Résumé
For chronic lymphocytic leukaemia (CLL) and intermediate risk factors (unmutated IGHV and/or 11q deletion and/or complex karyotype; no TP53 alteration), the best first-line treatment is unclear. We compared an MRD-guided, fixed-duration ibrutinib-venetoclax (IV) regimen to fludarabine-cyclophosphamide-rituximab (FCR) in this population.
The ERADIC randomised, phase 2 trial (NCT04010968), conducted at 35 French hospitals, recruited previously untreated, fit adults with intermediate-risk CLL. Randomisation was 1:1 to: 6x4-weekly cycles of FCR (Months 1–6); or ibrutinib 420 mg/day from Month 1 plus venetoclax (ramp-up to 400 mg/day from Month 4) for a duration depending on the bone marrow measurable residual disease level at Month 9 (if undetectable at a threshold of <0·01% [BM uMRD4] to Month 15; otherwise to Month 27). Primary outcome was the BM uMRD4 rate at Month 27, by assessment oligocentrally (intent-to-treat, worst-case scenario method).
Between 27 September 2019 and 31 January 2021, 120 patients were enrolled (73% male). At Month 27, the BM uMRD4 rate was 37% (22/59; 95% confidence interval [CI] 25, 51) with IV versus 13% (8/61; 95% CI 6, 24) with FCR. The high amount of missing BM MRD data, along with imbalance in missing data between arms, meant that no confirmatory statistics were performed. Best rate of BM uMRD4 plus peripheral blood uMRD5 was 47% (22/47) with IV versus 19% (8/43) with FCR (p = 0·0090). With median 43 months’ follow-up, progression-free survival was longer with IV versus FCR (estimated hazard ratio 0·35, 95% CI 0·16, 0·80, p = 0·012). By Month 27, six deaths had occurred (FCR: acute myeloid leukaemia, septic shock, myelodysplastic syndrome; IV: 2 sudden deaths, COVID-19). By the time of follow-up, the most common serious grade 3/4 events were infections and haematological toxicities with FCR, and infections and cardiovascular/metabolic toxicities with IV.
Due to the high amount of missing BM MRD data at Month 27, the primary outcome statistical analysis was not deemed feasible. The outcomes reported are secondary and exploratory, and were not been powered for in the study design. A patient profile suitable for an MRD-guided, fixed-duration IV regimen requires consideration of potential toxicities.
Abbvie and Janssen France.