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Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.
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Análisis Costo-Beneficio , Inmunoterapia Adoptiva , Lenalidomida , Mieloma Múltiple , Talidomida , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/mortalidad , Mieloma Múltiple/tratamiento farmacológico , Lenalidomida/uso terapéutico , Lenalidomida/administración & dosificación , Inmunoterapia Adoptiva/economía , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Talidomida/economía , Talidomida/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Masculino , Femenino , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Persona de Mediana Edad , Supervivencia sin Progresión , Resultado del Tratamiento , Anciano , Resistencia a Antineoplásicos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/economíaRESUMEN
Chimeric Antigen Receptor T-cell (CAR-T) therapy uses genetically engineered T-cells with specific binding sites. This therapy allows for tumor specificity and durable treatment responses for patients with hematological malignancies. In this review, we study the risk of venous thromboembolism (VTE) associated with CAR-T therapy. We searched the National Institutes of Health library, Cochrane Library Databases, ClinicalTrials.gov database, and medical literature search engines PubMed and Google Scholar for Phase 2 and Phase 3 drug-efficacy and safety trials to determine the aggregate incidence and risk of VTE treated with CAR-T. Of 1127 search results, nine studies were identified and included in our meta-analysis. Of the 1017 patients who received therapy, 805 patients (79.15%) experienced some degree of CRS, and 122 patients (11.9%) experienced severe CRS (higher than grade 3). Only three out of one thousand and seventeen patients were reported to have experienced venous thromboembolism. Our study did not find a statistically significant association between increased VTE incidence (OR = 0.0005, 95% CI [0.0001, 0.0017]) and CRS/ICANS (p < 0.0001). There was a 0.0050 (95% confidence interval [0.0019, 0.0132]) relative risk for VTE. In our study, we did not find a statistically significantly increased risk of developing VTE despite CRS and underlying malignancy, which have been associated with increased risk of VTE.
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Neoplasias Hematológicas , Tromboembolia Venosa , Humanos , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/complicaciones , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/uso terapéutico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/etiologíaRESUMEN
The use of chimeric antigen receptor T (CAR-T) cells is a significant therapeutic improvement increasing the prognosis for patients with a variety of hematological malignancies. However, this therapy has also sometimes life-threatening, complications. Therefore, knowledge of the treatment and management of these complications, especially in treatment centers and intensive care units, respectively, is of outstanding importance. This review provides recommendations for the diagnosis, management, and treatment of CAR-T cell-associated complications such as cytokine release syndrome, immune effector cell associated neurotoxicity syndrome, hematotoxicity, hypogammaglobulinemia, and CAR-T cell-induced pseudo-progression amongst others for physicians treating patients with CAR-T cell-associated complications and intensivists.
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Síndrome de Liberación de Citoquinas , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/terapia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunología , Síndromes de Neurotoxicidad/etiologíaRESUMEN
The European society for Blood and Marrow Transplantation (EBMT) has a long-standing interest in the evaluation of hematopoietic cell transplantation. More than three decades ago, its members established a continental registry. Today, more than 700,000 patients have been registered, and information has been gathered on more than 800,000 transplants. This huge amount of information has allowed conducting multiple retrospective studies, evaluating changes in practices over time and for different categories of diseases, benchmarking outcome across EBMT affiliated centers, and increasingly serves to build synthetic comparators to evaluate the introduction of therapeutic innovations in the field of hematology. CAR-T cells therapies draw on human and technical resources that are also used to deliver HCT; they elicit side effects that require the implementation of risk mitigation plans; they are living drugs that persist in the body of the recipient and thus deserve prolonged follow-up; the introduction of CAR-T cells in the pharmacopeia is likely to significantly impact on the practice of BMT; for all these reasons and even before the first approvals of CAR-T Cells in Europe, EBMT engaged in a project aiming at complementing the EBMT Registry with a Cellular Therapy Form, with the objective to register CAR-T cells treated patients and collect information on their short-, middle- and long-term outcome. The goal is to provide EBMT investigators with a tool for primary analyses of the collected information and to support secondary use of data transferred at the individual level to Marketing Authorization Holders and other interested parties, to fulfill their obligations to health authorities and further evaluate the actual medical values of CAR-T Cells in different contexts and indications. The EBMT Registry received a positive opinion from the European Medicines agency in 2019, and five years later contains information on more than 9.000 treated patients. This article describes the journey to start this new activity, lessons to be drawn in view of improving the collection of real-world data, and what existing information tells us in terms of patient access.
