P411: longitudinal characterization of molecular variants at remission and relapse: subanalysis of the quazar aml-001 trial

Background: Acute myeloid leukemia (AML) is characteristically heterogeneous, with outcomes impacted by age, cytogenetics and molecular factors. Despite achieving remission with frontline intensive chemotherapy (IC), most patients (pts) eventually relapse. In the QUAZAR trial (NCT01757535), oral azacitidine (Oral-AZA) prolonged OS and RFS vs placebo (PBO) in older pts with AML in remission post IC, including pts with investigator-reported NPM1-mutant (mut) AML at diagnosis (Dx; Wei et al., N Engl J Med 2020; Döhner et al., Blood 2022). The prognostic relevance of gene variants characterized at screening, prior to Oral-AZA maintenance, and the molecular architecture at relapse after Oral-AZA has not been reported. Aims: To 1) evaluate the association between baseline (BL; post IC) gene mutations on survival outcomes after Oral-AZA vs PBO; 2) compare the gene mutation profile at relapse in the two treatment (Tx) arms. Methods: In QUAZAR, 472 pts (≥55 years) with AML with intermediate- or poor-risk cytogenetics in remission after IC were randomized 1:1 to Oral-AZA or PBO. Among pts who consented, targeted NGS was performed using 37 myeloid-related genes in DNA isolated from bone marrow (BM) mononuclear cells at BL (n=310) and relapse (n=160). Mean NGS coverage was 13K reads and the median locus-specific minimal detectable variant allele frequency (VAF) was 0.12% (range: 0.02–2.79). RFS was time from randomization until relapse (≥5% BM blasts) or death, estimated by Kaplan–Meier methods. Nominal P values were derived from log-rank tests. Results: In the NGS biomarker population (n=310), median RFS (mRFS) for Oral-AZA vs PBO was 10.2 vs 4.7 months (mo), respectively. Of these, 221 (71.3%) had detectable mutations at BL, most frequently in DNMT3A (28.4%), TP53 (15.5%), IDH2 (12.3%), TET2 (11.9%), SRSF2 (11.0%), IDH1 (6.1%) and ASXL1 (5.5%). The frequency of gene mutations detected at BL was similar between Tx arms. The presence of ≥3 mutations was associated with shorter RFS in both Tx arms (≥3 vs <3 mutations: mRFS 7.4 vs 12.9 mo [P=0.008], respectively). RFS favored Oral-AZA in pts with low mutational burden at BL (<3 mutations: mRFS 12.9 vs 4.9 mo [P<0.001]; n=143 vs 128 [PBO]), but there was no significant difference between Tx arms in pts with higher mutational burden (≥3 mutations: mRFS 7.4 vs 1.9 mo [P=0.12]; n=22 vs 17 [PBO]). Analysis of BL gene variants showed RFS benefit for Oral-AZA (n=51) vs PBO (n=37) among pts with DNMT3A mutations (Figure). To determine if this effect was related to concurrent NPM1 mutations at Dx, we compared RFS between Tx arms in pts who had either single DNMT3Amut or co-mutated DNMT3Amut/NPM1mut AML (23.7% of the NPM1mut cohort). In pts with DNMT3Amut/NPM1mut AML, mRFS was not reached vs 6.2 mo for Oral-AZA vs PBO, respectively (HR [CI]: 0.04 [0.008, 0.235]; P<0.001). In pts with DNMT3Amut/NPM1wildtype AML, mRFS was 10.0 vs 4.6 mo for Oral-AZA vs PBO, respectively (HR [CI]: 0.40 [0.225, 0.724]; P=0.002; Figure). At relapse, the frequency of mutations was comparable between Tx arms (not shown). Summary/Conclusion: In pts with AML in remission post IC, post hoc analyses showed that Oral-AZA improved RFS vs PBO in pts with lower mutational burden at BL. RFS was improved by Oral-AZA in pts with DNMT3A mutations independent of NPM1 status at Dx. As DNMT3A mutations at BL could either be preleukemic or related to clonal hematopoiesis, factors responsible for improved outcome after Oral-AZA independent of NPM1 mutations remain to be determined. The spectrum of mutations at relapse was similar between Tx arms. Figure. RFS according to gene mutation status at BLKeywords: Acute myeloid leukemia, Genomics, AML, Clinical trial