Cochrane Library and China Biology Medicine (CBM). Two investigators independently screened eligible studies and extracted data. Meta-analysis was conducted with Review Manager version 5.4; pooled hazard ratios (HRs) for time-to-event outcomes were obtained using a generic inverse-variance method, and pooled risk ratios (RRs) for dichotomous data were obtained using the Mantel-Haenszel method. A fixed-effects model was adopted if there was no significant heterogeneity. The primary outcome is incidence of acute GVHD.
Results: Literature search and study selection identified 14 eligible studies, including both 1 randomized controlled trial and 13 retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is
{"title":"Combination of Anti-thymocyte Globulin with Post-transplant Cyclophosphamide for GVHD Prophylaxis in Patients Undergoing Haploidentical Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-analysis.","authors":"Chengxin Luo, Xiangtao Huang, Guixian Wu, Yarui Huang, Yaqun Ding, Zhen Huang, Qiuyue Song, Jieping Chen, Xi Li, Shuangnian Xu","doi":"10.1016/j.jtct.2024.07.017","DOIUrl":"10.1016/j.jtct.2024.07.017","url":null,"abstract":"<p><p>A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for graft-versus-host disease (GVHD) prevention was developed. This study aims to perform a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haploidentical hematopoietic stem cell transplantation. Meta-analysis was conducted with Review Manager version 5.4; pooled risk ratios (RRs) and hazard ratios (HRs) were calculated for dichotomous data and time-to-event data, respectively. A fixed-effects model was used if there was no significant heterogeneity. Literature search and study selection identified 14 eligible studies, including both randomized controlled trial and retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is associated with significantly lower risk of grades II-IV acute GVHD compared with ATG (RR 0.52; 95% CI: 0.41-0.65; P < .00001) and PTCy (RR 0.53; 95% CI: 0.34-0.83; P = .005) without increasing risk of disease relapse. In addition, ATG/PTCy is associated with significantly better overall survival and GVHD-free/relapse-free survival than ATG and PTCy. Future research is required to further establish the benefits of ATG/PTCy and determine the optimal dosage adjustment strategies.</p><p><strong>Background: </strong>Haploidentical stem cell transplantation (haplo-HSCT) is associated with higher incidences of graft-versus-host disease (GVHD). A new strategy combining anti-thymocyte globulin with post-transplant cyclophosphamide (ATG/PTCy) for GVHD prevention has been developed, but its benefits and risks remain unclear.</p><p><strong>Objective: </strong>This study aims to performs a systematic review and meta-analysis of studies comparing ATG/PTCy with ATG or PTCy in patients with hematological malignancies undergoing haplo-HSCT.</p><p><strong>Study design: </strong>Literature search was performed in databases including Ovid Medline, Embase, Cochrane Library and China Biology Medicine (CBM). Two investigators independently screened eligible studies and extracted data. Meta-analysis was conducted with Review Manager version 5.4; pooled hazard ratios (HRs) for time-to-event outcomes were obtained using a generic inverse-variance method, and pooled risk ratios (RRs) for dichotomous data were obtained using the Mantel-Haenszel method. A fixed-effects model was adopted if there was no significant heterogeneity. The primary outcome is incidence of acute GVHD.</p><p><strong>Results: </strong>Literature search and study selection identified 14 eligible studies, including both 1 randomized controlled trial and 13 retrospective comparative studies. Different dosage adjustment strategies were applied; the total dose was 2.5-10 mg/kg for ATG and 29-100 mg/kg for PTCy. Meta-analysis results suggest that ATG/PTCy is","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-27DOI: 10.1016/j.jtct.2024.07.020
