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1.
Clin Cancer Res ; 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39259292

RESUMO

PURPOSE: Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell therapy (CART). While bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data has evaluated the impact of BT on CART outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic. PATIENTS AND METHODS: Patients with large B-cell lymphoma (LBCL) treated with CD19-CART from 2016-2022 were included. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into 'High' and 'Low' disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression free survival (PFS). RESULTS: Of 191 patients treated with CART, 144 (75%) received BT. In the BT cohort, 56% had any reduction in MTV post-BT. On multivariate analysis, MTV trajectory across the bridging period remained significantly associated with PFS (p<0.001), however notably patients with improved MTV (High->Low) had equivalent PFS compared to those with initially and persistently low MTV (Low->Low) (HR for High->Low MTV: 2.74, CI: 0.82-9.18). There was a reduction in any Grade ICANS in the High->Low MTV cohort as compared to High->High (13 vs. 41%, p=0.05). CONCLUSIONS: This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real world LBCL cohort. We demonstrate that effective BT can enable initially high-disease burden patients to achieve post-CART outcomes comparable to low-disease burden patients.

2.
Transplant Cell Ther ; 29(4): 259.e1-259.e10, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36587744

RESUMO

Greater tumor burden before CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy predicts lower complete response rate and shorter overall survival (OS) in patients with aggressive non-Hodgkin lymphoma (NHL). Recent patterns of failure studies have identified lesion characteristics, including size, standard uptake value (SUV), and extranodal location, as associated with post-CAR-T therapy failure. Here we analyzed the effect of bridging radiation-containing treatment (BRT) on pre-CAR-T therapy lesion- and patient-level characteristics and post-CAR-T therapy outcomes, including patterns of failure. Consecutive NHL patients who received radiation therapy from 30 days before leukapheresis until CAR T cell infusion were reviewed. Metabolic tumor volume (MTV) was contoured with a threshold SUV of 4. The first post-CAR-T therapy failures were categorized as preexisting/new/mixed with respect to pre-CAR-T therapy disease and in-field/marginal/distant with respect to BRT. Forty-one patients with diffuse large B cell lymphoma (DLBCL; n = 33), mantle cell lymphoma (n = 7), or Burkitt lymphoma (n = 1) were identified. BRT significantly improved established high-risk parameters of post-CAR-T therapy progression, including in-field median MTV (45.5 cc to .2 cc; P < .001), maximum SUV (18.1 to 4.4; P < .001), diameter (5.5 cm to 3.2 cm; P < .001), and lactate dehydrogenase (LDH; 312 to 232; P = .025). DLBCL patients with lower LDH levels post-BRT had improved progression-free survival (PFS; P = .001). In DLBCL, first failures were new in 7 of 19 patients, preexisting in 5 of 19, and mixed in 7 of 19; with respect to BRT, 4 of 19 were in-field and 4 of 19 were marginal. Post-CAR-T therapy survival was similar in patients with initially low MTV and those with newly low MTV post-BRT using a statistically determined threshold of 16 cc (PFS, 26 months versus 31 months; OS unreached for both). BRT produced significant cytoreductions in diameter, SUV, MTV, and LDH, all predictors of poor post-CAR-T therapy outcomes. Similar PFS and OS in patients with initially low MTV and those who achieved newly low MTV after BRT suggest that BRT may "convert" poor-risk patients to better risk. In the future, the response to BRT may allow for risk stratification and individualization of bridging strategies.


Assuntos
Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Receptores de Antígenos Quiméricos , Humanos , Adulto , Receptores de Antígenos Quiméricos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Linfoma não Hodgkin/etiologia , Linfoma Difuso de Grandes Células B/radioterapia , Terapia Baseada em Transplante de Células e Tecidos
3.
Artigo em Inglês | MEDLINE | ID: mdl-33139290

RESUMO

Remdesivir was recently approved by the Food and Drug Administration for the treatment of hospitalized patients with coronavirus disease 2019 (COVID-19). Remdesivir is the prodrug of an adenosine analogue that inhibits viral replication of several RNA virus families, including Coronaviridae Preclinical data in animal models of coronavirus diseases, including COVID-19, have demonstrated that early treatment with remdesivir leads to improved survival, decreased lung injury, and decreased levels of viral RNA. Recent clinical data have demonstrated the clinical activity of remdesivir in terms of faster time to recovery in patients with severe COVID-19 and higher odds of improved clinical status in patients with moderate COVID-19. Here, clinical trials published to date are presented and appraised. Remdesivir's potential benefits and its favorable adverse-event profile make it an option for the treatment of COVID-19. This article examines the available literature describing remdesivir's pharmacology, pharmacokinetics, and preclinical and clinical data.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/administração & dosagem , Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/farmacologia , Alanina/administração & dosagem , Alanina/química , Alanina/farmacocinética , Alanina/farmacologia , Animais , Antivirais/química , Antivirais/farmacocinética , Aleitamento Materno , Ensaios Clínicos como Assunto , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Feminino , Humanos , Hospedeiro Imunocomprometido , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Gravidez , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética
4.
Leukemia ; 32(10): 2126-2137, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29654263

RESUMO

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.


Assuntos
Carcinogênese/genética , Transformação Celular Neoplásica/genética , Proteínas Hedgehog/genética , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Transdução de Sinais/genética , Adolescente , Animais , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Oncogenes/genética , Linfócitos T/fisiologia , Peixe-Zebra
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