RESUMO
Chromothripsis, the process of catastrophic shattering and haphazard repair of chromosomes, is a common event in cancer. Whether chromothripsis might constitute an actionable molecular event amenable to therapeutic targeting remains an open question. We describe recurrent chromothripsis of chromosome 21 in a subset of patients in blast phase of a myeloproliferative neoplasm (BP-MPN), which alongside other structural variants leads to amplification of a region of chromosome 21 in â¼25% of patients ('chr21amp'). We report that chr21amp BP-MPN has a particularly aggressive and treatment-resistant phenotype. The chr21amp event is highly clonal and present throughout the hematopoietic hierarchy. DYRK1A , a serine threonine kinase and transcription factor, is the only gene in the 2.7Mb minimally amplified region which showed both increased expression and chromatin accessibility compared to non-chr21amp BP-MPN controls. We demonstrate that DYRK1A is a central node at the nexus of multiple cellular functions critical for BP-MPN development, including DNA repair, STAT signalling and BCL2 overexpression. DYRK1A is essential for BP-MPN cell proliferation in vitro and in vivo , and DYRK1A inhibition synergises with BCL2 targeting to induce BP-MPN cell apoptosis. Collectively, these findings define the chr21amp event as a prognostic biomarker in BP-MPN and link chromothripsis to a druggable target.
RESUMO
Essential thrombocytosis (ET) is a rare haematological malignancy, with an incidence rate of 1.5-2.5/100,000 per year. For many patients with ET the first manifestation of their underlying disease is a thrombotic or haemorrhagic complication. A recent retrospective study revealed an incidence rate of at least 2.1% in people under 40 years presenting with an acute coronary syndrome, although the diagnosis was initially missed in all cases. Thus, cardiologists face a much higher than average incidence rate of ET in their daily practice, but seem insufficiently aware of the disease. The current review summarises symptoms, (differential) diagnosis, complications and treatment considerations of ET of relevance for a cardiologist. Typical symptoms, besides thrombosis and haemorrhage, include erythromelalgia and aquagenic pruritus, while platelets >â¯450â¯× 109/l are a diagnostic for ET once other myeloproliferative neoplasms, secondary and spurious thrombocytosis have been excluded. With regard to treatment, timing of revascularisation depends on the presence of ischaemia and concurrent platelet counts. In the presence of ischaemia, revascularisation should not be delayed and adequate platelet counts can be achieved by platelet apheresis. In the absence of ischaemia, revascularisation can be delayed until adequate platelet counts have been achieved by cytoreductive therapies. Cardiologists should be aware of/screen for possible ET.
RESUMO
We sought to appraise the value of overall response and salvage chemotherapy, inclusive of allogeneic hematopoietic stem cell transplant (AHSCT), in primary refractory acute myeloid leukemia (prAML). For establishing consistency in clinical practice, the 2017 European LeukemiaNet (ELN) defines prAML as failure to attain CR after at least 2 courses of intensive induction chemotherapy. Among 60 consecutive patients (median age 63 years) correspondent with ELN-criteria for prAML, salvage was documented in 48 cases, 30/48 (63%) being administered intensive chemotherapy regimens and 2/48 consolidated with AHSCT as first line salvage. 13/48 (27%) attained response: CR, 7/13 (54%), CRi, 2/13 (15%), MLFS, 4/13 (31%). The CR/CRi rate was 9/48 (19%), with CR rate of 7/48 (15%). On univariate analysis, intermediate-risk karyotype was the only predictor of response (44% vs 17% in unfavorable karyotype; P = 0.04). Administration of any higher-dose (>1 g/m2) cytarabine intensive induction (P = 0.50), intensive salvage chemotherapy (P = 0.72), targeted salvage (FLT3 or IDH inhibitors) (P = 0.42), greater than 1 salvage regimen (P = 0.89), age < 60 years (P = 0.30), and de novo AML (P = 0.10) did not enhance response achievement, nor a survival advantage. AHSCT was performed in 12 patients with (n = 8) or without (n = 4) CR/CRi/MLFS. 1/2/5-year overall survival (OS) rates were 63%/38%/33% in patients who received AHSCT (n = 12) vs 27%/0%/0% in those who achieved CR/CRi/MLFS but were not transplanted (n = 5), vs 14%/0%/0% who were neither transplanted nor achieved CR/CRi/MLFS (n = 43; P < 0.001); the median OS was 18.6, 12.6 and 5.6 months, respectively. Although CR/CRi/MLFS bridged to AHSCT (n = 8), appeared to manifest a longer median OS (20 months), vs (13.4 months) for those with no response consolidated with AHSCT (n = 4), the difference was not significant P = 0.47. We conclude AHSCT as indispensable for securing long-term survival in prAML (p = 0.03 on multivariate analysis), irrespective of response achievement.