TP53, KMT2D Abnormalities Linked With Poor Prognosis in MCL

Disruption of the TP53 gene and mutation of the KMT2D gene are predictive of poor outcomes in patients with mantle cell lymphoma (MCL) who are receiving high-dose therapy, according to a new study.

The findings, which build upon growing knowledge of the genetics of MCL, can be used to better classify patients into risk categories, the investigators said. The study was published in the journal Haematologica.¹

Corresponding author Simone Ferrero, MD, of the University of Torino, in Italy, noted that the current treatment paradigm for patients with MCL—cytarabine-based chemotherapy followed by autologous stem cell transplantation (ASCT)—has led to dramatic advancements in the outcomes of patients who are young and healthy enough for the therapy. However, Ferrero said as many as one-quarter of those patients will experience early treatment failure.

So far, the best tool clinicians have had to identify patients at high risk of relapse has been the MCL international prognostic index (MIPI), and the Ki-67 proliferation index. The combination of the 2 is known as the MIPI-c score. Although the tool is of value, Ferrero and colleagues asserted that the resulting scores lack the precision necessary to develop tailored schedules specifically for high-risk patients.

In an effort to better elucidate the factors associated with a high risk of failure, the investigators used samples from the phase III FIL-MCL0208 trial, which is a prospective, open-label, multicenter study designed to evaluate lenalidomide (Revlimid) as a maintenance therapy versus observation in patients in MCL remission following high-dose chemotherapy including rituximab (Rituxan) followed by ASCT (NCT02354313).

Ferrero and colleagues performed targeted resequencing and DNA profiling on purified tumor samples of the patients in the study. Out of 300 patients enrolled in the study, samples from 186 patients were able to be evaluated for genetic mutations and abnormalities in copy numbers.

The analysis confirmed earlier reports^2,3 that TP53 disruption is a significant prognostic factor. After 4 years, patients with mutations or deletions of TP53 had lower progression-free survival (PFS) and overall survival (OS) rates compared with patients without the disruptions.

However, the authors broke new ground by identifying KMT2D as another important genetic factor. In wild-type cases, those with KMT2D mutations had PFS rates of just 33.2%, versus 63.7% in those without the mutation after 4 years (P <.001). Overall survival was similarly affected; the 4-year OS rate among patients with KMT2D mutations was 62.3% versus 86.8% among those without the mutation (P = .002).

“In the FIL-MCL0208 trial, KMT2D mutations emerged as a novel biomarker heralding chemo-immunotherapy failure, with a predictive value similar to that of TP53 aberrations,” Ferrero and colleagues wrote.

The authors then used their findings to create a new scoring system to identify patients at the highest risk.

“The independent adverse prognostic value of TP53 and KMT2D aberrations prompted us to integrate the molecular results into the MIPI-c, aiming at further improving its ability to discriminate high-risk patients,” the authors said.

The model begins with MIPI-c score; those with low or intermediate risk scores under MIPI-c were given 0 points in the new model, and those placed in the high-risk category by the MIPI-c model were given one point. In addition, patients with TP53 disruptions were given 2 additional points, as were those with the KMT2D mutation. In this new scoring system, which the investigators dubbed “MIPI-g,” patients with a score of 0 were deemed “low risk,” patients with scores of 1 to 2 were deemed “intermediate risk,” and patients with scores of 3 or higher were categorized as “high risk.”

When investigators performed PFS and OS calculations based on their risk categories, they found PFS rates varied dramatically among the groups, from 72.0% in the low-risk group to 11.5% in the high-risk group after 4 years (P <.0001). Four-year OS rates similarly dropped from 94.5% in the low-risk group to 44.9% (P <.0001). Among patients in the intermediate group, the 4-year PFS rate was 42.2% and the OS rate was 65.8%.

In the Nordic validation series, patients with KMT2D mutations showed similar worse outcomes compared with wild-type patients (median OS, 8.4 vs 12.7 years). Among patients with TP53 mutations, the median OS was 2.0 years compared with 12.7 years for patients with wild-type TP53. The validation series also showed similar 4-year OS rates by risk groups: 91.3% for low-risk patients, 72.2% for intermediate risk, and 15.4% for high risk.

Among the study’s limitations, the authors noted that their analysis was performed only on CD19-positive bone marrow cells. The investigators also said they do not yet have sufficient randomization data to know whether and to what extent lenalidomide maintenance affected the patients with these mutations within the broader FIL-MCL0208 trial. However, they said it is unlikely that full data will be able to offer clear takeaways, since only 27 patients with the TP53/KMT2D mutations were finally randomized in the study, due to a high rate of progressive disease among these patients. Of those 27, only 9 were started on lenalidomide maintenance.

In their conclusion, Ferrero and colleagues said that the ability to distinguish the highest-risk patients could be used by clinicians to identify high-risk patients for novel therapeutic approaches.

“As in other lymphoid disorders, novel non-chemotherapeutic strategies specifically designed for [high-risk] patients need to be investigated in MCL,” the authors said. “Besides the approved drugs lenalidomide and ibrutinib [Imbruvica], new molecules such as the BCL-2 inhibitor venetoclax [Venclexta] might be very promising for these chemorefractory patients, especially for TP53 disrupted cases.”

_References:

_{1. Ferrero S, Rossi D, Rinaldi A, et al. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study. Haematologica. 2020;105(6):1604-1612. doi:10.3324/haematol.2018.214056}

_{2. Nordström L, Sernbo S, Eden P, et al. SOX11 and TP53 add prognostic information to MIPI in a homogeneously treated cohort of mantle cell lymphoma--a Nordic Lymphoma Group study. Br J Haematol. 2014;166(1):98-108. doi:10.1111/bjh.12854}

_{3. Halldórsdóttir AM, Lundin A, Murray F, et al. Impact of TP53 mutation and 17p deletion in mantle cell lymphoma. Leukemia. 2011;25(12):1904-1908. doi:10.1038/leu.2011.162}