Acalabrutinib In Combination With Rituximab And Reduced Dose Chop (r-minichop) In Older Adults With Untreated Diffuse Large B-cell Lymphoma
Topic: Aggressive Non-Hodgkin lymphoma — Clinical
Background:Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity and approximately 40% ofaffected patients are older than 70 years. Administration of full dose R-CHOP in older adults is often limited bytoxicity due to comorbidities/ frailty. However, efficacy of reduced-dose therapy (“R-miniCHOP”) is modest,with 2-year overall survival (OS) rates approximating 60%. Acalabrutinib is a selective, irreversible, second-generation small molecule inhibitor of Bruton Tyrosine Kinase (BTK) with promising data in DLBCL (Davies et alASH 2022). It has not yet been studied in patients with DLBCL ineligible for full-dose R-CHOP.
Aims:To examine whether outcome of patients with untreated DLBCL unfit for full-dose R-CHOP can be improvedwith the addition of acalabrutinib to standard therapy.
Methods:We conducted an investigator initiated, prospective, randomized, open-label, multicenter, phase 3 trial(ARCHED / GLA 2022–1). Treatment in the standard arm consists of 6 cycles of R-miniCHOP every 21 daysfollowed by 2 cycles of rituximab. Patients in the experimental arm receive the same regimen combined withacalabrutinib 100 mg p.o. twice daily from day 1 to day 21 for 8 cycles. Patients are randomized 1:1 and arestratified according to IPI (0–2 vs 3–5), age group (61–80 vs 80), and ADL score (≥5 vs <5 for patients aged 61–80 and ≥6 vs <6 for patients aged >80 years).Key inclusion criteria are age >80 or >60 years and ineligibility for full-dose R-CHOP according to investigatorassessment after standardized geriatric evaluation (ADL, IADL and CIRS-G), diagnosis of untreated CD20+DLBCL, primary mediastinal lymphoma, high grade B-cell lymphoma or follicular lymphoma grade 3B. An ECOGscore of 0–2 is required for enrolment but a score of 3 is allowed if attributable to lymphoma. Key exclusioncriteria are Richter transformation, Ann Arbor stage I without bulk (≥ 7.5 cm), CNS involvement, myocardialinfarction or stroke or intracranial hemorrhage in the past 6 months and relevant organ dysfunction.The primary endpoint is investigator assessed progression-free survival (PFS). Secondary endpoints include,among others, OS, PFS per blinded independent review, outcomes according to cell of origin and moleculargenotype, response rates, toxicity.ARCHED is an academic study of the German Lymphoma Alliance and is coordinated by the Saarland UniversityClinical Trials Unit. This study is funded by AstraZeneca GmbH. The trial is approved in the EU and is open forrecruitment in Germany. (EU-CTN: 2022–501187–18–00, NCT05820841).
Results:Recruitment started in June 2023. Twenty-three patients have been recruited as of 22 February 2024 (data cutoff). Patient characteristics are shown in Table 1. Most patients were >80 years old (74%), had an ECOG scoreof at least 2 (48%) and an IPI >2 (74%). The integration of prospective simplified geriatric evaluation wasfeasible in this multicenter study, and at least one third of patients (35%) was reported to have limitations intheir activities of daily living.