RESUMO
Polycythemia vera (PV) was first described by Vaquez in 1892. This is a chronic hematological malignancy which affects both older and young patients. Perhaps due to lack of a curative treatment and the perceived toxicities of prior therapies our focus in the past was to intensify treatment only for patients at higher risk of thrombosis. Recent triggers to challenge this approach include: a recognition that low-risk PV is not "no-risk", our ability to better recognize patients who would benefit from more intensive therapy from the perspective of thrombosis, and data showing that some treatments may reduce risk of transformation to myelofibrosis. Furthermore, there is emergent evidence that molecular monitoring may identify an improvement in disease state translating to improved overall survival. Here we describe clinical situations that would trigger the use of cytoreductive treatment for low-risk PV patients as well as our approach to choosing a specific cytoreductive agent and how to effectively monitor treatment.
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We report on a study of next-generation sequencing in 257 patients undergoing investigations for cytopenias. We sequenced bone marrow aspirates using a target enrichment panel comprising 82 genes and used T cells from paired blood as a control. One hundred and sixty patients had idiopathic cytopenias, 81 had myeloid malignancies and 16 had lymphoid malignancies or other diagnoses. Forty-seven of the 160 patients with idiopathic cytopenias had evidence of somatic pathogenic variants consistent with clonal cytopenias. Only 39 genes of the 82 tested were mutated in the 241 patients with either idiopathic cytopenias or myeloid neoplasms. We confirm that T cells can be used as a control to distinguish between germline and somatic variants. The use of paired analysis with a T-cell control significantly reduced the time molecular scientists spent reporting compared to unpaired analysis. We identified somatic variants of uncertain significance (VUS) in a higher proportion (24%) of patients with myeloid malignancies or clonal cytopenias compared to less than 2% of patients with non-clonal cytopenias. This suggests that somatic VUS are indicators of a clonal process. Lastly, we show that blood depleted of lymphocytes can be used in place of bone marrow as a source of material for sequencing.
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Citopenia , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Neoplasias , Humanos , Síndromes Mielodisplásicas/genética , Mutação , Linfócitos T/patologia , Transtornos Mieloproliferativos/genéticaRESUMO
The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.
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Policitemia Vera , Trombocitemia Essencial , Trombose , Progressão da Doença , Humanos , Hidroxiureia/efeitos adversos , Interferon-alfa/efeitos adversos , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética , Trombose/induzido quimicamente , Trombose/prevenção & controleRESUMO
Myeloid malignancies are a group of blood disorders characterized by the proliferation of one or more haematopoietic myeloid cell lineages, predominantly in the bone marrow, and are often caused by aberrant protein tyrosine kinase activity. The protein tyrosine phosphatase CD45 is a trans-membrane molecule expressed on all haemopoietic blood cells except that of platelets and red cells. CD45 regulates various cellular physiological processes including proliferation, apoptosis, and lymphocyte activation. However, its role in chemotherapy response is still unknown; therefore, the aim of this study was to investigate the role of CD45 in myeloid malignancies in terms of cellular growth, apoptosis, and response to chemotherapy. The expression of CD45 on myeloid leukaemia primary cells and cell lines was heterogeneous with HEL and OCI-AML3 cells showing the highest level. Inhibition of CD45 resulted in increased cellular sensitivity to cytarabine and ruxolitinib, the two main therapies for AML and MPN. Bioinformatics analysis identified genes whose expression was correlated with CD45 expression such as JAK2, ACTR2, THAP3 Serglycin, and PBX-1 genes, as well as licensed drugs (alendronate, allopurinol, and balsalazide), which could be repurposed as CD45 inhibitors which effectively increases sensitivity to cytarabine and ruxolitinib at low doses. Therefore, CD45 inhibition could be explored as a potential therapeutic partner for treatment of myeloid malignancies in combination with chemotherapy such as cytarabine especially for elderly patients and those showing chemotherapy resistance.
