ASH 2025 | AMPLIFY trial: how prognostic mutations impact outcomes with acalabrutinib-venetoclax in CLL

The AMPLIFY trial is a phase 3 trial. We already presented earlier the results and it’s a comparison between a combination of acalabrutinib, a second-generation BTK inhibitor, with venetoclax or acalabrutinib plus venetoclax plus obinutuzumab, the anti-CD20 antibody, and compared to immunochemotherapy, FCR or BR depending on the age and the fitness of the patient and we already showed that both AV or AVO are superior in terms of PFS compared to the chemoimmunotherapy arm but also in terms of overall survival when we look at the AV data. And also for AVO, there is an advantage in terms of overall survival if we exclude the deaths by COVID as the study was run during the COVID period. The analysis that we presented at ASH is digging a little bit more into the details of the population. So we try to define the different populations based on the genetic abnormalities they had. So unmutated or mutated immunoglobulin genes, which is the traditional marker, TP53, NOTCH1, SF3B1, ATM. And just to make a long story short, the AV and AVO can give an advantage in terms of PFS for all these subgroups of patients, regardless of the negative genetic markers they are carrying, compared to immunochemotherapy. We also presented for the first time the data of the time-to-next treatment, not PFS, not progression-free survival, but time-to-next treatment, which is very interesting because the time-to-next treatment for AV and AVO is very similar, 88-85% at three years, definitely superior to immunochemotherapy, which is around 75%, which is very interesting because in CLL what is more important is really the time-to-next treatment because when a patient progresses, they don’t need to change treatment or move to another line of treatment, but they have to wait again to meet the IWCLL criteria in order to be treated. And the interesting point here is that in the case of AV, there is a disadvantage for patients who carry unmutated immunoglobulin genes and NOTCH1. They have a shorter time to next treatment compared to the patients who don’t have NOTCH1 mutation. But if you add obinutuzumab in the triplet combination, that difference is overcome and therefore all patients benefit from the triplet association.

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