TP53 Mutations Are Associated With Unfavorable Prognosis in CLL

Consuelo Bertossi, MD

TP53 mutations have an adverse prognostic role in patients with chronic lymphocytic leukemia (CLL), regardless of 17p deletion and IGHV status, in the context of both chemoimmunotherapy and targeted therapies, according to findings from a retrospective study evaluating the prognostic impact of TP53 mutations in CLL, which were presented at the 2024 EHA Congress.¹

At a median follow-up of 65.7 months, patients with TP53 mutations had inferior progression-free survival (PFS) and overall survival (OS) outcomes vs those with TP53 wild-type disease (PFS HR, 2.605 [95% CI, 1.804-2.365; P < .001]; OS HR, 2.819 [95% CI, 2.377-3.344; P < .001]).

TP53 mutations are present in approximately 19% of patients with lymphoid diseases and have been shown to be a strong prognostic factor in CLL. A multivariable analysis of the phase 3 CLL8 trial (NCT00281918) showed that patients with TP53-mutated CLL who received frontline fludarabine plus cyclophosphamide and rituximab (Rituxan) had inferior OS outcomes vs those without TP53 mutations.² However, the prognostic impact of TP53 mutations with targeted therapy, including BCL-2 and BTK inhibitors.¹

“With our multicenter, retrospective analysis, we aimed to further describe the TP53 mutation landscape in CLL, and then to assess prognosis by TP53 mutation characteristics, by the presence of other genetic markers, and with different treatments,” lead study author Consuelo Bertossi, MD, of University Hospital Ulm in Germany, said in an oral presentation during the meeting.

This retrospective study evaluated 10,051 patients with CLL who were analyzed between 1998 and 2023 across 1 single institution and 39 prospective, multicenter CLL clinical trials.

In these trials, TP53 mutations were identified by denaturing high-performance liquid chromatography and Sanger sequencing of exons 4 through 10 in 66% of patients and next-generation sequencing of exons 2 through 11 in 33% of patients. Variant interpretations were based on 2024 European Research Initiative on CLL guidelines and Seshat.

Among the evaluated patients, 1368 had TP53 mutations. When broken down by number of mutations, 77%, 15%, and 8% of patients had 1, 2, and more than 2 mutations, respectively. Furthermore, 51% and 43% of patients had 17p deletions and no 17p deletions, respectively, and 6% of patients were not evaluable for 17p deletion status. Moreover, 66.5% of patients had multi-hit TP53 defects, and 33.5% of patients did not. When broken down by IGHV mutation status, 78% and 21% of patients had unmutated and mutated IGHV, respectively, and 1% of patients were not evaluable for IGHV mutation status.

When broken down by variant allele frequency (VAF), 90% of patients had major TP53 mutations—defined as more than 10% VAF—and 10% of patients had minor TP53 mutations—defined as less than 10% VAF. Eighty-seven percent of patients had pathogenic/deleterious TP53 mutations, 8% of patients had truncating mutations, and 5% had mutations of unknown significance. Moreover, 71% and 4.5% of patients had inactive and partially active TP53 mutations, respectively, and 24.5% of patients were not evaluable for TP53 activity.

In total, 1824 TP53 variants were found across the 1368 patients with TP53-mutated CLL. When broken down by mutation type, 69.8%, 13.4%, 7.2%, 6.9%, 1%, and 1.7% of mutations were missense, frameshift, nonsense, splice site, synonymous, and other mutation types, respectively. Overall, 1643 mutations were located at the DNA binding domain (89.5%), and 10.5% of mutations (n = 181) were located at other sites.

Among TP53 mutations that also had 17p deletions, 66%, 16.6%, 7%, 6.9%, 1.7%, and 1.8% of mutations were missense, frameshift, nonsense, splice site, synonymous, and other mutation types, respectively. Among TP53 mutations that had no 17p deletions, 73.5%, 10.7%, 6.4%, 6.7%, 0.7%, and 2% of mutations were missense, frameshift, nonsense, splice site, synonymous, and other mutation types, respectively. Investigators found the same distribution and number of TP53 mutations per patient regardless of 17p deletion status. However, 17p deletions were associated with a higher TP53 VAF, at 44% vs 20% in patients without 17p deletions (P < .001).

To correlate these genetic findings with patient outcomes, investigators selected an efficacy cohort of 3713 patients with untreated CLL, 9% of whom had TP53 mutations. These patients were enrolled across 9 German CLL Study Group trials. Among these patients, 71% received chemoimmunotherapy, 19% received venetoclax (Venclexta)–based regimens, and 10% received ibrutinib (Imbruvica)/idelalisib (Zydelig)–based regimens.