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Inmunoterapia Adoptiva , Sistema de Registros , Humanos , Inmunoterapia Adoptiva/métodos , Europa (Continente) , Trasplante de Células Madre Hematopoyéticas , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
PURPOSE: Chimeric antigen receptor T-cell (CART) therapy has shown clinical efficacy in refractory and relapsed large B-cell lymphomas, but is associated with serious acute and long-term toxicities. To understand the patient perspective, we measured a patient-reported outcome (PRO), specifically, health-related quality of life (HRQoL), at multiple time points over one year. METHODS: This was a prospective feasibility study of a cohort of patients who were eligible for standard of care CART therapy, tisagenlecleucel. Demographic data and disease characteristics were collected. HRQoL was measured using FACT-Lym at baseline, and months 1, 3, 6 and 12. FACT-Lym includes FACT-G (physical, social, emotional and functional well-being domains), plus a lymphoma subscale. RESULTS: Thirty-four of 35 patients approached, consented to participate. Two of them did not receive their infusion due to progressive disease. 50% were female and median age was 62 (23-77). Twenty-nine patients (91%) completed baseline FACT-Lym and 20 of 21 (95%) eligible patients completed 12-month FACT-Lym. 52% completed all 4 post-baseline FACT-Lym measures. Exploratory analyses for changes in FACT-Lym scores are reported. CONCLUSION: It is feasible to measure longitudinal PROs in patients who receive CART therapy. This study will inform future studies in evaluating the patient perspective on CART therapy.
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Estudios de Factibilidad , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Medición de Resultados Informados por el Paciente , Calidad de Vida , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Adulto , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Estudios Prospectivos , Adulto Joven , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores de Antígenos de Linfocitos T/inmunología , Estudios Longitudinales , Recurrencia Local de Neoplasia/inmunología , Resultado del TratamientoRESUMEN
Chimeric antigen receptor T cell therapy has been established in the treatment of various B cell malignancies. However, translating this therapeutic effect to treat solid tumors has been challenging because of their inter-tumoral as well as intratumoral heterogeneity and immunosuppressive microenvironment. Local interventions, such as surgery, radiotherapy, local ablation, and locoregional drug delivery, can enhance chimeric antigen receptor T cell therapy in solid tumors by improving tumor infiltration and reducing systemic toxicities. Additionally, ablation and radiotherapy have proven to (re-)activate systemic immune responses via abscopal effects and reprogram the tumor microenvironment on a physical, cellular, and chemical level. This review highlights the potential synergy of the combined approaches to overcome barriers of chimeric antigen receptor T cell therapy and summarizes recent studies that may pave the way for new treatment regimens.
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Inmunoterapia Adoptiva , Neoplasias , Receptores Quiméricos de Antígenos , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia Adoptiva/métodos , Microambiente Tumoral/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Terapia Combinada/métodos , Animales , Linfocitos T/inmunología , Linfocitos T/trasplanteRESUMEN
The Food and Drug Administration and the European Medicines Agency have recently approved chimeric antigen receptor-engineered (CAR) T cells to treat several refractory/relapsed B-cell lymphomas. This comprehensive review aims to demonstrate the pivotal role that [18F]-FDG PET/computed tomographic (CT) imaging can play to enhance the care of patients treated with CAR T-cell therapy. To this end, this review deciphers evidence showing the diagnostic, prognostic, predictive, and theragnostic value of [18F]-FDG PET/CT-derived parameters.
