RESUMO
Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10-15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10-12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10-9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10-14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10-11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (ß)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10-8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mastocitose/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/genética , Sistema y+ de Transporte de Aminoácidos/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , DNA Intergênico , Feminino , Humanos , Interleucina-13/genética , Íntrons , Masculino , RNA Longo não Codificante/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Telomerase/genética , Triptases/genéticaRESUMO
Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Humanos , Dasatinibe/farmacologia , Dasatinibe/uso terapêutico , Fator de Transcrição STAT5/metabolismo , Interleucina-2/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Transdução de Sinais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases da Família src , Receptores de Antígenos de Linfócitos T , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mieloide de Fase Crônica/tratamento farmacológicoRESUMO
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.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Fenótipo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Linfócitos T ReguladoresRESUMO
The American Initiative in Mast Cell Diseases (AIM) held its inaugural investigator conference at Stanford University School of Medicine in May 2019. The overarching goal of this meeting was to establish a Pan-American organization of physicians and scientists with multidisciplinary expertise in mast cell disease. To serve this unmet need, AIM envisions a network where basic, translational, and clinical researchers could establish collaborations with both academia and biopharma to support the development of new diagnostic methods, enhanced understanding of the biology of mast cells in human health and disease, and the testing of novel therapies. In these AIM proceedings, we highlight selected topics relevant to mast cell biology and provide updates regarding the recently described hereditary alpha-tryptasemia. In addition, we discuss the evaluation and treatment of mast cell activation (syndromes), allergy and anaphylaxis in mast cell disorders, and the clinical and biologic heterogeneity of the more indolent forms of mastocytosis. Because mast cell disorders are relatively rare, AIM hopes to achieve a coordination of scientific efforts not only in the Americas but also in Europe by collaborating with the well-established European Competence Network on Mastocytosis.
Assuntos
Mastocitose/diagnóstico , Mastocitose/etiologia , Mastocitose/terapia , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Mastocitose/complicações , Pesquisa , Pesquisa Translacional BiomédicaRESUMO
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.
Assuntos
Neoplasias Hematológicas , Transtornos Mieloproliferativos , Centros de Atenção Terciária , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/mortalidade , Transtornos Mieloproliferativos/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Reino UnidoRESUMO
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.
Assuntos
Imunidade/efeitos dos fármacos , Vírus da Influenza A/imunologia , Influenza Humana/prevenção & controle , Transtornos Mieloproliferativos/imunologia , Vacinação/efeitos adversos , Adulto , Idoso , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Imunidade/imunologia , Memória Imunológica/efeitos dos fármacos , Imunofenotipagem/métodos , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/patologia , Neoplasias/diagnóstico , Neoplasias/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
We report on 45 patients with myeloid neoplasms and concurrent Janus kinase 2 (JAK2) V617F and KIT proto-oncogene, receptor tyrosine kinase (KIT) D816V (JAK2pos. /KITpos. ) mutations, which are individually identified in >60% of patients with classical myeloproliferative neoplasms (MPN) and >90% of patients with systemic mastocytosis (SM) respectively. In SM, the concurrent presence of a clonal non-mast cell neoplasm [SM with associated haematological neoplasm (SM-AHN)] usually constitutes a distinct subtype associated with poor survival. All 45 patients presented with a heterogeneous combination of clinical/morphological features typical of the individual disorders (e.g. leuco-/erythro-/thrombocytosis and elevated lactate dehydrogenase for MPN; elevated serum tryptase and alkaline phosphatase for SM). Overlapping features identified in 70% of patients included splenomegaly, cytopenia(s), bone marrow fibrosis and additional somatic mutations. Molecular dissection revealed discordant development of variant allele frequency for both mutations and absence of concurrently positive single-cell derived colonies, indicating disease evolution in two independent clones rather than monoclonal disease in >60% of patients examined. Overall survival of JAK2pos. /KITpos. patients without additional somatic high-risk mutations [HRM, e.g. in serine and arginine-rich splicing factor 2 (SRSF2), additional sex combs like-1 (ASXL1) or Runt-related transcription factor 1 (RUNX1)] at 5 years was 77%, indicating that the mutual impact of JAK2 V617F and KIT D816V on prognosis is fundamentally different from the adverse impact of additional HRM in the individual disorders.
