{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T03:51:06Z","timestamp":1781236266038,"version":"3.54.1"},"reference-count":42,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T00:00:00Z","timestamp":1773532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T00:00:00Z","timestamp":1773532800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100014805","name":"Roche Italia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014805","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Concerns about the efficacy of high\u2010dose methotrexate (HD\u2010MTX) in preventing CNS recurrence in large B\u2010cell lymphomas (LBCL) are based on studies with interpretation biases and incomplete information about HD\u2010MTX dosing schedule and CNS events. We evaluated a pharmacokinetic\u2010informed, CNS\u2010directed HD\u2010MTX protocol (3\u2009g\/m\n                    <jats:sup>2<\/jats:sup>\n                    over 3\u2009h, preceded by a bolus) in 336 LBCL patients achieving CMR after RCHOP or derivatives. HD\u2010MTX use was based on institutional risk scores. In this study, CNS risk was reassessed using updated criteria: CNS\u2010IPI \u2265\u20094, \u2265\u20093 extranodal sites, or involvement of testis, kidney, adrenal gland, uterus, or breast. According to these criteria, risk was low in 228 (68%) patients and high in 108 (32%); HD\u2010MTX was given to 20 (9%) and 49 (45%), respectively. HD\u2010MTX was well tolerated: 96% completed therapy. After a median follow\u2010up of 77\u2009months, 13 (4%) patients experienced CNS relapse, always as isolated events. Among high\u2010risk patients, CNS relapse occurred in 19% (11\/59) without HD\u2010MTX versus 0% (0\/49) with HD\u2010MTX (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0009); significant reductions were seen in patients with high\u2010risk organ involvement (32% to 0%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002) or \u2265\u20093 extranodal sites (18% to 0%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.04). HD\u2010MTX was independently associated with improved PFS and OS in high\u2010risk patients, likely due to reduced CNS relapses (0% vs. 19%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0009), whereas rates of unrelated deaths (8% vs. 15%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.26) and systemic relapses (18% vs. 22%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.81) were similar. In conclusion, HD\u2010MTX, administered via a pharmacokinetic\u2010informed, CNS\u2010directed schedule, with or without intrathecal chemotherapy, significantly reduces CNS relapses and improves outcomes in high\u2010risk LBCL patients in CMR.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Trial Registration:<\/jats:bold>\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    Identifier: NCT07181785.\n                  <\/jats:p>","DOI":"10.1002\/ajh.70283","type":"journal-article","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T09:35:36Z","timestamp":1773567336000},"page":"1244-1254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Three\u2010Hour Infusion of Methotrexate at 3\u2009g\/m\n                    <sup>2<\/sup>\n                    With or Without Intrathecal Chemotherapy Significantly Reduces\n                    <scp>CNS<\/scp>\n                    Relapses and Improves Survival in Patients With Large B\u2010Cell Lymphomas at Increased\n                    <scp>CNS<\/scp>\n                    Risk"],"prefix":"10.1002","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9606-6124","authenticated-orcid":false,"given":"Andr\u00e9s J. M.","family":"Ferreri","sequence":"first","affiliation":[{"name":"University Vita\u2010Salute San Raffaele  Milan Italy"},{"name":"Strategic Program on Lymphomas IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0695-3480","authenticated-orcid":false,"given":"Federico","family":"Erbella","sequence":"additional","affiliation":[{"name":"Strategic Program on Lymphomas IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piera","family":"Angelillo","sequence":"additional","affiliation":[{"name":"Strategic Program on Lymphomas IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenza","family":"Pecciarini","sequence":"additional","affiliation":[{"name":"Pathology Unit IRCCS San Raffaele Scientific Institute  Milan 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Raffaele  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Saliani","sequence":"additional","affiliation":[{"name":"University Vita\u2010Salute San Raffaele  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Fiore","sequence":"additional","affiliation":[{"name":"University Vita\u2010Salute San Raffaele  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Bruno\u2010Ventre","sequence":"additional","affiliation":[{"name":"Hematology and BMT Unit, ASST Fatebenefratelli\u2010Sacco  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Girlanda","sequence":"additional","affiliation":[{"name":"Hematology and BMT Unit, ASST Fatebenefratelli\u2010Sacco  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Marino","sequence":"additional","affiliation":[{"name":"Strategic Program on 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