RESUMEN
The search for novel targets in chronic myeloid leukaemia (CML) is ongoing, to improve treatment efficacy in refractory disease and increase eligibility for tyrosine kinase inhibitor (TKI) discontinuation. Increased frequency of Tregs and effector Tregs was evident at diagnosis, together with increased expression of T-cell exhaustion markers, including in regulatory T cells at diagnosis and in patients with refractory disease. Plasma analysis revealed significantly increased levels of cytokines including tumour necrosis factor (TNF)-a and interleukin (IL)-6 at diagnosis, in keeping with a pro-inflammatory state prior to treatment. We hence demonstrate T-cell exhaustion and a pro-inflammatory state at diagnosis in CML, likely secondary to leukaemia-associated antigenic overload associated with increased disease burden.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Fenotipo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Linfocitos T ReguladoresRESUMEN
Myeloproliferative neoplasm-unclassifiable (MPN-U) presents an MPN-type phenotype that fails to meet diagnostic criteria for other MPN variants. Variability in the clinicopathological phenotypes presents many challenges. Amongst a registry cohort of 1512 patients with MPN, 82 with MPN-U were included, with a median (range) age of 49·7 (13-79) years. Albeit heterogeneous, common presentation features included raised lactate dehydrogenase, thrombocytosis and clustered/pleomorphic megakaryocytes on trephine biopsy. Thrombosis was common (21%), necessitating vigilance. The median event-free survival was 11·25 years (95% confidence interval 9·3-not reached), significantly shortened in cases with lower platelet counts (<500 × 109 /l) and a leucocytosis (≥12 × 109 /l) at presentation. Generation of potential MPN-U prognostic scores is required.
Asunto(s)
Neoplasias Hematológicas , Trastornos Mieloproliferativos , Centros de Atención Terciaria , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/sangre , Trastornos Mieloproliferativos/mortalidad , Trastornos Mieloproliferativos/patología , Estudios Retrospectivos , Tasa de Supervivencia , Reino UnidoRESUMEN
The seasonal influenza A vaccine is recommended for patients with myeloproliferative neoplasms (MPNs). We hypothesised that immune deregulation associated with MPNs may affect the immune response gained following vaccinations when compared to healthy controls. Using deep immunophenotyping with high-dimensional single-cell analysis and mass cytometry we could demonstrate an altered immune response in MPN patients following vaccination. We found that prior to vaccination, MPN patients had reduced numbers of naive CD4 T cells. Furthermore, at 3-weeks and 3-months post-vaccination there was evidence of both delayed and impaired B- and T-memory cells responses. Thus, although, the immune systems of MPN patients can 'recognise' the Influenza A vaccine, the response appears inferior compared to healthy controls.
Asunto(s)
Inmunidad/efectos de los fármacos , Virus de la Influenza A/inmunología , Gripe Humana/prevención & control , Trastornos Mieloproliferativos/inmunología , Vacunación/efectos adversos , Adulto , Anciano , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Estudios de Casos y Controles , Femenino , Humanos , Inmunidad/inmunología , Memoria Inmunológica/efectos de los fármacos , Inmunofenotipificación/métodos , Gripe Humana/inmunología , Gripe Humana/virología , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/patología , Neoplasias/diagnóstico , Neoplasias/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Patients receiving targeted cancer treatments such as tyrosine kinase inhibitors (TKIs) have been classified in the clinically extremely vulnerable group to develop severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), including patients with chronic myeloid leukaemia (CML) taking TKIs. In addition, concerns that immunocompromised individuals with solid and haematological malignancies may not mount an adequate immune response to a single dose of SARS-CoV-2 BNT162b2 (Pfizer-BioNTech) vaccine have been raised. In the present study, we evaluated humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. Seroconversion and cellular immune response before and after vaccination were assessed. By day 21 after vaccination, anti-Spike immunoglobulin G was detected in 14/16 (87·5%) of the patients with