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452 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Clinical Management of Aggressive B cell NHL
Hematology Disease Topics & Pathways:
Adults, Translational Research, Lymphomas, Non-Hodgkin Lymphoma, Non-Biological, Clinical Research, B Cell Lymphoma, Chemotherapy, Clinically Relevant, Diseases, Real World Evidence, Aggressive Lymphoma, Therapies, Registries, Lymphoid Malignancies, Study Population
Sunday, December 12, 2021: 12:15 PM

Matthew R Wilson1, Toby A. Eyre2*, Amy A Kirkwood, MSc3*, Nicole Wong Doo4,5*, Carole Soussain6,7*, Sylvain Choquet8*, Nicolas Martinex-Calle9*, Gavin Preston10*, Matthew J Ahearne11*, Elisabeth Schorb, MD12*, Marie-Pierre Moles-Moreau13*, Matthew Ku14, Chiara Rusconi, MD15*, Jahanzaib Khwaja16*, Mayur Narkhede, MD17, Katharine L Lewis, MBBS18, Teresa Calimeri19, Eric Durot20*, Loic Renaud21*, Andreas Kiesbye Oevlisen, MD, PhD22*, Graham McIlroy23*, Tim Ebsworth24*, Johnathon Elliot25*, Anna Santarsiere26*, Laure Ricard27*, Nimish Shah28*, Qin Liu29, Adam Zayac30*, Francesco Vassallo31*, Laure Lebras32*, Louise Roulin33*, Naelle Lombion34*, Kate Manos35*, Ruben Fernandez36*, Nada Hamad37,38,39, Alberto Lopez-Garcia40*, Deirdre O'Mahony41*, Praveen Gounder42,43*, Nathalie Forgeard8*, Charlotte Lees44*, Kossi Agbetiafa6*, Tim Strüßmann45*, Thura Win Htut10*, Aline Clavert13*, Hamish W Scott46*, Anna Guidetti47*, Brett R Barlow, MD17*, Jeffrey Smith48*, Tarec Christoffer El-Galaly, MD22, Chan Yoon Cheah49, Andres JM Ferreri, MD50, Fiona Miall11*, Christopher P Fox9*, Kate Cwynarski51* and Pamela McKay1*

1Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
2Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center, Oxford, United Kingdom
3Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, United Kingdom
4Concord Clinical School, Concord Hospital University of Sydney, Sydney, Australia
5Concord Clinical School, Concord Hospital University of Sydney, Sydney, Australia
6Institut Curie Hôpital René Huguenin, Saint-Cloud, FRA
7INSERM U932 Institut Curie, PSL Research University, Paris, France
8La Pitie Salpetriere Hospital, APHP-Sorbonne Universite, Paris, France
9Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
10Aberdeen Royal Infirmary, Aberdeen, United Kingdom
11University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
12Department of Medicine I, University Medical Center Freiburg, Freiburg, Germany
13Service des Maladies du Sang, CHU Angers, Angers, France
14St Vincent's Private Hospital Melbourne, Melbourne, VIC, Australia
15Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
16Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
17Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
18Department of Haematology, Linear Clinical Research and Sir Charles Gairdner Hospital, Nedlands, WA, Australia
19IRCCS San Raffaele Scientific Institute, Milano, Italy
20CHU Reims, Hôpital Robert Debré, Reims, France
21AP-HP, Hôpital Saint-Louis, Paris, France
22Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
23Centre for Clinical Haematology, University Hospitals Birmingham, Birmingham, United Kingdom
24University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
25Christie Hospital, Manchester, United Kingdom
26Cambridge University Hospitals, Cambridge, United Kingdom
27Hospital Saint-Antoine Ap-Hp, Paris, France
28Haematology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, United Kingdom
29Department of Haematology, Princess Margaret Cancer Centre, Toronto, Canada
30Brown University, Providence, RI
31Citta della Salute, Torino, Italy
32Hematology, Centre Leon Berard, Lyon, France
33Lymphoid Malignancies, Henri Mondor Hospital, Créteil, France
34Hopital Mignot Centre Hospitalier de Versailles, Versailles, FRA
35Austin Hospital, Melbourne, Australia
36Department of Hematology, Hospital de Cabueñes, Gijon, Spain
37Department of Haematology, St Vincent's Hospital Sydney, Sydney, NSW, Australia
38School of Medicine, University of Notre Dame, Sydney, NSW, Australia
39St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
40Fundacion Jimenez Diaz University Hospital, Health Research Institute IIS-FJD, Madrid, Spain
41Bon Secours Cork Cancer Centre, Cork, Ireland
42Concord Repatriation General Hospital, Sydney, Australia
43Liverpool Hospital, Sydney, Australia
44Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
45Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
46St Vincent's Hospital Melbourne, Melbourne, Australia
47Instituo Nazionale dei Tumori, Milan, Italy
48Clatterbridge Cancer Centre, Liverpool University Hospitals, Liverpool, United Kingdom
49Linear Clinical Research and Sir Charles Gairdner Hospital, Perth, Australia
50Lymphoma Unit, Department of Onco-Haematology, IRCCS San Raffaele Scientific Institute, Milano, Italy
51Department of Haematology, University College London Hospital, London, United Kingdom


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.