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Fluorodesoxiglucosa F18 , Inmunoterapia Adoptiva , Linfoma de Células B , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Receptores Quiméricos de Antígenos , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B/terapia , Receptores Quiméricos de Antígenos/uso terapéutico , Inmunoterapia Adoptiva/métodosRESUMEN
Chimeric antigen receptor T cell (CAR-T) therapy is a promising treatment for hematologic tumors, and adverse events of acute kidney injury (AKI) have been reported. However, its incidence, clinical characteristics, and prognosis remained unclear. We searched PubMed, EMBASE, and Web of Science for study about AKI after CAR-T therapy, a total of 15 studies, comprising 694 patients, were included. Among the 694 patients, 154 (22%) developed AKI, of which 89 (57.8%) were in stage 1, 59 (38.3%) were in stage 2 or 3, and 6 (3.9%) were not reported. Cytokine release syndrome is considered to be the most common cause of AKI. Of the 154 AKI patients, only 16 (10.4%) received renal replacement therapy, most AKI recovered renal function after symptomatic treatment. Although the occurrence of AKI after CAR-T therapy is rare and mostly mild, active knowledge of its pathogenesis, timely diagnosis and treatment are necessary for clinicians.
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Lesión Renal Aguda , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/inmunología , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Pronóstico , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunología , MasculinoRESUMEN
ABSTRACT: The safety and efficacy of chimeric antigen receptor T-cell therapy is not well described in older patients, a population that has higher frailty and comorbidities. In this multicenter retrospective study, we evaluated clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status in younger (aged <65 years) vs older (aged ≥65 years) patients who received commercial idecabtagene vicleucel (ide-cel). A total of 156 patients (n = 75, aged ≥65 years) were infused with ide-cel by data cutoff. In older patients (median age: 69 years; range, 65-83; 66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, best overall response rate (ORR) was 86.7%, which was comparable with pivotal KarMMa study results (ORR: 73%). Median progression-free survival and overall survival in older patients were 9.1 months and 26.5 months, respectively. Grade ≥3 cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome were observed in 1% and 4% of older patients, respectively. Compared with younger patients, the older patients had significantly higher prevalence of frailty, geriatric characteristics such as polypharmacy (≥5 drugs; 97%), ≥4 comorbidities (69%), and organ dysfunction (35%; P < .05). The safety and efficacy of ide-cel therapy were similar in younger and older patients. Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients did not confer an inferior overall outcome.
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Mieloma Múltiple , Humanos , Anciano , Masculino , Anciano de 80 o más Años , Femenino , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Resultado del Tratamiento , Estudios Retrospectivos , Productos Biológicos/uso terapéutico , Persona de Mediana Edad , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/uso terapéutico , Factores de EdadRESUMEN
Chimeric antigen receptor (CAR)-T cell-based immunotherapy has emerged as a path-breaking strategy for certain hematological malignancies. Assessment of the response to CAR-T therapy using quantitative imaging techniques such as positron emission tomography/computed tomography (PET/CT) has been broadly investigated. However, the definitive role of PET/CT in CAR-T therapy remains to be established. [18F]FDG PET/CT has demonstrated high sensitivity and specificity for differentiating patients with a partial and complete response after CAR-T therapy in lymphoma. The early therapeutic response and immune-related adverse effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome can also be detected on [18F]FDG PET images. In otherwise asymptomatic lymphoma patients with partial response following CAR-T therapy, the only positive findings could be abnormal PET/CT results. In multiple myeloma, a negative [18F]FDG PET/CT after receiving B-cell maturation antigen-directed CAR-T therapy has been associated with a favorable prognosis. In leukemia, [18F]FDG PET/CT can detect extramedullary metastases and treatment responses after therapy. Hence, PET/CT is a valuable imaging tool for patients undergoing CAR-T therapy for pretreatment evaluation, monitoring treatment response, assessing safety, and guiding therapeutic strategies. Developing guidelines with standardized cutoff values for various PET parameters and tumor cell-specific tracers may improve the efficacy and safety of CAR-T therapy.
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Neoplasias Hematológicas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/diagnóstico por imagen , Neoplasias Hematológicas/inmunología , Inmunoterapia Adoptiva/métodos , Inmunoterapia/métodos , Receptores Quiméricos de Antígenos/uso terapéutico , Fluorodesoxiglucosa F18RESUMEN
Multiple myeloma (MM) is an incurable plasma cell malignancy. In the context of the current standard of care therapies in Canada, outcomes among patients with relapsed/refractory multiple myeloma (RRMM), particularly those with triple-class (or more) refractory disease remain poor. Immunotherapies have significantly changed the treatment landscape of MM. Since 2021, two BCMA-targeting CAR T-cell therapy products have been approved for RRMM-namely Idecabtagene vicleucel (Ide-cel) (ABECMA®) and Ciltacabtagene autoleucel (Cilta-cel) (CARVYKTI®), both of which are available in the US and Europe. Although they have shown unprecedented efficacy in RRMM, their clinical and logistical limitations must be acknowledged. MM CAR T-cell therapy is likely to be approved in Canada soon. Therefore, it is timely that we review the latest evidence for commercially available CAR T-cell therapy in multiple myeloma, with a focus on its relevance and impact in the Canadian setting. There will be challenges to access and strategies must be in place to ensure equitable care for all Canadians with MM. Alongside haematologists working in the immune effector cell therapy programs, providers in the community will also play a role in the ongoing monitoring and management of long-term side effects including opportunistic infections and late neurotoxicity.
