Fixed-duration acalabrutinib (Calquence) plus venetoclax (Venclexta), given with or without obinutuzumab (Gazyva), produced generally similar within-treatment safety profiles in patients younger than 65 years and those 65 years or older with treatment-naive chronic lymphocytic leukemia (CLL), according to a post hoc analysis of the phase 3 AMPLIFY trial (NCT03836261) presented in a poster session at the
Increases in adverse effects (AEs) among older patients were modest and were most pronounced in AE-related treatment discontinuations, which were driven largely by COVID-19–related events. No new safety signals were identified in either age group, and both the acalabrutinib/venetoclax (AV) and acalabrutinib/venetoclax/obinutuzumab (AVO) regimens retained a progression-free survival (PFS) benefit vs chemoimmunotherapy in patients 65 years or older.
The analysis included patients who received at least 1 dose of acalabrutinib in the AV (n = 291) and AVO (n = 284) arms. The median follow-up duration was 40.5 months (range, 0.0-58.5) and 42.3 months (range, 0.4-53.8) for patients younger than 65 years of age and 65 years of age or older, respectively, in the AV arm; the respective follow-ups were 41.1 months (range, 1.9-57.7) and 42.2 months (range, 0.5-57.1) in the AVO arm.
Any-grade AEs occurred at generally similar frequencies across age and treatment groups, affecting 93.8% of patients younger than 65 years and 90.7% for those 65 years or older in the AV arm; these respective rates were 96.5% and 93.0% in the AVO arm. Grade 3 or higher AEs and serious AEs (SAEs) were numerically higher in the AVO arm than in the AV arm and among older patients compared with younger patients. In the AV arm, grade 3 or higher AEs occurred in 51.0% of patients in the younger subgroup vs 58.8% of patients in the older group. In the AVO arm, these respective rates were 67.2% and 74.4%. SAEs were reported in 23.7% and 26.8% of patients in the AV arm, respectively, and 36.4% and 43.0% of patients in the AVO arm, respectively.
SAEs with a fatal outcome were numerically more frequent among patients 65 years of age or older and in the AVO arm, occurring in 2.6% and 5.2% of patients younger than 65 years and 65 years or older in the AV arm, respectively, vs 3.5% and 11.6% of patients in the AVO arm, respectively. These events were largely COVID-19–related; SAEs of COVID-19–related pneumonia led to death in 2.6% of younger patients treated with AV, 4.1% of older patients treated with AV, 2.5% of younger patients treated with AVO, and 5.8% of older patients treated with AVO. The respective rates of COVID-19 SAEs were 1.0%, 0%, 1.0%, and 3.5%.
“The results suggest that AV and AVO are treatment options with manageable safety profiles for both patients aged less than 65 years and at least 65 years with previously untreated CLL,” lead study author John F. Seymour, MBBS, PhD, and colleagues wrote in a poster presentation of the data.
Seymour is director of Clinical Haematology of The Royal Melbourne Hospital and the Peter MacCallum Cancer Centre in Australia.
Prior results from AMPLIFY
AMPLIFY was a randomized, phase 3 study that evaluated fixed-duration AV or AVO vs investigator’s choice of chemoimmunotherapy (fludarabine, cyclophosphamide, and rituximab [Rituxan]; or bendamustine plus rituximab) in patients with treatment-naive CLL.1
In the experimental arms, acalabrutinib and venetoclax were administered for approximately 14 months; in the AVO arm, intravenous obinutuzumab was given during the first 6 months.
For this post hoc analysis, descriptive statistics were used to evaluate the frequency of AEs and AEs leading to treatment discontinuation among patients younger than 65 years or 65 years or older who received AV or AVO. Dose modifications encompassed dose withholding and dose reductions. Acalabrutinib and venetoclax dose withholding was defined as missing a dose for at least 7 consecutive days, and obinutuzumab dose withholding was defined as missing at least 1 scheduled infusion per protocol-specified treatment course. The safety population comprised as-treated patients who received at least 1 dose of any study drug in the experimental arms.
Discontinuation of any treatment due to a treatment-emergent AE (TEAE) increased with age and was more frequent with AVO. In the AV arm, 5.7% of younger patients and 12.4% of older patients discontinued any treatment due to a TEAE, compared with 14.6% and 32.6% of patients, respectively, in the AVO arm; COVID-19 and COVID-19–related pneumonia were the most common reasons for discontinuation.
Dose withholding and dose reductions of acalabrutinib and venetoclax were also numerically more common among older patients. Among events of clinical interest, the frequencies of thrombocytopenia and leukopenia were higher with AVO than with AV; cardiac AEs were low overall, with low-grade palpitations the most common, and rates of atrial fibrillation and ventricular arrhythmia were low.
Despite the modest increases in grade 3 or higher AEs, SAEs, and AE-related discontinuations with AVO, both experimental regimens improved progression-free survival (PFS) vs chemoimmunotherapy in patients 65 years or older (AV vs chemoimmunotherapy: HR, 0.47; 95% CI, 0.29-0.76; AVO vs chemoimmunotherapy: HR, 0.47; 95% CI, 0.28-0.79).
Among patients younger than 65 years, PFS benefits were also observed vs chemoimmunotherapy for AV (HR, 0.84; 95% CI, 0.58-1.22) and AVO (HR, 0.42; 95% CI, 0.27-0.64).
