Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 115
Filtrar
1.
Br J Haematol ; 204(1): 324-328, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38013240

RESUMO

Multiple studies have reported immune thrombocytopenia (ITP) relapse following SARS-CoV-2 vaccination, however baseline ITP relapse rate and antibody response to vaccination are not known. Patients with ITP who received at least one of the first three SARS-CoV-2 vaccination doses were included in the study. One hundred and twenty-four patients met the inclusion criteria. Relapse rate was 4.2% following a first vaccine dose, 9.1% after a second and 2.9% after a third; baseline relapse rate was 7.6%. Ninety-four per cent of patients who received three vaccine doses developed a clinical antibody response. SARS-CoV-2 vaccination appears to be safe and effective in patients with ITP.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Púrpura Trombocitopênica Idiopática , Humanos , Anticorpos Antivirais , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Púrpura Trombocitopênica Idiopática/complicações , Recidiva , Vacinação
2.
Blood ; 139(13): 1939-1953, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35015835

RESUMO

Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small molecule inhibitor (T417) is selectively toxic against chr1q-amp myeloma and solid tumor cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes, and proposes novel CNA-targeted therapy strategies in MM and other types of cancer.


Assuntos
Mieloma Múltiplo , Cromossomos Humanos Par 1/metabolismo , Proteína Forkhead Box M1/genética , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Fator de Transcrição 1 de Leucemia de Células Pré-B/genética , Prognóstico , Análise de Sistemas , Fatores de Transcrição/genética
3.
Eur J Haematol ; 113(1): 32-43, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38511389

RESUMO

OBJECTIVES: NKG2D is an activating receptor expressed by natural killer (NK) and CD8+ T cells and activation intensity varies by NKG2D expression level or nature of its ligand. An NKG2D gene polymorphism determines high (HNK1) or low (LNK1) expression. MICA is the most polymorphic NKG2D ligand and stronger effector cell activation associates with methionine rather than valine at residue 129. We investigated correlation between cord blood (CB) NKG2D and MICA genotypes and haematopoietic stem cell (HSC) transplant outcome. METHODS: We retrospectively studied 267 CB HSC recipients (178 adult and 87 paediatric) who underwent transplant for malignant disease between 2007 and 2018, analysing CB graft DNA for NKG2D and MICA polymorphisms using Sanger sequencing. Multivariate analysis was used to correlate these results with transplant outcomes. RESULTS: In adult patients, LNK1 homozygous CB significantly improved 60-day neutrophil engraftment (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.4-0.9; p = .003). In paediatrics, HNK1 homozygous CB improved 60-day engraftment (HR 0.4; 95% CI 0.2-0.7; p = .003), as did MICA-129 methionine+ CB grafts (HR 1.7 95% CI 1.1-2.6; p = .02). CONCLUSION: CB NKG2D and MICA genotypes potentially improve CB HSC engraftment. However, results contrast between adult and paediatric recipients and may reflect transplant procedure disparities between cohorts.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Antígenos de Histocompatibilidade Classe I , Subfamília K de Receptores Semelhantes a Lectina de Células NK , Humanos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Criança , Masculino , Antígenos de Histocompatibilidade Classe I/genética , Adulto , Feminino , Adolescente , Pré-Escolar , Pessoa de Meia-Idade , Estudos Retrospectivos , Lactente , Genótipo , Transplante Homólogo , Polimorfismo Genético , Adulto Jovem , Resultado do Tratamento , Idoso , Alelos , Doadores de Tecidos , Neoplasias/genética , Neoplasias/terapia , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/métodos
4.
Br J Clin Pharmacol ; 89(4): 1495-1501, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36437688

RESUMO

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear; one hypothesis is that loss of angiotensin-converting enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin-II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double-blind randomized, placebo-controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group; however, this did not reach statistical significance (P = .15). A Bayesian analysis demonstrated that there was a 92% probability that this change represented a true drug effect.


