Figure 5.
TP53 defects and clonal evolution of low-burden TP53 mutations in patients with relapsed disease treated with targeted agents. (A) Composition of TP53 defects. (B) TP53 mutations in 110 patients with CLL, in order according the highest VAF. The highest mutation VAF is depicted in black, and the cumulative mutation VAF is in white. (C) Swimmer plots depicting treatment and TP53 mutation history in patients with low-burden TP53 mutations show patients investigated at the beginning and at the end of inhibitor treatment (top) and patients investigated during inhibitor treatment (bottom). In patients with longer intervals between event and sampling, no intervening CIT was administered. (D) Mutation burden in 20 patients with low-burden TP53 mutations before treatment with targeted agents (ibrutinib, n = 11; acalabrutinib, n = 1; and idelalisib, n = 11), and at the end of treatment. Dashed line, 10% VAF threshold. Three patients were subsequently treated with second inhibitor (blue lines). For cumulative VAF see supplemental Figure 13B. (E) Mutation burden in patients with low-burden TP53 mutations before and during (>1 year) treatment with targeted agents (ibrutinib, n = 11; idelalisib, n = 8; and venetoclax n = 1). For cumulative VAF see supplemental Figure 13C. (F) TP53 mutation VAF fold change in different treatment context. Red line, median; black lines, quartiles. Only significant differences are depicted with asterisks. **P < .01; ***P < .001; ****P < .0001. (G) FISH plots depicting clonal evolution in patients treated with targeted agents with significant clonal shifts in TP53-mut cell population. Patient 338: the most abundant TP53 mutation changed from 1.75% before inhibitor treatment to 54.7% VAF in progression (accompanied with del[17p]), BTKC481S in progression, 71% VAF. Patient 842: the most frequent TP53 mutation changed from 79.2% before inhibitor treatment to 1.1% VAF at the time of Richter’s transformation; BCL2D103E mutation at the time of Richter’s transformation, 41% VAF. Data for creating FISH plots were obtained by whole-exome sequencing from purified peripheral blood CLL cells (supplemental Methods). BTK mutation: NM_000061.2:c.1442G>C, NP_000052.1:p.Cys481Ser; BCL2 mutation: NM_000633.2:c.309C>A, NP_000624.2:p.Asp103Glu.

TP53 defects and clonal evolution of low-burden TP53 mutations in patients with relapsed disease treated with targeted agents. (A) Composition of TP53 defects. (B) TP53 mutations in 110 patients with CLL, in order according the highest VAF. The highest mutation VAF is depicted in black, and the cumulative mutation VAF is in white. (C) Swimmer plots depicting treatment and TP53 mutation history in patients with low-burden TP53 mutations show patients investigated at the beginning and at the end of inhibitor treatment (top) and patients investigated during inhibitor treatment (bottom). In patients with longer intervals between event and sampling, no intervening CIT was administered. (D) Mutation burden in 20 patients with low-burden TP53 mutations before treatment with targeted agents (ibrutinib, n = 11; acalabrutinib, n = 1; and idelalisib, n = 11), and at the end of treatment. Dashed line, 10% VAF threshold. Three patients were subsequently treated with second inhibitor (blue lines). For cumulative VAF see supplemental Figure 13B. (E) Mutation burden in patients with low-burden TP53 mutations before and during (>1 year) treatment with targeted agents (ibrutinib, n = 11; idelalisib, n = 8; and venetoclax n = 1). For cumulative VAF see supplemental Figure 13C. (F) TP53 mutation VAF fold change in different treatment context. Red line, median; black lines, quartiles. Only significant differences are depicted with asterisks. **P < .01; ***P < .001; ****P < .0001. (G) FISH plots depicting clonal evolution in patients treated with targeted agents with significant clonal shifts in TP53-mut cell population. Patient 338: the most abundant TP53 mutation changed from 1.75% before inhibitor treatment to 54.7% VAF in progression (accompanied with del[17p]), BTKC481S in progression, 71% VAF. Patient 842: the most frequent TP53 mutation changed from 79.2% before inhibitor treatment to 1.1% VAF at the time of Richter’s transformation; BCL2D103E mutation at the time of Richter’s transformation, 41% VAF. Data for creating FISH plots were obtained by whole-exome sequencing from purified peripheral blood CLL cells (supplemental Methods). BTK mutation: NM_000061.2:c.1442G>C, NP_000052.1:p.Cys481Ser; BCL2 mutation: NM_000633.2:c.309C>A, NP_000624.2:p.Asp103Glu.

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