RESUMO
In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 µg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis.
Assuntos
Policitemia Vera , Humanos , Policitemia Vera/tratamento farmacológico , Policitemia Vera/diagnóstico , Hematócrito , Fatores de Risco , Flebotomia , SangriaRESUMO
Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%-20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and -in primary MF- also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p-y). This rate reached respectively 4.3% and 4.5% p-y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p-y and it reached 4.86% p-y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion-dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p-y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.
RESUMO
BACKGROUND: Whether phlebotomy alone can adequately maintain target hematocrit in patients with low-risk polycythemia vera (PV) remains elusive. METHODS: In a phase 2 open-label randomized trial, we compared ropeginterferon alfa-2b (ropeg; 100 µg every 2 weeks) with phlebotomy only regarding maintenance of a median hematocrit level (≤45%) over 12 months in the absence of progressive disease (primary end point). In follow-up, crossover to the alternative treatment group was allowed if the primary end point was not met. RESULTS: In total, 127 patients were enrolled (ropeg: n=64; standard group: n=63). The primary end point was met in 81% and 51% in the ropeg and standard groups, respectively. Responders continued the assigned treatment until month 24 and maintained response in 83% and 59%, respectively (P=0.02). Ropeg responders less frequently experienced moderate/severe symptoms (33% vs. 67% in the standard group) and palpable splenomegaly (14% vs. 37%) and showed normalization of ferritin levels and blood counts. Nonresponders at 12 months crossed over to the standard (n=9) or ropeg (n=23) group; in patients switched to ropeg only, 7 of 23 met the response criteria in 12 months, and phlebotomy need was high (4.7 per patient per year). Discontinuation because of adverse events occurred in seven patients treated with ropeg. CONCLUSIONS: In this 24-month trial, ropeg was superior to phlebotomy alone in maintaining hematocrit on target. No dose-limiting side effects or toxicities were noted; 9.2% of patients on ropeg and no patients on standard treatment developed neutropenia. (Funded by AOP Health and others; ClinicalTrials.gov number, NCT03003325.)
Assuntos
Policitemia Vera , Policitemia , Trombocitose , Trombose , Humanos , LeucocitoseRESUMO
Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.
Assuntos
Inibidores de Janus Quinases , Policitemia Vera , Mielofibrose Primária , Trombocitemia Essencial , Trombose , Humanos , Hidroxiureia/uso terapêutico , Policitemia Vera/complicações , Policitemia Vera/terapia , Mielofibrose Primária/etiologia , Mielofibrose Primária/terapia , Trombocitemia Essencial/complicações , Trombose/etiologiaRESUMO
Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX-DFX therapy was administered for a median time of 12.4 months (interquartile range 3.1-71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2 months respectively. Patients achieving an ER were more likely to obtain an ICR also (p = 0.04). In multivariable analysis, the absence of leukocytosis at baseline (p = 0.02) and achievement of an ICR at any time (p = 0.02) predicted improved survival. In many MF patients, the RUX-DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.
Assuntos
Sobrecarga de Ferro , Mielofibrose Primária , Benzoatos/efeitos adversos , Deferasirox/uso terapêutico , Humanos , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/induzido quimicamente , Sobrecarga de Ferro/etiologia , Nitrilas , Mielofibrose Primária/tratamento farmacológico , Pirazóis , Pirimidinas , Estudos RetrospectivosRESUMO
Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P = .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P = .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P = .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P = .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.
Assuntos
Mielofibrose Primária , Humanos , Nitrilas , Mielofibrose Primária/induzido quimicamente , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Prognóstico , Pirazóis/efeitos adversos , Pirimidinas , Estudos RetrospectivosRESUMO
Chronic Myeloid Leukemia is a clonal disorder characterized by the presence of the Ph-chromosome and the BCR-ABL tyrosine-kinase (TK). Target-therapy with Imatinib has greatly improved its outcome. Deeper and faster responses are reported with the second-generation TKI Nilotinib. Sustained responses may enable TKI discontinuation. However, even in a complete molecular response, some patients experience disease recurrence possibly due to persistence of quiescent leukemic CD34+/lin-Ph+ stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not clearly established. The PhilosoPhi34 study was designed to verify the in-vivo activity and timecourse of first-line Nilotinib therapy on BM CD34+/lin-Ph+ cells clearance. Eighty-seven CP-CML patients were enrolled. BM cells were collected and tested for Ph+ residual cells, at diagnosis, 3, 6 and 12 months of treatment. FISH analysis of unstimulated CD34+/lin- cells in CCyR patients were positive in 8/65 (12.3%), 5/71 (7%), 0/69 (0%) evaluable tests, respectively. Per-Protocol analysis response rates were as follows: CCyR 95% at 12 months, MR4.5 31% and 46% at 12 and 36 months, respectively. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin- cells was performed on 30 patients at diagnosis and after, on 79 patients at diagnosis vs 12 months of nilotinib treatment vs 10 healthy subjects. Data demonstrated some genes significantly different expressed: NFKBIA, many cell cycle genes, ABC transporters, JAK-STAT signaling pathway (JAK2). In addition, a correlation between different expression of some genes (JAK2, OLFM4, ICAM1, NFKBIA) among patients at diagnosis and their achievement of an early and deeper MR was observed.
