Background
We recently reported results of the prospective, open‐label HOVON‐100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first‐line treatment with or without ...clofarabine (CLO). No improvement of event‐free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity.
Aim
In order to investigate the effects of CLO in more depth, two multi‐state models were developed to identify why CLO did not show a long‐term survival benefit despite more MRD‐negativity.
Methods
The first model evaluated the effect of CLO on going off‐protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment‐related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models.
Results
Overall, patients receiving CLO went off‐protocol more frequently than control patients (35/168 21% vs. 18/166 11%, p = 0.019; HR 2.00 1.13–3.52, p = 0.02), especially during maintenance (13/44 30% vs. 6/56 11%; HR 2.85 95%CI 1.08–7.50, p = 0.035). Going off‐protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD‐negativity compared with control patients (HR MRD‐negativity: 1.35 0.95–1.91, p = 0.10), which did not translate into a significant survival benefit.
Conclusion
We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.
We developed two multi‐state models to identify in more depth why clofarabine (CLO) did not show a long‐term survival benefit despite more MRD‐negativity, as recently reported in the HOVON‐100 trial. Patients receiving CLO went off‐protocol (indicated by the left figures) more frequently than control patients (HR 2.00 1.13–3.52, p = 0.02)—especially during maintenance (HR 2.85 95%CI 1.08–7.50, p = 0.035)—and showed a trend towards an increased rate of MRD‐negativity (indicated by the right figures) (HR 1.35 0.95–1.91, p = 0.10); however, neither transition significantly affected subsequent survival estimates. We conclude that the intermediate states, i.e., going off‐protocol and MRD‐negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.
HighlightsActivation of NF-κB signaling in mesenchymal cells is common in LR-MDS.Activation of NF-κB in mesenchymal cells leads to transcriptional overexpression of inflammatory factors including ...negative regulators of hematopoiesis.Activation of NF-κB attenuates HSPC numbers and function ex vivo.
Graft versus host disease (GVHD) prophylaxis with posttransplantation cyclophosphamide (PTCY) has been established to reduce severe GVHD, and thereby potentially reducing nonrelapse mortality (NRM) ...after allogeneic stem cell transplantation (alloSCT). We evaluated the predictive capacity of established NRM‐risk scores in patients receiving PTCY‐based GVHD prophylaxis, and subsequently developed and validated a novel PTCY‐specific NRM‐risk model. Adult patients (n = 1861) with AML or ALL in first complete remission who received alloSCT with PTCY‐based GVHD prophylaxis were included. The PTCY‐risk score was developed using multivariable Fine and Gray regression, selecting parameters from the hematopoietic cell transplantation‐comorbidity index (HCT‐CI) and European Group for Blood and Marrow Transplantation (EBMT) score with a subdistribution hazard ratio (SHR) of ≥1.2 for 2‐year NRM in the training set (70% split), which was validated in the test set (30%). The performance of the EBMT score, HCT‐CI, and integrated EBMT score was relatively poor for discriminating 2‐year NRM (c‐statistic 51.7%, 56.6%, and 59.2%, respectively). The PTCY‐risk score included 10 variables which were collapsed in 3 risk groups estimating 2‐year NRM of 11% ± 2%, 19% ± 2%, and 36% ± 3% (training set, c‐statistic 64%), and 11% ± 2%, 18% ± 3%, and 31% ± 5% (test set, c‐statistic 63%), which also translated into different overall survival. Collectively, we developed an NRM‐risk score for acute leukemia patients receiving PTCY that better predicted 2‐year NRM compared with existing models, which might be applicable to the specific toxicities of high‐dose cyclophosphamide.
Introduction
Continuous progress in atrial fibrillation (AF) ablation techniques has led to an increasing number of procedures with improved outcome. However, about 30–50% of patients still ...experience recurrences within 1 year after their ablation. Comprehensive translational research approaches integrated in clinical care pathways may improve our understanding of the complex pathophysiology of AF and improve patient selection for AF ablation.
Objectives
Within the “IntenSive mOlecular and eLectropathological chAracterization of patienTs undergoIng atrial fibrillatiOn ablatioN” (ISOLATION) study, we aim to identify predictors of successful AF ablation in the following domains: (1) clinical factors, (2) AF patterns, (3) anatomical characteristics, (4) electrophysiological characteristics, (5) circulating biomarkers, and (6) genetic background. Herein, the design of the ISOLATION study and the integration of all study procedures into a standardized pathway for patients undergoing AF ablation are described.
Methods
ISOLATION (NCT04342312) is a two-center prospective cohort study including 650 patients undergoing AF ablation. Clinical characteristics and routine clinical test results will be collected, as well as results from the following additional diagnostics: determination of body composition, pre-procedural rhythm monitoring, extended surface electrocardiogram, biomarker testing, genetic analysis, and questionnaires. A multimodality model including a combination of established predictors and novel techniques will be developed to predict ablation success.
Discussion
In this study, several domains will be examined to identify predictors of successful AF ablation. The results may be used to improve patient selection for invasive AF management and to tailor treatment decisions to individual patients.
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