Assuntos
Transtornos da Coagulação Sanguínea , COVID-19 , Humanos , Teorema de Bayes , Projetos Piloto , Angiotensinas , Método Duplo-Cego , Resultado do Tratamento
5.
J Clin Apher ; 38(5): 562-572, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37309733

RESUMO

INTRODUCTION: Younger donor age in hematopoietic cell transplantation has been associated with improved overall and disease-free survival. Safety data on peripheral blood stem cell (PBSC) and bone marrow (BM) donation is well established, including in the <18-year old age group in the related setting. In response, Anthony Nolan became the first stem cell donor registry to lower the minimum age for unrelated donors to 16-years. MATERIALS AND METHODS: This retrospective study reviewed unrelated donors donating PBSC or BM for the first time between April 2015 and October 2017 since adoption of the lowered recruitment age. Data were collected from registry electronic database and structured follow-up questionnaires. Primary outcomes were turnaround time from VT to donation, optimal cell yield achievement, and physical and emotional recovery. RESULTS: Out of a total of 1013 donors, there were no differences between the different age groups in proportion of donors achieving optimal CD34+ or TNC (PBSC and BM, respectively). There was no increased central line requirement for younger donors or increased emergency telephone support. Youngest donors were more likely to report physical recovery 2 and 7 days post-PBSC (P = .024 and P = .015, respectively) as well as an earlier emotional recovery (P = .001) and fewer physical symptoms 1 week BM donation (P = .04). CONCLUSION: This study shows that younger donors are as reliable as older donors, and have favorable recovery profiles without need for increased support at any stage of the donation, supporting Anthony Nolan recruitment strategy and offering reassurance to donor registries considering the same.


Assuntos
Transplante de Células-Tronco de Sangue Periférico , Humanos , Adolescente , Estudos Retrospectivos , Reprodutibilidade dos Testes , Doadores de Tecidos , Doadores não Relacionados
6.
Perfusion ; 38(8): 1670-1681, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-36148887

RESUMO

INTRODUCTION: Thrombosis and bleeding are major complications in patients supported with left ventricular assist devices (LVADs). We aimed to assess the incidence of bleeding and thrombosis in patients supported with a HeartWare left ventricular assist device (HVAD), their predictive factors and their impact on mortality. METHODS: A single centre retrospective observational study of patients supported with HVAD over 5 years from January 2015 to October 2020. RESULTS: A total 139 patients (median age 52.5, 72.1% male) were included for analysis. The probability of 1-year survival was 73.1%. Advanced age (>60 years) and EuroSCORE II score (>20%) were independently associated with reduced survival. Major bleeding and thrombosis occurred in 46.8% and 35.3% respectively. Secondary mechanical circulatory support (MCS) increased likelihood of experiencing major bleeding (HR: 2.76, 95%1.65-4.62, p < 0.0001) whilst patients receiving aspirin were protected from bleeding and thrombosis (HR: 0.34 95% CI 0.19-0.58, p < 0.001). Pre-operative anaemia (HR: 3.02, 95% CI: 1.6-5.7, p = 0.014) and use of a secondary MCS device (HR: 2.78, 95% CI: 1.2-6.3, p = 0.001) were associated with an increased risk of thrombosis. Patients with any major bleeding (with or without thrombosis) had a 7.68-fold (95% CI 3.5-16.8) increased risk of death compared to those without. In contrast, 'thrombosis only' patients had 4.23-fold (95% CI 1.8-10.2) increased risk of death compared to those without thrombosis. The risk of mortality was increased in patients with any thrombosis and the risk of death was highest in patients with major bleeding and thrombosis (HR: 16.49 [95% CI 7.7-35.3]). CONCLUSIONS: Major bleeding and thrombosis significantly increase the 1-year mortality. Optimal perioperative haemostasis and anticoagulation remains crucial in patients supported with HVAD.


Assuntos
Insuficiência Cardíaca , Coração Auxiliar , Trombose , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Choque Cardiogênico/cirurgia , Choque Cardiogênico/complicações , Coração Auxiliar/efeitos adversos , Hemorragia/complicações , Trombose/etiologia , Estudos Retrospectivos , Resultado do Tratamento
7.
Br J Haematol ; 197(1): 52-62, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34997766

RESUMO

The clinical outcome of chronic myeloid leukaemia patients has vastly improved since the introduction of tyrosine kinase inhibitor treatment, with a significant proportion of patients able to achieve treatment-free remission. However, studies have shown that patients with the e13a2 transcript were less likely to achieve major molecular response compared to those with e14a2 transcripts. Most quantitative polymerase chain reaction (PCR) assays for detection of the BCR-ABL1 fusion gene do not differentiate between the two transcripts and we therefore hypothesised that technical bias linked to the qPCR assay could partially explain the discrepancy in outcomes. We designed an e14a2-specific assay and identified no difference in results compared to an e13a2 standard assay. We then demonstrated that the commercial e14a2 standards were causing a significant overestimation of the e13a2 transcripts. Finally, we reviewed patient management after the qPCR values were corrected, using our new evaluation. We concluded that despite statistically significant differences in qPCR results, there was no impact on patient management or outcome. We conclude that, at least in our institution, it would be inappropriate to perform separate assays for patients with e13a2 or e14a2.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Reação em Cadeia da Polimerase em Tempo Real , Tecnologia
8.
Br J Haematol ; 196(3): 566-576, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34622443

