High-Dose Methotrexate as CNS Prophylaxis in Ultra High-Risk Large B-Cell Lymphoma: An International Multicenter Analysis
Abstract
PURPOSE In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent CNS relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients deemed ultra high risk (UHR) because of a lack of robust data specific to these subgroups. This study was designed to examine the impact of HD-MTX specifically in UHR patients. METHODS Data from two previous retrospective analyses were combined to produce a cohort of UHR patients (≥1 of the following criteria: CNS international prognostic index score 5-6; testicular, renal/adrenal, or breast involvement; ≥3 extranodal sites), treated with or without HD-MTX. The primary outcome was CNS relapse rate (isolated or concurrent with systemic relapse) measured from diagnosis with additional landmark analysis of all responding patients with no progression event at 6 months. RESULTS Analyses were performed on 1,923 patients meeting UHR criteria. No significant difference in 3-year CNS relapse rate was observed between no HD-MTX (n = 1,051) versus HD-MTX patients (n = 872), including in multivariable analyses adjusting for baseline characteristics (3-year rate, 9.3% v 8.1%; adjusted hazard ratio [HR], 1.13 [95% CI, 0.82 to 1.57]). Analyses restricted to isolated CNS relapse also confirmed no difference (5.9% v 5.7%; adjusted HR, 1.03 [95% CI, 0.69 to 1.53]). In the landmark analysis (no HD-MTX n = 782, HD-MTX n = 773), no difference in 3-year CNS relapse was observed (6.7% v 6.6%, adjusted HR, 0.95 [95% CI, 0.62 to 1.44]). CONCLUSION To our knowledge, this is the largest international comparative data set of patients with LBCL with UHR features showing no significant reduction in CNS relapse with HD-MTX in all UHR or in any individual subgroup. Despite inherent limitations of retrospective analyses, the data strongly support previous studies in suggesting HD-MTX prophylaxis has no meaningful benefit for most patients.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (39)
Matthew R. Wilson
Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
Katharine L. Lewis
Sir Charles Gairdner Hospital, Perth, WA, Australia
Amy A. Kirkwood
CR UK and UCL Cancer Trials Centre, UCL Cancer Institute, University College London, London, United Kingdom
Kate Cwynarski
15Department of Haematology, University College London, London, United Kingdom
Chan Y. Cheah
12Department of Haematology, Sir Charles Gairdner Hospital, Perth, Australia
Tarec C. El-Galaly
Aalborg University Hospital, Aalborg, Denmark
Diego Villa
8Division of Medical Oncology, BC Cancer Centre for Lymphoid Cancer and The University of British Columbia, Vancouver, Canada
Kerry J. Savage
6BC Cancer, Vancouver, BC, Canada
Paola Ghione
4Memorial Sloan Kettering Cancer Center, New York, NY
Sabela Bobillo
Memorial Sloan Kettering Cancer Center, New York, NY
Karin E. Smedby
5Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Sara Harrysson
Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Marek Trneny
Magdalena Klanova
Robert Puckrin
2Arthur Child Comprehensive Cancer Centre & University of Calgary, Calgary, Canada
Christopher P. Fox
13Department of Haematology, School of Medicine, University of Nottingham, Nottingham, United Kingdom
Mark Bishton
4Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
Gita Thanarajasingam
1Mayo Clinic, Hematology/Oncology, Rochester, United States
Nicole Wong Doo
5Concord Hospital, Concord Clinical School, University of Sydney, Haematology, Sydney, Australia
Greg Hapgood
10Princess Alexandra Hospital, Department of Haematology, Brisbane, Australia
Carole Soussain
1Institut Curie, Hematology, Saint Cloud, France
Sylvain Choquet
18AP-HP – Hôpital Pitié-Salpêtrière, Paris, France
Michael Dickinson
Dipti Talaulikar
19Canberra Health Services, Haematology Unit, ACT Pathology, Canberra, Australia
Sanjay De Mel
6National University Health System, Department of Haematology-Oncology, Singapore, Singapore
Gavin Preston
9Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, United Kingdom
Matthew Ahearne
11University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
Eliza A. Hawkes
14Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia
Elisabeth Schorb
University of Freiburg
Aline Clavert
11CHU Angers, Angers, France
Matthew Ku
Anna Guidetti
1Fondazione IRCCS Istituto nazionale dei tumori, Unit of Biostatistics for Clinical Research, Department of Data Science, Milan, Italy
Mayur Narkhede
23University of Alabama, Birmingham, AL
Teresa Calimeri
1San Raffaele Scientific Institute, Lymphoma Unit, Milan, Italy
Eric Durot
8CHU Reims, Hematology, Reims, France
Jeffrey Smith
Loïc Renaud
1Gustave Roussy Cancer Center, Hematology, Villejuif, France
Pamela McKay
10Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
Toby A. Eyre
8Department of Hematology, Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center, Oxford, United Kingdom