TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy

Abstract

Nodal peripheral T-cell lymphomas (PTCL), the most common PTCLs, are generally treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based curative-intent chemotherapy. Recent molecular data have assisted in prognosticating these PTCLs, but most reports lack detailed baseline clinical characteristics and treatment courses. We retrospectively evaluated cases of PTCL treated with CHOP-based chemotherapy that had tumors sequenced by the Memorial Sloan Kettering Integrated Mutational Profiling of Actionable Cancer Targets next-generation sequencing panel to identify variables correlating with inferior survival. We identified 132 patients who met these criteria. Clinical factors correlating with an increased risk of progression (by multivariate analysis) included advanced-stage disease and bone marrow involvement. The only somatic genetic aberrancies correlating with inferior progression-free survival (PFS) were TP53 mutations and TP53/17p deletions. PFS remained inferior when stratifying by TP53 mutation status, with a median PFS of 4.5 months for PTCL with a TP53 mutation (n = 21) vs 10.5 months for PTCL without a TP53 mutation (n = 111). No TP53 aberrancy correlated with inferior overall survival (OS). Although rare (n = 9), CDKN2A-deleted PTCL correlated with inferior OS, with a median of 17.6 months vs 56.7 months for patients without CDKN2A deletions. This retrospective study suggests that patients with PTCL with TP53 mutations experience inferior PFS when treated with curative-intent chemotherapy, warranting prospective confirmation.

Graphical abstract

Figure 1.

Flowchart of patient identification and distribution into respective cohorts. The entire cohort includes 132 patients with NGS of tumor samples. CCD was available for 87 patients, and 72 patients were managed by an MSK oncologist for their first-line treatment and had tumor NGS before or during CHOP-based treatment. CNS, central nervous system; CR1, first complete remission; EATL, enteropathy-associated T-cell lymphoma.

Figure 2.

Oncoplot of the most frequent genetic aberrations in the entire cohort (N = 132). Each column represents a unique patient. The top row represents both the number and type of alterations detected in each biopsy. Each row represents the diagnosis, biopsy, sequencing panel, gene and type of mutation, and/or CNA. Gray tiles indicate wild type. Missing tiles represent a gene that is not included in that specific NGS panel. Percent frequencies in the far-right column represent both mutations and CNAs for that specific gene.

Figure 3.

Kaplan-Meier survival curves for each cohort. (A) PFS and (B) OS of the entire cohort (red), CCD cohort (blue), and prospective cohort (green). The prospective cohort had superior PFS compared with the entire cohort (P = .02). There were no other significant differences in PFS or OS. Living patients were censored at time of last follow-up (filled circles). The number of patients at risk for each time point and cohort is shown.

Figure 4.

Kaplan-Meier survival curves for the entire cohort (N = 132) stratified based on the TP53 mutation status. (A) PFS and (B) OS of patients with (TP53-mutated; red) or without (TP53-unmutated; blue) PTCL. Data of living patients were censored at the time of last follow-up (filled circles). The number of patients at risk for each time point and cohort is shown.

Figure 5.

TP53 median variant allele frequencies (MAFs) and mutation specifics among PTCL cases with a TP53 mutation (n = 21). (A) MAF of TP53 mutations as compared with all other gene mutations in each tumor sample (n = 21). Each of these 21 patients’ biopsies are represented on the x-axis. Red symbols represent the MAF of the TP53 mutation. Black symbols represent the MAF of any non-TP53–mutated gene found in the same biopsy. The solid lines represent the median MAF of all mutations occurring in the biopsy sample. (B) Lollipop plot of TP53 mutations (n = 21). Each colored symbol represents a specific TP53 mutation along the entire coding region. The green boxed region represents the transactivation domain (P53_TAD). The red boxed region represents the DNA binding domain (P53). The blue boxed region represents the tetramerization domain (P53_tetramer). The next 2 rows signify that all mutations are listed in the OncoKB database as likely oncogenic, and 15 have been reported as cancer hotspot mutations. The bottom row illustrates the exon structure of the TP53 gene.