Interferon Alpha Therapy Increases Pro-Thrombotic Biomarkers in Patients with Myeloproliferative Neoplasms

Faille, Dorothée; Lamrani, Lamia; Loyau, Stéphane; Huisse, Marie-Geneviève; Bourrienne, Marie‐Charlotte; Alkhaier, Sawsaneh; Cassinat, Bruno; Boulaftali, Yacine; Debus, Jérôme; Jandrot‐Perrus, Martine; Chomienne, Christine; Dosquet, Christine; Ajzenberg, Nadine

doi:10.3390/cancers12040992

Cited by 10 publications

(12 citation statements)

References 31 publications

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“…In this perspective, neither the "watch and wait strategy" in low-risk ET and PV patients nor treatment with HU seem rational. Instead, treatment with IFN might be highly relevant since it both normalizes elevated cell counts and importantly induces sustained normal cell counts, [47][48][49][50][51][52][53][54][55][56][57][58] which may even be maintained months and even years after the discontinuation of long-term treatment (>5 years) in some patients. 49 This is in sharp contrast to cell count kinetics after discontinuation of HU, which is followed by a recurrence of elevated cell counts after a few days off HU treatment.…”

Section: Discussionmentioning

confidence: 99%

“…52 Furthermore, a most recent study has shown that IFN increases pro-thrombotic biomarkers in patients with MPNs, although in this study, no association with an increased thrombosis risk was recorded. 53 Importantly, in recent randomized studies, comparing the safety and efficacy of IFN versus HU, 55,56,58 superiority of IFN in terms of a significant reduction in the JAK2V617F allelic burden was only evident after 36 months. 56,58 Overall, responses to IFN increased over time with improved responses compared with HU at 36 months.…”

Section: Discussionmentioning

confidence: 99%

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Data‐driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Dam

Pedersen

Knudsen

et al. 2021

European J of Haematology

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Background: Hydroxyurea (HU) treatment of patients with essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) (MPNs) normalizes elevated blood cell counts within weeks in the large majority of patients.Studies on the impact of HU upon the kinetics of the JAK2V617F allele burden, leukocyte, and platelet counts over time are scarce.Purpose: Using data-driven analysis as a novel tool to model the kinetics of the JAK2V617F allele burden and blood cell counts over time during treatment with HU. Material and methods:Using serial measurements of JAK2V617F and correlation analysis of routine hematological values (the Hb-concentration, leukocyte count, platelet count, and lactic dehydrogenase), we present a detailed description and analysis of the kinetics of the JAK2V617F, leukocyte, and platelet counts and lactic dehydrogenase in 27 patients (PV = 18; ET = 7; PMF = 2), who were followed in the Danish randomized trial (DALIAH). To further analyze the JAK2V617F kinetics, we use a machine learning clustering algorithm to group the response patterns.Results: Response patterns were highly heterogeneous, with clustering resulting in 3 groups and 3 outliers. In the large majority of patients, HU treatment was initially associated with a modest decline in the JAK2V617F allele burden in concert with a decline in leukocyte and platelet counts. However, HU did not induce a sustained and continuous decrease in the JAK2V617F allele burden. Conclusion:Using data-driven analysis of the JAK2V617F allele burden, leukocyte, and platelet kinetics during treatment with HU, we have shown that HU does not induce a sustained decrease in the JAK2V617F allele burden and neither induces sustained normalization of elevated cell counts in MPN patients. Our results may explain why MPN patients during treatment with HU still have a substantially increased risk of thrombosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Data‐driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Dam

Pedersen

Knudsen

et al. 2021

European J of Haematology

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“…Other areas of doubt in relation to treatment with IFN include its effect on thrombosis. One recent study observed the significant elevation of the pro-coagulant biomarkers thrombin, fibrinogen, Von Willebrand factor, shear-induced platelet aggregation, and factor VIII coagulant activity (FVIII:C) in the blood plasma of patients with PV or ET treated with IFN compared to those treated with HU or no treatment, independently of gender and patient age [ 207 ]. Whether these reported effects of IFN treatment on the haemostatic profile of PV patients are associated with an increased thrombotic risk remains to be determined; however, important differences were reported between the risk of thromboembolic events for PV patients treated with IFN (8.7%, 11/127) versus best-available therapy (BAT, 5.5%, 7/127) [ 201 ].…”

