Page 167 - 2019_04-Haematologica-web

TP53 mutations in CLL
AB
Figure 4. Stratified analysis in newly diagnosed patients based on TP53 and IGHV status. Kaplan Meier curves for (A) overall survival (OS) and (B) treatment-free survival (TFS) in newly diagnosed patients stratified for IGHV status and for TP53 aberrations based on variant allele frequencies (VAF) ≤10% and >10%. Four and three del(17p) are included for mutated (IGHV-M) and unmutated IGHV (IGHV-U), respectively. P-values indicated in tables within the panels.
with higher Binet stage and more frequent del(17p), result- ing in lower frequencies of TP53-mutated patients with- out del(17p) than in our cohort. Furthermore, patients in our cohort had a lower CLL-IPI score compared to the Danish nation-wide CLL cohort, probably due to varying regional referral patterns.
In contrast to previously published data,25 IGHV-U sta- tus was not higher in newly diagnosed TP53 mutated patients, which may in part explain the indolence of our cohort. In our study, synergy was demonstrated for IGHV mutational status and TP53ab.25 For patients with IGHV-U status, high burden TP53ab correlated with poor outcome among newly diagnosed patients. However, TP53ab (whether high or low burden) had no negative prognostic impact on the more indolent disease course for patients with IGHV-M status, in accordance with previous studies.26-29 Thus, the less aggressive phenotype in our cohort may diminish any independent impact of TP53muts, especially due to the proportion of IGHV-M status among TP53 mutated patients. High cell prolifera- tion, shorter time to treatment, and a distinct pattern of nucleotide shifts in patients with IGHV-U may contribute to the mechanisms causing this interaction between IGHV mutational status and TP53ab.18,30
Like the majority of NGS studies investigating the clini- cal impact of TP53muts,13,14,16,18,31,32 we confirm the negative impact on OS of TP53muts over 1% VAF at time of treat- ment. A recent study, however, was unable to show this association for patients harboring low burden TP53muts only.15
In our study, minor TP53muts were common among pretreated patients. However, minor TP53muts were observed exclusively as the only TP53ab in treatment- naïve patients. These newly diagnosed patients with only a single minor TP53mut were mainly older patients with an otherwise favorable risk profile and outcome. Even the 4 patients with minor TP53mut requiring initial treatment (3 with IGHV-U status) were still alive and in complete remission at end of follow up. This may indicate that minor TP53muts as the sole TP53ab is an age-related phe- nomenon of a more benign character, similar to reports on clonal hematopoiesis in myeloid malignancies.33 In accor- dance with this, a recent study found TP53muts enriched among older CLL patients.17
Current guidelines for assessment of TP53muts prior to treatment recommend an LOD at 10% VAF for clinical decisions, with the option to report low burden mutations down to 5% VAF by NGS as long as the unresolved clini- cal significance of such mutations is stated.12 The reason for a caveat when reporting TP53muts below 10% VAF results from: 1) low reproducibility between different NGS platforms in this range; and 2) an uncertain clinical significance of low burden mutations.12 To address the technical question of reproducibility, we here report a SEM of both nucleotide and position specific variants from deep tNGS in combination with an algorithm based on the dilution of patient DNA. By this approach, we have developed a technically robust method for detection of TP53mut that could easily be transferred across different platforms and laboratories. For clinical use, we do, howev-
haematologica | 2019; 104(4)
795