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Leucemia Mieloide Aguda , Leucemia Mieloide , Transtornos Mieloproliferativos , Humanos , Idoso , Leucemia Mieloide/tratamento farmacológico , Pirazóis/uso terapêutico , Nitrilas/uso terapêutico , Citarabina , Transtornos Mieloproliferativos/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismoRESUMO
OBJECTIVES: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2. METHODS: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement. RESULTS: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs. CONCLUSIONS: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies.
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Mielofibrose Primária , Pirimidinas , Qualidade de Vida , Humanos , Mielofibrose Primária/tratamento farmacológico , Pirimidinas/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Estudos Retrospectivos , Pirazóis/uso terapêutico , Benzamidas/uso terapêutico , Nitrilas/uso terapêuticoRESUMO
Hereditary erythrocytosis is a rare hematologic disorder characterized by an excess of red blood cell production. Here we describe a European collaborative study involving a collection of 2,160 patients with erythrocytosis sequenced in ten different laboratories. We focused our study on the EGLN1 gene and identified 39 germline missense variants including one gene deletion in 47 probands. EGLN1 encodes the PHD2 prolyl 4-hydroxylase, a major inhibitor of hypoxia-inducible factor. We performed a comprehensive study to evaluate the causal role of the identified PHD2 variants: (i) in silico studies of localization, conservation, and deleterious effects; (ii) analysis of hematologic parameters of carriers identified in the UK Biobank; (iii) functional studies of the protein activity and stability; and (iv) a comprehensive study of PHD2 splicing. Altogether, these studies allowed the classification of 16 pathogenic or likely pathogenic mutants in a total of 48 patients and relatives. The in silico studies extended to the variants described in the literature showed that a minority of PHD2 variants can be classified as pathogenic (36/96), without any differences from the variants of unknown significance regarding the severity of the developed disease (hematologic parameters and complications). Here, we demonstrated the great value of federating laboratories working on such rare disorders in order to implement the criteria required for genetic classification, a strategy that should be extended to all hereditary hematologic diseases.
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Policitemia , Humanos , Policitemia/diagnóstico , Policitemia/genética , Policitemia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Mutação em Linhagem Germinativa , Sequência de BasesRESUMO
BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that affect approximately 8 people in every 100,000 individuals in the UK. Little is known about the aetiology of MPNs, as previous studies have been hampered by small sample sizes, thus it is important to understand the cause of MPNs in a larger study to identify prevention strategies and improve treatment strategies. This study aims to determine environmental, lifestyle, genetic and medical causes of MPNs and to assess the relevance of occupational carcinogen exposures and quality of life impacts. METHODS: A UK-wide case-control study of 610 recently diagnosed MPN patients (within 24 months) receiving clinical care at 21 NHS study sites in Scotland, England, Wales and Northern Ireland and 610 non-blood relative/friend controls is underway. Data on occupational and residential history, medical and environmental factors, and quality of life are being collected from the participants via a structured interview and self-complete questionnaires. Clinical data is being provided by the clinical team. Blood, saliva and toenail samples are also being collected for genetic and elemental analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (95%CI) will be calculated using a p < 0.05 to investigate potential risk factors for the MPN clinical and genetic subtypes, and further analyses will be conducted based on the type of data and outcome of interest at a later stage. DISCUSSION: The study design is most effective for investigating the aetiology of rare diseases. The study will enable identification of potential causes of MPNs through in-depth assessment of potential risk factors with potential for longer follow-up of a number of outcomes.
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Neoplasias Hematológicas , Transtornos Mieloproliferativos , Humanos , Qualidade de Vida , Estudos de Casos e Controles , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/genética , Reino Unido/epidemiologiaRESUMO
Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.