Febrile neutropenia (FN) is a complication in approximately 90% of autologous stem cell transplant (SCT) patients. Guidelines support early broad-spectrum antibiotics (BSA) to prevent morbidity and mortality. However, in patients who are clinically stable and deemed to have a fever of unknown origin, the optimal duration of BSA is unknown. Accumulating evidence suggests that de-escalation of BSA in select patients may decrease duration of BSA exposure without compromising clinical outcomes such as infection, recurrent fever, and readmission. With this, a de-escalation protocol was implemented at Vanderbilt University Medical Center (VUMC) to identify autologous SCT patients who may benefit from early de-escalation of BSA. The objectives of this study were to analyze the impact of early empiric antibiotic de-escalation on the duration of BSA as well as its impact on the incidence of recurrent fever and documented infection in autologous SCT patients. This was a single-center, retrospective study evaluating patients older than 18 years of age who underwent autologous SCT and experienced an episode of FN from January 2018 to December 2022 at VUMC (N = 195). The protocol was initiated on January 1, 2020, to de-escalate BSA back to prophylaxis in stable neutropenic patients determined to have a fever of unknown origin. The primary outcome was the number of BSA days within 30 days. Secondary clinical outcomes included recurrent fever, documented infection, readmission, 30-day mortality, and 90-day non-relapsed mortality (NRM). Outcomes were compared across pre- and postprotocol groups with a Wilcoxon rank sum test, Pearson chi-square test, or regression analysis as appropriate. The median BSA duration was 4.7 and 2.7 days in the pre- and postprotocol groups, respectively (P < .001). Recurrent fever (14.2% versus 16.0%, P = .726), documented infection (1.7% versus 6.7%, P = .068), and readmission (13.3% versus 22.7%, P = .091) within 30 days were not significantly different between the two groups. Neither 30-day mortality (0.8% versus 1.3%, P = .736) nor 90-day NRM (0.8% versus 1.3%, P = .736) differed. The implementation of an early de-escalation protocol for autologous SCT patients who develop FN was associated with a reduction in duration of BSA compared to the preprotocol group without a significant difference in readmission, recurrent fevers, and documented infections. This study adds to existing evidence that early de-escalation of BSA in FN patients with a fever of unknown origin who are afebrile and clinically stable is safe and reduces unnecessary antibiotic use.
{"title":"Evaluating Antibiotic De-escalation for Autologous Stem Cell Transplant Patients With Febrile Neutropenia in a Real-World Clinical Setting","authors":"","doi":"10.1016/j.jtct.2024.07.020","DOIUrl":"10.1016/j.jtct.2024.07.020","url":null,"abstract":"<div><div>Febrile neutropenia (FN) is a complication in approximately 90% of autologous stem cell transplant (SCT) patients. Guidelines support early broad-spectrum antibiotics (BSA) to prevent morbidity and mortality. However, in patients who are clinically stable and deemed to have a fever of unknown origin, the optimal duration of BSA is unknown. Accumulating evidence suggests that de-escalation of BSA in select patients may decrease duration of BSA exposure without compromising clinical outcomes such as infection, recurrent fever, and readmission. With this, a de-escalation protocol was implemented at Vanderbilt University Medical Center (VUMC) to identify autologous SCT patients who may benefit from early de-escalation of BSA. The objectives of this study were to analyze the impact of early empiric antibiotic de-escalation on the duration of BSA as well as its impact on the incidence of recurrent fever and documented infection in autologous SCT patients. This was a single-center, retrospective study evaluating patients older than 18 years of age who underwent autologous SCT and experienced an episode of FN from January 2018 to