PF359 TP53 CLONAL AND SUBCLONAL ARCHITECTURE IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS UNDER IBRUTINIB TREATMENT

Le résumé fourni par la source

Background: Ibrutinib (IBR) is active in chronic lymphocytic leukemia (CLL) patients (pts) with TP53 aberrations. Aims: To investigate the dynamics of TP53 mutations (TP53‐mut) in treatment‐naïve and relapsed CLL pts treated with IBR. Methods: Fifty‐four pts (33 unmutated, 21 mutated IGHV; 7/50 del17p) underwent a longitudinal TP53 monitoring (234 samples), by ultra‐deep sequencing. Forty pts received IBR+rituximab (IBR+RTX) front‐line in the GIMEMA LLC1114 protocol (NCT02232386) (median IBR exposure: 32 months; range 14–44) (cohort 1), while 14 pts received IBR single agent after a median of 1.5 (range 1–4) lines of chemoimmunotherapy (IBR exposure: 2.1 to 4 years in 12 pts) (cohort 2). Samples were sequenced to obtain a 5000X coverage/base on a MiSeq Illumina platform. Mutations were checked on the IARC TP53 database. VAF was corrected to cancer cell fraction (CCF) by the % of CD19+/CD5+ cells. Results: In cohort 1, at baseline (T0) 16/40 (40%) pts showed a total of 22 TP53 mutations (1.4 TP53‐mut/pt; range: 1–5) and 24/40 (60%) were wild‐type (WT). Of 22 mutations, 16 (73%) were clonal (mean VAF: 60.3%; range: 18–94%) and 6 (27%) subclonal (mean VAF: 5.3%; range: 2.1–9.2%). According to CCF, TP53‐mutated pts followed 4 patterns (Figure): 1) clonal TP53‐mut present from T0 and persisting clonal with a stable CCF (n = 6); 2) clonal TP53‐mut present from T0 and persisting clonal with a decreasing CCF (n = 6); 3) subclonal TP53‐mut evolving to clonal (n = 1); 4) subclonal TP53‐mut disappearing (n = 1). In addition, 2 cases showed coexisting clonal and subclonal TP53‐mut at T0 without a distinct mutational pattern. Overall, 9 TP53‐mut (41%) (8 clonal+1 subclonal) persisted stable, 7 (32%) clonal decreased, 1 (4%) subclonal increased, 5 (23%) (2 clonal+3 subclonal) were lost and none emerged. In the 24 TP53‐WT pts, no novel mutation was acquired over time. In cohort 2, prior to IBR 10/14 (71%) pts showed a total of 31 TP53 mutations (3.1 TP53‐mut/pt; range: 1–11) and 4/14 (29%) were WT. Of 31 mutations, 11 (35.5%) were clonal (mean VAF: 31.9%; range: 10.5–78.8%) and 20 (64.5%) were subclonal (mean VAF: 2.9%; range: 0.9–6.8%). After IBR, 17 TP53‐mut (55%) (7 clonal+10 subclonal) persisted stable, 2 (6.5%) clonal decreased, 11 (35.5%) (2 clonal+9 subclonal) were lost, 1 (3%) subclonal evolved to clonal and 2 novel subclonal emerged. No mutation was identified in the 4 WT pts over time. Overall, in both cohorts, most of TP53‐mut remained stable (41% vs 55% in cohort 1 and 2, respectively), some decreased (32% vs 6.5%) and some others were lost (23% vs 35.5%) (p = NS). Notably, while no novel mutation arose in cohort 1, 2 novel mutations emerged in cohort 2. Although the lymphocyte count significantly decreased during IBR+RTX/IBR exposure (cohort 1: 39.1x109/L vs 11.1x109/L, p < 0.017; cohort 2: 48.5x109/L vs 15.3x109/L, p = 0.015), the mean CCF of the existing mutations remained stable on treatment (cohort 1: 62.4% vs 45.3%, p = NS; cohort 2: 16.9 % vs 13.02%; p = NS). Summary/Conclusion: In most TP53‐mutated pts, IBR appears to decrease the TP53 clonal and subclonal numerosity and complexity both when used front‐line or as a subsequent line of therapy. The emergence of novel mutations or the expansion of a pre‐existing mutation is a rare event. In TP53 WT pts, treatment with IBR never induced the emergence of novel TP53‐mut after an exposure of more than 2 years. The significant decrease of lymphocytosis with stable CCF, proves the IBR effectiveness both on TP53 mutated and WT cells, regardless of previous therapies. image

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.