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Artérias/patologia , Transtornos Mieloproliferativos/patologia , Segunda Neoplasia Primária/patologia , Cromossomo Filadélfia , Trombose/patologia , Estudos de Casos e Controles , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Análise MultivariadaRESUMO
Management of chronic myeloid leukaemia (CML) has recently undergone dramatic changes, prompting the European LeukemiaNet (ELN) to issue recommendations in 2013; however, it remains unclear whether real-world CML management is consistent with these goals. We report results of UK TARGET CML, a retrospective observational study of 257 patients with chronic-phase CML who had been prescribed a first-line TKI between 2013 and 2017, most of whom received first-line imatinib (n = 203). Although 44% of patients required ≥1 change of TKI, these real-world data revealed that molecular assessments were frequently missed, 23% of patients with ELN-defined treatment failure did not switch TKI, and kinase domain mutation analysis was performed in only 49% of patients who switched TKI for resistance. Major molecular response (MMR; BCR-ABL1IS ≤0·1%) and deep molecular response (DMR; BCR-ABL1IS ≤0·01%) were observed in 50% and 29%, respectively, of patients treated with first-line imatinib, and 63% and 54%, respectively, receiving a second-generation TKI first line. MMR and DMR were also observed in 77% and 44% of evaluable patients with ≥13 months follow-up, receiving a second-generation TKI second line. We found little evidence that cardiovascular risk factors were considered during TKI management. These findings highlight key areas for improvement in providing optimal care to patients with CML.
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Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Gerenciamento Clínico , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido/epidemiologiaRESUMO
The aim of this literature review is to examine the significance of the nucleophosmin 1 (NPM1) gene in acute myeloid leukaemia (AML). This will include analysis of the structure and normal cellular function of NPM1, the type of mutations commonly witnessed in NPM1, and the mechanism by which this influences the development and progression of AML. The importance of NPM1 mutation on prognosis and the treatment options available to patients will also be reviewed along with current guidelines recommending the rapid return of NPM1 mutational screening results and the importance of employing a suitable laboratory assay to achieve this. Finally, future developments in the field including research into new therapies targeting NPM1 mutated AML are considered.
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DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , Mutação/genética , Proteínas Nucleares/genética , Tirosina Quinase 3 Semelhante a fms/genética , DNA Metiltransferase 3A , Humanos , NucleofosminaRESUMO
One out of ten patients with Philadelphia-negative myeloproliferative neoplasms (MPN) develop a second cancer (SC): in such patients we aimed at assessing the survival impact of SC itself and of MPN-specific therapies. Data were therefore extracted from an international nested case-control study, recruiting 798 patients with SC diagnosed concurrently or after the MPN. Overall, 2995 person-years (PYs) were accumulated and mortality rate (MR) since SC diagnosis was 5.9 (5.1-6.9) deaths for every 100 PYs. A "poor prognosis" SC (stomach, esophagus, liver, pancreas, lung, ovary, head-and-neck or nervous system, osteosarcomas, multiple myeloma, aggressive lymphoma, acute leukemia) was reported in 26.3% of the patients and was the cause of death in 65% of them (MR 11.0/100 PYs). In contrast, patients with a "non-poor prognosis" SC (NPPSC) incurred a MR of 4.6/100 PYs: 31% of the deaths were attributed to SC and 15% to MPN evolution. At multivariable analysis, death after SC diagnosis was independently predicted (HR and 95% CI) by patient age greater than 70 years (2.68; 1.88-3.81), the SC prognostic group (2.57; 1.86-3.55), SC relapse (1.53; 10.6-2.21), MPN evolution (2.72; 1.84-4.02), anemia at SC diagnosis (2.32; 1.49-3.59), exposure to hydroxyurea (1.89; 1.26-2.85) and to ruxolitinib (3.63; 1.97-6.71). Aspirin was protective for patients with a NPPSC (0.60; 0.38-0.95). In conclusion, SC is a relevant cause of death competing with MPN evolution. Prospective data are awaited to confirm the role of cytoreductive and anti-platelet drugs in modulating patient survival after the occurrence of a SC.
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Neoplasias Hematológicas/mortalidade , Transtornos Mieloproliferativos/mortalidade , Segunda Neoplasia Primária/mortalidade , Fatores Etários , Idoso , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P = .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in CALR-positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.com as #ISRCTN61925716.
