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153 Impact of Double Expression of MYC and BCL-2 on Outcomes in Primary CNS Lymphoma: A UK Multicentre AnalysisClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 627. Aggressive Lymphomas: Clinical and Epidemiological: Treatment of CNS Lymphoma, Neurologic Toxicities, and Relapsed/Refractory DLBCL
Hematology Disease Topics & Pathways:
Research, adult, Lymphomas, elderly, Clinical Research, B Cell lymphoma, Diseases, real-world evidence, aggressive lymphoma, Lymphoid Malignancies, Study Population, Human
Saturday, December 10, 2022: 12:30 PM

Edward Poynton1,2*, Emily Chernucha3*, James Day2*, Catherine Prodger4*, David Hopkins5*, Pallav Rakesh6*, Tess O’Neill7*, Nisha Thakrar2*, Ayse Akarca8*, Sabine Pomplun8*, Teresa Marafioti, MD8*, Maria Calaminici, MD, PhD1*, Sridhar Chaganti, MD9*, Pam McKay, MBChB, FRCP, FRCPath5*, Jeffery Smith, MBChB, MRCP, FRCPath10*, Toby A. Eyre, MBChB, DipMedEd, MRCP, FRCPath, MD11*, Nicolas Martinez-Calle3*, Kate Cwynarski, MD12*, Christopher P. Fox13* and Jessica Okosun, PhD1,7

1Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
2Department of Clinical Haematology, University College London Hospital, London, United Kingdom
3Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
4Churchill Cancer Center, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
5Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
6Centre for Clinical Haematology, University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
7Department of Haemato-Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, United Kingdom
8Department of Histopathology, University College London Hospital, London, United Kingdom
9Department of Haematology, Queen Elizabeth Hospital, Birmingham, United Kingdom
10Clatterbridge Cancer Centre, Liverpool University Hospital, Liverpool, United Kingdom
11Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center, Oxford, United Kingdom
12University College London Hospitals NHS Foundation Trust, London, United Kingdom
13Department of Hematology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom

Introduction

Primary central nervous system lymphoma (PCNSL) is a rare B cell lymphoma with an aggressive course. Relapses remain common even with intensive immuno-chemotherapy treatment options such as MATRix and consolidation with autologous stem cell transplant (ASCT), and prognostic tools are limited. Although, double expressor status (co-expression of both MYC and BCL-2) is well established in systemic de novo DLBCL, its prognostic impact in PCNSL has been understudied. Here we evaluated the prognostic value of BCL-2, BCL-6, and MYC expression in a retrospective cohort of treated PCNSL patients diagnosed at 7 academic centres in the UK.

Methods
We performed this retrospective analysis on histologically-confirmed PCNSL patients diagnosed consecutively between 1
st May 2015 and 31st May 2020. Treatment with a high-dose methotrexate-based chemotherapy regimen was a mandatory inclusion criterion. BCL-2 and MYC immunohistochemistry (IHC) protein expression data were collated from local diagnostic histology reports and double expressor (DE) status was defined as per WHO criteria (MYC: surface expression > 40% of cells and BCL-2: >50% of cells). Outcomes included response rates, progression-free survival (PFS) and overall survival (OS). Where available, diagnostic fluorescence in situ hybridisation (FISH) data was collected for BCL-2, BCL-6 and MYC loci translocations. Cox-regression for PFS and OS were used to determine baseline predictors of response and survival and to construct multivariable models for factors associated with outcome.

Results
In total, 242 patients were analysed. Key baseline patient characteristics and IHC data are summarised in
Table 1. Median age was 65 years (IQR 56-71), 60% were male and 64% of patients had an ECOG performance status (PS) of 0-1. One hundred and seventy-four (72%) patients received treatment with MATRix chemotherapy; these patients were younger (median age 62 vs. 73 years, p< 0.01), had better baseline PS (PS ≤ 1: 75% vs. 37%, p< 0.01) and higher rates of consolidation with BCNU-thiotepa ASCT (58% vs. 7%, p< 0.01).