December 2022 at VUMC (<em>N</em> = 195). The protocol was initiated on January 1, 2020, to de-escalate BSA back to prophylaxis in stable neutropenic patients determined to have a fever of unknown origin. The primary outcome was the number of BSA days within 30 days. Secondary clinical outcomes included recurrent fever, documented infection, readmission, 30-day mortality, and 90-day non-relapsed mortality (NRM). Outcomes were compared across pre- and postprotocol groups with a Wilcoxon rank sum test, Pearson chi-square test, or regression analysis as appropriate. The median BSA duration was 4.7 and 2.7 days in the pre- and postprotocol groups, respectively (<em>P</em> < .001). Recurrent fever (14.2% versus 16.0%, <em>P</em> = .726), documented infection (1.7% versus 6.7%, <em>P</em> = .068), and readmission (13.3% versus 22.7%, <em>P</em> = .091) within 30 days were not significantly different between the two groups. Neither 30-day mortality (0.8% versus 1.3%, <em>P</em> = .736) nor 90-day NRM (0.8% versus 1.3%, <em>P</em> = .736) differed. The implementation of an early de-escalation protocol for autologous SCT patients who develop FN was associated with a reduction in duration of BSA compared to the preprotocol group without a significant difference in readmission, recurrent fevers, and documented infections. This study adds to existing evidence that early de-escalation of BSA in FN patients with a fever of unknown origin who are afebrile and clinically stable is safe and reduces unnecessary antibiotic use.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666636724005505/pdfft?md5=009f624367c9ef6e2c2d5a5a848564ad&pid=1-s2.0-S2666636724005505-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-26DOI: 10.1016/j.jtct.2024.07.016
Sebastian Giebel, Myriam Labopin, Zinaida Peric, Jakob Passweg, Didier Blaise, Urpu Salmenniemi, David Beauvais, Péter Reményi, Patrice Chevallier, Stephan Mielke, Tobias Gedde-Dahl, Jan J Cornelissen, Marie Balsat, Gesine Bug, Ali Bazarbachi, Eolia Brissot, Arnon Nagler, Fabio Ciceri, Mohamad Mohty
The use of tyrosine kinase inhibitors (TKIs) during induction and consolidation, followed by allogeneic hematopoietic cell transplantation (allo-HCT), is a standard of care for patients with Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL). The goal of this study was to compare results of allo-HCT according to the type of TKI used pre-transplant, either imatinib, dasatinib or both. This was a retrospective, registry-based analysis including adult patients with Ph-positive ALL treated with allo-HCT between years 2010-2022. The analysis included 606 patients pre-treated with imatinib, 163 with dasatinib and 94 with both imatinib and dasatinib. Allo-HCTs were performed in first complete remission from either unrelated (56%), matched sibling (36%) or haploidentical donors (8%). Relapse incidence at 2 years was 26% in the imatinib group and 21% in the dasatinib group and 19% in the imatinib + dasatinib group (P = .06) while non-relapse mortality was 19%, 15%, and 23%, respectively (P = .37). No significant differences were found for leukemia-free survival (55% vs. 63% vs. 58%, P = .11) and overall survival (72% vs. 76% vs. 65%, P = .32). The incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD was comparable across study groups, while the incidence of grade 3-4 acute GVHD was significantly increased for patients pre-treated with dasatinib alone (20%) than in the imatinib group (10%) or imatinib + dasatinib group (13%) (P = .002). On multivariate analysis a chance of GVHD and relapse-free survival (GRFS) was significantly decreased while the risk of grade 3-4 acute GVHD was increased for the dasatinib compared to imatinib group (hazard ratio, HR = 1.27, P = .048 and HR = 2.26, P = .0009, respectively). This study provides no evidence for the advantage of one TKI over another in terms of LFS and OS. However, the use of dasatinib is associated with increased risk of severe acute GVHD and decreased GRFS.