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Resistência a Medicamentos , Hidroxiureia/uso terapêutico , Pirazóis/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Hemorragia/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Nitrilas , Pirazóis/efeitos adversos , Pirimidinas , Trombocitemia Essencial/complicações , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Resultado do Tratamento , Suspensão de TratamentoRESUMO
Biological sample collection is becoming more common in epidemiology research to obtain DNA for genetic analysis. There are many different DNA collection methods but little evidence on their relative effectiveness. Therefore, we took the opportunity of a prospective case-control study in myeloproliferative neoplasms (MPNs) to compare DNA yield from 8.5 mL PAXgene tubes for whole blood collection versus 2 mL Oragene OG-500 saliva collection kits. MPNs include polycythaemia vera, essential thrombocythaemia, and primary myelofibrosis. These are rare diseases and our exploratory case-control study (MOSAICC) sought to improve knowledge regarding their aetiology and to determine optimal methodology for a larger UK-wide study. Overall, 233 participants were recruited to the MOSIACC study, and we collected 187 blood and 214 saliva samples. The mean DNA yield from blood was 659.18 ng/µL, significantly higher than the mean DNA yield from saliva samples (275.79 ng/µL). The higher provision of saliva samples might reflect its non-invasive and more convenient nature, compared to blood sample provision. The differences in mean DNA yields might reflect differences in clinical assistance, adherence to instructions, and health status of individuals. In conclusion, both sample collection techniques are simple, effective, and suitable for DNA collection for genetic analysis in future epidemiological research studies but OG-500 kits offer a less invasive alternative for those who refuse to provide blood.
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DNA/sangue , DNA/isolamento & purificação , Saliva/química , Manejo de Espécimes , Estudos de Casos e Controles , Análise Custo-Benefício , Estudos de Viabilidade , Humanos , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Estudos Prospectivos , Manejo de Espécimes/economiaRESUMO
The myeloproliferative neoplasms (MPN), polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are linked by a propensity to thrombosis formation and a risk of leukaemic transformation. Activation of cytokine independent signalling through the JAK/STAT cascade is a feature of these disorders. A point mutation in exon 14 of the JAK2 gene resulting in the formation of the JAK2 V617F transcript occurs in 95% of PV patients and around 50% of ET and PMF patients driving constitutive activation of the JAK/STAT pathway. Mutations in CALR or MPL are present as driving mutations in the majority of remaining ET and PMF patients. Ruxolitinib is a tyrosine kinase inhibitor which inhibits JAK1 and JAK2. It is approved for use in intermediate and high risk PMF, and in PV patients who are resistant or intolerant to hydroxycarbamide. In randomised controlled trials it has demonstrated efficacy in spleen volume reduction and symptom burden reduction with a moderate improvement in overall survival in PMF. In PV, there is demonstrated benefit in haematocrit control and spleen volume. Despite these benefits, there is limited impact to induce complete haematological remission with normalisation of blood counts, reduce the mutant allele burden or reverse bone marrow fibrosis. Clonal evolution has been observed on ruxolitinib therapy and transformation to acute leukaemia can still occur. This review will concentrate on understanding the clinical and molecular effects of ruxolitinib in MPN. We will focus on understanding the limitations of JAK inhibition and the challenges to improving therapeutic efficacy in these disorders. We will explore the demonstrated benefits and disadvantages of ruxolitinib in the clinic, the role of genomic and clonal variability in pathogenesis and response to JAK inhibition, epigenetic changes which impact on response to therapy, the role of DNA damage and the role of inflammation in these disorders. Finally, we will summarise the future prospects for improving therapy in MPN in the JAK inhibition era.
