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Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients

Wilson, Matthew R.; Eyre, Toby A.; Kirkwood, Amy A.; Wong Doo, Nicole; Soussain, Carole; Choquet, Sylvain; Martinez-Calle, Nicolás; Preston, Gavin; Ahearne, Matthew; Schorb, Elisabeth; Moles-Moreau, Marie-Pierre; Ku, Matthew; Rusconi, Chiara; Khwaja, Jahanzaib; Narkhede, Mayur; Lewis, Katharine L.; Calimeri, Teresa; Durot, Eric; Renaud, Loïc; Øvlisen, Andreas Kiesbye; McIlroy, Graham; Ebsworth, Timothy J.; Elliot, Johnathan; Santarsieri, Anna; Ricard, Laure; Shah, Nimish; Liu, Qin; Zayac, Adam S.; Vassallo, Francesco; Lebras, Laure; Roulin, Louise; Lombion, Naelle; Manos, Kate; Fernandez, Ruben; Hamad, Nada; Lopez-Garcia, Alberto; O'Mahony, Deirdre; Gounder, Praveen; Forgeard, Nathalie; Lees, Charlotte; Agbetiafa, Kossi; Strüßmann, Tim; Htut, Thura Win; Clavert, Aline; Scott, Hamish; Guidetti, Anna; Barlow, Brett R.; Tchernonog, Emmanuelle; Smith, Jeffery; Miall, Fiona; Fox, Christopher P.; Cheah, Chan Y.; El Galaly, Tarec Christoffer; Ferreri, Andrés J. M.; Cwynarski, Kate; McKay, Pam...

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Matthew R. Wilson

Toby A. Eyre

Amy A. Kirkwood

Nicole Wong Doo

Carole Soussain

Sylvain Choquet

Nicolás Martinez-Calle

Gavin Preston

Matthew Ahearne

Elisabeth Schorb

Marie-Pierre Moles-Moreau

Matthew Ku

Chiara Rusconi

Jahanzaib Khwaja

Mayur Narkhede

Katharine L. Lewis

Teresa Calimeri

Eric Durot

Loïc Renaud

Andreas Kiesbye Øvlisen

Graham McIlroy

Timothy J. Ebsworth

Johnathan Elliot

Anna Santarsieri

Laure Ricard

Nimish Shah

Qin Liu

Adam S. Zayac

Francesco Vassallo

Laure Lebras

Louise Roulin

Naelle Lombion

Kate Manos

Ruben Fernandez

Nada Hamad

Alberto Lopez-Garcia

Deirdre O'Mahony

Praveen Gounder

Nathalie Forgeard

Charlotte Lees

Kossi Agbetiafa

Tim Strüßmann

Thura Win Htut

Aline Clavert

Hamish Scott

Anna Guidetti

Brett R. Barlow

Emmanuelle Tchernonog

Jeffery Smith

Fiona Miall

Clinical Professor in Haematology

Chan Y. Cheah

Tarec Christoffer El Galaly

Andrés J. M. Ferreri

Kate Cwynarski

Pamela McKay


Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P =.98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Journal Article Type Article
Acceptance Date Dec 30, 2021
Online Publication Date Jan 11, 2022
Publication Date Apr 21, 2022
Deposit Date Feb 8, 2023
Publicly Available Date Feb 9, 2023
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 139
Issue 16
Pages 2499-2511
Keywords Cell Biology; Hematology; Immunology; Biochemistry
Public URL
Publisher URL
Additional Information This research was originally published in Blood. Matthew R. Wilson et al. Title. Blood. 2022;139(16): 2499–2511. © the American Society of Hematology.


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