Section: Treatmentmentioning

confidence: 99%

Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera

Stuckey

Gómez‐Casares

2021

IJMS

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Genetic studies in the past decade have improved our understanding of the molecular basis of the BCR-ABL1-negative myeloproliferative neoplasm (MPN) polycythaemia vera (PV). Such breakthroughs include the discovery of the JAK2V617F driver mutation in approximately 95% of patients with PV, as well as some very rare cases of familial hereditary MPN caused by inherited germline mutations. Patients with PV often progress to fibrosis or acute myeloid leukaemia, both associated with very poor clinical outcome. Moreover, thrombosis and major bleeding are the principal causes of morbidity and mortality. As a result of increasingly available and economical next-generation sequencing technologies, mutational studies have revealed the prognostic relevance of a few somatic mutations in terms of thrombotic risk and risk of transformation, helping to improve the risk stratification of patients with PV. Finally, knowledge of the molecular basis of PV has helped identify targets for directed therapy. The constitutive activation of the tyrosine kinase JAK2 is targeted by ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor for PV patients who are resistant or intolerant to cytoreductive treatment with hydroxyurea. Other molecular mechanisms have also been revealed, and numerous agents are in various stages of development. Here, we will provide an update of the recent published literature on how molecular testing can improve the diagnosis and prognosis of patients with PV and present recent advances that may have prognostic value in the near future.

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“…Focusing on the first 30 min post-particle administration when infusion responses are often seen, we observe that INF-α increases following treatment in animals without clots but stays constant or decreases slightly for animals with clots. Increases in INF-α has been correlated with thrombi in several models of disease, − which makes the fact that the increase correlates with animals that did not exhibit clots surprising although at the longer time points INF-α decreased in all the animals studied (Figure B). Lymphocytes increased more 15 min post-treatment for animals with clots than for those without (Figure C).…”

Section: Resultsmentioning

confidence: 94%

PEGylated Polyester Nanoparticles Trigger Adverse Events in a Large Animal Model of Trauma and in Naı̈ve Animals: Understanding Cytokine and Cellular Correlations with These Events

et al. 2022

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Intravenously infusible nanoparticles to control bleeding have shown promise in rodents, but translation into preclinical models has been challenging as many of these nanoparticle approaches have resulted in infusion responses and adverse outcomes in large animal trauma models. We developed a hemostatic nanoparticle technology that was screened to avoid one component of the infusion response: complement activation. We administered these hemostatic nanoparticles, control nanoparticles, or saline volume controls in a porcine polytrauma model. While the hemostatic nanoparticles promoted clotting as marked by a decrease in prothrombin time and both the hemostatic nanoparticles and controls did not active complement, in a subset of the animals, hard thrombi were found in uninjured tissues in both the hemostatic and control nanoparticle groups. Using data science methods that allow one to work across heterogeneous data sets, we found that the presence of these thrombi correlated with changes in IL-6, INF-alpha, lymphocytes, and neutrophils. While these findings might suggest that this formulation would not be a safe one for translation for trauma, they provide guidance for developing screening tools to make nanoparticle formulations in the complex milieux of trauma as well as for therapeutic interventions more broadly. This is important as we look to translate intravenously administered nanoparticle formulations for therapies, particularly considering the vascular changes seen in a subset of patients following COVID-19. We need to understand adverse events like thrombi more completely and screen for these events early to make nanomaterials as safe and effective as possible.

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Interferon Alpha Therapy Increases Pro-Thrombotic Biomarkers in Patients with Myeloproliferative Neoplasms

Cited by 10 publications

References 31 publications

Data‐driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Data‐driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera

PEGylated Polyester Nanoparticles Trigger Adverse Events in a Large Animal Model of Trauma and in Naı̈ve Animals: Understanding Cytokine and Cellular Correlations with These Events

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