Ibrutinib-Rituximab Is Superior to Rituximab-Chemotherapy in Previously Untreated Older Mantle Cell Lymphoma Patients: Results from the International Randomised Controlled Trial, Enrich

Introduction: Current standard of care approaches for older patients with untreated mantle cell lymphoma (MCL) are rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP) or Bendamustine-rituximab (BR) followed by maintenance rituximab (MR). The addition of the Bruton tyrosine kinase inhibitors (BTKis) ibrutinib and acalabrutinib to chemotherapy improve progression-free survival (PFS) versus BR, but the use of a first-line ibrutinib (+/- rituximab) (IR) has not been prospectively compared to immunochemotherapy. ENRICH is the first randomised open-label phase II/III trial comparing IR with R-chemotherapy (clinician choice of R-CHOP or BR, R-chemo), each with MR.

Patients & methods: Patients>=60 years (ys) with untreated, stage II-IV MCL were randomised to IR or R-chemo, stratified by clinician choice of BR or R-CHOP. Baseline tumour biopsies were collected for molecular analysis. Treatment consisted of 6-8 cycles of chemotherapy or daily ibrutinib, both in combination with 6-8 cycles of rituximab in the schedule of pre-randomisation choice of chemotherapy. MR was given in both arms for 2 ys and intervention participants continued daily ibrutinib until disease progression or unacceptable toxicity. The primary outcome was PFS, analysed with a test of superiority at the 2.5% level from a Cox proportional hazards model, stratified by choice of chemotherapy.

Results: Between December 2015 and June 2021, 397 patients were randomised to IR (n=199) and R-chemo (n=198; R-CHOP n=53, BR n=145) from 65 United Kingdom and Nordic sites. Median age was 74 years, 74.6% were male, 94.5% had ECOG 0-1, 56.5% had high-risk MIPI score, and 6.4% had blastoid MCL. Baseline characteristics were well balanced between treatment arms and choice of R-chemo. The median follow-up was 47.9 months.

The PFS with IR was superior to R-chemo, with a hazard ratio (HR) of 0.69, (95% CI 0.52-0.90, p=0.003), median PFS 65.3 vs 42.4 months, respectively. There were 94/199 (47.2%) PFS events in the IR arm compared to 121/198 (61.1%) in the R-chemo arm, of which 49 (52.1%) and 77 (63.6%) were progressive disease, respectively.

There was a significant interaction (p=0.004) between choice of chemotherapy and treatment effect. For the pre-randomisation choice R-CHOP subgroup, the HR = 0.37 (95% CI 0.22-0.62), median PFS NR vs 26.6 mo. For the subgroup with selection BR, the HR = 0.91 (95% CI 0.66-1.25), median PFS 65.3 vs 50.5 mo.

The 5 y Overall Survival (OS) for IR is 57.7% compared to 54.5% for R-Chemo, HR = 0.87 (95% CI 0.64-1.18). For the pre-randomisation choice R-CHOP subgroup, the HR = 0.64 (95% CI 0.36-1.13), 5 year OS probability 59.4% vs 46.3%, for IR and R-CHOP, respectively. For the subgroup with selection BR, the HR = 1.00 (0.70, 1.44), 5 year OS probability 57.2% vs 58.1%, for IR and BR, respectively.

Across the treatment and maintenance phases, 61.1%, 51.9% and 51.7% of the IR, R-CHOP and BR participants reported grade ≥3 non-haematological adverse events (AEs), respectively. Grade≥3 haematological AEs were reported in 16.7%, 50.0% and 33.6%, respectively. Grade≥3 atrial fibrillation was reported in 6.6% of IR and 0.5% of R-chemo participants.

Quality of life (EORTC QLQ-C30) at mid-treatment was higher for the IR arm compared to R-chemo, median (IQR) 91 (84, 95) and 85 (76, 92), respectively.

COVID-19 accounted for 19 deaths in the IR arm and 14 deaths in R-Chemo (2 R-CHOP, 12 BR), these events contributed to 16 PFS events in the IR arm (17.0%) and 10 in the R-chemo arm (8.3%) (2/44 (4.5%) for R-CHOP and 8/77 (10.4%) for BR). A PFS sensitivity analysis censoring at COVID-19 death did not alter the primary analysis conclusions.

Conclusions:

With a median follow up of 47.9 months, ENRICH is the first randomised trial to demonstrate a significant improvement in PFS for IR compared to R-chemo. When PFS was analysed by choice of chemotherapy IR was superior to R-CHOP, and comparable to BR despite more Covid-19 events in the IR arm. Haematological toxicity was lower with IR, and quality of life scores were improved at mid-treatment. IR is the first non-chemotherapy approach to demonstrate superiority over R-chemotherapy and should be considered a standard of care for first-line treatment for older patients with MCL. Further data on high-risk subgroups including those with TP53 mutation will be presented.