RESUMO

Bleeding and thrombosis are major complications in patients supported with extracorporeal membrane oxygenation (ECMO). In this multicentre observational study of 152 consecutive patients (≥18 years) with severe COVID-19 supported by veno-venous (VV) ECMO in four UK commissioned centres during the first wave of the COVID-19 pandemic (1 March to 31 May 2020), we assessed the incidence of major bleeding and thrombosis and their association with 180-day mortality. Median age (range) was 47 years (23-65) and 75% were male. Overall, the 180-day survival was 70·4% (107/152). The rate of major bleeding was 30·9% (47/152), of which intracranial bleeding (ICH) was 34% (16/47). There were 96 thrombotic events (63·1%) consisting of venous 44·7% [68/152 of which 66·2% were pulmonary embolism (PE)], arterial 18·6% (13/152) and ECMO circuit thrombosis 9·9% (15/152). In multivariate analysis, only raised lactate dehydrogenase (LDH) at the initiation of VV ECMO was associated with an increased risk of thrombosis [hazard ratio (HR) 1·92, 95% CI 1·21-3·03]. Major bleeding and ICH were associated with 3·87-fold (95% CI 2·10-7·23) and 5·97-fold [95% confidence interval (CI) 2·36-15·04] increased risk of mortality and PE with a 2·00-fold (95% CI1·09-3·56) risk of mortality. This highlights the difficult balancing act often encountered when managing coagulopathy in COVID-19 patients supported with ECMO.


Assuntos
COVID-19 , Oxigenação por Membrana Extracorpórea , Hemorragia , SARS-CoV-2/metabolismo , Trombose , Adulto , COVID-19/sangue , COVID-19/mortalidade , COVID-19/terapia , Intervalo Livre de Doença , Feminino , Hemorragia/sangue , Hemorragia/mortalidade , Hemorragia/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Trombose/sangue , Trombose/mortalidade , Trombose/terapia , Reino Unido/epidemiologia
9.
Br J Haematol ; 196(1): 79-94, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34500500

RESUMO

Coagulation dysfunction and thrombosis are major complications in patients with coronavirus disease 2019 (COVID-19). Patients on oral anticoagulants (OAC) prior to diagnosis of COVID-19 may therefore have better outcomes. In this multicentre observational study of 5 883 patients (≥18 years) admitted to 26 UK hospitals between 1 April 2020 and 31 July 2020, overall mortality was 29·2%. Incidences of thrombosis, major bleeding (MB) and multiorgan failure (MOF) were 5·4%, 1·7% and 3·3% respectively. The presence of thrombosis, MB, or MOF was associated with a 1·8, 4·5 or 5·9-fold increased risk of dying, respectively. Of the 5 883 patients studied, 83·6% (n = 4 920) were not on OAC and 16·4% (n = 963) were taking OAC at the time of admission. There was no difference in mortality between patients on OAC vs no OAC prior to admission when compared in an adjusted multivariate analysis [hazard ratio (HR) 1·05, 95% confidence interval (CI) 0·93-1·19; P = 0·15] or in an adjusted propensity score analysis (HR 0·92 95% CI 0·58-1·450; P = 0·18). In multivariate and adjusted propensity score analyses, the only significant association of no anticoagulation prior to diagnosis of COVID-19 was admission to the Intensive-Care Unit (ICU) (HR 1·98, 95% CI 1·37-2·85). Thrombosis, MB, and MOF were associated with higher mortality. Our results indicate that patients may have benefit from prior OAC use, especially reduced admission to ICU, without any increase in bleeding.


