Ibrutinib plus venetoclax with MRD-directed duration of treatment as a potential novel standard of care for previously untreated CLL
Data from the phase III FLAIR trial demonstrated that the BTK inhibitor ibrutinib in combination with the BCL2 inhibitor venetoclax with a minimal residual disease (MRD) directed treatment duration significantly improved progression-free survival (PFS) and overall survival (OS) compared with the chemotherapy regimen fludarabine, cyclophosphamide, and rituximab. These results indicate that directing the treatment duration according to individual MRD responses maximizes outcomes.
The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemo-immunotherapy. Whether the ibrutinib–venetoclax combination and personalisation of treatment duration according to measurable residual disease (MRD) is more effective than the fludarabine–cyclophosphamide–rituximab (FCR) regimen is unclear and was assessed in the phase III FLAIR study.
Study design
FLAIR is a multi-centre, randomised, open-label phase III trial conducted in the United Kingdom, enrolling untreated CLL patients aged 18-75 years. Patients with >20% 17p deleted cells were excluded. Initially, patients were randomised to treatment with ibrutinib (420 mg/day for up to 6 years) and rituximab (375 mg/m2 IV on day 1 of cycle 1 and 500 mg/m2 IV on day 1 of cycles 2-6) or chemo-immunotherapy with fludarabine (24 mg/m2 oral per day), cyclophosphamide (150 mg/m2 oral per day on days 1-5) and rituximab. In 2017, two groups were added, namely treatment with ibrutinib alone and treatment with ibrutinib and venetoclax. In the latter group, participants were first treated with ibrutinib for two months, after which venetoclax was added and increased to a dose of 400 mg/day over 4 weeks. The duration of treatment with ibrutinib and venetoclax was up to six years and dependent on MRD status. MRD status in peripheral blood was assessed at 12 months and every 6 months thereafter. If MRD status was negative (<1 CLL cell per 104 cells), assessment was repeated at 3 months and 6 months in peripheral blood and bone marrow. If all were MRD negative, the duration of treatment with ibrutinib and venetoclax was double the time between the start of treatment and the initial MRD negative peripheral blood (treatment duration: 2-6 years). The primary outcome measure was investigator-assessed progression-free survival (PFS).
Results
In total, 523 patients were randomised to ibrutinib-venetoclax (N= 260) or FCR (N= 263). Among participants, 71.3% were male, median age was 62 years (31.2% > 65 years), and 42.1% were at Binet Stage C. Based on the MRD discontinuation rules, 49.9% of patients had stopped treatment with ibrutinib and venetoclax at 27 months, 63.1% of patients at 39 months, and 72.9% of patients at 51 months. After a median follow-up of 43.7 months, disease progression had occurred in 12 patients in the ibrutinib-venetoclax group and in 75 patients in the FCR group (HR[95% CI]: 0.13[0.07-0.24], p< 0.0001). The 3-year PFS was 97.2% with ibrutinib-venetoclax and 76.8% with FCR. After a median follow-up of 43.0 months, 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group had died (HR[95% CI]: 0.31[0.15-0.67], p= 0.0029). The 3-year OS rate was 98.0% in the ibrutinib-venetoclax group and 93.0% in the FCR group.
Serious adverse events (SAEs) were reported by 123 patients in the ibrutinib-venetoclax group and 129 patients in the FCR group. Notable SAEs were: infections (22.2% vs. 18.8%), blood and lymphatic disorders (5.0% vs. 31.0%), and cardiac disorders (10.7% vs. 0.4%). The incidence of other cancers per 100 patient-years was greater for FCR than for ibrutinib plus venetoclax (5.4 vs. 2.6). There were 8 cases of MDS/AML with FCR and 1 with ibrutinib plus venetoclax. There were 31 deaths reported, 7 of which were treatment-related (1 in the ibrutinib-venetoclax arm and 6 in the FCR arm).
Conclusion
Ibrutinib plus venetoclax significantly improved responses, progression-free and overall survival compared to FCR in fit patients with previously untreated CLL. More patients achieve an MRD negative remission with ibrutinib plus venetoclax, than with FCR. The ibrutinib-venetoclax combination was well tolerated, with no unexpected toxicities. These results indicate that directing the treatment duration according to individual MRD responses maximizes outcomes.
Reference
Hillmen P, et al. Ibrutinib plus venetoclax with MRD-directed duration of treatment is superior to FCR and is a new standard of care for previously untreated CLL: report of the phase III UK NCRI FLAIR. Presented at ASH 2023; Abstract 631.
