Asunto(s)
Leucemia Linfoide/sangre , Leucemia Linfoide/diagnóstico , Leucemia de Células Plasmáticas/sangre , Leucemia de Células Plasmáticas/diagnóstico , Diagnóstico Diferencial , Humanos , Leucemia Linfoide/patología , Leucemia de Células Plasmáticas/patología , Masculino , Persona de Mediana EdadRESUMEN
Idelalisib (IDL) is an oral first-in-class phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for chronic lymphocytic leukaemia (CLL) alongside rituximab (R) since 2014. However, little data exist on routine practice. The RETRO-idel was a protocol-led, retrospective study of 110 patients [n = 27 front-line (1L)] who received IDL-R. The primary end-point was clinical overall response rate (ORR). The median (range) follow-up of the whole cohort was 30·2 (0·1-51·9) months. The median (range) age was 72 (48-89) years. Tumour protein p53-disruption was common [100% 1L, 32·5% relapsed/refractory (R/R)]. The best ORR (intention-to-treat) was 88·2% (1L 96·3%, R/R 85·5%). Overall, the median event-free survival (mEFS) was 20·3 months and time-to-next treatment was 29·2 months. The mEFS for 1L patients was 18·7 months and R/R patients was 21·7 months. The 3-year overall survival was 56·1% (95% confidence interval 45·7-65·3). IDL was discontinued in 87·3% (n = 96). More patients discontinued due to adverse events in the front-line setting (1L 63·0% vs. R/R 44·6%) and due to progressive disease in R/R patients (20·5% vs. 3·7% in 1L). Lower respiratory tract infection/pneumonia were reported in 34·5% (Grade ≥3, 19·1%), diarrhoea in 30·9% (Grade ≥3, 6·4%), and colitis in 9·1% (Grade ≥3, 5·5%). Overall, these data describe clear efficacy for IDL-R in routine practice. No new safety signals were identified, although careful management of known toxicities is required.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Irlanda/epidemiología , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/epidemiología , Masculino , Persona de Mediana Edad , Inhibidores de las Quinasa Fosfoinosítidos-3/administración & dosificación , Supervivencia sin Progresión , Purinas/administración & dosificación , Purinas/efectos adversos , Quinazolinonas/administración & dosificación , Quinazolinonas/efectos adversos , Enfermedades Respiratorias/inducido químicamente , Estudios Retrospectivos , Rituximab/administración & dosificación , Rituximab/efectos adversos , Terapia Recuperativa , Resultado del Tratamiento , Reino Unido/epidemiologíaAsunto(s)
COVID-19/mortalidad , Atención a la Salud/métodos , Neoplasias Hematológicas/mortalidad , Hospitalización/estadística & datos numéricos , SARS-CoV-2/aislamiento & purificación , Población Urbana/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , COVID-19/transmisión , COVID-19/virología , Femenino , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/virología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Reino Unido/epidemiologíaAsunto(s)
Anemia Hemolítica Autoinmune , COVID-19 , Leucemia Linfocítica Crónica de Células B , SARS-CoV-2/metabolismo , Anciano de 80 o más Años , Anemia Hemolítica Autoinmune/sangre , Anemia Hemolítica Autoinmune/diagnóstico por imagen , Anemia Hemolítica Autoinmune/patología , COVID-19/sangre , COVID-19/diagnóstico por imagen , COVID-19/patología , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/diagnóstico por imagen , Leucemia Linfocítica Crónica de Células B/patología , Recuento de LinfocitosRESUMEN
Retinoic acid-related drugs have shown promising pre-clinical activity in Adult T-cell Leukemia/Lymphoma, but RORC signaling has not been explored. Therefore, we investigated transcriptome-wide interactions of the RORC pathway in HTLV-1 and ATL, using our own and publicly available gene expression data for ATL and other leukemias. Gene expression data from ATL patients were analyzed using WGCNA to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4+ T-Cells exhibited decreased RORC expression in four different ATL cohorts. A small subset of RORChi ATL patients was identified with significantly lower pathognomonic CADM1 and HBZ levels but similar levels of other ATL markers (CD4/CD25/CCR4), hinting at a less aggressive ATL subtype. An age-dependent decrease in RORC expression was found in HTLV-1-infected individuals, but not in healthy controls, suggesting an early molecular event predisposing to leukemogenesis. Genes upstream of RORC signaling were members of a proliferative gene module (containing proliferation markers PCNA/Ki67), whereas downstream members clustered in an anti-proliferative gene module. IL17C transcripts showed the strongest negative correlation to PCNA in both ATL cohorts, which was replicated in two large cohorts of T- and B-cell acute lymphoid leukemia (ALL). Finally, IL17C expression in purified CD4 + CCR4 + CD26-CD7- "ATL-like" cells from HTLV-1-infected individuals and ATL patients was negatively correlated with clonality, underscoring a possible antileukemic/antiproliferative role. In conclusion, decreased RORC expression and downstream signaling might represent an early event in ATL pathogenesis. An antiproliferative IL17C/PCNA link is shared between ATL, T-ALL and B-ALL, suggesting (immuno)therapeutic benefit of boosting RORC/IL17 signaling.
