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1.
Blood ; 137(5): 702-717, 2021 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-32905596

RESUMEN

Gastrointestinal (GI) graft-versus-host disease (GVHD) is a major barrier in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The metabolite retinoic acid (RA) potentiates GI-GVHD in mice via alloreactive T cells expressing the RA receptor-α (RARα), but the role of RA-responsive cells in human GI-GVHD remains undefined. Therefore, we used conventional and novel sequential immunostaining and flow cytometry to scrutinize RA-responsive T cells in tissues and blood of patients who had received allo-HSCT and to characterize the impact of RA on human T-cell alloresponses. Expression of RARα by human mononuclear cells was increased after exposure to RA. RARαhi mononuclear cells were increased in GI-GVHD tissue, contained more cellular RA-binding proteins, localized with tissue damage, and correlated with GVHD severity and mortality. By using a targeted candidate protein approach, we predicted the phenotype of RA-responsive T cells in the context of increased microenvironmental interleukin-23 (IL-23). Sequential immunostaining confirmed the presence of a population of RARαhi CD8 T cells with the predicted phenotype that coexpressed the effector T-cell transcription factor T-bet and the IL-23-specific receptor (IL-23R). These cells were increased in GI- but not skin-GVHD tissues and were also selectively expanded in the blood of patients with GI-GVHD. Finally, functional approaches demonstrated that RA predominantly increased alloreactive GI-tropic RARαhi CD8 effector T cells, including cells with the phenotype identified in vivo. IL-23-rich conditions potentiated this effect by selectively increasing ß7 integrin expression on CD8 effector T cells and reducing CD4 T cells with a regulatory cell phenotype. In summary, we have identified a population of RA-responsive effector T cells with a distinctive phenotype that is selectively expanded in human GI-GVHD and that represents a potential new therapeutic target.


Asunto(s)
Linfocitos T CD8-positivos/efectos de los fármacos , Enfermedades Gastrointestinales/inmunología , Enfermedad Injerto contra Huésped/inmunología , Interleucina-23/análisis , Tretinoina/farmacología , Anciano , Linfocitos T CD8-positivos/inmunología , División Celular , Células Cultivadas , Técnicas de Cocultivo , Femenino , Enfermedades Gastrointestinales/metabolismo , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/metabolismo , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Receptores de Interleucina/análisis , Receptor alfa de Ácido Retinoico/biosíntesis , Receptor alfa de Ácido Retinoico/genética , Proteínas de Dominio T Box/análisis , Adulto Joven
2.
Br J Haematol ; 196(4): 892-901, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34761389

RESUMEN

Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1-2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96-1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09-5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08-2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments.


Asunto(s)
Antígenos CD20/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , COVID-19/complicaciones , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/tratamiento farmacológico , Adulto , Antineoplásicos Inmunológicos/efectos adversos , COVID-19/etiología , COVID-19/inmunología , Femenino , Neoplasias Hematológicas/inmunología , Humanos , Leucemia/complicaciones , Leucemia/tratamiento farmacológico , Leucemia/inmunología , Masculino , Mieloma Múltiple/complicaciones , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Estudios Prospectivos , Factores de Riesgo
6.
Blood Adv ; 8(2): 343-352, 2024 01 23.
Artículo en Inglés | MEDLINE | ID: mdl-38039513

RESUMEN

ABSTRACT: Molecular failure in NPM1-mutated acute myeloid leukemia (AML) inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low-dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here, we report on an international multicenter cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66 patients (84%) and MRD negativity in 56 (71%). Eighteen of 79 patients (23%) required hospitalization, and no deaths were reported during treatment. Forty-one patients were bridged to allogeneic transplant with no further therapy, and 25 of 41 were MRD negative assessed by reverse transcription quantitative polymerase chain reaction before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45%, and in responding patients, there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs 91%; P < .01), worse OS (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.86; P = .036), and EFS (HR, 1.87; 95% CI, 1.06-3.28; P = .03). Eighteen of 35 patients who did not undergo transplant became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax-based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1-mutated AML, either as a bridge to transplant or as definitive therapy.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Proteínas Nucleares , Sulfonamidas , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Proteínas Nucleares/genética , Nucleofosmina/genética , Recurrencia , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico
7.
Leukemia ; 37(10): 2066-2072, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37558736

RESUMEN

Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure.  This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated.  We identified 56 patients treated with FLT3i at molecular failure.  The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69-93) and molecular event-free survival 56% (95%CI 44-72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.


Asunto(s)
Leucemia Mieloide Aguda , Terapia Recuperativa , Humanos , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Recurrencia Local de Neoplasia , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico
9.
Curr Hematol Malig Rep ; 9(3): 227-32, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24906351

RESUMEN

Hodgkin lymphoma (HL) is more frequent in patients with Human Immunodeficiency Virus (HIV) infection than in immunocompetent patients. The relationship between the immune system and HL is complex. Whilst the incidence of HL in HIV patients has most likely increased since the introduction of combined anti-retroviral therapy (cART), there is no doubt that the outcomes for patients with HIV and HL (HIV-HL) have improved since its introduction. Improved CD4 counts and risk-adapted treatment schedules have resulted in outcomes for patients with HIV-HL that are comparable to those in HIV-negative patients with HL. Thus, HIV-HL should be treated in the same way as HL in immunocompetent patients, including the use of salvage chemotherapy and autologous transplant in the relapsed setting in HIV-HL. Along the same lines, patients with HIV-HL should not be excluded from trials based on their immune status alone.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Enfermedad de Hodgkin/complicaciones , Enfermedad de Hodgkin/tratamiento farmacológico , Recuento de Linfocito CD4 , VIH/efectos de los fármacos , VIH/aislamiento & purificación , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/epidemiología , Humanos , Linfoma Relacionado con SIDA/complicaciones , Linfoma Relacionado con SIDA/diagnóstico , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma Relacionado con SIDA/epidemiología , Pronóstico
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