Indirect comparison of bendamustine-rituximab and R-CHOP with rituximab maintenance in first-line treatment of elderly Mantle Cell Lymphoma: Data from the enrich trial Free

Background ENRICH is the first randomised open-label phase II/III trial comparing Ibrutinib plus rituximab (IR) with Rituximab-chemotherapy (R-chemo, clinician choice of RCHOP or Bendamustine plus rituximab (BR)), each followed by maintenance rituximab (MR) for two years. IR was superior to R-chemo with respect to progression-free survival (PFS), with an adjusted hazard ratio (HR) of 0.69 (95% CI, 0.52–0.90; p = 0.003).

However, there was little evidence of a difference between IR and BR (HR 0.91; 95% CI, 0.66–1.25). In contrast, IR demonstrated a substantial benefit vs RCHOP (HR 0.37; 95% CI, 0.22–0.62). This could reflect differences in patient (pt) characteristics between the choice groups or a difference in efficacy between the selected chemotherapy regimens (BR vs RCHOP). BR has been shown to be superior to RCHOP in randomised studies (eg Rummel et al, Lancet, 2013) but these studies were performed without MR, and the benefit for MR has previously been demonstrated post RCHOP but, not BR, in a trial setting. No study thus far has compared BR with RCHOP with routine MR in both arms.

This analysis presents an indirect comparison between BR and RCHOP with both arms receiving MR, using data from the ENRICH trial. By allowing physician choice of chemotherapy (BR or RCHOP), the trial design enabled a comparison between BR and RCHOP with IR serving as a common comparator.

Methods Pts ≥60 years with untreated, stage II-IV MCL were recruited into ENRICH. Pre-randomisation, clinician choice of chemotherapy (BR or RCHOP) was determined; this choice was the treatment administered if the pt was randomised to the control arm. Pts were then randomised to receive either IR or R-chemo, stratified by chemotherapy choice. Treatment consisted of 6-8 cycles of chemotherapy or daily ibrutinib, both combined with rituximab administered according to the chemotherapy schedule. All participants received MR for two years, and intervention participants continued daily ibrutinib until disease progression or unacceptable toxicity.

A planned secondary analysis of the ENRICH trial data evaluated PFS between the control arm chemotherapies of BR and RCHOP using the common comparator, IR. A Cox proportional hazards model adjusted for the pre-randomisation choice of chemotherapy type and allocated treatment group was used to determine the HR and 95% CI of RCHOP/BR.

Results 397 pts from the UK and Nordic countries were recruited to ENRICH, of which 270 had the pre-randomisation choice of BR and 107 RCHOP. Pts were randomised to receive IR (n=199) or R-chemo(n=198, n=145 BR and n=53 RCHOP). Pt characteristics were strikingly similar across the choice of chemotherapy and across allocated treatment arms (BR vs RCHOP: median age 74 vs 72 years, high risk MIPI 59% vs 52%, Ki67>30% 44% vs 49%, blastoid morphology 8% vs 6%, TP53 mutation 26% vs 19%). However, the choice of RCHOP differed between countries, with 37.8% (99/262) of UK pts having the pre-randomisation chemotherapy choice of RCHOP compared to just 5.9% (8/135) of patients in the Nordic countries.

The 5-year PFS probability for those treated with BR was 47.4% (95% CI 39.5% to 56.9%), R-CHOP was 19.2% (95% CI 10.6% to 35.1%), and IR was 51.1% (95% CI 44.2% to 59.2%). The analysis of PFS showed the adjusted HR for R-CHOP/BR was 2.41 (95% CI 1.33 to 4.37).

The adjusted HR for Overall Survival was 1.59 (95% CI 0.81 - 3.11) for RCHOP/BR.

Grade>= 3 (G3) adverse events (AE)s were more common in RCHOP treated patients; 35/52 (67%) experienced at least one G3 AE vs 73/143 (51%) for BR. Neutropenic sepsis was more common in RCHOP treated patients at 15% vs 1% in BR during induction. During maintenance, G3 AEs were more experienced by 44/143 (31%) of BR patients vs 11/52 (21%) of RCHOP patients. G3 Infections including COVID-19 were experienced by 10/143 (7%) of BR patients during maintenance compared with 1/52 (2%) of RCHOP patients.

Conclusions ENRICH is the first study with BR and RCHOP in the first line treatment of MCL with the routine use of MR in both arms. Whilst the comparison of BR vs RCHOP was not randomised, the two groups were well matched and an adjusted analysis demonstrated a PFS benefit in favour of BR over R-CHOP, with more G3 AEs in RCHOP patients, and a trend for an improved OS in BR treated patients.