Characterization of AML cases with primary resistance. (A) Genomic landscape of AML cases with primary resistance. Molecular profile of 20 AMLs that were refractory to venetoclax-based combinations. The presence of adverse cytogenetic risk, complex karyotype, del(17p), indicated mutations, study ID number, and cytotoxic therapy received (AZA, azacitidine; DEC, decitabine or LDAC, low-dose cytarabine) are shown for each case. Mutations detected by RNA-seq are represented by a dark gray box. For case #353, the KIT-ITD increased in frequency from 0.9% to 27% VAF from screening to after cycle 1 assessment. (B) TP53 abnormalities at baseline in refractory AML cases. TP53 VAFs % were quantitated by targeted NGS. (C) Baseline VAF of TP53 mutations according to patients with late relapse (>12 months), early relapse (<12 months), or primary refractory to treatment. AMLs with baseline and acquired del(17p) are indicated by orange and red, respectively. Each patient in a group is represented by a symbol. Some AML cases had >1 TP53 mutation: late relapse (#182 [inverted triangle], #335 [open circle] and #330 [upright triangle]); early relapse (#056 [square]); and refractory disease (#053 [hexagon], #176 [black circle] and #212 [upright triangle]). (D) Single-cell analysis of clonal architecture at screening and after treatment. Mission Bio Tapestri clonogram of case #064 showing the relative mutation composition (%) of samples at patient screening or at the time of refractory disease. In this case, within the EZH2mut clone, 5 parallel RASmut subclones are shown to emerge, with concurrent suppression of EZH2mut-only cells.