The Prognostic Value of TP53 in MCL

Christian W. Eskelund, MD

Patients with mantle cell lymphoma (MCL) are associated with a poor prognosis, though strides are being made in the 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 thatTP53mutations are associated with poor outcomes. Deletions ofTP53andCDKN2Ahave shown to confer a negative impact as well.

More importantly though, investigators noted, is thatTP53mutations have an independent prognostic value in MCL. Meaning,TP53mutations have a role as a biomarker for response to standardof-care immuno-chemotherapy.

In an interview withTargeted Therapies in Oncology™ (TTO™), Christian W. Eskelund, MD, in the Department of Hematology at Copenhagen University Hospital, Rigshospitalet, in Cophenhagen, Denmark, discussed the prognostic role of TP53 mutations in patients with MCL and the importance of these findings.

TARGETED ONCOLOGY:Could you provide some background on this research?

ESKELUND: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 thatTP53was the main interest.

We looked for point mutations and small indoles using next-generation sequencing. We used a targeted panel consisting of 8 genes that have been shown to be recurrently mutated in patients with MCL. We checked for 2 other markers of deletions of larger regions of theTP53[gene] and another gene calledCDKN2A.

TARGETED ONCOLOGY: What were the significant findings from this analysis?

ESKELUND:Patients who hadTP53mutations did far worse than patients who were unmutated. We showed a median overall survival [OS] 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.

It wasn’t so surprising though.TP53is normally associated with poor outcome in most cancers, but especially in hematologic cancers. We were surprised that even though treatment works so well in younger patients with MCL, stillTP53-mutated patients do so poorly.

TARGETED ONCOLOGY: How do these findings impact the treatment landscape of MCL?

ESKELUND:Understandably, people need to feel certain that this information is valid—but we are not the only ones showing this.TP53has been associated with poor outcomes in patients with 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.

We think the data suggests that you should measureTP53mutational status upfront when you diagnose a patient with MCL, and, if there are any experimental trials, to include patients withTP53-mutated MCL. So far, these trials aren’t around, but there is a big European study called the Triangle trial that has 2 arms that include ibrutinib [Imbruvica], which has [shown a] better effect, at least in patients with chronic lymphocytic leukemia withTP53mutations. So, that is a potential option.

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

ESKELUND:The main message is thatTP53mutations 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 stem cell transplant.

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

ESKELUND: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 forTP53.

There is a Nordic trial for relapsed and refractory patients being treated with ibrutinib and lenalidomide [Revlimid] and rituximab [Rituxan]. 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.