47 | IBRUTINIB AND RITUXIMAB IS SUPERIOR TO IMMUNOCHEMOTHERAPY IN PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA DESPITE LOWER RATES OF MRD NEGATIVITY

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The ENRICH trial compared the chemotherapy-free combination of Ibrutinib and rituximab with standard immunochemotherapy in older patients with untreated mantle-cell lymphoma (MCL). Here we present the primary analysis and minimal residual disease (MRD) negativity rates during induction treatment. Methods: This randomised open label superiority trial was performed at 66 sites in 5 European countries. 397 patients aged ≥ 60 years with untreated MCL were randomised to ibrutinib (560 mg od) and rituximab (IR), or immunochemotherapy (investigator choice: bendamustine-rituximab (BR) or R-CHOP with rituximab maintenance, stratified by immunochemotherapy choice. Assessments for MRD were performed from peripheral blood and bone marrow at baseline, mid-induction (MI), end of induction (EI) and end of maintenance, using 8-marker flow cytometry (CD19, CD5, ROR1, CD200, CD11a, HLADR, CD25 and CD81) validated to a detection limit of 10E-5/0.001%. Results: At a median follow-up of 47.9 months, the median PFS of IR was superior to immunochemotherapy with an adjusted hazard ratio (HR) of 0.69 (95% confidence interval (CI), 0.52–0.90, p = 0.0034). For those with pre-randomisation choice R-CHOP, the HR was 0.37 (95% CI 0.22–0.62), and with BR, the HR was 0.91 (95% CI 0.66–1.25). A complete response was observed in 107/199 (53.8%) patients in the IR arm, and in 105/198 (53.0%) of the immunochemotherapy arm (25/53 (47.2%) for R-CHOP and 80/145 (55.2%) for BR). Of 175 patients with available MRD samples, the pre-treatment phenotype was suitable for disease monitoring in > 95%. At the MI timepoint 100/175 (57%) of patients were MRD positive (MRD+), 58/175 (33%) were MRD negative (MRD-). 17/175 (9.7%) were non evaluable (NE). Rates of MRD- were 10/91 (11%) for patients treated with IR (72/91 MRD+, 9/91 NE), 37/44 (84%) for those treated with BR (MRD+ n = 4, NE n = 3) and 11/40 (27.5%) for those treated with RCHOP (MRD+ n = 24, NE n = 5). At EI, 59/169 (34.9%) were MRD+, 84/169 (49.7%) of patients were MRD- and 26/169 (15.3%) NE. Rates of MRD- at EI were 30/85 (35.3%) for IR (MRD+ n = 44, NE n = 11), 36/44 (81.8%) (NE n = 8, MRD+ n = 0) for BR and 18/40 (45%) (MRD+ n = 15, NE n = 7) for those treated with RCHOP. In IR-treated patients MRD- patients at EI had a 3 year PFS of 60% (95% CI 44.8, 80.4) versus 72.5% (95% CI 60.3%, 87%) for MRD+ patients. Conclusions: These data demonstrate that MRD assessment for MCL using flow cytometry is feasible in a prospective randomised trial. More BR treated patients were MRD negative compared to those treated with RCHOP, potentially reflecting the difference in efficacy of these regimens. Patients treated with IR showed improving MRD responses over time. PFS did not correlate with MRD status at MI and EI timepoints (similar to the MRD response kinetics seen in CLL for patients on continuous BTKi). We will report further data on the correlation between PFS and MRD negativity in the different treatment arms. Research funding declaration: Funding from Cancer Research UK, Johnson and Johnson Pharmaceuticals Keywords: molecular targeted therapies; diagnostic and prognostic biomarkers; indolent non-Hodgkin lymphoma Potential sources of conflict of interest: D. Lewis Consultant or advisory role: J+J, Beigene, Astrazeneca, Roche, Abbive Honoraria: J+J Educational grants: J+J, AZD, Beigene C. Burton Consultant or advisory role: Roche, Kite, Takeda, J+J, Abbvie, AZD M. Jerkeman Consultant or advisory role: Johnson and Johnson, Abbvie, Roche, AZD, Kite/Gilead I. Glimelius Consultant or advisory role: Kite/Gilead, Takeda, Johnson and Johnson A. Davies Consultant or advisory role: Roche, BMS, Kite/Gilead, Sobi, Incyte, Abbvie, Genmab Honoraria: Astrazeneca N. Crosbie Consultant or advisory role: Abbvie M. Bishton Consultant or advisory role: Abbvie, Incyte, Genmab T. Eyre Consultant or advisory role: Beigene, Astrazeneca, Roche, Gilead, Kite, Takeda, J+J, Loxo S. Rule Employment or leadership position: Astrazeneca

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