Double expressor (DE) status was assessable in 169/242 (69%) patients. Reasons for absent DE status were missing IHC expression data (BCL-2: n=28; MYC: n=44) or IHC expression data not reported in line with WHO recommended criteria (BCL-2: n=45; MYC: n=7). In the DE-assessable cohort (n = 169 patients), 40% of patients had DE PCNSL, higher than estimates of DE prevalence in systemic DLBCL (reported rates between 20 and 30%). As only 40 cases (17%) underwent FISH assessment for concurrent MYC and BCL-2 loci translocation (double hit status), correlation between double hit and DE status was not possible. DE status was not associated with patient age at diagnosis, baseline PS or treatment received. With a median follow up of 1.7 years, 34% of patients relapsed and 45% died. Although single MYC or BCL-2 expression alone had no significant association with OS or PFS in the entire cohort, DE status was associated with significantly poorer PFS, and earlier relapse (median 0.86 years vs. 2.77 years; HR 1.61 (1.07 – 2.41); p=0.021) (Fig. 1). In a subgroup analysis restricted to patients treated with MATRix chemotherapy (n = 116 patients), there was a trend towards inferior PFS and OS, although this did not reach significance in a univariable analysis. However, the adverse prognostic impact of DE status on PFS was maintained in a multivariable analysis modelling age, baseline PS, treatment received, ASCT consolidation status and DE status both for the entire cohort (HR 1.75 (1.15 – 2.66); p<0.01) and the MATRix treated subgroup (HR 1.91 (1.08 – 3.36); p=0.03). A trend towards an association between DE status and OS was noted but did not reach significance in either a univariable or multivariable analysis.

We observed no significant difference in PFS or OS between DE-PCNSL and non-DE-PCNSL patients who received MATRix and consolidation with ASCT, perhaps indicating that the adverse impact of DE status is modified by this treatment strategy, although the sample size was small (n=66).

Conclusions

In a large, retrospective cohort of PCNSL patients treated at 7 UK academic treatment centres, double expression of MYC and BCL-2 by IHC was associated with inferior PFS even in patients treated with MATRix chemotherapy. Validation of this finding in independent cohorts is warranted.

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JO, CPF and KC share senior authorship

Disclosures: Marafioti: UCL-BRC: Research Funding. Chaganti: AbbVie: Consultancy, Honoraria; Adicet Bio: Consultancy, Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Orion Pharma: Consultancy, Honoraria; Pierre Fabre: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. McKay: Gilead/Kite, Incyte, Janssen: Speakers Bureau; Abbvie, AstraZeneca, Beigene, Celgene/BMS, Epizyme, Gilead/Kite, Incyte, Janssen, Recordati Rare Diseases, Roche, Takeda: Consultancy. Smith: Abbvie, AstraZeneca, Janssen: Consultancy; Abbvie, AstraZeneca: Speakers Bureau; AstraZeneca: Other: Travel to scientific congress. Eyre: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology @ Lilly: Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; PeerView: Speakers Bureau; Medscape: Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Calle: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Other: travel support; Abbvie: Consultancy, Honoraria, Other: travel support; Janssen: Honoraria. Cwynarski: BeiGene: Research Funding; Roche, Celgene/BMS, Takeda, KITE: Other: Travel to scientific congress; Roche, Takeda, KITE/Gilead, Incyte: Speakers Bureau; Roche, Takeda, Celgene/BMS, Atara, Gilead/KITE, Janssen, Incyte: Consultancy. Fox: Roche: Other: Travel to scientific congress; BeiGene: Research Funding; Celgene/BMS, Gilead/Kite, Incyte, Janssen, Roche, Takeda: Speakers Bureau; Abbvie, AstraZeneca, Atarabio, Celgene/BMS, GenMab, Gilead/Kite, Incyte, Janssen, Morphosys, Ono, Roche, Takeda: Consultancy. Okosun: Gilead: Honoraria, Research Funding; Eisai: Honoraria; AstraZeneca: Honoraria; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

*signifies non-member of ASH