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Terapia de Salvação , Transplante Homólogo , Resultado do Tratamento , Adulto JovemAssuntos
Hematopoese Extramedular , Adulto , Idoso , Biópsia , Diagnóstico por Imagem , Feminino , Hematopoese Extramedular/genética , Humanos , Janus Quinase 2/genética , Fígado/diagnóstico por imagem , Fígado/patologia , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/terapia , Baço/diagnóstico por imagem , Baço/patologia , Adulto JovemAssuntos
Benzamidas/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/metabolismo , Trombocitose/tratamento farmacológico , Trombocitose/metabolismoRESUMO
In a recent International Working Group on Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) study, prior arterial events and hypertension were predictors of subsequent arterial thrombosis whereas prior venous events and age ≥65 years predicted venous thrombosis in polycythemia vera (PV). In the current study, we sought to validate the above findings and identify additional predictors of arterial versus venous thrombosis. At a median follow up of 109 months, thrombosis after diagnosis occurred in 128 (22%) patients; 82 (14%) arterial and 57 (10%) venous events. On multivariate analysis, prior arterial events (<0.0001), hyperlipidemia (p = 0.03), and hypertension (p = 0.02) predicted subsequent arterial events. In comparison, prior venous events (p = 0.05), leukocytosis ≥11 × 109/L (p = 0.002), and major hemorrhage (p = 0.02) were predictors of subsequent venous events. Salient associations with arterial thrombosis included age ≥ 60 years, hypertension, diabetes, hyperlipidemia and normal karyotype whereas age ≤ 60 years, females, palpable splenomegaly and history of major hemorrhage were associated with venous thrombosis. TET2 or ASXL1 mutations did not impact arterial nor venous thrombosis. In conclusion, we identify distinct associations for arterial versus venous thrombosis in PV and confirm that a prior arterial or venous thrombotic event is the most reliable predictor of subsequent events.
Assuntos
Policitemia Vera/complicações , Trombose/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores de Risco , Trombose/epidemiologia , Adulto JovemAssuntos
Policitemia Vera/patologia , Mielofibrose Primária/patologia , Trombocitemia Essencial/patologia , Idoso , Feminino , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Policitemia Vera/metabolismo , Mielofibrose Primária/metabolismo , Prognóstico , Trombocitemia Essencial/metabolismoRESUMO
Current prognostic models for myelodysplastic syndromes (MDS), including the Revised International Prognostic Scoring System (IPSS-R), do not account for host immunity. We retrospectively examined the prognostic relevance of monocytopenia, lymphocytopenia and lymphocyte-to-monocyte ratio (LMR) in a cohort of 889 patients with primary MDS. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformation were documented. In univariate analysis, subnormal absolute lymphocyte count (ALC) <0.9 × 109/l; P=0.001), ALC<1.2 × 109/l (P=0.0002), subnormal absolute monocyte count (AMC) <0.3 × 109/l (P=0.0003), LMR (P⩽0.0001) and LMR⩾5 (P=0.03) were all associated with inferior overall survival. In multivariable analysis that included other risk factors, significance was retained for LMR (P=0.02) and became borderline for ALC <1.2 × 109/l (P=0.06). Analysis in the context of IPSS-R resulted in P-values of 0.06 for ALC<1.2 × 109/l, 0.7 for monocytopenia and 0.2 for LMR. Leukemia-free survival was not affected by ALC, AMC or LMR. The observations from the current study suggest a possible detrimental role for altered host immunity in primary MDS, which might partly explain the therapeutic benefit of immune-directed therapy, including the use of immune modulators; however, IPSS-R-independent prognostic value for either ALC or AMC was limited.