背景：在诱导和巩固治疗期间使用酪氨酸激酶抑制剂（TKIs），然后进行异基因造血细胞移植（allo-HCT），是费城（Ph）阳性急性淋巴细胞白血病（ALL）患者的标准治疗方法：本研究的目的是根据移植前使用的TKI类型（伊马替尼、达沙替尼或两者兼而有之）比较allo-HCT的结果：这是一项基于登记的回顾性分析，包括2010-2022年间接受allo-HCT治疗的Ph阳性ALL成人患者。分析包括606名接受伊马替尼预处理的患者、163名接受达沙替尼治疗的患者以及94名同时接受伊马替尼和达沙替尼治疗的患者。首次完全缓解的患者接受了异体供体移植，其中56%来自非亲属供体，36%来自配对同胞供体，8%来自单倍体供体：伊马替尼组、达沙替尼组和伊马替尼+达沙替尼组2年内的复发率分别为26%、21%和19%（P=0.06），而非复发死亡率分别为19%、15%和23%（P=0.37）。无白血病生存率（55% vs. 63% vs. 58%，p=0.11）和总生存率（72% vs. 76% vs. 65%，p=0.32）无明显差异。各研究组的2-4级急性移植物抗宿主疾病（GVHD）和慢性GVHD发生率相当，而单用达沙替尼预处理患者的3-4级急性GVHD发生率（20%）显著高于伊马替尼组（10%）或伊马替尼+达沙替尼组（13%）（p=0.002）。多变量分析显示，达沙替尼组与伊马替尼组相比，发生GVHD和无复发生存期（GRFS）的几率显著降低，而发生3-4级急性GVHD的风险增加（危险比分别为HR=1.27，p=0.048和HR=2.26，p=0.0009）：本研究没有提供证据表明某种TKI比另一种TKI在LFS和OS方面更有优势。然而，使用达沙替尼与严重急性GVHD风险增加和GRFS下降有关。
{"title":"Impact of the Type of Tyrosine Kinase Inhibitor (imatinib or dasatinib) Used Before allo-HCT on Outcome of Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia. A Study on Behalf of the Acute Leukemia Working Party of the EBMT.","authors":"Sebastian Giebel, Myriam Labopin, Zinaida Peric, Jakob Passweg, Didier Blaise, Urpu Salmenniemi, David Beauvais, Péter Reményi, Patrice Chevallier, Stephan Mielke, Tobias Gedde-Dahl, Jan J Cornelissen, Marie Balsat, Gesine Bug, Ali Bazarbachi, Eolia Brissot, Arnon Nagler, Fabio Ciceri, Mohamad Mohty","doi":"10.1016/j.jtct.2024.07.016","DOIUrl":"10.1016/j.jtct.2024.07.016","url":null,"abstract":"<p><p>The use of tyrosine kinase inhibitors (TKIs) during induction and consolidation, followed by allogeneic hematopoietic cell transplantation (allo-HCT), is a standard of care for patients with Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL). The goal of this study was to compare results of allo-HCT according to the type of TKI used pre-transplant, either imatinib, dasatinib or both. This was a retrospective, registry-based analysis including adult patients with Ph-positive ALL treated with allo-HCT between years 2010-2022. The analysis included 606 patients pre-treated with imatinib, 163 with dasatinib and 94 with both imatinib and dasatinib. Allo-HCTs were performed in first complete remission from either unrelated (56%), matched sibling (36%) or haploidentical donors (8%). Relapse incidence at 2 years was 26% in the imatinib group and 21% in the dasatinib group and 19% in the imatinib + dasatinib group (P = .06) while non-relapse mortality was 19%, 15%, and 23%, respectively (P = .37). No significant differences were found for leukemia-free survival (55% vs. 63% vs. 58%, P = .11) and overall survival (72% vs. 76% vs. 65%, P = .32). The incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD was comparable across study groups, while the incidence of grade 3-4 acute GVHD was significantly increased for patients pre-treated with dasatinib alone (20%) than in the imatinib group (10%) or imatinib + dasatinib group (13%) (P = .002). On multivariate analysis a chance of GVHD and relapse-free survival (GRFS) was significantly decreased while the risk of grade 3-4 acute GVHD was increased for the dasatinib compared to imatinib group (hazard ratio, HR = 1.27, P = .048 and HR = 2.26, P = .0009, respectively). This study provides no evidence for the advantage of one TKI over another in terms of LFS and OS. However, the use of dasatinib is associated with increased risk of severe acute GVHD and decreased GRFS.</p>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141789116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-26DOI: 10.1016/j.jtct.2024.06.022
