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181 High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk PatientsClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 905. Outcomes Research-Lymphoid Malignancies: Lymphoma/CLL Real-World Data
Hematology Disease Topics & Pathways:
Clinically Relevant, Clinical Practice (e.g. Guidelines, Health Outcomes and Services, and Survivorship, Value; etc.)
Saturday, December 11, 2021: 12:00 PM

Katharine Louise Lewis, BMBS, FRCPath, MRCPath1,2, Lasse H. Jakobsen, MSc, PhD3*, Diego Villa, MD, MPH, FRCPC4, Sabela Bobillo, MD, PhD5*, Karin Ekstroem Smedby, MD, PhD6*, Kerry J. Savage, MD, MSc, FRCPC4, Toby A. Eyre7*, Kate Cwynarski8*, Paris L Caporn, BBiomedSc9*, Joan Van Zyl, BBioMedSc9*, Magdalena Klanova, MD, PhD10,11*, Marek Trněný, MD, Prof12,13, Robert Puckrin, MD FRCPC14*, Douglas A. Stewart, MD, FRCPC15,16, Mark J Bishton, MB ChB, PhD17*, Christopher P. Fox17*, Aung M Tun, MD18*, Gita Thanarajasingam, MD18, Faouzi Djebbari19*, Erel Joffe, MD, MSc20, Sandra Eloranta, PhD21*, Sara Harrysson, MD21*, Laurie H. Sehn, MD22, Seth M Maliske, MD23, Kittika Poonsombudlert, MD24, Xiao Guo, MD25*, Greg Hapgood, MD, PhD25*, Kate Manos26*, Eliza Hawkes, MD27, Jahanzaib Khwaja28*, Adrian Minson, MBBS29*, Michael Dickinson, MBBS29,30, Andreas Kiesbye Oevlisen, MD, PhD3*, Gareth P Gregory, MBBS PhD31, Michael Gilbertson, MBBS (Hons) FRACP FRCPA32*, Isaac T Streit, MSc4*, Hamish W Scott33*, Matthew Ku34,35, Sanjay de Mel, BSc (Hons) BM (Hons), MRCP(UK), FRCPath36*, Kar Ying Yong, MBBS, MRCP37*, Liu Xin, M.A. in Counselling and Guidance, MSc in Biomedical Engineering37*, Mridula Mokoonlall, MBBS38*, Dipti Talaulikar, PhD, FRACP, FRCPA, MBBS38, Nicholas L McVilly, MBBS39*, Anna Johnston, MBBS, FRACP, FRCPA39,40*, Matthew J Brunner, MD41*, Priyanka A Pophali, MD42,43, Matthew J. Maurer, MS, DMSc44*, Tarec Christoffer El-Galaly, MD3 and Chan Yoon Cheah2,9,45

1Department of Haematology, Sir Charles Gairdner Hospital, West Leederville, WEA, Australia
2Department of Haematology, Sir Charles Gairdner Hospital, Perth, WA, Australia
3Department of Hematology, Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
4BC Cancer Centre for Lymphoid Cancer and The University of British Columbia, Vancouver, BC, Canada
5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
6Department of Medicine Solna, Division of clinical epidemiology, Karolinska Institutet, Stockholm, Stockholm, Sweden
7Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Old Road, United Kingdom
8Department of Haematology, University College London Hospital NHS Foundation Trust, London, United Kingdom
9University of Western Australia, Perth, WA, Australia
101st Internal Department - Department of Haematology, General University Hospital, Prague, Czech Republic
11First Deptartment of Internal Medicine - Hematology, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic
12First Dept. of Medicine- Hematology, Charles University General Hospital and First Faculty of Medicine, Praha 2, Czech Republic
13Urologicka Klinika, Vseobecna Fakultni Nemocnice, Interni Klinika—Klinika Hematologie, Prague, Czech Republic
14Department of Oncology, University of Calgary, Calgary, AB, Canada
15Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Calgary, AB, Canada
16Tom Baker Cancer Centre, Calgary, AB, Canada
17Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
18Mayo Clinic, Division of Hematology, Rochester, MN, USA, Rochester, MN
19Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
20Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY
21Department of Medicine Solna, Division of clinical epidemiology, Karolinska Institutet, Stockholm, Sweden
22Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada
23Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa Hospital and Clinics, Iowa City, IA
24Holden Comprehensive Cancer Center, University of Iowa Hospital and Clinics, Iowa city, IA
25Princess Alexandra Hospital, Brisbane, QLD, Australia
26Department of Clinical Haematology, Austin Health, Melbourne, Australia
27Department of Clinical Haematology, Austin Health, Heidelberg, VIC, Australia
28Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
29Department of Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
30Royal Melbourne Hospital, Melbourne, Australia
31Monash Haematology, Monash Health, Melbourne, Australia
32Department of Haematology, Monash Health, Melbourne, Australia
33Department of Haematology, St Vincent’s Hospital, Melbourne, Australia, Melbourne, Australia
34Department of Haematology, St Vincent’s Hospital and University of Melbourne, Melbourne, Australia
35University of Melbourne, Melbourne, Australia
36Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore, Singapore
37National University Health System, Kent Ridge, Singapore
38Department of Haematology, The Canberra Hospital, Canberra, Australia
39Department of Haematology, Royal Hobart Hospital, Hobart, Australia
40University of Tasmania, Hobart, Australia
41Division of Hematology, University of Wisconsin, Madison, Madison, WI
42Division of Hematology, Department of Medicine, University of Wisconsin- Carbone Cancer Center, Madison, WI
43Carbone Cancer Center, Madison
44Mayo Clinic, Division of Clinical Trials and Biostatistics, Rochester, MN, USA, Rochester, MN
45Linear Clinical Research, Perth, Australia

Introduction

Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited.

