By late 2018, 2 chimeric antigen receptor T (CAR T) cell products have been approved by US and European regulatory authorities. Tisagenlecleucel (Kymriah, Novartis) is indicated in the treatment of ...patients up to 25 years of age with B‐cell acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse, or adult patients with large B‐cell lymphoma relapsed or refractory (r/r) after 2 or more lines of systemic therapy, including diffuse large B‐cell lymphoma (DLBCL) not otherwise specified, high grade B‐cell lymphoma and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel (Yescarta, Kite) is indicated for the treatment of adult patients with large B‐cell lymphoma relapsed or refractory after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary mediastinal large B‐cell lymphoma, high grade B‐cell lymphoma, and DLBCL arising from follicular lymphoma (ZUMA‐1 trial).
This review will offer a practical guide for the recognition and management of the most important toxicities related to the use of the current commercial CAR T cells, and also highlight strategies to diminish these side effects in the future.
Chimeric antigenreceptor (CAR) T cell therapy has demonstrated efficacy in B cell malignancies, particularly for acute lymphoblastic leukaemia (ALL) and non‑Hodgkin lymphomas. However, this regimen ...is not harmless and, in some patients, can lead to a multi organ failure. For this reason, the knowledge and the early recognition and management of the side effects related to CAR-T cell therapy for the staff is mandatory. In this review, we have summarised the current recommendations for the identification, gradation and management of the cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, as well as infections, and related to CAR-T cell therapy.
Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell ...lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (
CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.
Older patients with advanced hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplantation (allo-HCT) yet their survival outcomes remain suboptimal. We and ...others have previously shown that pre-HCT multi-morbidity and functional limitation and post-HCT geriatric syndromes significantly impact outcomes. Sarcopenia, an accelerated loss of muscle mass and function, has been increasingly recognized in older cancer patients. We identified 146 lymphoma patients 50 years or older who were allografted from 2008 to 2018 at our institution and found that before allo-HCT, 80 (55%) patients were sarcopenic. Pre-HCT sarcopenia was significantly associated with overall survival, progression-free survival, and nonrelapse mortality independent of multi-morbidity and functional limitation. In 6-month landmark analysis, post-HCT sarcopenia remained significantly associated with survival. Our findings illustrate the high prevalence and profound impact of sarcopenia on survival. While requiring prospective confirmation, preemptive, longitudinal, and multidisciplinary interventions for sarcopenia are warranted to improve HCT outcomes for older patients.
Although it is known that increasing age is associated with increased morbidity and mortality in allogeneic transplantation (allo-HSCT), individualization of the process may allow to perform it in ...progressively older patients.
This study analyzed the outcome of 97 patients older than 60 years with a first allo-HSCT performed at our institution between 2011 and 2019.
Median age was 66 years (range 60–79) and 15.4% were older than 70 years. The most frequent diagnosis was acute leukemia (50.5%), and 58.8% received a myeloablative conditioning. With a median follow-up of 33.9 months (range 7.9-111.5), at 3-years overall survival (OS) was 50%; progression-free survival (PFS), 46%; cumulative incidence of relapse, 22%; and non-relapse mortality (NRM), 32%. There were no significant differences in OS (
p
= 0.415), PFS (
p
= 0.691), cumulative incidence of relapse (
p
= 0.357) or NRM (
p
= 0.658) between patients of 60–64 years (
n
= 37), 65–69 (
n
= 45) and ≥ 70 years (
n
= 15). No differences were observed either depending on the intensity of the conditioning regimen in terms of OS (
p
= 0.858), PFS (
p
= 0.729), cumulative incidence of relapse (
p
= 0.416) or NRM (
p
= 0.270).
In conclusion, older adults can safely and effectively undergo allo-HSCT with proper patient selection and individualized transplantation procedures.
Abstract
Introduction
Hematology analyzers occasionally encounter interferences that prevent correct generation of the five-part WBC differential (5PWD). Although the cause of interference is usually ...unknown, we hypothesized that bilirubin excess drives specific and measurable changes.
Methods
We retrospectively identified 125 CBC samples run on the Beckman Coulter UniCel DXH800 analyzer (Brea, CA) that yielded an optical scatter pattern that interfered with the differential and had a subsequent 1:2 dilution. Abnormal scatterplots were visually clustered into distinct patterns. The % difference for each component of the differential pre- vs postdilution was calculated for each pattern. Kruskal-Wallis with Dunn’s correction was used to determine whether these changes were significantly different among patterns. Spearman correlation was used to calculate correlation between bilirubin concentration and neutrophil absolute % difference (NAD), a surrogate variable for the magnitude of the interference.
Results
For 114 (91%) samples, 1:2 dilution resolved interference. We identified four visually distinct optical scatter patterns. The majority showed the hereinafter called type 1 and 2, which yielded the most relevant changes in the 5PWD following dilution and were significantly different from the two other minor patterns. Type 1 (38% of samples) resulted in a NAD of +11.28% (95% CI, +8.93% to +13.63%) and a lymphocyte absolute difference (LAD) of –13.35% (95% CI, –16.16% to –10.54%). The mean bilirubin concentration was 1.45 mg/dL (95% CI, 0.56 to 2.34). Alternatively, type 2 (47%) resulted in a NAD of +25.24% (95% CI, +20.99 to +29.50) and LAD of –26.19 (95% CI, –30.66% to –21.73%). The mean bilirubin concentration was 12.51 mg/dL (95% CI, 9.94 to 15.08), significantly higher than in any other pattern, and with a significant positive correlation with the NAD (r = 0.386; P = .006; NAD = 13.853 + 0.874 * Bili mg/dL).
Conclusion
Our results suggest that bilirubin produces common and recognizable interference in DXH800 analyzers that responds to dilution, bringing the opportunity to reflexively dilute samples.
•Median overall survival (OS) in a contemporary cohort of patients who relapsed after allogeneic hematopoietic cell transplantation (allo-HCT) was 6 months.•The disease burden at relapse and time to ...relapse were correlated with OS.•Second cellular therapy could improve survival after early relapse.•Survival at 2 years after second cellular therapy (donor leukocyte infusion or second allo-HCT) was 44.9%.•Molecular features may influence the efficacy of second cellular therapy.
Patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) generally have poor overall survival (OS). Interventions that result in improved OS after relapse are not well established. The efficacy of second cellular therapy and specific indications are matters of debate. This study was conducted to evaluate factors associated with postrelapse survival and the efficacy of a second course of cellular therapy. We retrospectively analyzed consecutive patients with AML and MDS who underwent a first allo-HCT between 2010 and 2017 at our center but subsequently relapsed. One hundred and four patients with AML and 44 patients with MDS were included (total n = 148). Bone marrow (BM) and peripheral blood stem cell grafts were either unmodified or T cell-depleted (TCD) by CD34+ selection ex vivo. Forty-five patients (30.4%) received a second cellular therapy after relapse, either a second allo-HCT (n = 28; 18.9%) or donor leukocyte infusion (DLI) (n = 17; 11.5%). The median age at transplantation was 60 years (range, 24 to 78 years). The median time to relapse (TTR) after transplantation was 6.5 months (range, 1 to 60.9 months), and the ensuing median OS was 6 months (95% confidence interval CI, 4.8 to 8.9 months). In univariable analysis, longer TTR, relapse type (measurable residual disease versus morphologic), relapse occurring in the most recent years, and receipt of cellular therapy after relapse were associated with better outcomes, whereas adverse cytogenetics and/or abnormality of TP53, as well as NPM1 mutation in patients with AML, were associated with adverse outcomes. Relapse type, year of relapse, and a variable resulting from the combination of TTR and receipt of second cellular therapy remained significantly associated with postrelapse survival in multivariable analysis. In a separate multivariable model, adjusted only for TTR, relapse type, and receipt of second cellular therapy, an adverse effect of NPM1 mutation on survival was confirmed. We could not show an effect of post-transplantation maintenance on survival after relapse. In both univariable and multivariable analysis, we found a positive association for second cellular therapy with survival after relapse in patients who relapsed early (<6 months) after allo-HCT and a similar trend in patients who relapsed late (>12 months) after transplantation. Two-year OS after a second cellular therapy was 44.9% (95% CI, 28.5% to 61.4%), and it was significantly better in patients with <5% BM blasts before cell infusion. We could not show different effects on survival after second cellular therapy for DLI versus second allo-HCT in univariable analysis. Survival after relapse is improving over time, but this remains a challenging event, especially for patients who relapse early after transplantation. We found that a second cellular therapy could offer a benefit even in these cases. Nonetheless, more research is needed to clarify the most appropriate treatment choices after relapse. These are probably driven by underlying genetic and immunologic conditions, which should be the focus of future studies.
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