Speaker
Description
Anaplastic Large Cell Lymphoma (ALCL) is the most common peripheral lymphoma in children, with ~95% of pediatric cases driven by oncogenic ALK mutations \cite{1,2}. Although ALK inhibitors initially reduce tumor burden, continuous therapy (CT) leads to natural selection of resistant populations. Critically, this process in ALCL produces a strong reduction in cell viability in drug-free conditions (a phenomenon known as "drug addiction"), introducing an evolutionary trade-off that could be exploited with intermittent therapy (IT) \cite{3}. However, this concept has found limited translation into clinical practice. In this work, we used patient-derived cell lines (PDCLs) and mathematical modeling to design an optimal treatment strategy based on evolutionary steering of drug resistance and addiction in ALCL.
Using a 180-day dose-escalation protocol, we confirm that PDCLs evolve resistance and addiction in vitro. We leverage the measure of the dose-response curve in time to calibrate a mathematical model recapitulating this process, and we simulate over 500 possible treatment schedules. An optimal strategy combining induction (60 days CT) followed by IT extended tumor control beyond one year, whereas CT alone predicted relapse within 150 days. To account for parameter uncertainty, we generated a virtual cohort by sampling 1000 parameter sets from estimated distributions. Across this cohort, the proposed schedule reduced tumor growth four-fold compared with CT, supporting the robustness of the strategy.
In conclusion, these results illustrate how integrating experiments with evolutionary modeling can identify treatment schedules that exploit adaptive trade-offs to prolong tumor control.
Bibliography
@article{1,
title={Anaplastic large cell lymphoma in children and adolescents},
author={Lowe, Eric J and Woessmann, Wilhelm},
journal={British Journal of Haematology},
volume={207},
number={2},
pages={336--349},
year={2025},
publisher={Wiley Online Library}
}
@article{2,
title={Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group},
author={Brugi{`e}res, Laurence and Le Deley, Marie-C{\'e}cile and Rosolen, Angelo and Williams, Denise and Horibe, Keizo and Wrobel, Grazyna and Mann, Georg and Zsiros, Jozsef and Uyttebroeck, Anne and Marky, Ildiko and others},
journal={Journal of clinical oncology},
volume={27},
number={6},
pages={897--903},
year={2009},
publisher={American Society of Clinical Oncology}
}
@article{3,
title={Evidence suggesting that discontinuous dosing of ALK kinase inhibitors may prolong control of ALK+ tumors},
author={Amin, Amit Dipak and Rajan, Soumya S and Liang, Winnie S and Pongtornpipat, Praechompoo and Groysman, Matthew J and Tapia, Edgar O and Peters, Tara L and Cuyugan, Lori and Adkins, Jonathan and Rimsza, Lisa M and others},
journal={Cancer research},
volume={75},
number={14},
pages={2916--2927},
year={2015},
publisher={American Association for Cancer Research}
}