Assuntos
Anticoagulantes/uso terapêutico , COVID-19/complicações , Trombose/complicações , Trombose/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/terapia , Feminino , Hemorragia/induzido quimicamente , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Trombose/epidemiologia , Reino Unido/epidemiologia
10.
Nephrol Dial Transplant ; 37(8): 1576-1584, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34320215

RESUMO

BACKGROUND: The diagnosis of antibody-mediated rejection (AMR) is reached using the Banff Classification for Allograft Pathology, which now includes gene expression analysis. In this study, we investigate the application of 'increased expression of thoroughly validated gene transcripts/classifiers strongly associated with AMR' as diagnostic criteria. METHOD: We used quantitative real-time polymerase chain reaction for 10 genes associated with AMR in a retrospective cohort of 297 transplant biopsies, including biopsies that met the full diagnostic criteria for AMR, even without molecular data (AMR, n = 27), biopsies that showed features of AMR, but that would only meet criteria for AMR with increased transcripts [suspicious for AMR (AMRsusp), n = 49] and biopsies that would never meet criteria for AMR (No-AMR, n = 221). RESULTS: A 10-gene AMR score trained by a receiver-operating characteristic to identify AMR found 16 cases with a high score among the AMRsusp cases (AMRsusp-high) that had significantly worse graft survival than those with a low score (AMRsusp-low; n = 33). In both univariate and multivariate Cox regression analysis, the AMR 10-gene score was significantly associated with an increased hazard ratio (HR) for graft loss (GL) in the AMRsusp group (HR = 1.109, P = 0.004 and HR = 1.138, P = 0.012, respectively), but not in the whole cohort. Net reclassification index and integrated discrimination improvement analyses demonstrated improved risk classification and superior discrimination, respectively, for GL when considering the gene score in addition to histological and serological data, but only in the AMRsusp group, not the whole cohort. CONCLUSIONS: This study provides evidence that a gene score strongly associated with AMR helps identify cases at higher risk of GL in biopsies that are suspicious for AMR but do not meet full criteria.


Assuntos
Transplante de Rim , Anticorpos , Biópsia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/genética , Sobrevivência de Enxerto , Humanos , Transplante de Rim/efeitos adversos , Estudos Retrospectivos
11.
Br J Haematol ; 193(2): 346-355, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33368155

RESUMO

Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near-normal patient life-expectancy; however, quality of life and aggravation of existing co-morbidities have posed new treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective 'real-world practice' review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow-up of 27·3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow-up. Seventy-six patients eventually discontinued LD TKI and the two-year treatment-free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.


Assuntos
Redução da Medicação/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Indução de Remissão/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Compostos de Anilina/uso terapêutico , Comorbidade , Dasatinibe/administração & dosagem , Dasatinibe/efeitos adversos , Dasatinibe/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/administração & dosagem , Mesilato de Imatinib/efeitos adversos , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Mutação , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Qualidade de Vida , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Estudos Retrospectivos , Segurança , Resultado do Tratamento
12.
Br J Haematol ; 190(2): 284-293, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32128791

RESUMO

In this retrospective, single-centre, observational study, we assessed (i) use of anticoagulant and antiplatelet (AP) therapy, (ii) the duration of direct-acting oral anticoagulant (DOAC) discontinuation, (iii) renal function and (iv) PT and APTT as predictors of bleeding and blood product usage; in adults (>18 years) undergoing major cardiac surgery from 01.01.2015 to 31.12.2018. Comparisons were made between each treatment group (warfarin, DOAC and DOAC + AP) and untreated controls, and between warfarin and DOAC. A total of 2928 patients were included for analysis. Median (range) of DOAC discontinuation prior to surgery was five days (1-22) for DOAC and five days (2-7) for DOAC + AP. There were no differences in bleeding between anticoagulant groups versus control, or DOAC versus warfarin. There were no differences in blood product use between DOAC and warfarin patients. The duration of DOAC discontinuation but not the creatinine clearance influenced bleeding and blood products use. Thrombosis occurred in 0·7% and 3·1% in controls and patients on warfarin respectively (P = 0·099) with none among patients on DOAC or DOAC + AP. The PT/APTT had no predictive value. Median five-day discontinuation of DOAC +/- AP irrespective of renal function prevents an increase in bleeding compared to patients on warfarin or controls with no increase in thrombosis.