Assuntos
Antineoplásicos/uso terapêutico , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Farmacológicos , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Medula Óssea/patologia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Feminino , Perfilação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Cromossomo Filadélfia , Estudos Prospectivos , RecidivaRESUMO
BACKGROUND: There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone. METHODS: In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18-60 years, with a diagnosis of polycythaemia vera according to 2008-16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 µg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325. FINDINGS: Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0-12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7-41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred. INTERPRETATION: Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera. FUNDING: AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro.
Assuntos
Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Flebotomia , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Adolescente , Adulto , Medula Óssea/patologia , Feminino , Humanos , Interferon alfa-2/efeitos adversos , Interferon-alfa/efeitos adversos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Polietilenoglicóis/efeitos adversos , Polimorfismo de Nucleotídeo Único , Qualidade de Vida , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Adulto JovemAssuntos
Inibidores de Janus Quinases/efeitos adversos , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/etiologia , Mielofibrose Primária/complicações , Pirazóis/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Duração da Terapia , Feminino , Humanos , Itália/epidemiologia , Inibidores de Janus Quinases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Taxa de Mutação , Segunda Neoplasia Primária/epidemiologia , Nitrilas , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/epidemiologia , Mielofibrose Primária/etiologia , Pirazóis/uso terapêutico , Pirimidinas , Adulto JovemRESUMO
Patients with myeloproliferative neoplasms (MPN) are known to have higher incidence of nonhematological second primary malignancies (SPM) compared to general population. In the MYSEC study on 781 secondary myelofibrosis (SMF) patients, the incidence of SPM after SMF diagnosis resulted 0.98/100 patient-years. When including non-melanoma skin cancers (NMSC), the incidence arose to 1.56/100 patient-years. In SMF, JAK inhibitor treatment was associated only with NMSC occurrence. Then, we merged the MYSEC cohort with a large dataset of PV and ET not evolving into SMF. In this subanalysis, we did not find any correlation between SPM and SMF occurrence. These findings highlight the need of studies aimed at identifying MPN patients at higher risk of SPM.
Assuntos
Segunda Neoplasia Primária/epidemiologia , Policitemia Vera/epidemiologia , Mielofibrose Primária/epidemiologia , Neoplasias Cutâneas/epidemiologia , Trombocitemia Essencial/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Inibidores de Janus Quinases/uso terapêutico , Masculino , Segunda Neoplasia Primária/tratamento farmacológico , Policitemia Vera/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Resultado do TratamentoAssuntos
Deferasirox/uso terapêutico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Idoso , Deferasirox/farmacologia , Feminino , Humanos , Quelantes de Ferro/farmacologia , Masculino , Mielofibrose Primária/complicações , Estudos RetrospectivosRESUMO
EEXPAND (phase Ib, dose-finding study) evaluated the starting dose of ruxolitinib in patients with myelofibrosis with baseline platelet counts of 50-99×109/L. The study consisted of dose-escalation and safety-expansion phases. Based on the baseline platelet counts, patients were assigned to stratum 1 (75-99×109/L) or stratum 2 (50-74×109/L), with the primary objective of determining the maximum safe starting dose (MSSD); key secondary objectives included safety and efficacy. At week 48 data cutoff (stratum 1, n=44; stratum 2, n=25), 24.6% (17 out of 69) of patients were still receiving treatment. The MSSD was established as ruxolitinib 10 mg twice daily in both strata. Thrombocytopenia [grade 4 (stratum 1, n=1; stratum 2, n=2)] was the only reported dose-limiting toxicity (study drug related) at 10 mg twice daily. In the MSSD cohort (stratum 1, n=20; stratum 2, n=18), adverse events (regardless of study drug relationship) led to treatment discontinuation in 15.0% and 33.3% of patients in stratum 1 and stratum 2, respectively, and dose adjustment/interruption in 45.0% and 66.7% of patients in stratum 1 and stratum 2, respectively. Three cases of on-treatment deaths were reported at the MSSD. Spleen response was achieved at week 48 in 33.3% and 30.0% of patients in stratum 1 and stratum 2, respectively. Improvements in the Total Symptom Score were also observed. In this study, ruxolitinib demonstrated acceptable tolerability in both the strata at the MSSD of 10 mg twice daily. (Registered at: clinicaltrials.gov identifier: 01317875).
