Patients with TP53-mutated mantle cell lymphoma have ‘dismal’ outcomes

TP53 mutations identify a “phenotypically distinct and highly aggressive” type of mantle cell lymphoma that does not respond to conventional therapies, researchers in Denmark reported.

“Historically, mantle cell lymphoma was associated with a dismal outcome with a median OS of only 3 to 5 years; however, during the past decades the outcome for especially younger patients has improved substantially by an intensified frontline regimen including cytarabine, rituximab and consolidation with high-dose therapy and autologous stem-cell transplant,” Kirsten Grønbaek, MD, DMSc, of the department of hematology at Rigshospitalet in Copenhagen, and colleagues wrote. “Despite this marked improvement, mantle cell lymphoma remains an incurable albeit heterogeneous disease with a wide span of early and late relapses. However, none of the existing risk stratification systems have yet been incorporated into clinical decision-making.”

The researchers evaluated recurring genetic aberrations in bone marrow specimens from 183 patients who participated in mantle cell lymphoma trials between 2000 and 2009. All of the patients were aged younger than 66 years, and all had stage II, III or IV disease. All were fit for autologous stem-cell transplantation.

Grønbaek and colleagues performed targeted sequencing of eight genes recurrently mutated in mantle cell lymphoma, identifying 154 mutations from 176 samples. ATM was the most frequently mutated gene (27%), followed by KMT2D (14%), TP53 (11%) and CCND1 (9%). The majority of patients (51%; n = 90) had at least one mutated gene, with 19% (n = 33) carrying more than one.

Mutations of TP53 and NOTCH1 (4%), as well as deletions of TP53 (16%) and CDKN2A (20%) were associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology and Ki67 > 30%) in a univariate model. However, multivariate analysis showed that only TP53 mutations impacted OS (HR = 6.2; P < .0001). Furthermore, TP53 mutations (HR = 6.9; P < .0001) and MIPI-c high risk (HR = 2.6; P = .003) both had “independent prognostic impact on time to relapse.”

Patients with TP53 mutations had a “dismal” outcome, the researchers wrote, with 50% relapsing at 1 year and a median OS of 1.8 years. Significant associations appeared between TP53 mutations and Ki67 greater than 30%, blastoid morphology, MIPI high risk and poor responses to both induction and high-dose chemotherapy.

“We show that TP53-mutated mantle cell lymphoma represents a phenotypically distinct and highly aggressive disease entity with poor or no response to the high-dose regimens including cytarabine, rituximab and autologous stem-cell transplantation,” the researchers wrote. “Thus, we suggest stratification of mantle cell lymphoma patients according to TP53 mutational status and inclusion in separate clinical trials exploring novel targeted agents.” – by Andy Polhamus

Disclosures: Grønbaek reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.