CML and all developed a neutralising antibody response [serum dilution that inhibits 50% infection (ID50 ) >50], including medium (ID50 of 200-500) or high (ID50 of 501-2000) neutralising antibodies titres in nine of the 16 (56·25%) patients. T-cell response was seen in 14/15 (93·3%) evaluable patients, with polyfunctional responses seen in 12/15 (80%) patients (polyfunctional CD4+ response nine of 15, polyfunctional CD8+ T-cell response nine of 15). These data demonstrate the immunogenicity of a single dose of SARS-CoV-2 BNT162b2 vaccine in most patients with CML, with both neutralising antibodies and polyfunctional T-cell responses seen in contrast to patients with solid tumour or lymphoid haematological malignancies.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra la COVID-19/administración & dosificación , COVID-19 , Neoplasias Hematológicas/inmunología , Inmunidad Celular/efectos de los fármacos , Inmunoglobulina G/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , SARS-CoV-2/inmunología , Adulto , Anciano , Vacuna BNT162 , COVID-19/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
Standard first-line therapy choice for essential thrombocythaemia (ET) requiring cytoreduction, supported by randomized trials, is low-dose aspirin with hydroxycarbamide, but the role of recombinant interferon-alfa (IFNα)-2a/2b and pegylated (PEG)-IFN-α-2a/2b is increasingly highlighted. Longer-term outcome data, however, remains somewhat scarce, particularly in the 'real world'. We hereby report on a large, well-annotated cohort of ET patients from a single referral centre undergoing therapy with either IFNα or (PEG)-IFN-α-2a/2b and demonstrate high rates of complete haematological responses, good tolerability and safety, low rates of thromboembolic events in compliant patients and confirm feasibility of long-term therapy in a significant proportion of patients.
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Interferones/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Trombocitemia Esencial/tratamiento farmacológico , Adulto , Calreticulina/genética , Femenino , Humanos , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interferón-alfa/uso terapéutico , Interferones/administración & dosificación , Interferones/efectos adversos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Mutación , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Trombocitemia Esencial/etiología , Reino UnidoAsunto(s)
COVID-19/inmunología , Trastornos Mieloproliferativos/patología , Neoplasias/inmunología , Linfocitos T/inmunología , Adulto , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/virología , Estudios de Casos y Controles , Enfermedad Crónica , Femenino , Personal de Salud , Humanos , Inmunidad Celular , Memoria Inmunológica/efectos de los fármacos , Inhibidores de las Cinasas Janus/farmacología , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/virología , Neoplasias/virología , SARS-CoV-2/genética , SARS-CoV-2/inmunologíaRESUMEN
UNLABELLED: Ruxolitinib, a JAK1/JAK2 inhibitor, is currently the only pharmacological agent approved for the treatment of myelofibrosis. Approval was based on findings from two phase 3 trials comparing ruxolitinib with placebo (COMFORT-I) and with best available therapy (COMFORT-II) for the treatment of primary or secondary myelofibrosis. In those pivotal trials, ruxolitinib rapidly improved splenomegaly, disease-related symptoms, and quality of life and prolonged survival compared with both placebo and conventional treatments. However, for reasons that are currently unclear, there were only modest histomorphological changes in the bone marrow, and only a subset of patients had significant reductions in JAK2 V617F clonal burden. Here we describe a patient with post-polycythemia vera myelofibrosis who received ruxolitinib at our institution (Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom) as part of the COMFORT-II study. While on treatment, the patient had dramatic improvements in splenomegaly and symptoms shortly after starting ruxolitinib. With longer treatment, the patient had marked reductions in JAK2 V617F allele burden, and fibrosis of the bone marrow resolved after approximately 3 years of ruxolitinib treatment. To our knowledge, this is the first detailed case report of resolution of fibrosis with a JAK1/JAK2 inhibitor. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00934544.
Asunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , Pirazoles/uso terapéutico , Anciano , Humanos , Masculino , Nitrilos , Pirazoles/farmacología , Pirimidinas , Resultado del TratamientoRESUMEN
Despite widespread use of Pegylated forms of Inteferon in the management of Myeloproliferative Neoplasms (MPN), most clinicians have experience predominantly with peginterferon alfa-2a (Pegasys). Third generation pegylated IFNα, ropeginterferon alfa-2b (ropegIFN; Besremi), was recommended by the European Medicine Authority (EMA) for treatment of Polycythaemia Vera (PV) following a Phase III trial (PROUD-PV / CONTINUATION-PV). FDA approval for PV, regardless of treatment history, was subsequently granted in November 2021. We hereby demonstrate the safety and tolerability of ropegIFN in a series of MPN patients at variable doses. It corroborates reports of efficacy of ropegIFN in patients with PV and use in pregnancy.
RESUMEN
Supplemental Digital Content is available in the text.
RESUMEN
Approximately 10% to 15% of patients with essential thrombocythemia (ET) lack the common driver mutations, so-called "triple-negative" (TN) disease. We undertook a systematic approach to investigate for somatic mutations and delineate gene expression signatures in 46 TN patients and compared the results to those with known driver mutations and healthy volunteers. Deep, error-corrected, next-generation sequencing of peripheral blood mononuclear cells using the HaloPlexHS platform and whole-exome sequencing was performed. Using this platform, 10 (22%) of 46 patients had detectable mutations (MPL, n = 6; JAK2V617F, n = 4) with 3 of 10 cases harboring germline MPL mutations. RNA-sequencing and DNA methylation analysis were also performed by using peripheral blood mononuclear cells. Pathway analysis comparing healthy volunteers and ET patients (regardless of mutational status) identified significant enrichment for genes in the tumor necrosis factor, NFκB, and MAPK pathways and upregulation of platelet proliferative drivers such as ITGA2B and ITGB3. Correlation with DNA methylation showed a consistent pattern of hypomethylation at upregulated gene promoters. Interrogation of these promoter regions highlighted enrichment of transcriptional regulators, which were significantly upregulated in patients with ET regardless of mutation status, including CEBPß and NFκB. For "true" TN ET, patterns of gene expression and DNA methylation were similar to those in ET patients with known driver mutations. These observations suggest that the resultant ET phenotype may, at least in part and regardless of mutation type, be driven by transcriptional misregulation and may propagate downstream via the MAPK, tumor necrosis factor, and NFκB pathways with resultant JAK-STAT activation. These findings identify potential novel mechanisms of disease initiation that require further evaluation.
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Trombocitemia Esencial , Calreticulina/genética , Humanos , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Leucocitos Mononucleares/metabolismo , Receptores de Trombopoyetina , Trombocitemia Esencial/genética , TranscriptomaAsunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , SARS-CoV-2 , COVID-19/prevención & control , Vacunas de ARNmAsunto(s)
Anemia de Células Falciformes , Antidrepanocíticos/administración & dosificación , Hidroxiurea/administración & dosificación , Ácidos Nucleicos/sangre , Talasemia alfa , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/tratamiento farmacológico , Femenino , Humanos , Lactante , Masculino , Talasemia alfa/sangre , Talasemia alfa/complicaciones , Talasemia alfa/tratamiento farmacológicoAsunto(s)
COVID-19 , Neoplasias , COVID-19/prevención & control , Humanos , Nitrilos , Pirazoles , Pirimidinas , SARS-CoV-2 , Linfocitos T , VacunaciónAsunto(s)
Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Trastornos Mieloproliferativos/inmunología , SARS-CoV-2/inmunología , Linfocitos T/inmunología , COVID-19/complicaciones , Vacunas contra la COVID-19/administración & dosificación , Humanos , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología , Vacunas de ARNmRESUMEN
The present report focuses on management strategies for the myeloproliferative neoplasm according to the structure and processes we use within our center, a large tertiary unit in central London. The standard procedures for achieving an accurate diagnosis and risk stratification and therapeutic strategies for these diseases with a detailed focus on contentious areas are discussed. In the 9 years after the description of the Janus kinase 2 mutation, this field has altered quite radically in several aspects. For example, a new therapeutic paradigm exists, especially for myelofibrosis. We share how our unit has adapted to these changes.