Asunto(s)
Regulación hacia Abajo , Interleucina-17/genética , Leucemia-Linfoma de Células T del Adulto/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Transducción de Señal , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Molécula 1 de Adhesión Celular/genética , Estudios de Cohortes , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Persona de Mediana Edad , Antígeno Nuclear de Célula en Proliferación/genética , Proteínas de los Retroviridae/genética , Adulto JovenRESUMEN
Adult T-cell leukaemia/lymphoma (ATL) arises from chronic non-malignant human T lymphotropic virus type-1 (HTLV-1) infection which is characterized by high plasma pro-inflammatory cytokines whereas ATL is characterized by high plasma anti-inflammatory (IL-10) concentrations. The poor prognosis of ATL is partly ascribed to disease-associated immune suppression. ATL cells have a CD4+CCR4+CD26-CD7- immunophenotype but infected cells with this immunophenotype ('ATL-like' cells) are also present in non-malignant HTLV-1 infection. We hypothesized that 'ATL-like' and ATL cells have distinct cytokine producing capacity and a switch in the cytokines produced occurs during leukemogenesis. Seventeen asymptomatic carriers (ACs), 28 patients with HTLV-1-associated myelopathy (HAM) and 28 with ATL were studied. Plasma IL-10 concentration and the absolute frequency of IL-10-producing CD4+ T cells were significantly higher in patients with ATL compared to AC. IL-10-producing ATL cells were significantly more frequent than 'ATL-like' cells. The cytokine-producing cells were only a small fraction of ATL cells. Clonality analysis revealed that even in patients with ATL the ATL cells were composed not only of a single dominant clone (putative ATL cells) but also tens of non-dominant infected clones ('ATL-like' cells). The frequency of cytokine-producing cells showed a strong inverse correlation with the relative abundance of the largest clone in ATL cells suggesting that the putative ATL cells were cytokine non-producing and that the 'ATL-like' cells were the primary cytokine producers. These findings were confirmed by RNAseq with cytokine mRNA expression in ATL cells in patients with ATL (confirmed to be composed of both putative ATL and 'ATL-like' cells by TCR analysis) significantly lower compared to 'ATL-like' cells in patients with non-malignant HTLV-1 infection (confirmed to be composed of hundreds of non-dominant clones by TCR analysis). A significant inverse correlation between the relative abundance of the largest clone and cytokine mRNA expression was also confirmed. Finally, 'ATL-like' cells produced less pro- and more anti-inflammatory cytokines than non 'ATL-like' CD4+ cells (which are predominantly HTLV uninfected). In summary, HTLV-1 infection of CD4+ T cells is associated with a change in cytokine producing capacity and dominant malignant clonal growth is associated with loss of cytokine producing capacity. Non-dominant clones with 'ATL-like' cells contribute to plasma cytokine profile in patients with non-malignant HTLV-1 infection and are also present in patient with ATL.