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.


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<0.0001).

78 CNS relapses (42 i-HDMTX, 36 EOT) were observed: parenchymal in 41 (53%), parenchymal and leptomeningeal in 16 (21%) and isolated leptomeningeal in 21 (27%). There was no significant difference in 2y CNS relapse rates between i-HDMTX and EOT in all pts: 5.2% vs 3.9%, adjusted hazard ratio (HR) 0.92 (95% CI 0.58-1.47), p=0.74, 2y difference -0.2% (-2.0-2.5) or landmark analysis: 2.8% vs 4.1%, HR: 0.93 (0.56-1.55), p=0.79, 2y difference: -0.3% (-1.8-2.2%) (Fig 1a/b). Exploratory analyses focusing on pts with isolated CNS relapse (n=57) demonstrated similar results (2y rates 3.6% vs 3.0%, p=0.99). On multivariable analysis (MVA) of risk factors for CNS relapse, renal/adrenal involvement was the only variable associated with increased CNS relapse risk (adjusted HR 1.74 (1.03-2.92), p=0.038). Notably, IT prophylaxis was not associated with reduction in CNS relapse.

In 600 high CNS IPI (4-6) pts, there was no difference in CNS relapse risk between i-HD-MTX and EOT (3y rates 9.4% vs 8.6%, HR 0.92 (95% CI 0.52-1.62)). In a composite high risk group including CNS IPI 4-6 and/or any of the following: ≥3 extranodal sites, renal, adrenal, testicular or breast involvement (n=885) there was no difference in 3y CNS relapse rates between groups (i-HDMTX 7.6% vs EOT 7.4%, HR 0.94 (0.58-1.53)).

Progression-free survival (PFS) and overall survival (OS) in the i-HDMTX and EOT groups were as follows: 3y PFS 70.7% vs 76.7% (p=0.098), 3y OS 79.9% vs 87.0% (p=0.0016). However, there were no PFS/OS differences between groups on landmark analysis (n=1259) (Fig 1c).

On analysis of pts experiencing ≥1 R-CHOP delay of ≥7 days, use of i-HDMTX was the only factor on MVA associated with increased delays (p<0.0001).


We found no evidence that EOT delivery increases CNS relapse risk when compared to i-HDMTX in this large analysis of pts treated with 1L R-CHOP. Delays to R-CHOP cycles were increased with i-HDMTX. Findings in a high risk subgroup were unchanged and rates of CNS relapse in this HDMTX treated group were similar to published comparable high risk cohorts receiving infrequent CNS prophylaxis. Where HDMTX prophylaxis is used, delivery could be deferred until R-CHOP completion.

Disclosures: Wilson: Takeda: Other: Conference fees; Janssen: Other: Conference fees; Abbvie: Honoraria. Eyre: Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Incyte: Consultancy; Secura Bio: Consultancy, Honoraria; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Janssen: Honoraria; Beigene: Honoraria, Research Funding. Soussain: Janssen: Other: travel funds; Gossamer: Other: travel funds. Ahearne: Pfizer: Research Funding; Takeda: Honoraria; Roche: Honoraria. Schorb: Roche: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding; AbbVie: Research Funding. Ku: Antegene: Consultancy; Roche: Consultancy; Genor Biopharma: Consultancy. Narkhede: Genentech/Roche: Research Funding; Gilead: Research Funding; Genmab: Other: Medical writing support, Research Funding; TG Therapeautics: Research Funding. Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria. Oevlisen: Abbvie: Other: Travel expenses. Santarsiere: Janssen: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roulin: Janssen: Other: Travel and meetings. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Celgene: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Novonordisk: Other: Speaker Honoraria. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee. Cheah: Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory. Ferreri: Gilead, Novartis, Juno, PletixaPharm, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; BMS, Beigene, Pharmacyclics, Hutchison Medipharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, Pfizer: Research Funding. Fox: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: speaker fees. Cwynarski: Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH