Transplantation and Cellular Therapy最新文献

The global multi-institutional registration trial (ELIANA) of CD19.41BB.zeta chimeric antigen receptor (CAR) T cell therapy forged the path to the first FDA-approved CAR T product, tisagenlecleucel. Since its approval, extensive post-market experience with CAR T cells in children and young adults has amassed, allowing several multi-institutional efforts to leverage real-world data. Real-world data has validated clinical trial findings and provided insights into CAR T-cell use in patient groups not included in early clinical trials, such as children <3 years, patients with active CNS and isolated extramedullary disease, and patients treated in first relapse. Data from multi-centered consortia has also identified cohorts who experienced inferior outcomes post-tisagenlecleucel, informing high-risk groups for whom further treatment optimization is needed, and delineating treatment variables, such as CAR T cell dose and lymphodepleting chemotherapy pharmacokinetics, that impact outcomes. In this early stage of CAR T-cell therapies, real-world experience provides an increasingly rich data reservoir and an invaluable resource to investigate and address clinical gaps for CAR T recipients. This review highlights key insights gained from post-market studies that have informed clinical use of CAR T-cell therapy for children and young adults with B-ALL.

Adoptive cellular therapy (ACT) is an increasingly widely used treatment approach for malignancy. While infectious complications of ACT have been well described in patients with hematologic malignancies, limited data are available on the epidemiology of infections in patients with solid tumors. The purpose of this study was to describe the epidemiology of infections occurring within the first 180 days in adult patients with solid tumors treated with ACT and to identify risk factors predisposing these patients to infection. Data on 132 adult patients with solid tumors undergoing ACT between August 2014 and November 2021 at Memorial Sloan Kettering Cancer Center were collected. Infections were documented from the day of ACT infusion through day 180 postinfusion. Overall, 28 of 132 patients (21.2%) experienced 33 infections within the first 30 days of ACT, and 17 of 131 surviving patients (13%) were diagnosed with 24 infections between day 31 and day 180. Infection-related mortality was low. The majority of infections were bacterial. While male gender, older age, Eastern Cooperative Oncology Group (ECOG) performance status (PS) at time of ACT infusion, tocilizumab receipt, and cytokine release syndrome treated with tocilizumab were associated with shorter time to first infection on univariable analysis, only ECOG PS and tocilizumab receipt remained independent risk factors in the multivariable analysis. The proportion of patients with solid tumors experiencing early or late infections after ACT was lower compared to that reported among patients with B cell malignancies after chimeric antigen receptor T cell therapy. Most observed infections were primarily bacterial with low infection-related mortality; the incidence of viral and fungal infections was low. Based on the low frequency and timing of infections relative to neutropenia, antibacterial and antifungal prophylaxis are not likely to be beneficial. ECOG PS ≥2 and tocilizumab receipt were identified as significant predictors for infection after ACT, likely signaling an individual's debilitated state that predisposes to infection. Additional work to parse out confounders is needed to better identify risk factors for infection.

Circulating nucleosomes are representative of cell death, which is a feature of acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We explored whether plasma nucleosome levels were prognostic for acute GVHD. We examined the level of circulating nucleosomes in 131 patients who underwent a myeloablative allo-HSCT between June 2015 and August 2018. The measurements were made using quantitative photometric sandwich-ELISA on stored plasma samples obtained pretransplantation (at a median of day -23) and around days +7, +14, and +28 after allo-HSCT. The median plasma nucleosome level remained constant until day +28, where they increased significantly (P < .001 compared to all other times of measurement). The plasma nucleosome level at day +28 was inversely associated with the risk of later grade II to IV acute GVHD (odds ratio [OR] 0.86 per 5 arbitrary unit [AU] increase [95% confidence intervals (CI): 0.66 to 0.99], P = .03), also after adjustment for risk factors of acute GVHD (OR 0.78 per 5 AU increase [95% CI: 0.56 to 0.96], P = .01). We found no support for an association between the plasma level of nucleosomes measured pretransplantation or around day +7 or +14 and the risk of subsequent grade II to IV acute GVHD. We observed a positive correlation between nucleosomes, suppressor of tumorigenesis 2, and C-reactive protein at day +28 (Spearman's ρ = 0.522, P < .001; and Spearman's ρ = 0.386, P < .001; respectively). A lower level of plasma nucleosomes at day +28 after HSCT was associated with a higher risk of subsequent acute GVHD. Additional studies are needed to validate circulating nucleosomes as a prognostic biomarker of acute GVHD.

It is widely accepted that allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole potentially curative option available for secondary acute myeloid leukemia (sAML). However, clinical factors impacting outcomes after allo-HSCT and the potential role of autologous HSCT (auto-HSCT) in real-life series are needed. Previously, the PETHEMA group reported a series of 2310 patients with sAML in the nationwide registry. Of these, 876 were candidates to receive chemotherapy and 274 underwent HSCT (55 auto-HSCT and 219 allo-HSCT). In this study, we analyzed the role of auto-HSCT or allo-HSCT as front-line treatment for sAML patients included in the Spanish PETHEMA AML registry. Here we report an analysis of outcomes as well as prognostic variables in this series of patients undergoing auto-HSCT or allo-HSCT as part of the front-line treatment for sAML. We used the multinational PETHEMA AML registry (Clincial Trials.gov identifier NCT02607059) to identify adult patients (age ≥18 years) with a diagnosis of sAML who underwent auto- or allo-HSCT as front-line treatment in Spanish and Portuguese institutions between August, 1, 1992, and July, 31, 2020. Patient characteristics, diagnostic findings, and management, including treatments, characteristics of HSCT, and outcomes, were retrieved from the PETHEMA AML registry in this retrospective multicenter analysis. With a median follow-up of 32.7 months, better 5-year overall survival (OS) and leukemia-free survival (LFS) were obtained with allo-HSCT in first complete response (CR) (44.5% and 39.9%, respectively) compared with auto-HSCT in CR1 (30% and 20.5%, respectively) but without reaching statistical differences for OS (P = .22 and .03, respectively). The higher incidence of relapse in auto-HSCT is counterbalanced with the significantly lower nonrelapse mortality rate. For allo-HSCT recipients, 5-year outcomes were significantly influenced by the cytogenetic/genetic risk. In multivariate analysis, the adverse cytogenetic/genetic risk group retained statistical significance for all endpoints. We confirmed the role of allo-HSCT as a potential curative option for patients and report that auto-HSCT in CR can still provide a 5-year LFS of 20% in sAML patients. Finally, our results confirm adverse cytogenetic/genetic risk category as an independent negative factor in sAML patients undergoing HSCT.

Geriatric assessment (GA) may identify vulnerabilities and promote risk-stratification in older adults predisposed to toxicities after autologous (auto), allogeneic (allo) hematopoietic cell transplantation (HCT) and chimeric antigen T-cell therapies (CAR T). With increased utilization cellular therapies for older adults the American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines and its Special Interest Group for Aging (SIG) conducted an online cross-sectional survey between April 2023 and August 2023 to determine transplantation and cellular therapy physicians' practice patterns regarding GA in older patients receiving HCT and CAR T-cell therapies. E-mail surveys were sent to 1168 ASTCT physician members and only 96 (8.2%) respondents completed the survey. Most (86%) were affiliated with university/teaching centers and 70% had a combined HCT and cellular therapy practice. More than 50% of respondents were interested in pursuing GA but 68% described barriers. The top two recognized barriers to GA were lack of time (96%) and clinical support staff (90%). Despite interest, only 15% respondents reported to know the domains of GA 'well'. Among those using GA, the minimum age used for routine GA was 65 years for allo-HCT and CAR T in over 91% respondents. Taken together, we recommend the HCT community leadership and GA experts combine efforts to address the gap in GA uptake and implementation.

While chimeric antigen receptor (CAR-T) targeting CD19 as second-line therapy for diffuse large B cell lymphoma (DLBCL) is a promising strategy, the high costs and limited access to CAR-T pose significant challenges. When assessing the cost-effectiveness of CAR-T, we need to consider not only individual outcomes but also how to effectively integrate CAR-T into the overall treatment approach for relapsed DLBCL. We conducted a cost-effective analysis for patients with DLBCL in early relapse or primary refractory, to compare "immediate CAR-T," which proceeds directly to CAR-T, and "late CAR-T," which initially aims at ASCT and quickly switches to third-line CAR-T if non-responsive. The primary analysis used a patient age of 60 years, and it also examined variations from 40 to 70 years. The analysis was performed for both Japanese and US settings using a Markov model incorporating life expectancy in both countries, with extensive sensitivity analysis including factors such as age, the choice of CAR-T (lisocabtagene maraleucel or axicabtagene ciloleucel), and the opportunity to receive third-line CAR-T, to reflect real-world situations. The length of a Markov cycle was defined to be 1 month, and patients in the model were assumed to age 1 year every 12 Markov cycles. The analysis was made over a lifetime horizon, and the outcome was measured based on incremental cost-effectiveness ratio (ICER), with willingness-to-pay (WTP) thresholds of ¥7,500,000 and $150,000 per quality-adjusted life years (QALY) in Japan and the US, respectively, with an annual discount rate of 3%. Compared with "late CAR-T," the "immediate CAR-T" strategy gained QALYs of 0.97 and 0.89 with an incremental cost of ¥5,998,354 and $88,440 in Japan and the US, respectively. The ICERs were ¥6,170,058/QALY in Japan and $99,596/QALY in the US. In the probabilistic sensitivity analysis for patients aged 60, "immediate CAR-T" was cost-effective in 54.8% and 61.7% of the 10,000 Monte Carlo iterations in Japan and the US, respectively. Sensitivity analyses showed that "immediate CAR-T" was not cost-effective when patients were over 68.4 in Japan, when the standardized mortality ratio of CAR-T and ASCT survivors was close, and when utility during treatment-free remission was low. Incorporating various clinical factors, the analysis showed that "immediate CAR-T" is more cost-effective than "late CAR-T." However, this conclusion should be interpreted with caution, as the ICERs were very close to the WTP thresholds, and the results were highly sensitive to parameter changes.

Chronic graft-versus-host disease (cGVHD) has a profound impact on the endocrinologic and cardiovascular health of survivors of transplantation performed in childhood. The impact of cGVHD is long-lasting and contributes to morbidity and early mortality through multiple mechanisms. Organs and tissues may be direct targets of alloreactive donor-derived immune cells. Corticosteroids and other cGVHD-directed therapies influence hormonal actions, alter bone metabolism, and negatively impact cardiometabolic health. Pediatric survivors are particularly vulnerable to the endocrinologic and cardiovascular effects of cGVHD as it develops during periods of intense growth and development, although little is known about the direct contribution to late effects. The Research and Education Toward Solutions for Late Effects to Innovate, Excel, and Nurture after cGVHD (RESILIENT after cGVHD) effort brought together content experts to determine the state of the science, develop clinical recommendations, and propose a research agenda in endocrine, cardiovascular, and metabolic cGVHD survivorship, which are detailed in this report.

Bacterial bloodstream infections (BSIs) are a serious complication after hematopoietic stem cell transplantation (HSCT), especially when caused by multidrug-resistant (MDR) bacteria. However, data on BSIs post-HSCT from centers in sub-Saharan Africa are limited. This study aims to describe the incidence, etiology, and outcomes of BSIs, including those caused by carbapenem-resistant Enterobacterales (CRE), in both autologous and allogenic HSCT recipients in South Africa. Furthermore, this study examines the incidence and clinical impact of colonization with CRE. A retrospective analysis was performed on clinical data from HSCT recipients, transplanted between January 2018 and December 2023 at Groote Schuur Hospital (GSH) and Red Cross War Memorial Children's Hospital, the academic hospitals of the University of Cape Town. Data were extracted from the transplant unit electronic and paper patient records, Hematology Patient Registry, and the National Health Laboratory Service electronic database. Surveillance cultures were taken upon admission and subsequently repeated weekly for GSH patients. In total, 270 HSCT recipients were included: 145 underwent autologous HSCT, and 124 an allogenic HSCT. The most common indication for autologous HSCT was multiple myeloma (52%), while acute myeloid leukemia was the most frequent for allogenic HSCT (34%). The overall incidence of BSIs was 35%, with a higher rate observed in allogeneic HSCT recipients (48%) compared to autologous HSCT recipients (23%). Gram-negative bacteria were the most common pathogens, and CRE were responsible for 9% of BSIs. Carbapenem-resistant Klebsiella pneumonia spp. was the most common CRE found in BSI and rectal surveillance cultures. Surveillance cultures with CRE were detected in 19% of the HSCT recipients during admission to the transplant unit, with oxacillinase-48 (and variants) the most prevalent carbapenemase. Colonization by CRE was an independent risk factor for developing BSIs. Within 100 days post-HSCT, 25 HSCT recipients (9%) died, of whom nine (36%) had a BSI in the last 7 days of life. Bivariate analysis revealed that BSIs significantly reduced overall survival in both autologous and allogenic HSCT recipients, with a further decrease in survival when the BSI was caused by MDR bacteria. BSIs are a frequent and severe complication among HSCT recipients in South Africa, particularly in those receiving allogenic HSCT. Colonization with CRE significantly increases the risk of BSIs, underscoring the need for vigilant infection control and targeted antimicrobial strategies in this vulnerable population.

Respiratory syncytial virus (RSV) is a common cause of respiratory infections in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. The immunodeficiency scoring index (ISI) has shown predictive value in assessing the risk of progression to lower respiratory tract disease (LRTD) and mortality in allo-HCT recipients developing RSV infection but requires further validation in external cohorts. This retrospective study examined RSV episodes in adult allo-HCT recipients from December 2013 to June 2023 at 2 Spanish hospitals. The aim was to validate the predictive value of ISI for LRTD progression and infectious mortality at day +100 after RSV detection and to identify other conditions associated with disease severity. A total of 207 allo-HCT recipients developed 262 episodes of RSV infection, of which 102 (39%) progressed to LRTD. Independent variables significantly associated with LRTD risk were umbilical cord blood transplant [odds ratio (OR) 2.72, P = .016], high-risk ISI (OR 4.4, P = .008), the transplant periods between 2014 and 2016 (OR 0.31, P = .007) and after 2020 (OR 0.13, P = .026), and ribavirin use (OR 0.49, P = .047). The 100-day infectious mortality rate after RSV detection was 8.7%, increasing to 18% in those with LRTD. Variables significantly associated with the risk of mortality were donor/recipient HLA mismatch [hazard ratio (HR) 5.09, P = .011] and absolute lymphocyte count (ALC) [<0.2 × 10^9/L (HR 11.27, P = .003) and 0.2 to 1 × 10^9/L (HR 8.21, P = .008)]. ISI was associated with mortality (HR 6.8, P = .006) only when ALC categories were excluded from the multivariable model. In transplant recipients with RSV infection, a high-risk ISI category is associated with an increased risk of progression to LRTD, whereas ribavirin appears to have a protective role. Mortality in LRTD cases was influenced by HLA mismatch and different levels of lymphopenia, factors which if incorporated may enhance the ISI's ability to predict mortality.