Assuntos
Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Mutação Puntual , Proteínas Proto-Oncogênicas c-kit/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Masculino , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/patologiaRESUMO
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.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas contra COVID-19/administração & dosagem , COVID-19 , Neoplasias Hematológicas/imunologia , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Vacina BNT162 , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
Mastocytosis is a rare disease with varied presentation, myriad symptomatology and variable prognosis. Most patients present with cutaneous disease and mediator-related symptomatology with a small subset having systemic disease (systemic mastocytosis, SM). A subset of the latter develops synchronous or metachronous haematologic neoplasms (SM-AHN), most commonly chronic myelomonocytic leukaemia (CMML). Advanced systemic mastocytosis (ASM) is seen in a relatively small number of patients and is usually associated with organ dysfunction, and may present with hepatosplenomegaly, lymphadenopathy and ascites with progression to leukaemic transformation (mast cell leukaemia/acute myeloid leukaemia) occurring in a few patients. This paper discusses the clinical and pathologic features of the entire spectrum of SM in adults.
Assuntos
Leucemia Mielomonocítica Crônica , Mastocitose Sistêmica , Adulto , Humanos , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/metabolismo , Leucemia Mielomonocítica Crônica/patologia , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/metabolismo , Mastocitose Sistêmica/patologiaRESUMO
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.
Assuntos
Interferons/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Calreticulina/genética , Feminino , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Interferons/administração & dosagem , Interferons/efeitos adversos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Trombocitemia Essencial/etiologia , Reino UnidoRESUMO
Although it is well known that myeloproliferative neoplasms occur in younger patients, few large cohorts of such patients have been reported. Thus, our knowledge about circumstances of diagnosis, outcome and treatment is limited, especially for children and young adults. We therefore performed a systematic review of cases, published since 2005, concerning patients aged below 20 years at the time of diagnosis of essential thrombocythemia or polycythemia vera. We identified 396 cases of essential thrombocythemia and 75 of polycythemia vera. The median age at diagnosis was 9.3 and 12 years, respectively, and females constituted 57.6% and 45% of the groups, respectively. Half of the patients were asymptomatic at diagnosis. The proportion of so-called triple negativity was high: 57% in essential thrombocythemia and 73% in polycythemia vera. The incidence of thrombosis during the follow-up was 9.3% in patients with polycythemia vera and less, 3.8%, in those with essential thrombocythemia. Venous events were predominant (84.2%), with hemorrhagic episodes being rarer (<5%). The risk of evolution also seemed low (2% to myelofibrosis and no reports of acute leukemia), but the median follow-up was only 50 months. Survival curves were not available. Half of the patients received an antithrombotic drug and 40.5% received a cytoreductive drug. All data should be analyzed with care because of the proportion of missing data (10.7% to 74.7%). This review highlights interesting points concerning this population of young patients with myeloproliferative neoplasms, including that such patients were identified as negative for all common driver mutations, but also shows the need for larger contemporary cohorts with longer follow-up to assess the true prognosis of these patients.
Assuntos
Hemorragia/diagnóstico , Policitemia Vera/diagnóstico , Esplenomegalia/diagnóstico , Trombocitemia Essencial/diagnóstico , Trombose/diagnóstico , Adolescente , Doenças Assintomáticas , Criança , Citotoxinas/uso terapêutico , Diagnóstico Precoce , Fibrinolíticos/uso terapêutico , Expressão Gênica , Hemorragia/tratamento farmacológico , Hemorragia/genética , Hemorragia/patologia , Humanos , Janus Quinase 1/genética , Janus Quinase 2/genética , Mutação , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Policitemia Vera/patologia , Prognóstico , Esplenomegalia/tratamento farmacológico , Esplenomegalia/genética , Esplenomegalia/patologia , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Trombose/tratamento farmacológico , Trombose/genética , Trombose/patologia , Adulto JovemRESUMO
The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.
Assuntos
Transtornos Mieloproliferativos/epidemiologia , Fenótipo , Qualidade de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/mortalidade , Prognóstico , Fatores Sexuais , Inquéritos e Questionários , Adulto JovemRESUMO
Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.
