High Grade B Cell NHL Outcomes: Real World Experience from the UK

Incidence of non-Hodgkin lymphoma (NHL) is increasing; it is already the sixth most common malignancy in UK (Cancer Research UK NHL incidence statistics 2022). It can present in aggressive or indolent form. Whilst for those with chemo-sensitive disease prognosis is good, with 5 year overall survival (OS) >50%, those with relapsing/refractory (R/R) forms have consistently poor outlook. Historically only 30-40% of these tolerate/respond to salvage therapy with <30% of those who respond able to proceed to consolidation with autologous stem cell transplant (ASCT). Despite this ~50% will relapse (Crump et al, Blood 2017 doi: 10.1182/blood-2017-03-769620).

Recent treatment advances seek to address this area of unmet need. CAR-T cell therapy is presented as a highly effective solution for this cohort of patients. The pivotal studies leading to licensing and widespread adoption of these therapies drew comparison from SCHOLAR-1 which pooled data from 2 phase 3 clinical trials and 2 observational cohorts enabling data on 636 patients with refractory NHL to be analysed. There are challenges with this dataset and notably it does not include UK patients.

We analysed patient level data for a UK NHL cohort and compare these to other, more historical data sets. 165 patients were identified. Diagnoses included primary DLBCL, DLBCL-transformed follicular lymphoma and PMBCL. Demographics: 92 male, 73 female; median age 64 (24-86yrs). Stage at diagnosis: I 10.3%, II 13.3%, III 21.2%, IV 54.5%, unknown <1%. IPI: 0- 2.4%, 1 - 13.3%, 2 - 27.3%, 3 - 26.7%, 4 - 18.8%, 5 - 3.6%, unknown 7.8%. C-MYC present in 20.7% of those where evaluated (24/116); of those 41.7% (10) double hit, 12.5% (3) triple hit. Cell of origin available for 54.5% (ACB 36.7%, GCB 63.3%). >90% considered suitable for intensive therapy; PS: 0 - 43%, 1 - 33.9%, 2 - 12.7%, 3 - 9.1%, 4 - <1%, unknown 4.2%. Nearly 2 thirds required >1 line treatment: 1 - 37%, 2 - 33.3%, 3 - 20.6%, 4 - 6.1%, 5 or greater - 3%.

First line: 57.6% (95/165) 6-8 cycles R-CHOP (22% also received CNS prophylaxis - HD or intrathecal methotrexate, 16.8% additional radiotherapy (IFRT)); 10.3% abbreviated R-CHOP +/- IFRT; 9.7% dose attenuated R-CHOP, 16.4% R-CODOX-M/R-IVAC, 4.8% R-mini-CHOP, 1.8% non-intensive regimes and <1% IFRT alone. Best response was CR 52.7%, PR 11.5%, SD 13.3%, PD 11.5%, not available 10.9%. 63% (104/165) required second line treatment; time to treatment ranged from <6 months (27.9%), 6-12 months (32.7%), >12 months (37.5%), unknown in 2 cases. PS at first relapse: PS 0 - 36.6%, 1 - 45.5%, 2 - 7.1%, 3 - 7.1%, 4 - <1%. 35.6% with refractory disease had improvement in PS with treatment despite suboptimal response. 7.1% were considered too frail for further treatment. Second line therapy was primarily platinum based +/- IFRT +/- HD Mtx 71.2%; other intensive regimes included R-IVE, R-DHAP, R-ESHAP, R-CHOP and MATRIX (11.5%), less intensive regimes included R-lenalidomide, R-BP, R-miniCHOP, R-CVP, IFRT and R-CEPP (17.3%). Best response was CR 24.0%, PR 18.3%, SD 7.7%, PD 44.2%, not evaluated 5.8%. 31.7% proceeded to ASCT, 6 required >1 line of salvage therapy prior to ASCT. Exclusion basis: refractory disease 26.3%, declining PS and suboptimal response 7.5%, age only (>72years) 8.75%, frailty (PS > 2 - treatment induced/ comorbidities) 16.25%, age and frailty 13.75%, failed harvest 6.25%, patient choice 6.3%. 22 (66.6%) achieved CR after ASCT. 45 had suboptimal response to ≥2 lines intensive therapy but maintained fitness and would have been eligible for CAR-T. 47% (49/104) of those requiring salvage therapy proceeded to third line, 38.8% had refractory disease requiring treatment within 12months of first salvage treatment. 14.3% (7/49) had received ASCT. 57.1% (28/49) received intensive therapy, 18.4% (9/49) proceeded to ASCT. 42.9% were treated non-intensively.

This UK dataset, analysing real world experience, highlights the challenge of high grade NHL. Whilst OS is: 2 year 63%, 5 year 29.1% with an additional 4.2% and 27.9% alive but <2 and <5 years from diagnosis respectively, for those with R/R disease OS is significantly reduced: 2 year 35.8%, 5 year 21.8%. CR rate after first line is 53.9%. However, 63% of patients required second line treatment; 4.8% relapsed >12months, 33.3% refractory; objective response rate (ORR) 42.3% (CR 24.0%), 35.8% alive at 2 years, 21.8% at 5 years. This is comparable to results from the referenced SCHOLAR-1 study supporting it as a reference point for new therapies.

Campbell:Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, and Novartis: Consultancy, Speakers Bureau; Kite/Gilead: Research Funding.