1157 - Significance of TP53 aberrations in context of other pathogenic sequence variants in patients with chronic lymphocytic leukemia in the era of targeted therapy

Backround: Significant progress has been made in the treatment of chronic lymfocytic leukemia (CLL) over the past few decades. Targeted therapy replaced chemoimunotherapy in most patients. Improvement of progression-free survival (PFS) first-and other-line Bruton tyrosin kinase inhibitors (BTKi)-based therapy, even in patients with TP53 disrupted CLL, has been seen.

Aim: Analysis of the prognostic value of both isolated TP53 aberrations and in combination with other CLL associated pathogenic sequence variants (PSV) in the cohort of mostly pretreated CLL patients treated with BTKi.

Methods: We analyzed a cohort of 83 BTKi treated patients with CLL, who were treated between years 2014 and 2022 at University Hospital in Olomouc. Patients were mostly pretreated N = 77 (93 %), even 11 patients (13 %) by four and more lines of therapy, 6 patients (7 %) were treatment naive. Men slightly predominated, N = 49 (59 %), median of age was 67 years in range of 46–85 years. According to BTKi type, Ibrutinib was mostly used N = 73 (88 %). We evaluated TP53 mutations by next-generation sequencing (NGS) and 17p deletions by fluorescence in situ hybridization (FISH), other PSV by both NGS and FISH according to type. As part of the analysis, we compared patients in individual subgroups, who were TP53wt (without mutation and/or 17p deletion) versus patients with TP53 aberration (with mutation and/or deletion of 17p), subsequently significance of individual type of TP53 aberrations and PFS effect of other CLL associated PSV alone and in combination with TP53 disruption.

Results: In the whole cohort of patients, 38 (46 %) patients with TP53 aberration were identified. Improvement of survival has been seen in both wtTP53 and TP53 disrupted groups comparing to patients treated with chemoimmunotherapy, however longer PFS was demonstrated in patients with TP53wt (p = 0.017). Median PFS was not reached in these patients compared to 40 months in patients with TP53 disruption. Significant effect of biallelic aberration compared to TP53wt patients was demonstrated (p = 0.012), while in TP53 mutated patients this trend was only indicated (p = 0.086). High proportion of other CLL PSV in TP53 disrupted subgroup were observed (N = 29; 76 %). The most common aberrations were SF3B1 mutation and del(11q) in 32% respectively 48%. PFS impact of isolated other CLL PSV (most common NOTCH1 p = 0.870, ATM p = 0.127, SF3B1 p = 0.799) was not confirmed in wtTP53 subgroup in comparison with noNOTCH resp. noATM resp. noSF3B1 together with noTP53. While PFS impact of combination of other variants (NOTCH1 p = 0.021, ATM p = 0.002, SF3B1 0.009) in presence of TP53 was confirmed compared to noPSV together with wtTP53. To support these results that TP53 disruption has impact only in combination of other pathogenetic sequence variants, we analyzed subgroup of patients with isolated TP53 disruption without any other most common changes compared to patient with no changes at all and we found that the difference of PFS between these two groups did not reached significance (p = 0.312).

Conclusion: Despite improvement of survival in our BTKi treated cohort, negative prognostic value of TP53 aberration remained preserved. Importantly, negative effect of TP53 on PFS/OS only occurred in combination with other pathogenetic sequence variants in NOTCH1 or ATM or SF3B1 genes. Studies on larger cohorts are needed to confirm our observations.

Supported by grant IGA_LF_2023_005, IGA_LF_2023_010, MH_CZ-DRO (FNOL, 00098892)
*Kubová, Kašková contributed equally