Early Integration of High Dose Methotrexate to Frontline DLBCL Therapy Does Not Impact CNS Relapse Compared to End of Treatment Delivery: A Multicentre International Analysis of 1384 Patients

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.452-452
• Main Authors: Wilson, Matthew R, Eyre, Toby A., Kirkwood, Amy A, Wong Doo, Nicole, Soussain, Carole, Choquet, Sylvain, Martinex-Calle, Nicolas, Preston, Gavin, Ahearne, Matthew J, Schorb, Elisabeth, Moles-Moreau, Marie-Pierre, Ku, Matthew, Rusconi, Chiara, Khwaja, Jahanzaib, Narkhede, Mayur, Lewis, Katharine L, Calimeri, Teresa, Durot, Eric, Renaud, Loic, Øvlisen, Andreas Kiesbye, McIlroy, Graham, Ebsworth, Tim, Elliot, Johnathon, Santarsiere, Anna, Ricard, Laure, Shah, Nimish, Liu, Qin, Zayac, Adam, 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, Win Htut, Thura, Clavert, Aline, Scott, Hamish W, Guidetti, Anna, Barlow, Brett R, Smith, Jeffrey, El-Galaly, Tarec Christoffer, Cheah, Chan Yoon, Ferreri, Andres JM, Miall, Fiona, Fox, Christopher P, Cwynarski, Kate, McKay, Pamela
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-144820

Introduction: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is uncommon but is associated with poor outcomes. In selected high risk patients (pts), high dose methotrexate (HDMTX) is often used as CNS prophylaxis with frontline (1L) DLBCL therapy despite uncertain efficacy, optimum dose and timing of delivery. A recent UK study (Wilson et al 2020) showed that intercalated HDMTX (i-HDMTX) was associated with increased toxicity and R-CHOP delays compared to end of treatment (EOT) delivery. Although hypothesis generating, the study size was insufficient to determine whether EOT was non-inferior in terms of CNS relapse risk. Methods: We conducted an international, multicentre retrospective analysis of consecutive DLBCL or high grade BCL pts between 2007-20 from 47 centers in Europe, Australia and N. America. Pts were included if they received R-CHOP or R-CHOP-like 1L therapy with curative intent as well as HDMTX CNS prophylaxis (≥1 cycle). Concurrent intrathecal (IT) prophylaxis was permitted. Pts with known CNS involvement at baseline and those treated with more intensive protocols (e.g. R-DA-EPOCH) were excluded. i-HDMTX was defined as any pt receiving a HD-MTX cycle before the final R-CHOP cycle. CNS relapse events were excluded if occurring after first systemic lymphoma relapse/progression. Time to event endpoints were measured from diagnosis to first event or censor and analysed using Kaplan-Meier and Cox regression methods. Time to CNS relapse was analysed using competing risk Fine and Gray method (for death and non-synchronous systemic relapse). To mitigate for possible immortality bias in the EOT arm, a landmark analysis for pts alive and free from progression at 6 months was conducted. We aimed to exclude a 5% difference in 2-year (y) CNS relapse rates. Results: 1,384 pts were analysed. 750 received i-HDMTX and 634 received EOT HDMTX. Key baseline characteristics are summarised in Table 1. Median follow up was 37.9 months. 44.2% had high CNS IPI (4-6) with no significant difference between i-HDMTX and EOT groups (45.1% vs 43.1%, p=0.087). ≥2 cycles of HDMTX were used in 86.6% with no difference between groups (85.6% vs 87.9%, p=0.22). Concurrent IT prophylaxis use was higher for EOT pts (55.6% vs 38.1% p