The triplet combination of acalabrutinib, venetoclax and obinutuzumab (AVO) was recently established as a front-line standard-of-care (SOC) for patients with chronic lymphocytic leukaemia (CLL), based on the AMPLIFY trial.1 However, patients with TP53 aberration were excluded in AMPLIFY, since the selected chemoimmunotherapy control arm is not SOC for this patient population. The effect of AVO in patients with CLL with TP53 aberration therefore remained unknown. The first efficacy and safety results of AVO in this patient population have now been reported.2
Methods:
This single-arm, investigator-sponsored, multicentre, phase II study initially enrolled patients with treatment-naïve CLL with any genetic risk profile (cohort 1). Based on early results, the study was expanded with a second cohort with exclusively patients with TP53 aberrations.
Patients initially received AVO combination therapy for 15 cycles of 28 days in the following sequence: acalabrutinib (A) through-out, obinutuzumab (O) during cycles two to seven, and venetoclax (V) during cycles four to fifteen. Treatment duration was guided by measurable residual disease (MRD). Patients that achieved complete remission (CR) with undetectable MRD in the bone marrow (BM-uMRD) at the start of cycle 16 were allowed to discontinue treatment. Patients that did not achieve criteria for cessation remained on A + V for another 9 cycles. At the start of cycle 25, patients could discontinue therapy if they had BM-uMRD and at least partial remission. MRD-positive patients continued A + V until progression or unacceptable toxicity.
The primary end point was prespecified as achieving CR with BM-uMRD in 55% of patients with TP53 aberration at the start of cycle 16.
Results:
In total, 45 of the 72 enrolled patients (63%) with CLL had TP53 aberration. Of them, 10 patients were included in the initial cohort and 35 patients were enrolled in the expanded cohort. At data cutoff, median follow-up was 55.2 months in cohort 1 and 38.5 months in cohort 2.
The CR with BM-uMRD rates at the start of cycle 16 were 42%, regardless of TP53 status. The BM-uMRD rates were 71% and 78% in patients with TP53 aberration and all-comers, respectively. The best overall response rate, best rate of CR with BM-uMRD, and best rate of BM-uMRD at any time on study for patients with TP53 aberration was 98%, 58%, and 80%, respectively.
Four-year progression-free survival (PFS) was 70% and 96% in patients with and without TP53 aberration, respectively. Four-year OS was 88% in patients with TP53 aberration and 100% in patients with wild-type TP53.
In total 24% of patients had a serious grade ≥3 adverse event (AE). Haematologic toxicities were mainly low grade, with grade ≥3 neutropenia occurring in 36% of patients. Cardiovascular toxicities were infrequent: hypertension was the most common cardiac AE (11% any grade, 10% grade ≥3), while any-grade and grade ≥3 atrial fibrillation were reported in respectively 6% and 3% of patients.
Conclusion
While the prespecified primary endpoint was not met, AVO with MRD-guided therapy duration was well tolerated and highly active in terms of BM-uMRD rates and 4-year PFS in patients with aberrant TP53. These results complement the data reported on TP53 wild-type patients in the AMPLIFY study and support AVO as a new SOC option for front-line therapy of CLL patients, regardless of their TP53 status.
References
Top
