Safety of Front-Line R-Mini-CHOP with or without Acalabrutinib in Older Adults with DLBCL – an Interim Analysis of Serious Adverse Events in the Arched / GLA 2022-1 Randomized, Open-Label, Phase 3 Trial

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity and has increased incidence in the elderly. Approximately 40% of pts with DLBCL are >70 yrs old. In older/frail pts with untreated DLBCL, the attenuated chemotherapy regimen R-miniCHOP is the standard of care with a 2-yr overall survival (OS) of approximately 60% (Peyrade 2011). BTK inhibition added to R-CHOP improved OS in pts <60 yrs, but not in older pts where tolerability was limited (Younes 2019). A BTK inhibitor with a more favorable safety profile may improve survival also in elderly pts. Acalabrutinib is a second-generation BTK-inhibitor with promising data in combination with R-CHOP in pts with DLBCL up to 80 yrs (Davies ASH 2022). ARCHED/GLA 2022-1 is an investigator-initiated, randomized, open-label, phase 3 trial to evaluate the addition of acalabrutinib to R-miniCHOP in pts with untreated DLBCL aged >80 yrs or 61-80 yrs old and unfit for full-dose R-CHOP. Patients are randomized to receive either R-miniCHOP (control, C) or R-miniCHOP + Acalabrutinib (A). Stratification is based on age, ADL score and IPI. The primary endpoint is progression free survival.

Methods

This is a safety analysis based on the per protocol quarterly evaluation of serious adverse events (SAE) of the first year of recruitment. Recruitment started in June 2023. All pts randomized until 01/07/2024 were included. Baseline characteristics, SAE incidence and severity were analyzed. Adverse events of special interest (AESI) were reported as SAE.

Results

At data cut off 57 pts had been randomized (C: 28, A: 29). Median age was 83 yrs (range 66-94), 68% pts were >80 yrs old and 63% male. ECOG status was 0-1 in 67% and ADL score <6 in 28%. Extranodal disease was present in 77%, and 72% had an IPI score ≥3. Baseline characteristics were balanced between arms.

A total of 44 SAE were reported in 29 pts (C: 18 events [13 pts; 46%]; A: 26 events [16 pts; 55%]). Fifteen (34%) of them were grade 1-2 (C: 6 events [5 pts; 18%]; A: 9 events [5 pts; 17%]). Twenty (45%) were grade 3 (C: 7 events [6 pts; 21%]; A: 13 events [9 pts; 31%]). One pt in arm C and one in arm A had one grade 4 SAE each. Four deaths (grade 5 SAE) occurred in arm C (14%, one lymphoma-related, one heart failure and two unknown cause) vs three (10%, one due to vascular causes and two unknown cause) in arm A.

The most common SAE were infections. In arm C, 4 pts (14%) had one grade 2 and four grade 3 infections, and 5 pts (17%) in arm A had one grade 2 and five grade 3 infections. Cardiac events accounted for 10 SAE. Specifically, in two pts (7%) in arm C one heart failure grade 5, one grade 2 and one grade 3 hypertensive crisis occurred. Six pts (20%) in arm A had five grade 1-2 (three asymptomatic ventricular extrasystoles [AESI], one asymptomatic non-sustained ventricular tachycardia [AESI], and one angina pectoris) and two grade 3 (one atrial fibrillation and one heart failure). Three pts had bleeding SAE, two in arm C (hemoptysis and melena, both grade 1) and one in arm A (grade 3 rectal bleeding).

Conclusion

Acalabrutinib with R-miniCHOP resulted in increased but manageable toxicity. Rates of serious infections and bleeding were similar between groups. One third of all SAE reported were grade 1-2. More cardiologic SAE were reported in the experimental arm, mostly asymptomatic grade 1-2 AESI. Importantly, no increased rate of treatment emergent deaths was seen with acalabrutinib + R-miniCHOP in this frail, high-risk population. Thus, acalabrutinib with R-miniCHOP has the potential to improve outcomes in older/frail adults with untreated DLBCL.

ARCHED is an academic study of the German Lymphoma Alliance and is funded by AstraZeneca GmbH. The trial is approved in the EU and is recruiting in Germany. (EU-CTN: 2022-501187-18-00, NCT05820841).