Methods

We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS.

Results –

2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts ≤60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and 5.5 years from diagnosis (range 0.0-18.7), 201/2300 and 84/1455 pts experienced CNS events in the all-pts and CR-pts analyses respectively.

For all-pts(n=2300), CNS-IPI was 4-6 in 2052(89.2%), with R-CHOP-like therapy given to 93.8%. 410 pts (17.8%) received HD-MTX (265 HD-MTX alone, 145 in combination with intrathecal methotrexate (IT-MTX);435 received IT-MTX alone;1455 received neither. There were 32/410 and 169/1890 SCNS events, with median time from diagnosis to SCNS of 8.8 and 6.7 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 70% (95% CI, 65-76%) and 55% (95% CI 53-57%) in HD-MTX and no HD-MTX groups respectively. There was no difference in the adjusted 5-year risk of SCNS between the HD-MTX and no HD-MTX groups (8.4% vs 9.1%, adjusted hazard ratio [HR] 0.71, p=0.100) (Figure 1).

For CR-pts(n=1455), CNS-IPI was 4-6 in 1267(87.0%), with R-CHOP-like therapy given to 93.3%. 284 pts (19.5%) received HD-MTX (170 HD-MTX alone, 114 with IT-MTX);298 received IT-MTX alone;873 received neither. There were 16/284 and 68/1171 SCNS events, with median time from diagnosis to SCNS of 11.0 and 10.3 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 74%(95% CI 67-81%) and 75%(95% CI 72-78%) in the HD-MTX groups and no HD-MTX groups respectively (adjusted HR 1.08, p=0.622). There was no difference in the 5-year risk of CNS relapse between the HD-MTX and no HD-MTX groups 5.0% vs 6.0% (adjusted HR 1.03, p=0.903) (Figure 2).

Exploratory analysis of the impact of HD-MTX among the highest risk groups CNS IPI 5 (n=368), CNS-IPI 6 (n=59) and CNS-IPI 6 plus all pts with testicular, renal or adrenal involvement (n=349) did not reveal differences in SCNS rates in HD-MTX treated pts. Additional subgroup analyses will be presented at the meeting.

Conclusions

To our knowledge, this is the largest study of the efficacy of HD-MTX in reducing SCNS events focusing exclusively on high-risk pts. The overall incidence of CNS relapse observed was consistent with previous reports in similar patient cohorts at 9%. The use of HD-MTX did not lower SCNS rates overall or when analysis was confined to CR pts at completion of curative intent therapy to compensate for potential immortal bias associated with HD-MTX therapy. Despite the limitations of the non-randomized and retrospective design, it appears unlikely that HD-MTX is associated with a clinically meaningful reduction in SCNS rates in pts with high risk for SCNS.

Disclosures: Lewis: AstraZeneca: Consultancy, Honoraria; Novartis: Patents & Royalties: Conference attendance; Janssen: Honoraria, Patents & Royalties: Conference attendance; Roche: Consultancy, Honoraria. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Bobillo: F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Ekstroem Smedby: Takeda: Consultancy; Janssen Cilag: Research Funding. Savage: Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Eyre: AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Beigene: Honoraria, Research Funding; Incyte: Consultancy; Roche: Consultancy, Honoraria; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences. Cwynarski: Incyte: Consultancy, Speakers Bureau; Gilead: 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. Stewart: Teva: Honoraria; Sandoz: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Bishton: Gilead: Honoraria, Other: Travel grants; AbbVie: Honoraria, Other: Travel grants; Celgene/BMS: Honoraria, Other: travel grants; Celltrion: Honoraria, Other: Travel grants; Takeda.: Honoraria, Other: Travel grants . Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. Sehn: Debiopharm: Consultancy; Teva: Consultancy, Research Funding; Novartis: Consultancy; Genmab: Consultancy; Roche/Genentech: Consultancy, Research Funding; AbbVie: Consultancy; Acerta: Consultancy; Amgen: Consultancy; Apobiologix: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Kite: Consultancy; Karyopharm: Consultancy; Lundbeck: Consultancy; Merck: Consultancy; Morphosys: Consultancy; Sandoz: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hawkes: Specialised Therapeutics: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Minson: Novartis: Research Funding; Hoffman La Roche: Research Funding. Dickinson: Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding; Amgen: Honoraria. Oevlisen: Abbvie: Other: Travel expenses. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Talaulikar: Roche: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Maurer: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months. Cheah: 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; 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.

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