Selection for clones harboring mutant TP53 during submaximal venetoclax treatment in some human patients with primary AML. (A) Rapid leukemic clearance in a patient with biallelic TP53-aberrant AML (monosomy 17 and pathogenic TP53 mutation; also carrying an IDH1 R132C mutation, but negative for FLT3-ITD, FLT3-TKD, NPM1, or CEBPa mutations) after treatment with the BCL-2 inhibitor S55746. Although the leukemia in this patient was refractory to 2 cycles of standard AML induction chemotherapy (cytarabine+idarubicin; with the second cycle incorporating high-dose cytarabine) with blasts comprising 70% BM cells, it rapidly responded after administration of a single 21-day cycle of 100 mg/d of the oral BCL-2 inhibitor S55746, achieving morphological remission (4th column from left). Sustained reduction in the leukemic clone was confirmed by cytogenetics and whole-exome sequencing during ongoing BCL-2i therapy bridging to allogeneic BM transplantation (7th column from left) (variant allele frequency [VAF]: TP53 refers to NM_001126112.2:c.452C>A, and IDH1 refers to NM_005896.2:c.394C>T). (B) BM blast changes among patients exposed to 7 days of venetoclax monotherapy stratified by TP53 status. The median blast reductions for TP53 WT (n = 31) or TP53 mutant cases (n = 9) are represented by a red line. Open circles, TP53 mutation VAFs >50%; open squares, VAFs <50%. (C-F) Single-cell DNA sequencing analyses using a Mission Bio Tapestri instrument of BM (CAL-012, CAL-030, and CVC-001) or peripheral blood (PB; CAU-001) samples from 4 patients with AML. The bar graphs indicate the proportion of TP53 wild-type (in gray) and TP53-mutant (red/blue) clones in each sample during venetoclax treatment (CAL-012 [C]; CAL-030 [D]; CVC-001 [E]; and CAU-001 [F]). TP53 status, as well as the commutations (N-RAS, K-RAS, and PTPN11) present in TP53-mutated subclones (blue) are also indicated.