Time to third-line treatment after bendamustine-rituximab with or without acalabrutinib in patients with previously untreated mantle cell lymphoma: Updated analysis of the phase 3 ECHO trial after 50 months of follow-up

Abstract Introduction: The introduction of the Bruton tyrosine kinase inhibitor acalabrutinib combined with bendamustine and rituximab (ABR) as first-line (1L) therapy for mantle cell lymphoma (MCL) in older patients (pts) is reshaping the approach to treatment sequencing in this disease. The primary analysis of the phase 3 ECHO trial (NCT02972840) with data cutoff Feb 15, 2024 (median time on study 44.9 mo) demonstrated improved progression-free survival (PFS) with ABR vs placebo plus BR (PBR; hazard ratio HR 0.73; 95% confidence interval CI 0.57–0.94; P=0.0160) in pts ≥65 y with treatment-naive (TN) MCL. Here we present updated results after 50 mo of follow-up, including time to next treatment 2 (TTNT2; ie, initiation of third-line 3L therapy). Methods: Pts aged ≥65 y with TN MCL and ECOG performance status ≤2 were randomly assigned 1:1 to receive ABR or PBR. Randomization was stratified according to geographic region and simplified MIPI score. BR was given for 6 cycles followed by rituximab maintenance for 2 y in pts achieving a partial or complete response (CR). Acalabrutinib (100 mg twice daily) or placebo was administered at study start until progressive disease (PD) or unacceptable toxicity. Crossover to acalabrutinib was permitted at PD. The primary endpoint was PFS per independent review committee. TTNT2, which was used as a surrogate for PFS2 (time from initial treatment to second disease progression), was defined as time from randomization to second subsequent (3L) antilymphoma therapy after discontinuation of randomized treatment or death. Results: In total, 299 pts were randomized to each arm; median age was 71 y. At data cutoff (February 15, 2025), median (range) time on study was 51.86 (0.03–93.04) mo and median (range) follow-up through reverse Kaplan-Meier method for PFS was 60.8 (0–88.5) mo. Median TTNT2 was not reached (NR) in the ABR arm and 73.8 mo in the PBR arm, establishing a 24% reduction in the risk of initiating 3L therapy or death with ABR vs PBR (stratified HR 0.76; 95% CI 0.59–0.98). In total, 33 (11.0%) and 100 (33.4%) pts received second-line 2L treatment (median time to 2L therapy, 26.3 vs 19.6 mo) and 10 (3.3%) and 37 (12.4%) received 3L treatment in the ABR and PBR arms, respectively. When COVID-19 deaths were censored (in alignment with prespecified analyses from the primary study), the HR further improved (stratified HR 0.67; 95% CI 0.50–0.89; median TTNT2 NR in any arm). In total, 71.6% and 78.3% of pts discontinued acalabrutinib and placebo, respectively; the most common reasons (5%) for discontinuation were adverse events (AEs; 44.5%, ABR; 32.4%, PBR) and objective PD (12.7%, ABR; 30.8%, PBR). Median PFS was 72.5 and 47.8 mo in the ABR and PBR arms, respectively (stratified HR 0.68; 95% CI 0.53–0.87; P=0.002). In total, 108 (36.1%) and 116 (38.8%) pts in each arm died; median overall survival (OS) was NR in both arms (stratified HR 0.87; 95% CI 0.67–1.13), with a 36-mo OS rate of 73.8% with ABR vs 68.3% with PBR. With 1 additional year of follow-up since the primary analysis, rates of grade ≥3 AEs and serious AEs in the ABR arm were comparable to previously reported rates, indicating that prolonged acalabrutinib exposure does not appear to result in cumulative toxicities. Three new cases of grade 3/4 neutropenia were reported, with no marked changes in the rates of grade ≥3 or serious infections. The rate of grade ≥3 cardiac events remained consistent with the primary analysis. In the ABR arm, 1 new case of grade 3/4 atrial fibrillation and 1 new case of grade 3/4 hypertension were reported. Rates of thrombocytopenia, major hemorrhage, and ventricular tachyarrhythmia remain unchanged. Conclusion: In this updated analysis of the ECHO trial, despite crossover to acalabrutinib being permitted in the PBR arm, fewer pts in the ABR arm were in need of subsequent treatment (2L and 3L), with longer TTNT2 in the ABR arm. These results suggest that 1L treatment with ABR provides a 24% reduction in risk of initiating 3L therapies or death. Further follow-up has demonstrated that ABR offers improved efficacy (ie, PFS) vs PBR, with no long-term safety concerns with acalabrutinib maintenance. The updated safety findings further support the favorable benefit–risk profile of acalabrutinib in TN MCL. Altogether, these data support the potential of acalabrutinib in combination with BR as 1L treatment, rather than in later lines, to modify long-term treatment outcomes in pts with TN MCL.