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Epigênese Genética , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Pirazóis/uso terapêutico , Animais , Evolução Clonal , Epigênese Genética/efeitos dos fármacos , Humanos , Nitrilas , Pirazóis/farmacologia , Pirimidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: Splanchnic Vein Thrombosis (SVT) is strongly associated with underlying JAK2 V617F positive myeloproliferative neoplasms (MPN). METHODS: Patients attending the tertiary haematology service in Northern Ireland with SVT and underlying JAK2 V617F MPN were identified by consultant staff. A retrospective audit was undertaken to examine therapeutic interventions and relevant outcomes. Descriptive statistics were used for qualitative data whilst students t-test allowed comparison of quantitative data. RESULTS: We report on the medium to long term follow-up of fourteen patients presenting with SVT on the basis of JAK2 V617F positive MPN. Females comprised 78.5% of the patients and there was an average age of 47.3 years at time of diagnosis. There was significant morbidity evident at diagnosis with liver transplantation attempted in all patients with Budd Chiari (n = 3), oesophageal varices present in 57.1%, ascites present in 42.8% and splenomegaly evident in 71.4%. 42.8% of patients did not exhibit classical phenotypic blood count findings for MPN at time of diagnosis. Over a median follow-up of 88.5 months (range = 8-211 months) recurrence of SVT was only documented in the setting of interventional liver procedure. Major haemorrhagic complications were recorded in 35.7% of patients and there was an association with dual anticoagulation and antiplatelet use. Recurrent thrombosis outside of the splanchnic venous system occurred in 28.5% of patients, predominantly occurring off therapeutic anticoagulation. No deaths were recorded and one transformation to myelofibrosis was seen during follow-up. Cytoreduction therapies were routinely used but had a high discontinuation rate due to cytopenias and intolerance. CONCLUSION: This analysis highlights the complexities of management of this group of patients over a period of long follow-up with a focus on the evidence behind therapeutic options.
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A decade on from the description of JAK2 V617F, the MPNs are circumscribed by an increasingly intricate landscape. There is now evidence that they are likely the result of combined genetic dysregulation, with several mutated genes involved in the regulation of epigenetic mechanisms. Epigenetic changes are not due to a change in the DNA sequence but are reversible modifications that dictate the way in which genes may be expressed (or silenced). Among the epigenetic mechanisms, DNA methylation is probably the best described. Currently known MPN-associated mutations now include JAK2, MPL, LNK, CBL, CALR, TET2, ASXL1, IDH1, IDH2, IKZF1 and EZH2. Enhancing our knowledge about the mutation profile of patients may allow them to be stratified into risk groups which would aid clinical decision making. Ongoing work will answer whether the use of epigenetic therapies as alterative pathway targets in combination with JAK inhibitors may be more effective than single agent treatment.
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Epigênese Genética , Transtornos Mieloproliferativos/genética , Cromatina/metabolismo , Metilação de DNA , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , MutaçãoAssuntos
Leptina , Pirazóis , Encéfalo , Humanos , Janus Quinase 2 , Nitrilas , Pirimidinas , Fator de Transcrição STAT3 , Aumento de PesoRESUMO
The development of new treatments for older patients with acute myeloid leukemia is an active area, but has met with limited success. Vosaroxin, a quinolone-derived intercalating agent has several properties that could prove beneficial. Initial clinical studies showed it to be well-tolerated in older patients with relapsed/refractory disease. In vitro data suggested synergy with cytarabine (Ara-C). To evaluate vosaroxin, we performed 2 randomized comparisons within the "Pick a Winner" program. A total of 104 patients were randomized to vosaroxin vs low-dose Ara-C (LDAC) and 104 to vosaroxin + LDAC vs LDAC. When comparing vosaroxin with LDAC, neither response rate (complete recovery [CR]/complete recovery with incomplete count recovery [CRi], 26% vs 30%; odds ratio [OR], 1.16 (0.49-2.72); P = .7) nor 12-month survival (12% vs 31%; hazard ratio [HR], 1.94 [1.26-3.00]; P = .003) showed benefit for vosaroxin. Likewise, in the vosaroxin + LDAC vs LDAC comparison, neither response rate (CR/CRi, 38% vs 34%; OR, 0.83 [0.37-1.84]; P = .6) nor survival (33% vs 37%; HR, 1.30 [0.81-2.07]; P = .3) was improved. A major reason for this lack of benefit was excess early mortality in the vosaroxin + LDAC arm, most obviously in the second month following randomization. At its first interim analysis, the Data Monitoring and Ethics Committee recommended closure of the vosaroxin-containing trial arms because a clinically relevant benefit was unlikely.