Assuntos
Anticoagulantes/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/métodos , Hemorragia/induzido quimicamente , Varfarina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Varfarina/farmacologia , Adulto Jovem
13.
Haematologica ; 105(11): 2639-2646, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131253

RESUMO

Poor graft function is a serious complication following allogeneic hematopoietic stem cell transplantation. Infusion of CD34+-selected stem cells without pre-conditioning has been used to correct poor graft function, but predictors of recovery are unclear. We report the outcome of 62 consecutive patients who had primary or secondary poor graft function who underwent a CD34+-selected stem cell infusion from the same donor without further conditioning. Forty-seven of 62 patients showed hematological improvement and became permanently transfusion and growth factor-independent. In multivariate analysis, parameters significantly associated with recovery were shared CMV seronegative status for recipient/donor, the absence of active infection and matched recipient/donor sex. Recovery was similar in patients with mixed and full donor chimerism. Five -year overall survival was 74.4% (95% CI 59-89) in patients demonstrating complete recovery, 16.7% (95% CI 3-46) in patients with partial recovery and 22.2% (CI 95% 5-47) in patients with no response. In patients with count recovery, those with poor graft function in 1-2 lineages had superior 5-year overall survival (93.8%, 95% CI 82-99) than those with tri-lineage failure (53%, 95% CI 34-88). New strategies including cytokine or agonist support, or second transplant need to be investigated in patients who do not recover.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Homólogo
14.
Biol Blood Marrow Transplant ; 25(11): 2167-2171, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31284069

RESUMO

This retrospective study by the European Society for Blood and Marrow Transplantation analyzed the outcome of 2224 patients with myelofibrosis (MF) who underwent allogeneic stem cell transplantation (allo-SCT) between 2000 and 2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced-intensity conditioning (RIC). Median patient age was 52.9 years (range, 18 to 74 years) and 57.5 years (range, 21 to 76 years) in the MAC and RIC cohorts, respectively. Donor type was similar: matched sibling donors (MAC, 317 [41%]; RIC, 552 [38%]) and unrelated donors (MAC, 464 [59%]; RIC, 891 [62%]). Median time to both neutrophil and platelet (>20 × 109/L) engraftment did not differ between cohorts. Rates of grade II to IV acute GVHD were 28% (MAC) and 31% (RIC; P = NS). Cumulative chronic GVHD rates (limited/extensive) were 22%/27% (MAC) and 19%/31% (RIC; P = .10). Cumulative incidences of nonrelapse mortality (NRM) at 1, 3, and 5 years were 25.5%, 32.2%, and 34.6% (MAC) and 26.3%, 32.8%, and 34.4% (RIC), respectively. There was a trend toward a higher relapse rate with RIC regimens compared with MAC (P = .08); rates at 1, 3, and 5 years were 10.9%, 17.2%, and 20.1% (MAC) and 14%, 19.7%, and 23.2% (RIC), respectively. No significant difference in 5-year probabilities of overall survival (OS) was noted: MAC (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and RIC (51.0%; 95% CI, 48.3% to 53.7%); P = .78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI, 29.0% to 36.1%) in the MAC group and 26.1% (95% CI, 23.9% to 28.2%) in the RIC group (P = .001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 years), using an unrelated donor and a Karnofsky Performance Status of 80 or less. For the RIC cohort, worse OS and NRM were associated with age 60 to 70 years compared with younger recipients, use of a mismatched donor, and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend toward less relapse and an overall suggested advantage of improved GRFS, albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient, and optimization to reduce significant relapse and NRM rates is required.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária/mortalidade , Mielofibrose Primária/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Idoso , Aloenxertos , Doença Crônica , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sociedades Médicas , Taxa de Sobrevida
15.
Biol Blood Marrow Transplant ; 25(3): 443-450, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30935664

RESUMO

HLA matching at an allelic-level resolution for volunteer unrelated donor (VUD) hematopoietic cell transplantation (HCT) results in improved survival and fewer post-transplant complications. Limitations in typing technologies used for the hyperpolymorphic HLA genes have meant that variations outside of the antigen recognition domain (ARD) have not been previously characterized in HCT. Our aim was to explore the extent of diversity outside of the ARD and determine the impact of this diversity on transplant outcome. Eight hundred ninety-one VUD-HCT donors and their recipients transplanted for a hematologic malignancy in the United Kingdom were retrospectively HLA typed at an ultra-high resolution (UHR) for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 using next-generation sequencing technology. Matching was determined at full gene level for HLA class I and at a coding DNA sequence level for HLA class II genes. The HLA matching status changed in 29.1% of pairs after UHR HLA typing. The 12/12 UHR HLA matched patients had significantly improved 5-year overall survival when compared with those believed to be 12/12 HLA matches based on their original HLA typing but were found to be mismatched after UHR HLA typing (54.8% versus 30.1%, P = .022). Survival was also significantly better in 12/12 UHR HLA-matched patients when compared with those with any degree of mismatch at this level of resolution (55.1% versus 40.1%, P = .005). This study shows that better HLA matching, found when typing is done at UHR that includes exons outside of the ARD, introns, and untranslated regions, can significantly improve outcomes for recipients of a VUD-HCT for a hematologic malignancy and should be prospectively performed at donor selection.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Teste de Histocompatibilidade/normas , Histocompatibilidade/imunologia , Análise de Sequência de DNA/normas , Adulto , Alelos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade/genética , Teste de Histocompatibilidade/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Doadores não Relacionados
16.
Br J Haematol ; 184(5): 808-816, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30515764

