Abstract
Introduction. In the CLL8 trial for treatment-naïve patients with CLL, the FCR group had a PFS of 56.8 months compared with 32.9 months in the FC arm. IGHV-mutated patients had most benefit from FCR. However, chemoimmunotherapy is less effective with negative impact on PFS and OS in patients with unmutated IGHV, mutated TP53 and del(17p), del(11q), and some gene mutations such as NOTCH1, SF3B1, and BIRC. Adding ibrutinib to the FCR program with a two-year course of ibrutinib resulted in durable deep responses in patients with various genetic markers, in particular unmutated IGHV variants CLL. The combination of ibrutinib and venetoclax resulted in further increases in overall response rates, PFS, and OS. The 1-year progression-free survival and overall survival were 98% and 99% respectively. Responses were observed in all high-risk subgroups, regardless of change in IGHV alterations, FISH category, TP53 mutations, NOTCH1 mutations, and SF3B1 mutations. However, in most studies, targeted therapy was predominantly administered over a long period of time, which leads to increased toxicity and financial burden. Currently, most research is moving towards the concept of stop therapy in the treatment of CLL.
Aim. To evaluate the efficacy and safety of a time-limited treatment strategy, FCR with ibrutinib with/without venetoclax, in previously untreated patients with CLL in a multicenter study.
Materials and methods. Previously untreated CLL patients received 3 to 6 cycles of FCR (standard dose) in combination with ibrutinib 420 mg (n = 11) or ibrutinib 420 mg and venetoclax 200 mg (n = 19) for each cycle. After completion of the entire treatment program, PET/CT was performed and minimal residual disease was assessed using multicolor flow cytometry.
Results. A total of 30 patients (median age group: 52.6 years [range: 29–77 years]; 78% male) were enrolled in the study from 2020 to 2025. Genetic abnormalities included unmutated IGHV gene (69%, 23/30), TP53 deletion (30%, 3/10), ATM deletion (20%, 2/10), RB1 deletion (40%, 1/10), trisomy 12 (10%, 1/10), TP53 mutation (20%, 2/10) and SF3B1 mutation (100%, 2/2). Among patients who completed induction therapy, the overall response rate (ORR) was 100%, complete remission with negative MRD status (peripheral blood + bone marrow) and complete metabolic response was 100%. The average follow-up period was 19 (1-48) months. The median PFS and OS were not reached. PFS and OS rates were 100% and 100%, respectively.
Conclusion. The first experience with the FCR-I/I-Ven regimen demonstrated the achievement of rapid clearance of minimal residual disease in a CLL patient. No significant differences in PFS or OS were observed between the IGHV mutation/non-mutation or TP53 deletion/mutation subgroups. In addition, the use of the stop therapy concept allows to reduce the financial burden. Besides, in case of relapse, ibrutinib and venetoclax can be used as retreatment. The addition of obinutuzumab to the FC regimen is promising due to its superior results over rituximab.
