Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients
Matthew R. Wilson, Toby A. Eyre, Amy A. Kirkwood, Nicole Wong Doo, Carole Soussain, Sylvain Choquet, Nicolás Martínez‐Calle, Gavin Preston, Matthew J. Ahearne, Elisabeth Schorb, Marie‐Pierre Moles‐Moreau, Matthew Ku, Chiara Rusconi, Jahanzaib Khwaja, Mayur Narkhede, Katharine L. Lewis, Teresa Calimeri, Éric Durot, Loïc Renaud, Andreas Kiesbye Øvlisen, Graham McIlroy, Timothy Ebsworth, Johnathan Elliot, Anna Santarsieri, Laure Ricard, Nimish Shah, Qin Liu, Adam Zayac, Francesco Vassallo, Laure Lebras, Louise Roulin, Naëlle Lombion, Kate Manos, Rubén Fernández, Nada Hamad, Alberto López‐García, Deirdre O’Mahony, Praveen Gounder, Nathalie Forgeard, Charlotte Lees, Kossi Agbétiafa, Tim Strüßmann, Thura Win Htut, Aline Clavert, Hamish W Scott, Anna Guidetti, Brett Barlow, Emmanuelle Tchernonog, Jeffery Smith, Fiona Miall, Christopher P. Fox, Chan Y. Cheah, El Galaly, TC, Ferreri, AJM, Kate Cwynarski, Pam McKay
Abstract
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.