Chimeric antigen receptor (CAR)-T cell therapy is approved for the treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, elderly patients might not be candidates for this therapy due to its toxicity, and criteria for candidate selection are lacking. Our aim was to analyze efficacy and toxicity results of CAR-T cell therapy in the population of patients 70 years and older as compared to those obtained in younger patients in the real-world setting. A multicentric retrospective study was performed including patients with R/R aggressive LBCL who received commercial CAR-T cell therapy with either tisagenlecleucel or axicabtagene ciloleucel within the Spanish Group of Hematopoietic Transplant and Cell Therapy/Spanish Group of Lymphomas and Autologous Transplant (GETH-TC/GELTAMO) centers between 2019 and 2023. As of August 2023, 442 adult patients with aggressive LBCL underwent apheresis for CAR-T cell therapy as third or subsequent line and follow-up data was collected. Of 412 infused patients, 71 (17%) were 70 years or older. Baseline characteristics, product selection, and characteristics at apheresis (including disease status, Ann Arbor stage, revised international prognosis index (R-IPI), bulky disease, lactate dehydrogenase [LDH] and ECOG [Eastern Cooperative Group performance status]) were comparable between groups. Median time from both approval to infusion and apheresis to infusion did not differ. No differences were found between groups in overall and complete response rates at 1 and 3 months. With a median follow-up of 12.2 months (range 1-44), 12-month progression-free survival (PFS) and overall survival (OS) were comparable between groups (35.2% in <70 years vs. 35.9% in ≥70 years (P = .938) and 51.1% and 52.1% (P = .885), respectively). Age ≥70 years did not affect PFS (hazard ratio (HR) 0.98, P = .941) and OS (HR 0.97, P = .890) in the univariate and multivariate analysis. Cytokine release syndrome (CRS) was observed in 82% of patients <70 years old and 84.5% in ≥ 70 years old (P = .408). Grade ≥3 CRS was more frequent in the older group (5% vs. 15%, P = .002). In the multivariate analysis, age ≥70 years was associated with an increased risk of grade ≥3 CRS (OR 3.7, P = .013). No differences were observed in terms of overall neurotoxicity (35% vs. 42%, P = .281) or grade ≥3 (12% vs. 17%, P = .33). The proportion of patients with infections, admission to the intensive care unit within the first month, and non-relapse mortality were similar between both groups. CAR-T cell therapy in patients older than 70 years showed similar efficacy to that observed in younger patients in the real-world setting. However, age ≥70 years was an independent risk factor for grades 3-4 CRS. The need for additional strategies to reduce toxicity in this population should be addressed in future studies.
{"title":"Anti-CD19 CAR-T Cell Therapy in Elderly Patients: Multicentric Real-World Experience from GETH-TC/GELTAMO","authors":"","doi":"10.1016/j.jtct.2024.06.022","DOIUrl":"10.1016/j.jtct.2024.06.022","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR)-T cell therapy is approved for the treatment of relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, elderly patients might not be candidates for this therapy due to its toxicity, and criteria for candidate selection are lacking. Our aim was to analyze efficacy and toxicity results of CAR-T cell therapy in the population of patients 70 years and older as compared to those obtained in younger patients in the real-world setting. A multicentric retrospective study was performed including patients with R/R aggressive LBCL who received commercial CAR-T cell therapy with either tisagenlecleucel or axicabtagene ciloleucel within the Spanish Group of Hematopoietic Transplant and Cell Therapy/Spanish Group of Lymphomas and Autologous Transplant (GETH-TC/GELTAMO) centers between 2019 and 2023. As of August 2023, 442 adult patients with aggressive LBCL underwent apheresis for CAR-T cell therapy as third or subsequent line and follow-up data was collected. Of 412 infused patients, 71 (17%) were 70 years or older. Baseline characteristics, product selection, and characteristics at apheresis (including disease status, Ann Arbor stage, revised international prognosis index (R-IPI), bulky disease, lactate dehydrogenase [LDH] and ECOG [Eastern Cooperative Group performance status]) were comparable between groups. Median time from both approval to infusion and apheresis