ASCO 2024 | The SYMPATICO trial: ibrutinib plus venetoclax in TP53-mutated MCL

This meeting, I presented the SYMPATICO study in patients with TP53 mutations. The SYMPATICO study is a phase three clinical trial that has three portions. The first one is safety running portion one, and then the randomized part with 267 patients among many international centers. And the third one was in the front line treatment. In last ASH 2023 I presented the randomized trial, showing that ibrutinib-venetoclax has prolonged period of progression free survival compared with ibrutinib plus placebo without venetoclax. And not only is the PFS was statistically significant, but also the OS, there is a trend towards prolong with the two drug therapy.

So at this ASCO meeting I presented the same trial, but only on the TP53 mutated patients. We have 74 patients altogether, which is a considerable amount of rare lymphoma, and the TP53 is only a certain percentage of that rare lymphoma. 74 patients is the largest analysis in the history of mantle cell lymphoma TP53 mutation in the literature.

Let me tell you a little bit about TP53. TP53 is a guardian gene of the genomes. If it’s mutated, then there is many mutations or errors in the replication of the cell that would go undetected that give rise to drug resistance. So it’s actually the worst prognostic factor in mantle cell lymphoma. For patients, tens of thousands of patients around the world with mantle cell lymphoma, this is the number one threat. So we geared onto this topic. We showed that the people, the patients, who were treated with ibrutinib venetoclax two oral drugs has a median PFS of 20 months. This is outstanding times. I mean, other studies show that the PFS was short and the overall survival only 1.5 years. But with a PFS of 20 months in this clinical trial, we further had the overall survival of 47 months. 47 months, as you all know is approaching 48 months, four years. And so these two drug combination is really effective.

Although they are effective made a significant contribution to overcome the TP53 mutation. However they are not totally able to overcome the whole negative impact of TP53. So those people without mutations still do better with the PFS, still do better with the overall survival. But in order to eventually overcome the full risk factor, we need not only drugs like two drug therapy like this, we need to put more modalities such as immunotherapy, radiation, CAR-T cell therapies. And this is one of the most important progress with the doublet you know, so the data is very good and encouraging the patients with this mutation.