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Inmunoterapia Adoptiva , Mieloma Múltiple , Mieloma Múltiple/terapia , Humanos , Canadá , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/uso terapéuticoAsunto(s)
Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Mieloma Múltiple/tratamiento farmacológico , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Recurrencia Local de NeoplasiaRESUMEN
Chimeric antigen receptor (CAR)-T-cell therapy has demonstrated considerable efficacy and safety in the treatment of patients with relapsed/refractory haematological malignancies. Owing to significant advances, CAR-T-cell therapeutic modality has undergone substantial shifts in its clinical application. Coagulation abnormalities, which are prevalent complications in CAR-T-cell therapy, can range in severity from simple abnormalities in coagulation parameters to serious haemorrhage or disseminated intravascular coagulation associated with life-threatening multiorgan dysfunction. Nonetheless, there is a lack of a comprehensive overview concerning the coagulation abnormalities associated with CAR-T-cell therapy. With an aim to attract heightened clinical focus and to enhance the safety of CAR-T-cell therapy, this review presents the characteristics of the coagulation abnormalities associated with CAR-T-cell therapy, including clinical manifestations, coagulation parameters, pathogenesis, risk factors and their influence on treatment efficacy in patients receiving CAR-T-cell infusion. Due to limited data, these conclusions may undergo changes as more experience accumulates.
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Trastornos de la Coagulación Sanguínea , Neoplasias Hematológicas , Inmunoterapia Adoptiva , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Neoplasias Hematológicas/terapia , Trastornos de la Coagulación Sanguínea/terapia , Trastornos de la Coagulación Sanguínea/etiología , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
Despite Peng and colleagues providing an extensive review of the clinical and laboratory aspects of CAR-T-associated coagulopathy, the current literature often lacks specificity in nomenclature and gradings, and the clinical implications of coagulopathy may remain unclear. Clear recommendations on stratification and prophylaxis are still required to standardize the clinical approach to this topic. Commentary on: Peng et al. Coagulation abnormalities associated with CAR-T therapy in hematological malignancies: A review. Br J Haematol 2024;205:420-428.
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Trastornos de la Coagulación Sanguínea , Inmunoterapia Adoptiva , Humanos , Trastornos de la Coagulación Sanguínea/etiología , Trastornos de la Coagulación Sanguínea/diagnóstico , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/complicaciones , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
BACKGROUND: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern. METHODS: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient. RESULTS: A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques. CONCLUSIONS: Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).
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Antineoplásicos Inmunológicos , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Linfoma de Células T , Neoplasias Primarias Secundarias , Receptores Quiméricos de Antígenos , Femenino , Humanos , Persona de Mediana Edad , Productos Biológicos/efectos adversos , Productos Biológicos/uso terapéutico , Hematopoyesis Clonal , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/genética , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células T/etiología , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Linfoma de Células T/terapia , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/etiología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Integración ViralRESUMEN
T-cell redirecting therapies such as chimeric antigen receptor T-cells and bispecific antibodies, are emerging as a novel class of immunotherapeutic agents for treatment of relapsed refractory multiple myeloma (MM). Their use is associated with an increased risk of infectious adverse events, fostered by cytopenias, hypogammaglobulinemia and T-cell exhaustion. Multiple ongoing clinical trials and real-world studies are investigating safety of T-cell therapy, highlighting the need for strategies to prevent and monitor the risk of infection. Recommended measures for risk mitigation include intravenous immunoglobulin supplementation, adequate prophylaxis therapy, vaccination and careful assessment for early diagnosis and treatment of infection. Here, we summarize available data on the risk of infections with approved and under development T-cell redirecting therapies for the treatment of MM.
