P1127: final analysis of australasian leukaemia & lymphoma group nhl29: a phase ii study of ibrutinib, rituximab and mini-chop in very elderly patients with newly diagnosed dlbcl

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Treatment of very elderly patients (pts) with newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL) remains challenging. Rituximab-mini-CHOP (R-mCHOP) is an established standard of care with a 2yr OS of 59% and PFS of 47% (Peyrade et al, Lancet Oncol 2011). Ibrutinib has efficacy in combination with R-CHOP in younger pts, but with significant toxicity limiting the ability to complete therapy in pts ≥ 60 yrs (Younes et al, JCO 2019). Aims: In a prospective Phase II ALLG study in pts ≥75yrs with newly diagnosed DLBCL the aim was to assess the safety and efficacy of ibrutinib-R-mini-CHOP as measured by deliverability and 2-yr overall survival (OS). Methods: Pts received six 21-day cycles of ibrutinib 560mg daily and R-mCHOP (Rituximab 375mg/m2, cyclophosphamide 400mg/m2, doxorubicin 25mg/m2, vincristine 1mg on day 1 & prednisone 40mg/m2 or 100mg/d x 5) followed by an additional two 21-day cycles of rituximab + ibrutinib (or high dose methotrexate for CNS prophylaxis). Primary endpoints were deliverability and 2-year OS. Sample size calculations were made using a one-sample two-sided approach to detect a 15% improvement on the fixed Peyrade reference OS (59%) and progression free survival (PFS) (47%) rates. A key secondary endpoint was 2 yr PFS. This report is the final analysis of this study. Results: Eighty pts were recruited from Nov 2015 to Nov 2018. One died prior to treatment and is not included in the analysis. Median age was 82yrs (75-95); 81% stage III/IV; 54% age adjusted IPI 2-3. At a data cut-off 6 September 2022, with a median follow-up of 35.5 months (mo) (0.2, 71.7), there was a non-significant trend towards improvement in 2-year OS of 68% (55.6%, 77.4%) compared to the reference Peyrade cohort of 59% (p=0.11). Median OS was 72mo (95% CI 35m to not reached (NR)), with 3-year OS of 60.2%. The 2-year PFS of 60.0% (47.7%,70.3%) was significantly improved compared to the reference cohort of 47% (p=0.03). 3-year PFS was 52.5% with a median PFS of 40 mo (95% CI 20.41, NR). Cell of origin (COO) as determined by centralised immunohistochemistry had no significant impact of OS, PFS or disease response, nor COO as determined by gene expression profiling in the 47 patients with samples available for testing. Overall response was 76% (61/80 pts), with a complete response rate of 70% (56/80 pts). All 6 cycles of R-mCHOP were completed in 63/79 pts (80%). The median Average Relative Total Dose & Average Relative Dose Intensity for the entire regimen was 97% (IQR 82, 100; 88, 100). Deaths occurred in 34/79 pts (43%):17 (21.5%) due to progressive disease and 5 (6.3%) treatment-related. 67% pts experienced at least one SAE. Most common AEs were infections & diarrhoea (majority grade 1-2). In the EORTC QLQ-C30 there was an improvement in functional and symptom scales and on the EQ-5D-5L survey, there was a significant improvement in the median health state classification score and median visual analogue scale in responders over time. Summary/Conclusion: The addition of ibrutinib to R-mCHOP was deliverable with an improved 2-yr PFS compared to R-mCHOP alone. While there was a trend towards improvement in 2-yr OS, our ambitious target 15% increase on survival compared to a historical R-mCHOP cohort was not achieved. Despite considerable and not unexpected toxicity in this elderly cohort, the QOL and functional improvements in survivors are promising. These data support further study of the addition of BTK inhibitors to R-mini-CHOP in elderly patients with DLBCL.Keywords: Elderly, DLBCL, Chemotherapy, ibrutinib