to infusion did not differ. No differences were found between groups in overall and complete response rates at 1 and 3 months. With a median follow-up of 12.2 months (range 1-44), 12-month progression-free survival (PFS) and overall survival (OS) were comparable between groups (35.2% in <70 years vs. 35.9% in ≥70 years (<em>P</em> = .938) and 51.1% and 52.1% (<em>P</em> = .885), respectively). Age ≥70 years did not affect PFS (hazard ratio (HR) 0.98, <em>P</em> = .941) and OS (HR 0.97, <em>P</em> = .890) in the univariate and multivariate analysis. Cytokine release syndrome (CRS) was observed in 82% of patients <70 years old and 84.5% in ≥ 70 years old (<em>P</em> = .408). Grade ≥3 CRS was more frequent in the older group (5% vs. 15%, <em>P</em> = .002). In the multivariate analysis, age ≥70 years was associated with an increased risk of grade ≥3 CRS (OR 3.7, <em>P</em> = .013). No differences were observed in terms of overall neurotoxicity (35% vs. 42%, <em>P</em> = .281) or grade ≥3 (12% vs. 17%, <em>P</em> = .33). The proportion of patients with infections, admission to the intensive care unit within the first month, and non-relapse mortality were similar between both groups. CAR-T cell therapy in patients older than 70 years showed similar efficacy to that observed in younger patients in the real-world setting. However, age ≥70 years was an independent risk factor for grades 3-4 CRS. The need for additional strategies to reduce toxicity in this population should be addressed in future studies.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141789113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-25DOI: 10.1016/j.jtct.2024.07.013
Haploidentical stem cell transplantation (Haplo-SCT) and cord blood transplantation (CBT) are both effective alternative treatments in patients suffering from acute myeloid leukemia (AML) and lacking a matched HLA donor. In the last years, many centers have abandoned CBT procedures mostly due to concern about poorer immune recovery compared with Haplo-SCT. We conducted a retrospective multicenter study comparing the outcomes using both alternative approaches in AML.
A total of 122 transplants (86 Haplo-SCTs and 36 CBTs) from 12 Spanish centers were collected from 2007 to 2021. Median age at hematopoietic stem cell transplantation (HSCT) was 7 years (0.4-20). Thirty-nine patients (31.9%) showed positive minimal residual disease (MRD) at HSCT and a previous HSCT was performed in 37 patients (30.3%). The median infused cellularity was 14.4 × 106/kg CD34+ cells (6.0-22.07) for Haplo-SCT and 4.74 × 105/kg CD34+ cells (0.8-9.4) for CBT.
Median time to neutrophil engraftment was 14 days (7-44) for Haplo-SCT and 17 days (8-29) for CBT (P = .03). The median time to platelet engraftment was 14 days (6-70) for Haplo-SCT and 43 days (10-151) for CBT (P < .001). Graft rejection was observed in 13 Haplo-SCTs (15%) and in 6 CBTs (16%). The cumulative incidence of acute graft versus host disease (GvHD) grades II-IV was 54% and 51% for Haplo-SCT and CBT, respectively (P = .50). The cumulative incidence of severe acute GvHD (grades III-IV) was 22% for Haplo-SCT and 25% for CBT (P = .90). There was a tendency to a higher risk of chronic GvHD in the Haplo-SCT group being the cumulative incidence of 30% for Haplo-SCT and 12% for CBT (P = .09). The cumulative incidence of relapse was 28% and 20% for Haplo-SCT and CBT, respectively (P = .60). We did not observe statistically significant differences in outcome measures between Haplo-SCT and CBT procedures: 5-year overall survival (OS) was 64% versus 57% (P = .50), 5-year disease-free survival (DFS) 58% versus 57% (P = .80), GvHD-free and relapse-free survival (GFRFS) 41% versus 54% (P = .30), and cumulative incidence of transplant-related mortality (TRM) 14% versus 15% (P = .80), respectively. In the multivariate analysis, MRD positivity and a disease status >CR1 at the time of HSCT were significantly associated with poorer outcomes (P < .05).
