Long-Term Data Highlight Poor Prognosis With TP53-Mutant MCL

Patients with mantle cell lymphoma (MCL) who harbor a TP53 mutation demonstrated a median overall survival (OS) of approximately 4 years compared with patients with wild-type tumors whose median OS had not yet been reached, suggesting that the presence of TP53 mutations directly correlate with OS, according to a 10-year analysis presented at the 2019 European Hematology Association Congress.

TP53 mutations are identified in approximately 15% to 20% of patients with MCL, either through Sanger sequencing or next-generation sequencing (NGS). In the 10-year single-institution analysis, 29 patients with MCL were observed. Data on patient demographics, staging, treatment, risk status, and response to treatment were collected from the institution's lymphoma database. A total 83% of these patients were treated with standard frontline chemoimmunotherapy, and 20% of patients harbored a TP53 mutation.

Additional data from the analysis showed that the overall response rate in the TP53-mutant subgroup was 79%, which included a 55% complete response rate and a 24% partial response rate.

In an interview with OncLive, Ezzat Elhassadi, MD, a consulting hematologist at University Hospital Waterford, discussed the results from this analysis and how the presence of a TP53 mutation can correlate with survival outcomes in patients with MCL.

OncLive: How often are TP53 mutations observed in patients with MCL?

Elhassadi: The TP53 mutation confers a dismal prognosis in MCL with a reported incidence of 15% to 20% (blastoid, 29% vs classical, = 6%). These are detected by Sanger sequencing or, more recently, with NGS on the tumor DNA.

What were the methods of design for this 10-year analysis?

Elhassadi: Our cancer center's pathology department database was used to identify consecutive consented patients who were diagnosed with MCL over the study period, from 2006 to 2016, and this project was approved by our ethical committee. The patients' demographic, staging, treatment, and response to treatment, as well as their MCL International Prognostic Index (MIPI) score, were obtained from our lymphoma database and clinical records. Response to treatment was defined by original Cheson criteria. The study was carried out to examine the impact of TP53 mutational status using Sanger sequencing or NGS on treatment outcome in our cohort. Also, to correlate the p53 expression using immunohistochemistry (IHC) with mutational status.

What were your findings?

The median age was 65 years with male predominance (72%), and the majority of patients had advanced disease (90%) with a high MIPI score in 60% of the cases. Additionally, 9% of patients had a prior history of an indolent leukemic subtype, which evolved subsequently to aggressive disease requiring intervention. Thirteen patients (59%) had mutated IGHV, 9 with unmutated genes (41%), and there was no residual tissue in the remaining patients.

p53 overexpression (>30%) was seen in 6 samples (21%). Sanger sequencing detected TP53 mutations in only 3 samples (10%). The remaining samples were subjected to NGS to overcome Sanger sequencing sensitivity limitations. Interestingly, NGS analysis revealed the presence of mutations in all 6 samples (100%), confirming the existence of subclones beyond Sanger sequencing detection sensitivity.

In contrast, in all of the samples with low p53 expression, sequencing confirmed wild-type TP53 status, which was suggestive of high negative predictive values and higher sensitivity of IHC. These findings are reflective of a strong correlation between p53 expression by IHC and mutation status.

Sequencing analysis for all samples (n = 32) confirmed the presence of a deleterious mutation in 6 samples (21%), which is comparable with reported literature. For the entire cohort, the median OS was 6.5 years, and progression-free survival (PFS) was 3 years.

Most MCL cases harboring TP53 mutations have an aggressive disease course with multiple disease relapses and lymphoma-related deaths (80%). In subset analyses, the OS was only 4 years in TP53-mutated disease and was not reached in the wild-type TP53 cohort (P = .007, log rank test), which is comparable to the reported data.

How can these findings be used to better treat patients with TP53-mutated MCL?

Elhassadi: These findings highlight the importance of the acquisition of TP53 mutations in MCL and an unmet clinical need in these subtypes of MCL. The findings also bring [up a need for] clinical trials to focus on upfront novel agents for such high-risk variants.

The increasing number of therapeutic options is opening up new perspectives, like BCR inhibitors, BCL-2 inhibitors, and immunotherapy for patients with MCL, but the evaluation of these approaches will require correct stratification of the patients according to the specific biological risk of their disease. Therefore, introducing p53 expression evaluation in routine practice and streamlining the TP53 mutation screening process in MCL prior to initiation of treatment is of paramount importance in the era of novel, effective, but costly treatments for patients with MCL.

What challenges still exist in the treatment paradigm of MCL?

Although MCL usually responds well to initial treatment, many of these responses are not durable and relapse is inevitable. Individual heterogeneity in clinical behavior is still encountered, ranging from primary refractory disease to a PFS of 7 years.

Despite a significant improvement in disease outcomes achieved by the addition of rituximab (Rituxan) and high-dose cytarabine to chemotherapy regimens, and consolidation with allogeneic stem cell transplant, which is considered to be the current standard of care for younger patients; this approach does not solves the problem of TP53 disruption for patients with MCL. In addition, elderly or unfit patients with MCL will not be eligible for such an approach.

There is no standard second-line chemotherapeutic regimen and generally produces a short-lived response. Using novel agents late in disease course will not be as effective as in an upfront setting.

[There are] no standard therapeutic approaches for patients with high-risk MCL, including those with a blastoid variant and those harboring a TP53 mutation.

What do you hope the community oncologist takes away from these findings?

[These data are] highlighting the impact of TP53 mutations in MCL. In our study, patients harboring TP53 mutations had a short-lived initial response with multiple relapses with high lymphoma-related mortality.

Introducing p53 expression evaluation in routine practice and streamlining the TP53 mutation screening process in MCL prior to initiation of treatment is of paramount importance in the era of novel, effective, but costly treatment for MCL patients.

We believe patients with MCL and mutant TP53 status might be best treated upfront with specific therapy independent of the TP53 pathway using BCR inhibition, BCL-2 inhibitors, or combinations of the 2 with or without allogeneic stem cell transplantation (if eligible). Such approached should be confirmed by a large, randomized clinical trial.

Elhassadi E, Hennessy B, Kumar S, et al. TP53 status in mantle cell lymphoma (MCL)-a 10 year single center experience. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract PF493.