|BTK inhibitors in elderly chronic
lymphocytic leukaemia patients
|Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia in adults. B-cell receptor signalling plays a key role in driving tumorigenesis, and inhibition of Bruton’s tyrosine kinase (BTK) has shown to be an effective targeted therapy in pre-clinical settings and small-cohort clinical trials. Currently, the standard approach to elderly CLL patients (>65 years old) is chemoimmunotherapy with either chlorambucil (a cytotoxic agent) plus obinutuzumab (an anti-CD20 antibody triggering cell death), or bendamustine (a cytotoxic agent) plus rituximab (an anti-CD20 antibody).
In order to test whether ibrutinib (an irreversible BTK inhibitor) in treating CLL patients is superior to the standard regimen, or has synergic effects to the current approach, Dr. Woyach and colleagues conducted this phase 3 trial (here in NEJM). Elderly patients (>65 years old) with untreated CLL were recruited in the trial. Patients were treated with 28-day cycles. A total of 183 patients were randomly assigned to the bendamustine plus rituximab group, receiving 6 cycles of bendamustine (90 mg/m2, on days -1 and -2 of each cycle) and rituximab (375 mg/m2 on day -1 of cycle 1, and 500mg/m2 at the day starting of each cycle through cycle 2 to 6). A total of 182 individuals were randomly assigned to the ibrutinib group, receiving ibrutinib at a dose of 420 mg daily. Patients in the ibrutinib plus rituximab (182 patients) were treated with 6 cycles of ibrutinib before co-administration and rituximab at a dose of 375 mg/m2 for 4 weeks. Patients were balanced at baseline including unmethylated ZAP70 statues as a surrogate for IgVH-unmutated disease status, modified Rai stages, del(17p13.1), and del(11q22.3) among other variables. The primary end point was progression-free survival.
Only the bendamustine plus rituximab group reached median progression-free survival. The progression-free rate at 2 years was estimated to be 74% in the bendamustine plus rituximab group, with respect of 87% in the ibrutinib group and 88% in the ibrutinib plus rituximab group. No difference of overall survival among the three groups was observed. The rate of grade 3, 4, or 5 hematologic adverse events was higher in the bendamustine plus rituximab group (61%) than the ibrutinib group (41%) and the ibrutinib plus rituximab group (39%). The rate of grade 3, 4, or 5 non-hematologic advert events in the bendamustine plus rituximab was lower than the other two groups (63% v.s. 74%).
Treatment with ibrutinib is superior to that with bendamustine plus rituximab, but has no synergic effects when combined with rituximab in terms of progression-free survival and hematologic adverse event incidence.
This study was supported by both the National Cancer Institute and a pharmaceutical company.