A high TP53 mutation burden is a strong predictor of primary refractory mantle cell lymphoma

The mantle cell lymphoma (MCL) International Prognostic Index is widely used as a strong prognostic stratifier, but it has rarely been used for the selection of therapeutic approaches.1 New molecular prognostic predictors, which would reflect critical aspects of MCL biology and that would help in therapy decisions, have been under investigation.2 Recently, several key studies provided evidence of the poor prognostic impact of tumour protein p53 (TP53) gene aberrations or high p53 protein expression in patients with MCL.3-6 There is a growing body of evidence that TP53 aberrations could contribute to chemoresistance.7 In the present study, we analysed the prognostic impact of the extent of a TP53 gene aberration (TP53 mutation burden and deletion of 17p frequency) in a real-world cohort of patients with MCL. This was a retrospective study of 114 consecutive unselected adult patients with newly diagnosed MCL between April 2006 and October 2016. Tumour tissues (bone marrow, peripheral blood, and lymph nodes) from all the patients who were analysed were obtained before the initiation of treatment. The samples were examined by fluorescence in situ hybridisation (FISH) and next-generation sequencing (NGS). The deletion frequency was defined as the percentage of nuclei carrying a deletion of 17p (del17) out of the total number of nuclei carrying the translocation t(11;14). The TP53mut burden was defined as the variant allele frequency (VAF) of the mutations that were detected or the highest VAF in the case of multiple mutations present in one patient. Patients with stable or progressive disease during induction or with relapse or progression within 6 months after the completion of induction were considered as primary refractory (PrR). In all, 27 (23·7%) of the 114 patients who were analysed exhibited PrR. More detailed characteristics are summarised in Table I. A total of 43 patients (37·7%) had some type of TP53 disruption. The overall (OS) and progression-free survival (PFS) curves were not statistically different between the TP53mut, del17, and TP53mut + del17 cohorts (TP53mut/del17/TP53mut + del17) (P = 0·95 for OS; P = 0·86 for PFS) (Figure SA). A total of 24 patients had both TP53mut and del17, 13 patients had isolated TP53mut, and five had del17. The association between TP53mut and del17 was significant, at P < 0·001. Moreover, in the PrR cohort, there was almost unit correlation (c = 0·90, P < 0·001) between the TP53mut burden and del17 frequency (Figure SB). The TP53mut burden (mean 33%, range 3–85%) and del17 frequency (mean 47%, range 6–92%) varied significantly among the patients. As expected, a TP53 aberration was a strong predictor of PrR, regardless of age and therapeutic approach. Interestingly, PrR patients without a TP53 aberration tended to be older (Figure SC). Both the coefficients are significant, at P < 0·001. The value z in equation (1) is a linear combination of age and the mutation burden. Such a classifier produces a receiver operating characteristic curve (Figure SD). Thus, for any cut-off value of the probability, the decision boundary has the form of a line in the age-burden plane (Fig 1). The patients above the decision line are predicted as PrR and the patients below the line as non-PrR. In our cohort, the patients with MCL with an aberration of the TP53 gene had a significantly worse prognosis compared to those with the TP53-wild type. There was no difference in survival outcomes between those with TP53mut and del17. Our present findings thus further complement the results from Eskelund et al.3, who found lower OS and PFS in younger patients with MCL with TP53 mutations. In contrast to that study, our calculations were performed on a whole real-life spectrum of younger and older patients with MCL. The correlation between the TP53mut burden and del17 frequency in the PrR patients was almost perfect (Figure SB). Surprisingly, for the non-PrR patients, the del17 frequency tended to be higher than the TP53mut burden. We can hypothesise that an increasing TP53mut burden plays a more prominent role in the process of chemoresistance acquisition than del17. This is also supported by the observation that all the deletions were monoallelic. Partial preservation of the TP53 gene function in patients with deleted TP53 is therefore presumable, as previously discussed in another study.5 We found that the presence of a TP53 aberration was a strong predictor of PrR regardless of age. Moreover, the PrR patients without any TP53 aberration tended to be older (Figure SC). We noticed a strong correlation between older age and PrR. The main goal of our present study was to identify PrR MCL patients. The usual cut-off age for transplant eligibility is 65 years. In our present cohort, six of the seven PrR patients aged <65 years had a TP53mut burden from 26% to 80%. Only seven of the 42 younger non-PrR patients had TP53mut, and the burden only exceeded 10% in three cases. Thus, we propose that all younger patients with a TP53mut burden >10% should be offered a novel treatment strategy. In the elderly patients (aged >65 years), the association of TP53mut and PrR was not so close. With increasing age, other mutations plausibly complement TP53 in mediating chemoresistance. In our present cohort, 12 of 15 elderly PrR patients had a TP53mut burden from 3% to 86%, but it was <50% in most cases. In all, 12 of 45 non-PrR patients had TP53mut, and in all but one the burden was <50%. In this group, it was not possible to set a burden threshold to discriminate PrR patients with sufficient sensitivity. Thus, we suggest all elderly patients with a TP53mut be indicated for an innovative up-front therapy. To simplify the use of the predictive model (1)–(2), we introduce a nomogram in the form of a probability table (Figure SE). Robust data suggesting appropriate therapy for patients with MCL with TP53 alterations are still missing. Recently, Lin et al.8 published promising results regarding younger patients treated with allogeneic stem cell transplants. The authors found no significant differences in overall survival and the cumulative incidence of relapse among patients with and without TP53 alterations. Another effective treatment option, also for elderly patients with TP53 aberrations, might be the use of B-cell receptor (BCR) inhibitors with an acceptable toxicity profile.9 To conclude, we show that a high TP53 mutation burden predicts chemoresistance in younger patients with newly diagnosed MCL regardless of the routinely used treatment strategy. We also demonstrate that age correlates positively with chemoresistance, irrespective of the type and frequency of TP53 aberration. Although the results need to be validated in prospective clinical trials, we strongly support the implementation of a TP53 mutation as a therapy classifier in all patients with newly diagnosed MCL. We would like to thank all the patients and their families for their goodwill and patience while participating in our study. Our research was supported by Ministry of Health and Ministry of Education, Youth and Sports of the Czech Republic and by the Charles University grants AZV 17-28980A, IGA_LF_2020_002, IGA_LF_2020_016, MH CZ – DRO (FNOL, 00098892), AZV16-32339A, AZV16-31092A, RVO-VFN64165, PROGRES Q26/LF1, and PROGRES Q28/LF1 [Correction was added on 14 September 2020, after first online publication: The Acknowledgement section has been updated with funding information in this current version.] The authors declare no conflict of interests. The results of the FISH and NGS tests are available from the corresponding author upon reasonable request. 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