Ten-Year Analysis Confirms Poor Prognosis in TP53-Mutant Mantle Cell Lymphoma

Patients with mantle cell lymphoma (MCL) have a particularly dismal prognosis when they present with theTP53mutation, which is detected in about 15% to 20% of patients through either Sanger sequencing or next-generation sequencing (NGS). According to an analysis presented at the 2019 European Hematology Association Congress, the presence ofTP53mutations directly correlated with overall survival (OS).

Twenty-nine patients with MCL were observed over a 10-year single-institution analysis. Data on patient demographic, staging, treatment, risk status, and response to treatment were collected from the institution’s lymphoma database. Eighty-three percent of these patients were treated with standard frontline chemoimmunotherapy. Twenty percent of the patients harbored aTP53mutation.

The median OS in those patients harboring aTP53mutation was approximately 4 years, but the OS had not yet been reached in the wild-type subset of patients. The overall response rate was 79%, which included a 55% complete response rate and a 24% partial response rate.

In an interview withTargeted Oncology, Ezzat Elhassadi, MD, a consulting hematologist at University Hospital Waterford, discussed the results from this analysis and how the presence of aTP53mutation can impact the survival of patients with MCL. He also highlighted the remaining challenges in this space and how these challenges can be overcome.

TARGETED ONCOLOGY: How often areTP53mutations observed in patients with MCL?

Elhassadi:TheTP53mutation 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.

TARGETED ONCOLOGY: 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 impactofTP53mutational status using Sanger sequencing or NGS on treatment outcome in our cohort. Also, to correlate the p53 expression using immunohistochemistry (IHC) withmutational status.

TARGETED ONCOLOGY: What were your findings?

Elhassadi: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 mutatedIGHV, 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 detectedTP53mutations 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-typeTP53status, 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 harboringTP53mutations have an aggressive disease course with multiple disease relapses and lymphoma-related deaths (80%). In subset analyses, the OS was only 4 years inTP53-mutated disease and was not reached in the wild-typeTP53cohort (P= .007, log rank test), which is comparable to the reported data.

TARGETED ONCOLOGY: How can these findings be used to better treat patients withTP53-mutated MCL?

Elhassadi:These findings highlight the importance of the acquisition ofTP53mutations 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 theTP53mutation 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.

TARGETED ONCOLOGY: What challenges still exist in the treatment paradigm of MCL?

Elhassadi: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 ofTP53disruption 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 aTP53mutation.

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

Elhassadi:[These data are] highlighting the impact ofTP53mutations in MCL. In our study, patients harboring TP53mutations had a short-lived initial response with multiple relapses with high lymphoma-related mortality.

Introducing p53 expression evaluation in routine practice and streamlining theTP53mutation 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 mutantTP53status might be best treated upfront with specific therapy independent of theTP53pathway 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.

Reference:

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.