Among efficacy-evaluable patients with available TP53 mutation VAF status (n = 336), 76% had only major mutations, 15% had only minor mutations, and 9% had both. Regarding PFS, patients with major mutations (n = 284) had significantly worse outcomes than those with wild-type disease (n = 3377; HR, 2.17; P < .001). However, patients with minor mutations did not have significantly inferior PFS outcomes vs those with wild-type disease (HR, 1.39; P = .076). Overall, patients with major mutations had better outcomes than those with minor mutations. Regarding OS, patients with major mutations and patients with minor mutations had significantly worse outcomes than those with wild-type disease (major mutation HR, 2.86 [P < .001]; minor mutation HR, 1.78 [P = .039]), although those with minor mutations had better outcomes than those with major mutations.

Investigators found that both gain of function and loss of function TP53 mutations, mutations located both inside and outside the DNA binding domain, and inactive mutations all significantly affected PFS and OS. Between patients with gain of function TP53 mutations (n = 46) and those with wild-type disease, the respective PFS and OS HRs were 2.29 (P < .001) and 2.68 (P < .001). These respective HRs between patients with loss of function TP53 mutations (n = 290) and those with wild-type disease were 2.03 (P < .001) and 3.74 (P < .001).

Between patients with TP53 mutations located in the DNA binding domain (n = 306) and those with wild-type disease, the respective PFS and OS HRs were 2.05 (P < .001) and 2.86 (P < .001). These respective HRs between patients with TP53 mutations located in other domains (n = 30) and those with wild-type disease were 2.21 (P = .001) and 2.40 (P = .001).

Patients with inactive TP53 mutations (n = 236) had worse PFS outcomes vs those with wild-type disease (HR, 2.08; P < .001). However, partially active TP53 mutations (n = 23) did not have a significant impact on PFS or OS vs wild-type disease (HR, 1.15; P = not significant).

Patients with deleterious (n = 176), pathogenic (n = 105), and truncating (n = 29) TP53 mutations had significantly worse OS outcomes vs those with wild-type disease, with respective HRs of 2.88 (P < .0001), 3.05 (P < .001), and 5.10 (P < .001). However, those with variants of unclear significance (n = 26) had OS outcomes that were comparable with those observed with wild-type disease (HR, 0.59; P = not significant).

“Therefore, we do not recommend to assess variants of unclear significance as actual TP53 mutations,” Bertossi emphasized.

Among evaluable patients with mutated IGHV, those with TP53 mutations (n = 75) had worse PFS and OS outcomes vs those with wild-type disease (n = 1302; PFS HR, 2.27 [P < .001]; OS HR, 2.52 [P < .001]). Similarly, among patients with unmutated IGHV, those with TP53 mutations had worse PFS and OS outcomes vs those with wild-type disease (PFS HR, 1.78 [P < .001]; OS HR, 2.71 [P < .001]).

Among evaluable patients without 17p deletions, those with TP53 mutations (n = 177) had significantly worse PFS and worse OS outcomes vs those with wild-type disease (n = 3276; PFS HR, 1.609 [P < .001]; OS HR, 1.82 [P < .001]). Among patients with 17p deletions, those with TP53 mutations (n = 157) had significantly worse PFS and OS outcomes vs those with wild-type disease (n = 31; PFS HR, 1.010 [P = .96]; OS HR, 2.51 [P = .004]).

When prognostic impact was broken down by type of therapy, patients who received chemoimmunotherapy had worse PFS and OS outcomes vs those who received venetoclax. Among evaluable patients who received chemoimmunotherapy, those with TP53 mutations (n = 237) had worse PFS and OS outcomes vs those with wild-type disease (n = 2403; PFS HR, 2.55 [P < .001]; OS HR, 3.00 [P < .001]). Among patients who received venetoclax, those with TP53 mutations (n = 39) had worse PFS and OS outcomes vs those with wild-type disease (n = 673; PFS HR, 2.12 [P < .001; OS HR, 2.84 [P = .003]).

Moreover, patients who received time-limited ibrutinib had better outcomes than those who received chemoimmunotherapy. Among patients who received ibrutinib, those with TP53 mutations (n = 60) had worse PFS and OS outcomes vs those with wild-type disease (n = 285; PFS HR, 1.44 [P < .29; OS HR, 2.46 [P = .095]).

A multivariable analysis of clinical and laboratory parameters was conducted in 3371 patients. This analysis confirmed that TP53 mutations were some of the strongest prognostic factors for PFS and OS outcomes. Mutated TP53 retained its prognostic value in patients with both TP53 mutations and 17p deletions.

“As a key message, we want to underline the importance of central academic reference diagnostics and biobanking in prospective, multicenter clinical trials,” Bertossi concluded.

References

1. Bertossi C, Robrecht S, Ligtvoet R, et al. The landscape of TP53 mutations and their prognostic impact in chronic lymphocytic leukemia. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract S101.
2. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247-54. doi:10.1182/blood-2014-01-546150