AMPLIFY: fixed-duration acalabrutinib plus venetoclax, with or without obinutuzumab, versus chemo-immunotherapy in fit CLL patients
In AMPLIFY, an all-oral, 14-month course of acalabrutinib plus venetoclax beat FCR or BR chemo-immunotherapy in fit CLL patients, offering a time-limited alternative to indefinite pills.
AMPLIFY randomised 867 fit, previously untreated patients with CLL without del(17p) or TP53 mutation to acalabrutinib plus venetoclax (AV), acalabrutinib plus venetoclax plus obinutuzumab (AVO), or investigator's choice of FCR or bendamustine-rituximab. The primary endpoint was PFS for AV versus chemo-immunotherapy. Estimated 36-month PFS was 76.5% with AV, 83.1% with AVO and 66.5% with chemo-immunotherapy (hazard ratios 0.65 and 0.42 respectively). Overall survival favoured AV, driven largely by deaths from COVID-19 in the chemo-immunotherapy arm during the pandemic. AVO produced the deepest MRD responses but more infections and neutropenia.
- 867 fit patients without TP53 aberration; 14 cycles of AV or AVO vs 6 cycles of FCR or BR.
- 36-month PFS: 76.5% (AV), 83.1% (AVO), 66.5% (chemo-immunotherapy); HR 0.65 for AV and 0.42 for AVO vs chemo-immunotherapy.
- Overall survival better with AV than chemo-immunotherapy, but many chemo-immunotherapy deaths were from COVID-19.
- Undetectable MRD rates were highest with AVO; AV produced a lower MRD-negativity rate than AVO or venetoclax-obinutuzumab in other trials.
- Grade 3 or higher neutropenia and infections were more frequent with AVO than AV.
AMPLIFY delivered the first all-oral, fixed-duration doublet for front-line CLL and supported its approval, giving fit patients a way to avoid both chemotherapy and years of continuous BTK inhibitor. It does not settle whether a doublet or triplet is best, or how AV compares with venetoclax-obinutuzumab. Patients with TP53 aberration were excluded and still need different strategies.
- Chemo-immunotherapy is no longer the preferred comparator in many countries; the relevant question is AV versus venetoclax-obinutuzumab or continuous BTKi.
- The OS signal is confounded by pandemic-era deaths.
- Excluded del(17p)/TP53-mutated patients.
- AV MRD-negativity was lower than with AVO; long-term durability is still maturing.