Asunto(s)
Transformación Celular Viral/fisiología , Citocinas/metabolismo , Infecciones por HTLV-I/inmunología , Infecciones por HTLV-I/metabolismo , Virus Linfotrópico T Tipo 1 Humano/fisiología , Leucemia-Linfoma de Células T del Adulto/virología , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Evolución Clonal/fisiología , Estudios de Cohortes , Citocinas/sangre , Citocinas/genética , Progresión de la Enfermedad , Femenino , Infecciones por HTLV-I/patología , Virus Linfotrópico T Tipo 1 Humano/inmunología , Virus Linfotrópico T Tipo 1 Humano/patogenicidad , Humanos , Inmunofenotipificación , Leucemia-Linfoma de Células T del Adulto/inmunología , Leucemia-Linfoma de Células T del Adulto/metabolismo , Masculino , Persona de Mediana Edad , Paraparesia Espástica Tropical/inmunología , Paraparesia Espástica Tropical/metabolismo , Paraparesia Espástica Tropical/patología , Paraparesia Espástica Tropical/virología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Carga ViralRESUMEN
Retinoic acid-related drugs have shown promising pre-clinical activity in Adult T-cell Leukemia/Lymphoma, but RORC signaling has not been explored. Therefore, we investigated transcriptome-wide interactions of the RORC pathway in HTLV-1 and ATL, using our own and publicly available gene expression data for ATL and other leukemias. Gene expression data from ATL patients were analyzed using WGCNA to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4+ T-cells showed decreased RORC expression in four different ATL cohorts. A small subset of RORChi ATL patients was identified with significantly lower pathognomonic CADM1 and HBZ levels but similar levels of other ATL markers (CD4/CD25/CCR4), hinting at a less aggressive ATL subtype. An age-dependent decrease in RORC expression was found in HTLV-1-infected individuals, but not in healthy controls, suggesting an early molecular event predisposing to leukemogenesis. Genes upstream of RORC signaling were members of a proliferative gene module (containing proliferation markers PCNA/Ki67), whereas downstream members clustered in an anti-proliferative gene module. IL17C transcripts showed the strongest negative correlation to PCNA in both ATL cohorts, which was replicated in two large cohorts of T- and B-cell acute lymphoid leukemia (ALL). Finally, IL17C expression in purified CD4+CCR4+CD26-CD7- "ATL-like? cells from HTLV-1-infected individuals and ATL patients was negatively correlated with clonality, underscoring a possible antileukemic/antiproliferative role. In conclusion, decreased RORC expression and downstream signaling might represent an early event in ATL pathogenesis. An antiproliferative IL17C/PCNA link is shared between ATL, T-ALL and B-ALL, suggesting (immuno)therapeutic benefit of boosting RORC/IL17 signaling.
RESUMEN
Adult T-cell leukemia/lymphoma (ATL), a human T-lymphotropic virus type 1 (HTLV-1)-associated disease, has a highly variable clinical course and four subtypes with therapeutic and prognostic implications. However, there are overlapping features between ATL subtypes and between ATL and nonmalignant (non-ATL) HTLV-1 infection complicating diagnosis and prognostication. To further refine the diagnosis and prognosis of ATL, we characterized the immunophenotype of HTLV-1-infected cells in ATL and non-ATL. A retrospective study of peripheral blood samples from 10 HTLV-1-uninfected subjects (UI), 54 HTLV-1-infected patients with non-ATL, and 22 with ATL was performed using flow cytometry. All patients with ATL had CD4+ CCR4+ CD26- immunophenotype and the frequency of CD4+ CCR4+ CD26- T cells correlated highly significantly with the proviral load in non-ATL suggesting CD4+ CCR4+ CD26- as a marker of HTLV-1-infected cells. Further immunophenotyping of CD4+ CCR4+ CD26- cells revealed that 95% patients with ATL had a CD7- (≤30% CD7+ cells), whereas 95% HTLV+ non-ATL had CD7+ (>30% CD7+ cells) immunophenotype. All patients with aggressive ATL had a CCR7+ (≥30%), whereas 92% with indolent ATL and 100% non-ATL had a CCR7- (<30%) immunophenotype. Patients with nonprogressing indolent ATL were CD127+ but those with progressive lymphocytosis requiring systemic therapy had a CD127- (≤30%) immunophenotype. In summary, HTLV-1-infected cells have a CD4+ CCR4+ CD26- immunophenotype. Within this population, CD7- phenotype suggests a diagnosis of ATL, CCR7+ phenotype identifies aggressive ATL, while CCR7- CD127- phenotype identifies progressive indolent ATL.