Venetoclax-Based Measurable Residual Disease Directed Therapy in Acute Myeloid Leukemia Is Associated with Emergent TP53 Microclones in Remission

• Published in: Blood 2024-11, Vol.144, p.51-51
• Main Authors: Tiong, Ing Soo, Yerneni, Satwica, Nguyen, Tamia, Ivey, Adam, Anstee, Natasha S., Palfreyman, Emma, Bajel, Ashish, Abro, Emad Uddin, Hiwase, Devendra, Wei, Andrew H, Blombery, Piers
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-201145

Venetoclax (VEN) combined with low-dose cytarabine (LDAC) is highly effective in acute myeloid leukemia (AML) with either measurable residual disease (MRD) or oligoblastic (5-15% blasts) relapse (VALDAC study) (Tiong et al, JCO 2024). We have previously shown that VEN-based therapy enhances selection of TP53 deficient leukemic clones with TP53 variants observed in 32% of patients (pts) at relapse (DiNardo et al, Blood 2020 and Thijssen et al, Blood 2021). In order to further understand the origins of these clones, we aimed to sensitively assess the clonal hematopoietic landscape in remission in pts with AML treated with VEN-LDAC. Baseline samples from 18 pts from the VALDAC study, at MRD (n=10) or oligoblastic (n=8) relapses were sequenced using highly sensitive targeted NGS (TwinStrand Duplex SequencingTM AML-29 Panel; sensitivity approximately 0.01% variant allele frequency [VAF]). 330 variants were detected in these 18 pts with a median of 18 variants per pt (range 4-50). Most variants were present at very low VAF (median VAF of 0.063% [IQR 0.032, 0.267]). VAF >1% was observed in 12% vs 20% of the variants among pts with MRD vs oligoblastic relapses (p=0.03), respectively. Frequently mutated genes at study entry before VEN-LDAC exposure were DNMT3A (94%), TET2 (89%), ASXL1 (72%) and TP53 (50%). We then assessed samples from 22 pts whilst in morphological remission, tested at a median of 2.1 months post-VEN-LDAC therapy. This revealed 518 variants with a median of 19.5 variants per pt (range 4-60) and median VAF 0.057% (IQR 0.028, 0.191). Frequently mutated genes post-VEN-LDAC therapy were DNMT3A (100%), TET2 (91%), TP53 (77%), ASXL1 (64%) and CBL (50%). Comparing pre- (n=18) and post-VEN (n=22) timepoints, NPM1 mutations were most frequently cleared as expected (39% pre-VEN-LDAC vs 4.5% post-VEN-LDAC, p=0.01). The frequency for other variants were TP53 (50% vs 77%, p=0.10) and CBL (22% vs 50%, p=0.10). Strikingly, TP53 variants ≥0.1% VAF were more commonly identified post-VEN (50% of pts), compared to pre-VEN (5.6%) (p=0.004). We were able to assess clonal dynamics in 12 pts with available paired screening and post cycle 1 (n=2) or 2 (n=10) samples. While the median number of variants per pt (18 vs 16) and VAF (0.059% vs 0.072%) were similar between the 2 timepoints, 120 (56%) out of the 216 baseline variants were not detected post-VEN-LDAC, whereas 120 new variants emerged following therapy; net change ranged from -14 to +18 variants per pt. Gene varia