Assuntos
Contagem de Leucócitos , Linfócitos , Linfopenia/sangue , Monócitos , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
In 2012, the International Working Group for Myeloproliferative Neoplasms (MPN) Research and Treatment (IWG-MRT) reported an associations between mild bone marrow (BM) fibrosis (⩾grade 1) in polycythemia vera (PV) and a lower incidence of thrombosis during the clinical course and a higher risk of fibrotic progression. The objective in the current study of 262 patients with PV was to validate these observations and also identify other risk factors for myelofibrosis-free survival (MFFS). About 127 (48%) patients displayed ⩾grade 1 reticulin fibrosis at the time of diagnosis; presenting clinical and laboratory features were not significantly different between patients with or without BM fibrosis. In univariate analysis, BM fibrosis had no significant impact on overall, leukemia-free or thrombosis-free survival, whereas a significant association was noted for MFFS (P=0.009, hazard ratio 2.9; 95% confidence interval 1.32-6.78); other risk factors for MFFS included leukocytosis ⩾15 × 109/l, presence of palpable splenomegaly and abnormal karyotype. During multivariable analysis, leukocytosis ⩾15 × 109/l, palpable splenomegaly and ⩾grade 1 BM reticulin fibrosis remained significant. The current study validates the previously observed association between ⩾grade 1 BM reticulin fibrosis in PV and subsequent fibrotic progression, and identifies leukocytosis and palpable splenomegaly as additional risk factors for fibrotic progression; additional studies are required to clarify the impact of BM fibrosis on thrombosis and that of abnormal karyotype on MFFS.
Assuntos
Medula Óssea/patologia , Policitemia Vera/diagnóstico , Policitemia Vera/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Biópsia , Medula Óssea/metabolismo , Progressão da Doença , Feminino , Fibrose , Humanos , Janus Quinase 2/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Policitemia Vera/genética , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Prognóstico , Reticulina/metabolismo , Adulto JovemRESUMO
RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26%; P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 109/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence.
Assuntos
Fatores Imunológicos/uso terapêutico , Transtornos Mieloproliferativos/complicações , Mielofibrose Primária/etiologia , Mielofibrose Primária/terapia , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Transfusão de Eritrócitos/métodos , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/diagnóstico , Fenótipo , Mielofibrose Primária/diagnóstico , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Talidomida/uso terapêutico , Resultado do Tratamento , Fluxo de TrabalhoAssuntos
Mutação , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Esplenomegalia/diagnóstico , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Palpação , Mielofibrose Primária/patologia , Prognóstico , Fatores de Risco , Esplenomegalia/complicações , Esplenomegalia/genética , Trombocitemia Essencial/complicaçõesRESUMO
Clinical evidence supports the need of changing the diagnostic criteria of the 2008 updated WHO classification for polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). In JAK2-mutated patients who show characteristic bone marrow (BM) morphology, clinical studies demonstrated that a hemoglobin level of 16.5g/dL in men and 16.0g/dl for women or a hematocrit value of 49% in men and 48% in women are the optimal cut off levels for distinguishing JAK2-mutated ET from "masked/prodromal" PV. Therefore BM morphology was upgraded to a major diagnostic criterion. Regarding ET the key issue was to improve standardization of prominent BM features enhancing differentiation between "true" ET and prefibrotic/early primary myelofibrosis (prePMF). These two entities have shown a different epidemiology and clinical outcomes. Concerning prePMF a more explicit clinical characterization of minor criteria is mandated for an improved distinction from ET and overt PMF and accurate diagnosis and outcome prediction.