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

Author(s): Katharine L. Lewis, BMedSci, MBBS (Hons)1,2,3; Lasse H. Jakobsen, PhD, MSc4; Diego Villa, MD, MPH5; Karin E. Smedby, MD6; Kerry J. Savage, MD, MSc5; Toby A. Eyre, MD, MBChB7; Kate Cwynarski, MD, PhD8; Mark J. Bishton, PhD, MBChB9,10; Christopher P. Fox, MD, PhD9,10; Eliza A. Hawkes, MBBS(Hons), DMedSci11,12; Matthew J. Maurer, MS, DMSc13; Tarec C. El-Galaly, MD, DMSc14; Chan Y. Cheah, MBBS, DMSc1,2,3
Source: https://doi.org/10.1200/JCO.23.0036
Maem Hussein MD

Dr. Maen Hussein's Thoughts

Good review of high-risk patients, showing that prophylactic high dose MTX did not have lower risk of CNS disease.


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 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).


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.


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.

Author Affiliations

1Linear Clinical Research, Nedlands, WA, Australia; 2Division of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; 3Division of Internal Medicine, Medical School, University of Western Australia, Perth, WA, Australia; 4Department of Haematology, Aalborg University Hospital, Aalborg, Denmark; 5BC Cancer Centre for Lymphoid Cancer, The University of British Columbia, Vancouver, BC, Canada; 6Department of Medicine Solna, Division of Clinical Epidemiology, Karolinska Institutet, Stockholm, Sweden; 7Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom; 8University College London Hospital NHS Foundation Trust, London, United Kingdom; 9Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom; 10University of Nottingham, Nottingham, United Kingdom; 11Olivia Newton-John Cancer Research & Wellness Centre at Austin Health, Heidelberg, VIC, Australia; 12Monash University School of Public Health and Preventive Medicine, Melbourne, VIC, Australia; 13Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN; 14Department of Haematology, Aalborg University Hospital, Aalborg, Denmark

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