High-Dose Methotrexate at All Ages: Safety, Efficacy, and Outcomes from the HDMTX European Registry
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Bertrand Pourroy
1
,
Maria D. Aumente
2,
Christian Koenecke
3,
Martin Stanulla
3,
Andrés J. M. Ferreri
4,
Thais Murciano-Carillo
5,
Madhumita Dandapani
6,
Timothy A. Ritzmann
7,
Pere Barba
8,
Etienne Chatelut
9,
Katrina M. Ingley
10,
Emma Morris
11,
Elisabeth Schorb
12,
Sven Liebig
13,
Stefan Schwartz
13,
Scott C. Howard
14,15,
Ryan Combs
14,
Nicolás Tentoni
14,
Jennifer Lowe
14,
Gabriela Villanueva
14,
Claudia Sampor
14,†,
Miriam Hwang
14,* and
Carmelo Rizzari
16,‡add
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1
Oncopharma Unit, Hôpitaux Universitaires de Marseille La Timone, 13005 Marseille, France
2
Pharmacy Service, Reina Sofia University Hospital, 14004 Cordoba, Spain
3
Department of Pediatric Hematology and Oncology, University of Hannover, 30167 Hannover, Germany
4
Lymphoma Unit, IRCCS San Raffaele Scientific Institute, 20132 Milano, Italy
5
Pediatric Oncology & Hematology, Hospital Universitari Vall d’Hebron, 08035 Barcelona, Spain
6
Department of Pediatrics Oncology/Haematology, University of Nottingham, Nottingham NG5 1PB, UK
7
Children’s Brain Tumour Research Centre, University of Nottingham, Nottingham NG7 2UH, UK
8
Hematology Department, Hospital Universitari Vall d’Hebron, 08035 Barcelona, Spain
9
Department of Pharmacology, Institut Universitaire du Cancer-Oncopole, 31059 Toulouse, France
10
Sarcoma Department, University College London Hospital, London NW1 2PB, UK
11
Pharmacy Cancer Services, University College London Hospital, London NW1 2PB, UK
12
Comprehensive Cancer Center, University of Freiburg, 79106 Freiburg, Germany
13
Department of Hematology, Oncology and Tumor Immunology, Charite Universitätsmedizin, 10117 Berlin, Germany
14
Resonance, Memphis, TN 38104, USA
15
Global Development Office, Hospital Sant Joan de Deu, 08950 Barcelona, Spain
16
Department of Pediatrics, University of Milano-Bicocca, 20126 Milan, Italy
*
Author to whom correspondence should be addressed.
†
Current address: Pan American Health Organization (PAHO), Washington, DC 20037, USA.
‡
C. Rizzari is the Senior author of this paper and is currently affiliated with Pediatric Hematology and Oncology Unit, IRCCS San Gerardo dei Tinori, 20900 Monza, Italy.
Cancers 2026, 18(1), 124; https://doi.org/10.3390/cancers18010124
Submission received: 26 November 2025
/
Revised: 20 December 2025
/
Accepted: 25 December 2025
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Published: 30 December 2025
/
Corrected: 13 March 2026
(This article belongs to the Section Cancer Epidemiology and Prevention)
Simple Summary
This paper describes the incidence of delayed methotrexate elimination and acute kidney injury related to high-dose methotrexate (HDMTX) treatment in various cancers and reports their association with clinical outcomes from 12 treatment centers in 5 European countries. These real-world outcomes outside of the clinical trial setting provide insight into important aspects of HDMTX treatment that should be considered to provide safe and efficacious treatment.
Abstract
Objectives: To determine the incidence of delayed methotrexate elimination (DME) and acute kidney injury (AKI) and their associations with clinical outcomes in patients receiving high-dose methotrexate (HDMTX) for cancer treatment. Methods: The HDMTX European Registry collected medical records data from 12 institutions in 5 European countries to investigate the clinical practice patterns of healthcare providers utilizing HDMTX for cancer treatment. Cancer types included were acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL), non-Hodgkin lymphoma (NHL), osteosarcoma, and other CNS cancers. Primary endpoints were the incidence of DME and AKI; secondary endpoints were clinical outcomes, including hospital length of stay (LOS), delay in the subsequent course of treatment, methotrexate dose reduction, and omission of next course of treatment. Associations between the primary and secondary endpoints were analyzed with Chi-square and Wilcoxon rank-sum tests. Results: Among the 2501 total HDMTX courses analyzed, DME occurred in 302 courses (12.1%), and AKI in 384 courses (15.4%). DME incidence was highest in courses for PCNSL (18.2%) and NHL (17.2%); AKI incidence was highest in ALL courses (21.0%). Incidence of DME and AKI varied by age and methotrexate infusion duration among the different cancer types. Occurrence of DME was associated with longer delays prior to the next course of treatment, longer hospital LOS, and more frequent methotrexate dose reductions and dose omissions. Conclusions: While HDMTX is a very effective and safe treatment, administration of efficacious doses of methotrexate can lead to AKI and DME, and no single or combination of patient or treatment factors was found to reliably predict their occurrence. Thus, diligent monitoring of methotrexate levels is imperative for early detection and prompt management of nephrotoxicity in all settings where HDMTX treatment is administered.
