Results from the CLL12 trial reaffirm “Watch & wait” as the standard of care for patients with early-stage asymptomatic CLL

“Watch & wait” is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukaemia (CLL). However, it remains unclear whether certain patients with specific risk factors could benefit from early targeted interventions. In this light, the results of the CLL12 trial showed that ibrutinib does not prolong survival as compared to placebo, while it is associated with relevant cardiovascular toxicity and increased susceptibility to bleeding. Considering the excellent survival rates observed in untreated patients, this study reaffirms “watch & wait” as the standard of care in this population.

“Watch & wait” is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukaemia (CLL), as chemotherapy-based interventions have failed to demonstrate a survival advantage for these patients compared to delaying treatment until disease progression. However, it remains unclear whether certain patients with specific risk factors could benefit from early targeted interventions. To address this question, the CLL12 study was initiated nearly 10 years ago to evaluate whether early-stage CLL patients with increased risk of progression would benefit from early ibrutinib treatment. Three years ago, the primary endpoint analysis was presented, demonstrating superior event-free survival (EFS) for patients receiving ibrutinib compared to those receiving placebo. At that time, overall survival (OS) was not analysed due to a lacking number of events. The updated results of this trial were recently presented at EHA 2023.

Study design

The phase III CLL12 trial included 514 patients with asymptomatic, treatment-naïve, early-stage CLL (Binet stage A). The risk of disease progression was measured using eight different factors, i.e., 17p and 11q deletions, thymidine kinase and β2-microglobulin levels, immunoglobulin heavy chain gene (IGHV) status, age, sex and ECOG performance status. In total, 151 patients with no risk were assigned to the “watch & wait” cohort, while patients with increased risk were randomly assigned (1:1) to ibrutinib (N= 182) or placebo (N= 181). The primary endpoint was event-free survival (EFS). Secondary endpoints for treatment arms included progression-free survival (PFS), time to next treatment (TTNT), OS and safety.

Results

The updated results of the CLL12 study trial  confirmed the superiority of ibrutinib over placebo in terms of EFS. In the ibrutinib group, the median EFS was not reached, while it was 51.6 months in the placebo group (HR[95%CI]: 0.276[0.188-0.407]; p< 0.001). With the longer follow-up, the median PFS was not reached  in the ibrutinib group, and was 14 months in the placebo group (HR[95%CI]: 0.174[0.122-0.246], p< 0.001). Overall response rate (ORR) was 72.5% vs. 5% in the ibrutinib and placebo groups, respectively.  However, no differences in OS were observed between the ibrutinib and placebo groups, and median OS was not reached for either of them (HR[95%CI]: 0.791[0.358-1.748]; p= 0.562). Similarly, the analysis of OS from diagnosis, which also included the “watch & wait” group, did not reveal any differences among the groups. There were 32 documented deaths, with twelve (6.6%) occurring in the ibrutinib group, fourteen (7.7%) in the placebo group, and six (3.9%) in the “watch & wait” group.  Subsequent treatment was administered to 15.9%, 43.6%, and 9.9% of patients in the ibrutinib, placebo, and “watch & wait” groups, respectively. Approximately half of the patients in both the ibrutinib and placebo groups received targeted therapy, while the other half received chemo(immuno)therapy. The median TTNT was not reached in the ibrutinib group, while it was 68.5 months in the placebo group (HR[95%CI]: 0.244[0.156-0.380]; p< 0.001).

Adverse events (AEs) were documented in 99.4% of patients in both ibrutinib and placebo arms. However, the incidence of grade 3-5 was slightly higher in the ibrutinib group (71.8% vs. 66.1% in the ibrutinib group and placebo groups, respectively). Second malignancies were the only AEs also documented in the “watch & wait" group (12.9%, 21.4% and 9.9% in the ibrutinib, placebo and “watch & wait" arms, respectively). AEs of clinical interest were observed in 80% vs. 52.4% of patients in the ibrutinib and placebo groups, respectively, with  2.4% vs. 0.6% of patients  having grade 5 AEs. AEs of clinical interest included bleeding (36.5% vs. 14.9% of patients in the ibrutinib and placebo groups, respectively), cardiac arrhythmias (22.4 vs. 9.5%), cardiac events other than arrhythmia (17.6% vs. 15.5%), diarrhoea (40.6% vs. 28.6%) and hypertensive disorders (19.4 vs. 8.3%). The main reasons for discontinuation were AEs in the ibrutinib group as compared to disease progression in the placebo group.

Conclusions

The CLL12 trial showed that, in patients with high-risk early-stage asymptomatic CLL, ibrutinib is associated with relevant cardiovascular toxicity and increased susceptibility to bleeding. Although EFS, PFS and TTNT were significantly longer for patients in the ibrutinib group, this did not translate in an improvement in OS. Furthermore, the median survival for untreated patients is excellent (>20 years). These results suggest that the “watch & wait” strategy should remain the standard of care in patients with early-stage asymptomatic CLL.

Reference

Langerbeins P, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naïve early stage chronic lymphocytic leukemia (CLL): final results of the phase 3, double-blind, placebo-controlled CLL12 trial. Presented at EHA 2023; Abstract S200.