MINIMAL RESIDUAL DISEASE WITH BENDAMUSTINE-RITUXIMAB WITH OR WITHOUT ACALABRUTINIB IN PATIENTS WITH PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA: RESULTS FROM THE ECHO TRIAL

Introduction: The combination of acalabrutinib with bendamustine-rituximab (ABR) significantly improved progression-free survival (PFS) versus placebo with BR (PBR) in the phase 3 ECHO trial (NCT02972840) in older patients (pts) with previously untreated mantle cell lymphoma (MCL) (Wang M, et al. EHA 2024. Abstract #LB3439). Minimal residual disease (MRD) has been shown to be an impactful prognostic factor for outcomes in MCL. Previously presented data from the trial showed that a lower percentage of pts receiving ABR had molecular relapse during the maintenance period than pts receiving PBR (Dreyling M, et al. Blood. 2024;144(Suppl 1):1626). Herein, we examine the association between MRD status and clinical outcomes in the ECHO trial.

Methods: Pts aged ≥ 65 years with previously untreated MCL and Eastern Cooperative Oncology Group performance status ≤ 2 were randomly assigned 1:1 to receive ABR or PBR. BR was given for 6 cycles (induction) followed by rituximab maintenance for 2 years in pts achieving a partial or complete response (CR). Acalabrutinib (100 mg twice daily) or placebo was administered until disease progression or unacceptable toxicity. Crossover to acalabrutinib was permitted at disease progression. The primary endpoint was PFS per independent review committee. MRD (10⁻⁵) was assessed in peripheral blood every 24 weeks and at CR or progressive disease using the ClonoSEQ assay (Adaptive Biotechnologies).

Results: At the February 15, 2024 data cutoff, 266 pts in the ABR arm and 252 pts in the PBR arm were evaluable for MRD (89.0% and 84.3%, respectively). Pts who did not achieve MRD negativity at any time had a median PFS and overall survival (OS) of 13.8 and 22.8 months, respectively, while pts achieving MRD negativity had a median PFS of 66.7 months (hazard ratio [HR] 0.22; p < 0.0001) and median OS was not reached (HR: 0.31; p = 0.00015); pts who did not achieve MRD negativity were 4.5 times more likely to experience disease progression. Pts who became MRD negative at any time also had better outcomes with or without clinical complete response versus those who remained MRD positive (Figure). The probability of maintaining MRD negativity after induction was 2.3-fold greater for pts in the ABR arm (HR: 0.44; p = 0.022). Among all pts, those who maintained MRD negativity after 24 weeks had improved outcomes (median PFS 70.2 months) versus those who converted from MRD negative at 24 weeks to MRD positive during the maintenance period (median PFS 44.2 months; HR: 1.96; p < 0.0001).

Conclusions: In the phase 3 ECHO trial, achieving MRD negativity was associated with improved PFS. MRD was a stronger prognostic factor for outcome than clinical response. Continuous therapy with acalabrutinib increased the probability of maintaining MRD negativity after induction, and sustained MRD negativity was associated with improved PFS, suggesting potential benefit of continuous acalabrutinib therapy after chemoimmunotherapy induction.

Research funding declaration: Study funded by AstraZeneca.

Encore Abstract: EHA 2025

Keywords: non-Hodgkin; combination therapies; ongoing trials

Potential sources of conflict of interest:

P. L. Zinzani

Consultant or advisory role: BMS, Gilead, Roche, Kyowa Kirin, Sobi, Incyte, Novartis, Beigene, Janssen, AbbVie

Honoraria: BMS, Gilead, Roche, Kyowa Kirin, Sobi, Incyte, Novartis, Beigene, Janssen, AbbVie

S. Spurgeon

Consultant or advisory role: Genentech, Janssen, Beigene, ADC Therapeutics

Other remuneration: Research Funding: Beigene, Celgene/BMS, Incyte, Janssen, ADC Therapeutics, Shrodinger, Merck, Profound Bio, Gilead, Acutar. Expert Witness: AbbVie

M. Pavlovsky

Consultant or advisory role: Beigene, AstraZeneca, Ascentage Pharma

Honoraria: AbbVie, Janssen, AstraZeneca

Educational grants: Sanofi, Roche, AstraZeneca, Beigene

C. Y. Cheah

Consultant or advisory role: Roche, Janssen, Gilead, AstraZeneca, Lilly, Beigene, Menarini, Dizal, AbbVie, Genmab, Sobi, CRISPR Therapeutics, BMS, Regeneron

Honoraria: Roche, Janssen, Gilead, AstraZeneca, Lilly, Beigene, Menarini, Dizal, AbbVie, Genmab, Sobi, CRISPR Therapeutics, BMS, Regeneron

Educational grants: Lilly, Beigene

Other remuneration: Speaker’s bureau: Janssen, AstraZeneca, Beigene, Genmab, AbbVie, Roche, MSD. Research funding: BMS, Roche, AbbVie

D. Villa

Consultant or advisory role: AstraZeneca, Janssen, BeiGene, AbbVie, Kite/Gilead, BMS/Celgene, InCyte, Merck, Novartis, Zetagen

Honoraria: AstraZeneca, Janssen, BeiGene, AbbVie, Kite/Gilead, BMS/Celgene, InCyte, Merck, Novartis, Zetagen

Other remuneration: Research funding (institution): AstraZeneca, Roche

S. Luminari

Consultant or advisory role: Roche, AstraZeneca, Incyte, Kite, Novartis, BMS, Sobi, Regeneron, AbbVie, Beigene

V. Otero

Employment or leadership position: AstraZeneca

Stock ownership: AstraZeneca

G. De Jesus

Employment or leadership position: AstraZeneca

R. Lesley

Employment or leadership position: AstraZeneca

Stock ownership: AstraZeneca, Amgen

M. L. Wang

Consultant or advisory role: Acerta Pharma, AstraZeneca, Bristol Myers Squibb, Boxer Capital, Galapagos NV, Genmab, InnoCare, Janssen, Kite Pharma, Lilly, Merck, PER, Pfizer, Oncternal

Honoraria: AstraZeneca, BeiGene, Binaytara Foundation, Bristol Myers Squibb, CAHON, Editorial Medica AWWE SA, East Virtinia Medical School, Instituto Scientifico Romagnolo, Janssen, Kite Pharma, Mayo Clinic, MJH Life Sciences, Merck, MSC National Research Institute of Oncolgy, Pfizer, Physicians Education Resources (PER), Plexus Communications, PromCon S.R.E., Research to Practice, Studio ER Congressi, South African Clinical Hematology Society, Medscape/WebMD, VJHem

Other remuneration: Research: AbbVie, Acerta Pharma, AstraZeneca, Bantam Pharma, BeiGene, BioInvent, Celgene, Genmab, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Nurix Therapeutics, Oncternal, Pharmacyclics, Velosbio, Vincerx