Assuntos
Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Nitrilas , Mielofibrose Primária/patologia , Prognóstico , Pirimidinas , Adulto JovemAssuntos
Genótipo , Fenótipo , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/genética , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/mortalidade , Mielofibrose Primária/mortalidade , Prognóstico , Índice de Gravidade de Doença , Fatores Sexuais , Trombocitemia Essencial/mortalidadeAssuntos
Policitemia Vera/patologia , Mielofibrose Primária/patologia , Trombocitemia Essencial/patologia , Progressão da Doença , Humanos , Fenótipo , Policitemia Vera/sangue , Policitemia Vera/complicações , Mielofibrose Primária/complicações , Estudos Retrospectivos , Trombocitemia Essencial/sangue , Trombocitemia Essencial/complicaçõesAssuntos
Aberrações Cromossômicas , Policitemia Vera/genética , Mielofibrose Primária/genética , Trombocitemia Essencial/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/mortalidade , Policitemia Vera/patologia , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Prognóstico , Trombocitemia Essencial/mortalidade , Trombocitemia Essencial/patologiaRESUMO
Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 x 10(9)/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.
Assuntos
Mielofibrose Primária/mortalidade , Fatores Etários , Idoso , Feminino , Hemoglobinas/metabolismo , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Modelos Estatísticos , Mielofibrose Primária/sangue , Mielofibrose Primária/terapia , Prognóstico , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
The mechanism of air travel-related venous thrombosis is unclear. Although immobility plays a pivotal role, other factors such as fluid loss may contribute. We investigated whether fluid loss occurred more in individuals with coagulation activation after air travel than in subjects without. As a secondary aim, we investigated whether fluid loss per se occurred during air travel. In this crossover study, 71 healthy volunteers were exposed to eight hours of air travel, eight hours immobilization in a cinema, and a daily-life control situation. Markers of fluid loss (haematocrit, serum osmolality and albumin) and of coagulation activation were measured before and after each exposure. The study included 11 volunteers with and 55 volunteers without coagulation activation during the flight. The change in parameters of fluid loss was not different in volunteers with an activated clotting system from those without (difference between groups in haematocrit: -0.6%, 95% confidence interval [CI]: -1.9 to 0.6). On a group level, mean haematocrit values decreased during all three exposures. However, in some individuals it increased, which occurred in more participants during the flight (34%; 95% CI 22 to 46) than during the daily-life situation (19%; 95% CI 10 to 28). These findings do not support the hypothesis that fluid loss contributes to thrombus formation during air travel.
Assuntos
Aeronaves , Coagulação Sanguínea , Desidratação/complicações , Viagem , Trombose Venosa/sangue , Equilíbrio Hidroeletrolítico , Atividades Cotidianas , Adulto , Antitrombina III , Estudos Cross-Over , Desidratação/sangue , Desidratação/etiologia , Desidratação/fisiopatologia , Ingestão de Líquidos , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hematócrito , Humanos , Imobilização/efeitos adversos , Masculino , Concentração Osmolar , Fragmentos de Peptídeos/sangue , Peptídeo Hidrolases/sangue , Protrombina , Fatores de Risco , Albumina Sérica/metabolismo , Trombose Venosa/etiologia , Trombose Venosa/fisiopatologiaRESUMO
Post-polycythemia vera myelofibrosis (post-PV MF) is a late evolution of PV. In 647 patients with PV, we found that leukocytosis leukocyte count>(15x10(9)/L) at diagnosis is a risk factor for the evolution of post-PV MF. In a series of 68 patients who developed post-PV MF, median survival was 5.7 years. Hemoglobin level less than 100 g/L (10 g/dL) at diagnosis of post-PV MF was an independent risk factor for survival. The course of post-PV MF, however, is a dynamic process that implies a progressive worsening of clinical parameters. Using a multivariate Cox proportional hazard regression with time-dependent covariates, we found that a dynamic score based on hemoglobin level less than 100 g/L (10 g/dL), platelet count less than 100x10(9)/L, and leukocyte count more than 30x10(9)/L is useful to predict survival at any time from diagnosis of post-PV MF. The resulting hazard ratio of the score was 4.2 (95% CI: 2.4-7.7; P<.001), meaning a 4.2-fold worsening of survival for each risk factor acquired during follow up. In conclusion, leukocytosis at diagnosis of PV is a risk factor for evolution in post-PV MF. A dynamic score based on hemoglobin level, and platelet and leukocyte count predicts survival at any time from diagnosis of post-PV MF.