In conclusion, our study supports that both haploidentical and cord blood transplantation show comparable outcomes in pediatric AML patients. We obtained comparable survival rates, although CBT showed a trend to lower rates of chronic GvHD and higher GFRFS, demonstrating that it should still be considered a valuable option, particularly for pediatric patients.
{"title":"Haploidentical versus Cord Blood Transplantation in Pediatric AML. A Retrospective Outcome Analysis on Behalf of the Pediatric Subcommittee of GETH (Grupo Español de Trasplante Hematopoyético)","authors":"","doi":"10.1016/j.jtct.2024.07.013","DOIUrl":"10.1016/j.jtct.2024.07.013","url":null,"abstract":"<div><div>Haploidentical stem cell transplantation (Haplo-SCT) and cord blood transplantation (CBT) are both effective alternative treatments in patients suffering from acute myeloid leukemia (AML) and lacking a matched HLA donor. In the last years, many centers have abandoned CBT procedures mostly due to concern about poorer immune recovery compared with Haplo-SCT. We conducted a retrospective multicenter study comparing the outcomes using both alternative approaches in AML.</div><div>A total of 122 transplants (86 Haplo-SCTs and 36 CBTs) from 12 Spanish centers were collected from 2007 to 2021. Median age at hematopoietic stem cell transplantation (HSCT) was 7 years (0.4-20). Thirty-nine patients (31.9%) showed positive minimal residual disease (MRD) at HSCT and a previous HSCT was performed in 37 patients (30.3%). The median infused cellularity was 14.4 × 10<sup>6</sup>/kg CD34+ cells (6.0-22.07) for Haplo-SCT and 4.74 × 10<sup>5</sup>/kg CD34+ cells (0.8-9.4) for CBT.</div><div>Median time to neutrophil engraftment was 14 days (7-44) for Haplo-SCT and 17 days (8-29) for CBT (<em>P = .03)</em>. The median time to platelet engraftment was 14 days (6-70) for Haplo-SCT and 43 days (10-151) for CBT (<em>P</em> < .001). Graft rejection was observed in 13 Haplo-SCTs (15%) and in 6 CBTs (16%). The cumulative incidence of acute graft versus host disease (GvHD) grades II-IV was 54% and 51% for Haplo-SCT and CBT, respectively (<em>P</em> = .50). The cumulative incidence of severe acute GvHD (grades III-IV) was 22% for Haplo-SCT and 25% for CBT (<em>P =</em> .90). There was a tendency to a higher risk of chronic GvHD in the Haplo-SCT group being the cumulative incidence of 30% for Haplo-SCT and 12% for CBT (<em>P =</em> .09). The cumulative incidence of relapse was 28% and 20% for Haplo-SCT and CBT, respectively (<em>P =</em> .60). We did not observe statistically significant differences in outcome measures between Haplo-SCT and CBT procedures: 5-year overall survival (OS) was 64% versus 57% (<em>P</em> = .50), 5-year disease-free survival (DFS) 58% versus 57% (<em>P</em> = .80), GvHD-free and relapse-free survival (GFRFS) 41% versus 54% (<em>P</em> = .30), and cumulative incidence of transplant-related mortality (TRM) 14% versus 15% (<em>P =</em> .80), respectively. In the multivariate analysis, MRD positivity and a disease status >CR1 at the time of HSCT were significantly associated with poorer outcomes (<em>P</em> < .05).</div><div>In conclusion, our study supports that both haploidentical and cord blood transplantation show comparable outcomes in pediatric AML patients. We obtained comparable survival rates, although CBT showed a trend to lower rates of chronic GvHD and higher GFRFS, demonstrating that it should still be considered a valuable option, particularly for pediatric patients.</div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141789115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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