TP53 Predicts Poorer Survival in Mantle Cell Lymphoma

Christian Winther Eskelund, MD

Multivariate analysis of the Nordic MCL2 and MCL3 trials showed that the presence of TP53 mutations predicted worse overall survival (OS) in younger patients with mantle cell lymphoma (MCL).

Patients with TP53 mutations had a median overall survival (OS) of 1.8 years, a median PFS of 0.9 years, and a median time to relapse of 1.0 year. This compared to not reached, 10.2 years, and 12.3 years, respectively, in patients not harboring TP53 mutations.

In TP53-deleted patients, median OS was 8.0 years, and PFS and time to relapse were both 3.1 years.

TP53 mutations were an independent predictor for poorer OS (hazard ratio [HR], 6.2; P <.0001). MIPI-c high-risk was an independent predictor for time to relapse (HR, 2.6; P = .003).

“TP53-mutated MCL 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 transplant],” first author Christian W. Eskelund, MD, Copenhagen University Hospital, Rigshospitalet, and coinvestigators wrote. “Thus, we suggest stratification of MCL patients according to TP53 mutational status and inclusion in separate clinical trials exploring novel targeted agents.”

Investigators reviewed data collected in Nordic MCL2 (2000-2005) and Nordic MCL3 (2005-2009). All patients included in this analysis (N = 319) were treated with an intensified frontline regimen that included cytarabine, rituximab (Rituxan), and consolidation with high-dose therapy and autologous stem-cell transplant. Patients with available minimal residual disease (MRD) marker were monitored during follow-up and treated preemptively with rituximab upon MRD-positivity without concurrent clinical relapse.

Median age was 57 years (range, 29-65), 76% of patients were male, 51% were MIPI high- or intermediate-risk, 18% had blastoid morphology, and 41% had Ki67 ≥30%.

Investigators performed genomic studies on diagnostic bone marrow samples from 183 patients. Of these, deletions were analyzed in 177 patients, mutations in 176, and both in 170.

Of patients with TP53 mutations, 19 carried 1 mutation, while 1 patient carried 2. Of the 21 detected mutations, 16 were missense mutations in the DNA binding domain.

At a median follow-up of 9.2 years for all 319 patients, median OS was 12.5 years and median PFS was 8.2 years. Half of all patients had relapsed at 10.2 years. Investigators found that blastoid morphology, Ki67 ≥30%, and higher MIPI and MIPI-c risk groups were significantly more likely to experienced poorer outcomes. There was no difference in outcomes among patients with or without bone marrow involvement by morphological review.

Investigators found deletions of CDKN2A were detected 20% of patients, deletions of TP53 in 16%, and both deletions were detected in 7%. In total, deletion of either gene was detected in 30% of patients. The applied method did not discriminate between homo- and heterozygous deletions.

By targeted sequencing of 8 genes recurrently mutated in MCL, investigators detected a total of 154 mutations in the 176 patient samples examined. The most commonly mutated genes were ATM (27%), KMT2D (14%), TP53 (11%), and CCND1 (9%). Just over half of patients carried at least 1 mutated gene and 19% carried <1 mutated gene.

While only TP53 mutations showed independent prognostic impact for OS, both TP53 mutations (HR, 6.8; P <.0001) and MIPI-c high-risk (HR, 2.2; P =.01) were predictors for progression-free survival (PFS). Similarly, TP53 mutations (HR, 6.9; P <.0001) and MIPI-c high-risk (HR, 2.6; P =.003) were also independent predictors for cumulative incidence of relapse.

Combining TP53 mutations and deletions in the multivariate analyses also showed significant prognostic value for OS (HR, 3.1; P = .0004), PFS (HR, 2.8; P <.0001), and cumulative incidence of relapse (HR, 3.1; P <.0001). Inclusion of the combined NOTCH1 and NOTCH2 mutations did not change the multivariate results. MIPI high-risk and Ki67 ≥30% included as separate values did not show independent prognostic value.

The presence of TP53 mutations was significantly associated with NOTCH1 mutations (P = .0002), deletions of CDKN2A (P = .0002), and TP53 deletions (P = .001).

Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemotherapy [published online August 17, 2017]. Blood. doi: 10.1182/blood-2017-04-779736.