Add-on ibrutinib ENRICHes rituximab treatment effect for previously untreated MCL

In the phase II/III ENRICH trial, first-line (1L) ibrutinib with rituximab (IR) demonstrates superiority over rituximab plus chemotherapy (R-chemo; either R-CHOP* or bendamustine**-R) in older patients with previously untreated mantle cell lymphoma (MCL).

“The study was positive, with an improvement in PFS for a non-chemo regimen of IR over immunochemotherapy for previously untreated MCL,” said Dr David John Lewis from the University Hospitals Plymouth NHS Trust, Plymouth, UK, at ASH 2024.

The median PFS was 65.3 months with IR and 42.4 months with R-chemo. A comparison between arms yielded a hazard ratio (HR) of 0.69 (p=0.003). There were 94 and 121 PFS events in the respective IR and R-chemo arms (49 and 77 were progressive disease). [ASH 2024, abstract 235]

There was a significant interaction between treatment and the pre-randomization choice of immunochemotherapy (p=0.004). “This test was highly statistically significant, suggesting that the choice of immunochemotherapy was making a big difference to the PFS difference in the treatment arms,” Lewis explained.

The benefit of IR over R-chemo was much greater among patients with a pre-randomization choice of R-CHOP (5-year PFS 52.4 vs 19.2 months; HR, 0.37) than it was for those who had bendamustine-R (5-year PFS 50.8 vs 47.4 months; HR, 0.91).

IR was favoured over R-chemo in terms of PFS across most subgroups evaluated, including those with (median PFS 18.5 vs 8.9 months; HR, 0.77) and without TP53 mutation (HR, 0.65). Of note, there was a suggestion of inferior PFS for blastoid disease with the former vs the latter (6.9 vs 21.1 months; HR, 2.33) as opposed to the non-blastoid group (HR, 0.80).

OS, AEs

The 5-year overall survival (OS) was similar between IR and R-chemo (57.7 percent vs 54.5; HR, 0.87) and between IR and BR (57.2 percent vs 58.1 percent; HR, 1.00). Between IR and R-CHOP, there was a much more marked trend for an improved OS  with the former vs the latter (59.4 percent vs 46.3 percent; HR, 0.64), Lewis said.

Grade ≥3 bleeding adverse events were reported in 5.1, 2.1, and 5.8 percent of the respective IR, BR, and R-CHOP groups. About 6 percent of IR recipients had grade ≥3 atrial fibrillation as opposed to only 0.7 percent of BR recipients and none in the R-CHOP group.

First non-chemo approach to achieve superiority over R-chemo

The current standard of care (SoC) for untreated MCL in older patients are R-CHOP or BR followed by maintenance rituximab***. “The median age of MCL diagnosis is 71 years, and aggressive treatment approaches are not very good options for the majority of these patients,” Lewis said.

Bruton tyrosine kinase inhibitors such as ibrutinib are SoC for second-line treatment. In one study, the addition of ibrutinib to 1L BR prolonged PFS as opposed to BR. [N Engl J Med 2022;386:2482-2494]

ENRICH included 397 patients with previously untreated, measurable stage II–IV MCL. Of these, 290 (73 percent) were on BR prior to randomization while the remainder were on R-CHOP. They were then randomized 1:1 to receive induction IR in cycles as per choice of chemo or R-chemo every 21/28 days. During the maintenance phase, ibrutinib 560 mg was given daily and rituximab 375 mg/m² was administered every 56 days for 2 years. During follow-up, ibrutinib was given until disease progression.

The median age was 74 years, 74.6 percent were men, 94.5 percent had ECOG 0–1, and 6.7 percent had blastoid MCL. The median follow-up was 47.9 months.

“IR is the first non-chemotherapy approach to demonstrate superiority over R-chemo and should be considered SoC for 1L treatment for older patients with previously treated MCL,” Lewis concluded.