Assuntos
Mastocitose Cutânea/classificação , Alergia e Imunologia , Consenso , Humanos , Mastocitose Cutânea/diagnóstico , Mastocitose Cutânea/imunologia , Sociedades MédicasRESUMO
BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality-related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms. METHODS: A total of 1971 patients with MPN (827 with essential thrombocythemia, 682 with polycythemia vera, 456 with myelofibrosis, and 6 classified as other) were prospectively evaluated and patient responses to the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ C30) were collected, along with information regarding individual disease characteristics and laboratory data. Sexuality scores were compared with an age-matched, healthy control population. RESULTS: Overall, patients with MPN were found to have greater sexual dysfunction compared with the healthy population (MPN-SAF score of 3.6 vs 2.0; P<.001), with 64% of patients with MPN describing some degree of sexual dysfunction and 43% experiencing severe symptoms. The presence of sexual symptoms correlated closely with all domains of patient functionality (physical, social, cognitive, emotional, and role functioning) and were associated with a reduced quality of life. Sexual problems also were found to be associated with other MPN symptoms, particularly depression and nocturnal and microvascular-related symptoms. Sexual dysfunction was more severe in patients aged >65 years and in those with cytopenias and transfusion requirements, and those receiving certain therapies such as immunomodulators or steroids. CONCLUSIONS: The results of the current study identify the topic of sexuality as a prominent issue for the MPN population, and this area would appear to benefit from additional investigation and management. Cancer 2016;122:1888-96. © 2016 American Cancer Society.
Assuntos
Transtornos Mieloproliferativos/fisiopatologia , Transtornos Mieloproliferativos/psicologia , Disfunções Sexuais Fisiológicas/etiologia , Disfunções Sexuais Psicogênicas/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/fisiopatologia , Policitemia Vera/psicologia , Mielofibrose Primária/fisiopatologia , Mielofibrose Primária/psicologia , Qualidade de Vida , Comportamento Sexual , Sexualidade , Inquéritos e Questionários , Trombocitemia Essencial/fisiopatologia , Trombocitemia Essencial/psicologiaRESUMO
Myelofibrosis (MF) is a rare haematopoietic disorder, commonly diagnosed in the 6th decade: less than 20% are diagnosed before the age of 50 years. In this retrospective study we included all patients given a diagnosis of World Health Organization-defined primary or secondary MF when aged ≤50 years. Forty-three patients with a median age of 43 years were included. Median follow up was 44 months. Twenty-two (51%) harboured the JAK2 V617F mutation, 18/43 (42%) CALR, 0/43 (0%) MPL mutations and 3/43 (7%) were 'Triple Negative' (TN). At the time of diagnosis, no significant differences existed in haematological and clinical phenotypes between JAK2, CALR and TN patients. The frequency of splenomegaly was greater (P = 0·047) in the JAK2-mutated group compared to CALR-mutated patients. In the whole cohort, the 5-year probability of developing anaemia, thrombocytopenia and marked leucocytosis was 24%, 10% and 13% respectively. Finally, the cumulative incidence of thrombotic events and progression to acute myeloid leukaemia was 1% and 0·5% patient-year respectively. No death was reported during the follow-up. These findings suggest that MF in younger patients may have a more indolent course when compared to older patients.
Assuntos
Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Cariótipo Anormal , Adulto , Anemia/diagnóstico , Antineoplásicos/uso terapêutico , Biomarcadores , Progressão da Doença , Feminino , Humanos , Janus Quinase 2/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/mortalidade , Leucocitose/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Avaliação de Resultados da Assistência ao Paciente , Fenótipo , Mielofibrose Primária/etiologia , Mielofibrose Primária/terapia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Trombocitopenia/diagnóstico , Adulto JovemAssuntos
COVID-19/imunologia , Transtornos Mieloproliferativos/patologia , Neoplasias/imunologia , Linfócitos T/imunologia , Adulto , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/virologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Pessoal de Saúde , Humanos , Imunidade Celular , Memória Imunológica/efeitos dos fármacos , Inibidores de Janus Quinases/farmacologia , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/virologia , Neoplasias/virologia , SARS-CoV-2/genética , SARS-CoV-2/imunologiaRESUMO
Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.
Assuntos
Neoplasias da Medula Óssea/epidemiologia , Transtornos Mieloproliferativos/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Medula Óssea/complicações , Neoplasias da Medula Óssea/diagnóstico , Análise por Conglomerados , Feminino , Geografia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/diagnóstico , Policitemia Vera/diagnóstico , Policitemia Vera/epidemiologia , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/epidemiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/epidemiologiaRESUMO
Current treatments for polycythemia vera have remained unchanged for decades with phlebotomy, hydroxycarbamide (also named hydroxyurea) and to a lesser extent interferon being the cornerstones in our therapeutic armamentarium. However, some patients do not respond to, or indeed experience significant side effects to, these current agents and development of alternative therapeutic options is required. Ruxolitinib, a potent JAK1/2 inhibitor, initially approved for myelofibrosis, was recently approved for patients with polycythemia vera refractory or intolerant to hydroxycarbamide. In this article, we review the currently available efficacy and safety data.