RESUMO

This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000-4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47-759) and 159 ng/ml (45-255). Median International Normalised Ratio pre- and post-PCC in patients on warfarin were 3·4 (1·9-15·4) and 1·2 (1·0-1·9). Blood products use was the same between groups. Thirty-day mortality and re-bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post-PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30-day mortality, re-bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.


Assuntos
Fatores de Coagulação Sanguínea/administração & dosagem , Hemorragia Gastrointestinal , Hemorragias Intracranianas , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Varfarina/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Fatores de Coagulação Sanguínea/efeitos adversos , Intervalo Livre de Doença , Feminino , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia Gastrointestinal/mortalidade , Humanos , Hemorragias Intracranianas/tratamento farmacológico , Hemorragias Intracranianas/mortalidade , Masculino , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Rivaroxabana/efeitos adversos , Taxa de Sobrevida , Varfarina/efeitos adversos
17.
Br J Haematol ; 186(2): 321-326, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30980390

RESUMO

Diamond-Blackfan anaemia (DBA) is a rare bone marrow failure syndrome characterised by anaemia, congenital anomalies and cancer predisposition. Although infections are the second leading cause of mortality in non-transplanted patients, immune function is largely unexplored. We identified quantitative deficits in serum immunoglobulins and/or circulating T, natural killer and B lymphocytes in 59 of 107 unselected patients (55·1%) attending our centre over a 7-year period. Immune abnormalities were independent of ribosomal protein genotype and arose in both steroid-treated and steroid-untreated patients. In summary, these data highlight the high prevalence and spectrum of infections and immune defects in DBA.


Assuntos
Anemia de Diamond-Blackfan , Genótipo , Imunidade Celular , Imunidade Humoral , Adolescente , Anemia de Diamond-Blackfan/genética , Anemia de Diamond-Blackfan/imunologia , Anemia de Diamond-Blackfan/mortalidade , Anemia de Diamond-Blackfan/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/imunologia , Reino Unido/epidemiologia
18.
Br J Haematol ; 185(1): 89-92, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30637732

RESUMO

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses.


Assuntos
Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Adulto , Idoso , Pesquisa Biomédica , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento , Adulto Jovem
20.
Haematologica ; 104(11): 2206-2214, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30923102

RESUMO

The majority of patients with newly diagnosed chronic myeloid leukemia (CML) will enjoy a life expectancy equivalent to that of unaffected individuals, but will remain on life-long treatment with a concomitant requirement for on-going hospital interactions for molecular monitoring and drug dispensing. In order to determine more accurately the frequency of monitoring required, we performed a 'real-life' retrospective single-center cohort study of 450 patients with CML in at least major molecular remission (MR3) to analyze the risk of loss of MR3 [defined as at least 2 consecutive real-time quantitative polymerase chain reaction (RT-qPCR) results >0.1% International Scale (IS)]. Patients who achieved sustained MR4 (sMR4, BCR-ABL1 RT-qPCR <0.01% IS for 12 months) had a probability of loss of MR3 at 1 and 5 years of 0 and 2.6% (95%CI: 1.2-5.4) respectively, compared to 4.4% (95%CI: 1.9-9.8) and 25.4% (95%CI: 16.7-36.7) respectively, in those who achieved sustained MR3 (sMR3) but not sMR4 (P<0.001). No patient who improved their response to a deep molecular level (at least MR4) lost MR3 if they were considered compliant, had no history of resistance and remained on standard dose tyrosine kinase inhibitor (TKI). MR4 maintained for at least one year represents a secure response threshold for patients with CML, after which no MR3 loss occurs if certain conditions are satisfied (standard TKI dose, full compliance, and lack of previous TKI resistance). This finding may justify reduction of the frequency of hospital interaction, with an associated positive impact on quality of life, survivorship, and economic burden to both patients and healthcare providers.


Assuntos
Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Reação em Cadeia da Polimerase em Tempo Real , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transcrição Gênica , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA