RESUMEN
Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Neoplasias , Mielofibrosis Primaria , Humanos , Índice de Masa Corporal , Mielofibrosis Primaria/terapia , Estudios Retrospectivos , Acondicionamiento PretrasplanteRESUMEN
INTRODUCTION: Extracranial vascular characteristics determine the accessibility of the large vessel intracranial occlusion for endovascular treatment (EVT) in acute ischemic stroke. We developed and validated a prediction model for failure of the transfemoral approach to aid clinical decision making regarding EVT. METHODS: A prediction model was developed from data of patients included in the Dutch multicenter MR CLEAN Registry (March 18th 2014 until June 15th 2016) with penalized logistic regression. Predictor variables were available prior to the EVT procedure and included age, hypertension and extracranial vascular characteristics assessed on baseline CTA. The prediction model was internally validated, temporally validated within a second MR CLEAN Registry cohort (June 15th 2016 until November 1st 2017) and updated by re-estimating the coefficients using the combined cohort. RESULTS: Failure of the transfemoral approach occurred in 7% of patients, in both cohorts (derivation cohort: n=887, median age 71 years, interquartile range [IQR] 60-80, 52% men; validation cohort: n=1111, median age 73 years, IQR 62-81, 51% men). The prediction model had a c-statistic of 0.81 (95%CI: 0.76-0.86) in the derivation cohort, 0.69 (95%CI: 0.62-0.75) at temporal validation, and 0.75 (95%CI: 0.71-0.79) in the final prediction model, with the following penalized ß-coefficients for predictors age (per decade): 0.26, hypertension: -0.16, severe aortic arch elongation: 1.45, bovine aortic arch: 0.44, elongation of the supra-aortic arteries: 0.72, cervical ICA elongation: 0.44, and high-grade stenosis of the cervical ICA: 0.78. CONCLUSION: Our prediction model showed good performance for prediction of failure to reach the intracranial occlusion by the transfemoral approach.
RESUMEN
PURPOSE: Human leukocyte antigen (HLA) mismatching can reduce survival of patients with blood cancer after hematopoietic cell transplantation (HCT). How recent advances in HCT practice, in particular graft-versus-host disease (GVHD) prophylaxis by post-transplantation cyclophosphamide (PTCy), influence HLA risk associations is unknown. PATIENTS AND METHODS: The study included 17,292 unrelated HCTs with 6-locus high-resolution HLA typing, performed mainly for acute leukemia or related myeloid neoplasms between 2016 and 2020, including 1,523 transplants with PTCy. HLA risk associations were evaluated by multivariable Cox regression models, with overall survival (OS) as primary end point. RESULTS: OS was lower in HLA mismatched compared with fully matched transplants (hazard ratio [HR], 1.23 [99% CI, 1.14 to 1.33]; P < .001). This was driven by class I HLA-A, HLA-B, HLA-C (HR, 1.29 [99% CI, 1.19 to 1.41]; P < .001) but not class II HLA-DRB1 and HLA-DQB1 (HR, 1.07 [99% CI, 0.93 to 1.23]; P = .19). Class I antigen-level mismatches were associated with worse OS than allele-level mismatches (HR, 1.36 [99% CI, 1.24 to 1.49]; P < .001), as were class I graft-versus-host peptide-binding motif (PBM) mismatches compared with matches (HR, 1.42 [99% CI, 1.28 to 1.59]; P < .001). The use of PTCy improved GVHD, relapse-free survival compared with conventional prophylaxis in HLA-matched transplants (HR, 0.77 [0.66 to 0.9]; P < .001). HLA mismatching increased mortality in PTCy transplants (HR, 1.32 [1.04 to 1.68]; P = .003) similarly as in non-PTCy transplants (interaction P = .43). CONCLUSION: Class I but not class II HLA mismatches, especially at the antigen and PBM level, are associated with inferior survival in contemporary unrelated HCT. These effects are not significantly different between non-PTCy compared with PTCy transplants. Optimized HLA matching should still be considered in modern HCT.
RESUMEN
Missing data are frequently encountered across studies in clinical haematology. Failure to handle these missing values in an appropriate manner can complicate the interpretation of a study's findings, as estimates presented may be biased and/or imprecise. In the present work, we first provide an overview of current methods for handling missing covariate data, along with their advantages and disadvantages. Furthermore, a systematic review is presented, exploring both contemporary reporting of missing values in major haematological journals, and the methods used for handling them. A principal finding was that the method of handling missing data was explicitly specified in a minority of articles (in 76 out of 195 articles reporting missing values, 39%). Among these, complete case analysis and the missing indicator method were the most common approaches to dealing with missing values, with more complex methods such as multiple imputation being extremely rare (in 7 out of 195 articles). An example analysis (with associated code) is also provided using hematopoietic stem cell transplantation data, illustrating the different approaches to handling missing values. We conclude with various recommendations regarding the reporting and handling of missing values for future studies in clinical haematology.
Asunto(s)
Hematología , Humanos , Interpretación Estadística de Datos , Proyectos de InvestigaciónRESUMEN
Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance between GvL and GvHD can be shifted by removing T-cells via T-cell depletion (TCD) to reduce the risk of GvHD, and by introducing additional donor T-cells (donor lymphocyte infusions [DLI]) to boost the GvL effect. However, the association between T-cell kinetics and the occurrence of allo-immunological events has not been clearly demonstrated yet. Therefore, we investigated the complex associations between the T-cell kinetics and alloimmune responses in a cohort of 166 acute leukemia patients receiving alemtuzumab-based TCD alloSCT. Of these patients, 62 with an anticipated high risk of relapse were scheduled to receive a prophylactic DLI at 3 months after transplant. In this setting, we applied joint modelling which allowed us to better capture the complex interplay between DLI, T-cell kinetics, GvHD and relapse than traditional statistical methods. We demonstrate that DLI can induce detectable T-cell expansion, leading to an increase in total, CD4+ and CD8+ T-cell counts starting at 3 months after alloSCT. CD4+ T-cells showed the strongest association with the development of alloimmune responses: higher CD4 counts increased the risk of GvHD (hazard ratio 2.44, 95% confidence interval 1.45-4.12) and decreased the risk of relapse (hazard ratio 0.65, 95% confidence interval 0.45-0.92). Similar models showed that natural killer cells recovered rapidly after alloSCT and were associated with a lower risk of relapse (HR 0.62, 95%-CI 0.41-0.93). The results of this study advocate the use of joint models to further study immune cell kinetics in different settings.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Cinética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Linfocitos T CD8-positivos , Linfocitos T CD4-PositivosRESUMEN
In studies analyzing competing time-to-event outcomes, interest often lies in both estimating the effects of baseline covariates on the cause-specific hazards and predicting cumulative incidence functions. When missing values occur in these baseline covariates, they may be discarded as part of a complete-case analysis or multiply imputed. In the latter case, the imputations may be performed either compatibly with a substantive model pre-specified as a cause-specific Cox model [substantive model compatible fully conditional specification (SMC-FCS)], or approximately so [multivariate imputation by chained equations (MICE)]. In a large simulation study, we assessed the performance of these three different methods in terms of estimating cause-specific regression coefficients and predicting cumulative incidence functions. Concerning regression coefficients, results provide further support for use of SMC-FCS over MICE, particularly when covariate effects are large and the baseline hazards of the competing events are substantially different. Complete-case analysis also shows adequate performance in settings where missingness is not outcome dependent. With regard to cumulative incidence prediction, SMC-FCS and MICE are performed more similarly, as also evidenced in the illustrative analysis of competing outcomes following a hematopoietic stem cell transplantation. The findings are discussed alongside recommendations for practising statisticians.
Asunto(s)
Modelos Estadísticos , Simulación por Computador , Interpretación Estadística de Datos , Modelos de Riesgos ProporcionalesRESUMEN
Multi-state models provide an extension of the usual survival/event-history analysis setting. In the medical domain, multi-state models give the possibility of further investigating intermediate events such as relapse and remission. In this work, a further extension is proposed using relative survival, where mortality due to population causes (i.e. non-disease-related mortality) is evaluated. The objective is to split all mortality in disease and non-disease-related mortality, with and without intermediate events, in datasets where cause of death is not recorded or is uncertain. To this end, population mortality tables are integrated into the estimation process, while using the basic relative survival idea that the overall mortality hazard can be written as a sum of a population and an excess part. Hence, we propose an upgraded non-parametric approach to estimation, where population mortality is taken into account. Precise definitions and suitable estimators are given for both the transition hazards and probabilities. Variance estimating techniques and confidence intervals are introduced and the behaviour of the new method is investigated through simulations. The newly developed methodology is illustrated by the analysis of a cohort of patients followed after an allogeneic hematopoietic stem cell transplantation. The work has been implemented in the R package mstate.