Minimal Residual Disease-Guided Combination of Ibrutinib and Venetoclax Compared to FCR in Untreated Patients with CLL of Intermediate Risk : Final Results of the Eradic Trial from the Filo Group

With the emergence of targeted therapies, defining the best strategy for first-line treatment in patients with chronic lymphocytic leukemia (CLL) has become challenging. The aim of the ERADIC phase 2 trial (NCT04010968) was to compare the efficacy of a standard fludarabine-cyclophosphamide-rituximab (FCR) regimen to that of a combination of ibrutinib and venetoclax (IV), guided by measureable residual disease (MRD), in fit patients with CLL of intermediate risk defined by either unmutated IGHV status, del(11q) or complex karyotype in the absence of TP53 alteration. MRD was assessed in bone marrow (BM) or peripheral blood (PB) by flow cytometry. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with the IV combination was based on M9 BM-MRD. If it was <0.01% (uMRD) at that time, treatment was continued for 6 additional months (M15) then stopped. If M9 BM-MRD was ≥0.01%, IV treatment was continued for 18 additional months (M27). BM-MRD was reassessed at that time-point in both arms. Additionally, PB-MRD evaluation was performed every 6 months.The primary endpoint was the percentage of patients with BM uMRD at M27. Here, the final results of the study are presented.

Between September 2019 and February 2021, 120 patients were randomized 1:1 between the 2 treatment arms. Their median age was respectively of 59 [34-72] and 61 [34-74] years in the FCR and IV arms. Patient characteristics were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR ; 8.5%, 59% and 32% for IV). A del(11q) was found in respectively 20% and 24% patients in FCR and IV arms, and all patients but one had unmutated IGHV.

With a median follow-up of 42 months [range: 38– 46], 36 serious adverse events occurred in the FCR arm and 34 in the IV arm. Toxicities differed between the 2 arms with more infections and hematological toxicities due to myelosuppression (22%) and infections (40%) in the FCR arm, versus more cardiological events (23%), metabolic disorders (16%) and infections (27%) in the IV arm. Six grade 5 adverse events were reported, respectively 3 in the FCR arm (1 septic shock [M21], 1 acute myeloid leukemia [AML; M13] and 1 myelodysplastic syndrome [MDS; M24]) and 3 in the IV arm (2 sudden deaths [M7 and M12] and one COVID-19-related death at M27). In terms of secondary malignancies, in the FCR arm, squamous cell cancer, MDS, AML, colon cancer, basal cell carcinoma and lung cancer were reported while in the IV arm, liver, invasive skin, prostate, and squamous cell scalp cancers were observed as well as a bronchial carcinoma.

Treatment reduction and/or discontinuation involved 11 patients due to cardiac events (ibrutinib) and grade 4 neutropenia (venetoclax).

In terms of response (M27), complete response (CR) or CR with incomplete count recovery (CRi) rates were 53% for the FCR arm and 68% for the IV arm (p=0.097).Assessment of MRD in PB showed a statistically significant difference with 67% of PB uMRD for the FCR arm vs. 83% for the IV arm (p=0.056). BM uMRD rates were respectively of 54% and 68%, yet without reaching statistical significance.

Superiority for the IV arm was bserved in 3-year progression-free survival (PFS) at 78.5% for the FCR arm and 93% for the IV arm (p=0.029), yet without difference in overall survival (95% for both arms).

In conclusion, these final results confirm the superiority of the fixed and maximal duration of 27 months IV combination over chemotherapy, resulting in a very high PB uMRD rate and excellent 3-year PFS. Vigilance remains regarding cardiological toxicity which requires defining the best patient profile for this combination.