Abstract
Myeloproliferative neoplasms (MPNs) are hematologic malignancies that result from acquired driver mutations in hematopoietic stem cells (HSCs), causing overproduction of blood cells and an increased risk of thrombohemorrhagic events. The most common MPN driver mutation affects the JAK2 gene (JAK2V617F). Interferon alpha (IFNα) is a promising treatment against MPNs by inducing a hematologic response and molecular remission for some patients. Mathematical models have been proposed to describe how IFNα targets mutated HSCs, indicating that a minimal dose is necessary for long-term remission. This study aims to determine a personalized treatment strategy. First, we show the capacity of an existing model to predict cell dynamics for new patients from data that can be easily obtained in clinic. Then, we study different treatment scenarios in silico for three patients, considering potential IFNα dose-toxicity relations. We assess when the treatment should be interrupted depending on the response, the patient’s age, and the inferred development of the malignant clone without IFNα. We find that an optimal strategy would be to treat patients with a constant dose so that treatment could be interrupted as quickly as possible. Higher doses result in earlier discontinuation but also higher toxicity. Without knowledge of the dose-toxicity relationship, trade-off strategies can be found for each patient. A compromise strategy is to treat patients with medium doses (60–120 μg/week) for 10–15 years. Altogether, this work demonstrates how a mathematical model calibrated from real data can help build a clinical decision-support tool to optimize long-term IFNα therapy for MPN patients.
SIGNIFICANCE STATEMENT Myeloproliferative neoplasms (MPNs) are chronic blood cancers. Interferon alpha (IFNα) is a promising treatment with the potential to induce a molecular response by targeting mutated hematopoietic stem cells. MPN patients are treated over several years, and there is a lack of knowledge concerning the posology strategy and the best timing for interrupting therapy. The study opens avenues for rationalizing how to treat MPN patients with IFNα over several years, promoting a more personalized approach to treatment.
Footnotes
- Received December 15, 2022.
- Accepted June 21, 2023.
This work is supported in part by a grant from the Prism project and by the Agence Nationale de la Recherche [Grant ANR-18-IBHU-0002] (to P.-H.C. and I.P.). This work was also supported by grants from INCA Plbio2018, 2021 (to I.P.) and Ligue Nationale Contre le Cancer (équipe labellisée 2019) and by the Appel à Projets Pré-néoplasies 2021 (C21021LS) with financial support from Institut Thématique Multi-Organismes (ITMO) Cancer of Aviesan within the framework of the 2021–2030 Cancer Control Strategy, with funds administered by INSERM.
The authors declare no competing financial interests.
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- Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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