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Mieloma Múltiple , Linfocitos T , Humanos , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Linfocitos T/inmunología , Infecciones/etiología , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
BCMA-directed chimeric antigen receptor T-cell (CAR T) therapies, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have transformed the treatment landscape for relapsed-refractory multiple myeloma (RRMM), offering remarkable efficacy with hallmark toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA mandates a 4-week monitoring period at the treatment center as part of a Risk Evaluation and Mitigation Strategy (REMS) to monitor and manage these toxicities, which, while prudent, may add unnecessary challenges related to access and socioeconomic disparities. We sought to assess CRS and ICANS onset and duration, as well as causes of non-relapse mortality (NRM) in real-world BCMA CAR T recipients in order to better inform future changes to the monitoring guidelines for CAR T recipients. This is a retrospective study across four academic centers that examined 129 ide-cel and cilta-cel recipients that received CAR T cell infusions from May 2021 to June 2023. Infusion and toxicities were managed per institutional guidelines in accordance with previously published guidelines. While differences were noted in the incidence and duration of CRS/ ICANS between ide-cel and cilta-cel, late-onset CRS and ICANS were rare after 2 weeks following infusion (0% and 1.6%, respectively). NRM was driven by hemophagocytic lymphohistiocytosis and infections in the early follow-up period (1.1% until Day 29), then by infections through three months post-infusion (1.2%). Our findings suggest that 25% of patients had to relocate for 4 weeks due to distance from the treatment center. With the low risk of CRS and ICANS after 2 weeks, a flexible shorter monitoring period may be reasonable, emphasizing collaboration with referring oncologists to improve NRM.
Asunto(s)
Síndrome de Liberación de Citoquinas , Inmunoterapia Adoptiva , Mieloma Múltiple , Humanos , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Inmunoterapia Adoptiva/efectos adversos , Femenino , Persona de Mediana Edad , Masculino , Anciano , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/mortalidad , Estudios Retrospectivos , Antígeno de Maduración de Linfocitos B/inmunología , Adulto , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/mortalidad , Factores de TiempoRESUMEN
An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d'Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee-assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6â99.4), and CR rate was 94% (95% CI: 87.5â97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1â99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839 .
Asunto(s)
Inmunoterapia Adoptiva , Linfoma Folicular , Humanos , Linfoma Folicular/terapia , Linfoma Folicular/inmunología , Linfoma Folicular/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Femenino , Anciano , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Adulto , Antígenos CD19/inmunología , Antígenos CD19/uso terapéutico , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
ABSTRACT: Recent studies demonstrating the feasibility of outpatient chimeric antigen receptor (CAR)-modified T-cell therapy administration are either restricted to CARs with 41BB costimulatory domains or use intensive at-home monitoring. We report outcomes of outpatient administration of all commercially available CD19- and B-cell maturation antigen (BCMA)-directed CAR T-cell therapy using a strategy of no remote at-home monitoring and an early cytokine release syndrome (CRS) intervention strategy. Patients with hematologic malignancies who received CAR T-cell therapy in the outpatient setting during 2022 to 2023 were included. Patients were seen daily in the cancer center day hospital for the first 7 to 10 days and then twice weekly through day 30. The primary end point was to determine 3-, 7-, and 30-day post-CAR T-cell infusion hospitalizations. Early CRS intervention involved administering tocilizumab as an outpatient for grade ≥1 CRS. Fifty-eight patients received outpatient CAR T-cell infusion (33 myeloma, 24 lymphoma, and 1 acute lymphoblastic leukemia). Of these, 17 (41%), 16 (38%), and 9 patients (21%) were admitted between days 0 to 3, 4 to 7, and 8 to 30 after CAR T-cell infusion, respectively. The most common reason for admission was CAR T-cell-related toxicities (33/42). Hospitalization was prevented in 15 of 35 patients who received tocilizumab for CRS as an outpatient. The nonrelapse mortality rates were 1.7% at 1 month and 3.4% at 6 months. In conclusion, we demonstrate that the administration of commercial CAR T-cell therapies in an outpatient setting is safe and feasible without intensive remote monitoring using an early CRS intervention strategy.