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 [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) [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.
References
1. Lowe EJ, Woessmann W. Anaplastic large cell lymphoma in children and adolescents. Br J Haematol. 2025; 00: 1–14. https://doi.org/10.1111/bjh.20154
2. Brugières L, Le Deley MC, Rosolen A, Williams D, Horibe K, Wrobel G, Mann G, Zsiros J, Uyttebroeck A, Marky I, Lamant L, Reiter A. 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. J Clin Oncol. 2009 Feb 20;27(6):897-903. doi: 10.1200/JCO.2008.18.1487. Epub 2009 Jan 12. PMID: 19139435.
3. Amin, A. D. et al. Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors. Cancer Res. 75, 2916–2927 (2015).
