TP53 Mutations Have Independent Prognostic Value in MCL

Christian Winther Eskelund, MD

Mantle cell lymphoma (MCL) remains a poor prognosis disease, though strides are being made in treatment for younger populations of patients.

Investigators are trying to better understand this heterogeneous disease, specifically by analyzing samples from the Nordic MCL2 and MCL3 trials, which showed TP53 mutations are associated with poor outcomes.

Deletions of TP53 and CDKN2A have shown to confer a negative impact as well. This lead to an analysis which aimed to describe the prevalence and impact of TP53 and CDKN2A deletions in DNA samples from MCL2 and MCL3 in the context of TP53 mutations.

Findings validated previous reports of poor outcome associated with both TP53 and CDKN2A deletions of young patients with MCL. After a median follow-up of 9.2 years, median overall survival was 12.4 years and progression-free survival was 8.2 years for all patients.

More importantly though, investigators noted, is that TP53 mutations have an independent prognostic value in MCL. Meaning, TP53 mutations have a role as a biomarker for response to standard-of-care immune-chemotherapy.

Could you provide some background on this research?

In an interview with OncLive at the 2017 European Hematology Association Congress, Christian Winther Eskelund, MD, Copenhagen University Hospital, Rigshospitalet, discussed TP53 mutations in MCL.Mantle cell lymphoma is a pretty rare lymphoma and has been associated with a very poor outcome. From 2000 to 2005, the Nordic MCL2 trial was conducted and showed pretty good results. During that trial, DNA was taken from patients enrolled—which is the biobank that I used for my study. Basically, we wanted to explore genetic aberrations and see if any cells were associated with poor or better outcomes. The results showed the TP53 was the main interest.

What were the significant findings?

We looked for point mutations and small indoles by next-generation sequencing. We used a targeted panel consisting of 8 genes that have been shown to be recurrently mutated in MCL. We checked for 2 other markers of deletions of larger regions of TP53 and another gene called CDKN2A.Patients who had TP53 mutations did far worse than patients who were unmutated. We showed median overall survival of patients with TP53 mutations of only 1.8 years versus the median OS of unmutated patients were above 12 years. It is a pretty big difference and outweighed all of the other known prognostic markers in MCL.

How do these findings impact the treatment landscape of MCL?

It wasn't so surprising though, TP53 is normally associated with poor outcome in most cancers, but especially hematologic cancers. We were surprised that even though treatment works so well in younger patients with MCL, still TP53 mutated patients do so poorly.Understandably, people need to feel certain that this information is valid—but we are not the only ones showing this. TP53 has been associated with poor outcomes in MCL in different cohorts. We have now validated these findings in younger patients who are treated by what is currently the standard of care in MCL.

What would you like community oncologists to take away from these findings?

Are there any other significant developments in MCL you would like to highlight?

What we think the data suggests is that you should measure TP53 mutational status upfront when you diagnose a patient with MCL, and then, if there are any experimental trials, to include patients with TP53-mutated MCL. So far, they aren’t around, but there is a big European study called the Triangle trial that has 2 arms that include ibrutinib (Imbruvica), which has [has shown a] better effect, at least in patients with CLL with TP53 mutations. So, that is a potential option.The main message is that TP53 mutations are associated with very poor outcomes in MCL, even though patients are treated very heavily with chemotherapy. We need to see if we can do something else with these patients, or even upfront treatment with allogeneic transplant. There are more clinical trials in MCL, and of course trials including novel drugs—which, in light of these mutations, I am excited to see if they have a better effect there. But so far, I don’t think people are stratifying for TP53.

There is a Nordic trial for relapsed and refractory patients being treated with ibrutinib and lenalidomide and rituximab. We have a median follow-up of 8 months—which is not a lot, but it is preliminary. But so far in that cohort, patients with TP53 mutations do the same as unmutated patients, which is encouraging. We are waiting to have a longer follow-up to see if it holds true later on, as well.

CW Eskelund, C Dahl, JW Hansen, et al. TP53 Mutations, but not deletion of TP53 and CDKN2A, have independent prognostic value in mantle cell lymphoma treated by the Nordic (MCL2 and MCL3) regimen. (Abstract release date: May 18, 2017) EHA Learning Center. Eskelund C. Jun 23, 2017; 181396.