High-Dose Methotrexate as CNS Prophylaxis in High-Risk Aggressive B-Cell Lymphoma

Lewis, Katharine L.; Jakobsen, Lasse H.; Villa, Diego; Smedby, Karin E.; Savage, Kerry J.; Eyre, Toby A.; Cwynarski, Kate; Bishton, Mark J.; Fox, Christopher P.; Hawkes, Eliza A.; Maurer, Matthew J.; El-Galaly, Tarec C.; Cheah, Chan Y.; Bobillo, Sabela; Caporn, Paris L.; Van Zyl, Joan; Klanova, Magdalena; Trněny, Marek; Puckrin, Robert; Stewart, Douglas A.; Tun, Aung M.; Thanarajasingam, Gita; Nair, Ranjit; Nastoupil, Loretta; Djebbari, Faouzi; Joffe, Erel; Eloranta, Sandra; Harrysson, Sara; Sehn, Laurie H.; Maliske, Seth M.; Poonsombudlert, Kittika; Guo, Xiao Y.; Hapgood, Greg; Manos, Kate; Khwaja, Jahanzaib; Minson, Adrian; Dickinson, Michael; Øvlisen, Andreas K.; Gregory, Gareth P.; Gilbertson, Michael; Streit, Isaac T.; Scott, Hamish W.; Ku, Matthew; de Mel, Sanjay; Ying Yong, Kar; Xin, Liu; Mokoonlall, Mridula; Talaulikar, Dipti; Hamad, Nada; Srinivasan, Sathia S.; McVilly, Nicholas L.; Johnston, Anna M.; Brunner, Matthew J.; Pophali, Priyanka A.

Abstract

PURPOSE
CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication.

PATIENTS AND METHODS
Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti–CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts).

RESULTS
Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all-pts) and 1.4% (95% CI, –1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup.

CONCLUSION
In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Citation

Lewis, K. L., Jakobsen, L. H., Villa, D., Smedby, K. E., Savage, K. J., Eyre, T. A., Cwynarski, K., Bishton, M. J., Fox, C. P., Hawkes, E. A., Maurer, M. J., El-Galaly, T. C., Cheah, C. Y., Bobillo, S., Caporn, P. L., Van Zyl, J., Klanova, M., Trněny, M., Puckrin, R., Stewart, D. A., …Pophali, P. A. (2023). High-Dose Methotrexate as CNS Prophylaxis in High-Risk Aggressive B-Cell Lymphoma. Journal of Clinical Oncology, 41(35), 5376-5387. https://doi.org/10.1200/JCO.23.00365

• Journal Article Type: Article
• Acceptance Date: Jul 28, 2023
• Online Publication Date: Oct 5, 2023
• Publication Date: Dec 10, 2023
• Deposit Date: Oct 7, 2023
• Journal: Journal of Clinical Oncology
• Print ISSN: 0732-183X
• Electronic ISSN: 1527-7755
• Publisher: American Society of Clinical Oncology
• Peer Reviewed: Peer Reviewed
• Volume: 41
• Issue: 35
• Pages: 5376-5387
• DOI: https://doi.org/10.1200/JCO.23.00365
• Keywords: Cancer Research, Oncology
• Public URL: https://nottingham-repository.worktribe.com/output/25684629
• Publisher URL: https://ascopubs.org/doi/10.1200/JCO.23.00365
• Additional Information: Received: 2023-02-15; Revised: 2023-07-01; Accepted: 2023-07-28; Published: 2023-10-05