Prognostic Impact of NPM1 and FLT3 Mutations at Diagnosis and Presence of Measurable Residual Disease (MRD) after Intensive Chemotherapy (IC) for Patients with Acute Myeloid Leukemia (AML) in Remission: Outcomes from the QUAZAR AML-001 Trial of Oral Azacitidine (Oral-AZA) Maintenance

BACKGROUND: Current guidelines for AML ascribe disease-risk partly based on NPM1 and FLT3 mutational status. NPM1 mutations (^mut) occur in 25%–30% of patients (pts) with AML and are associated with favorable prognosis in the absence of co-occurring FLT3-ITD. FLT3-ITD alterations are observed in ~15–30% of AML pts and confer poor prognosis, whereas the prognostic implication of FLT3-TKD point mutations (~7% of pts) is less clear. Post-IC, absence of MRD is associated with favorable relapse-free and overall survival (RFS/OS). In the randomized, phase 3 QUAZAR AML-001 trial, Oral-AZA (CC-486) significantly prolonged OS and RFS vs placebo (PBO) in older pts with AML in first remission after IC (Wei, NEJM 2020). It is of high interest to understand the effects of Oral-AZA in pts with NPM1 and/or FLT3 mutations, and whether their outcomes are influenced by post-IC MRD status.

OBJECTIVE: Evaluate survival outcomes with Oral-AZA vs PBO in pts with NPM1^mut ± FLT3^mut at AML diagnosis (Dx), and OS by baseline (BL) MRD status (+/-) in pts with NPM1/FLT3 mutations.

METHODS: In QUAZAR AML-001, pts aged ≥55 years with AML and NCCN intermediate or poor-risk cytogenetics at Dx were randomized 1:1 to receive Oral-AZA 300 mg or PBO QD within 4 mo after attaining first CR/CRi with IC (induction ± consolidation). NPM1 and FLT3 statuses (^mut or wild-type [^wt]) at AML Dx (before IC) were collected from pt diagnostic case report forms. MRD analyses were conducted by MFC (≥0.1% MRD+ cutoff) in bone marrow aspirate samples collected at screening (post-IC; ie, BL). OS and RFS were estimated from the time of randomization using Kaplan-Meier methods. Multivariate (MV) Cox regression analyses of the prognostic effects on OS/RFS were performed, with NPM1 and FLT3 mutational status and cytogenetic risk at Dx; post-IC MRD status (+/-) at BL, and randomized Tx (Oral AZA vs PBO) as variables.

RESULTS: Of 472 pts enrolled , 469 (99.4%) had mutational data available at Dx, and the MRD-evaluable cohort comprised 463 pts (98.1%). In all, 137 pts (29%; Oral-AZA n = 66, PBO n = 71) had NPM1^mut at AML Dx, and NPM1^mut was significantly correlated with MRD- status at BL (post-IC) (P = 0.0178). Among pts with NPM1^mut, OS was prolonged in pts receiving Oral-AZA vs PBO, whether pts were MRD- (median 48.6 vs 26.2 mo, respectively) or MRD+ (median 39.4 vs 10.3 mo) at BL (Figure). While median OS for NPM1^mut pts in the Oral-AZA arm was nominally improved for MRD- pts vs. those MRD+ (48.6 vs. 39.4 mo, respectively), median OS for NPM1^mut pts in the PBO arm was substantially influenced by post-IC MRD status (26.2 vs 10.3 mo for MRD- and MRD+ pts, respectively) (Figure). Similarly, median RFS for pts with NPM1^mut/MRD- in the Oral-AZA and PBO arms was 24.9 vs 9.9 mo, respectively, and for pts with NPM1^mut/MRD+ was 19.4 vs 4.6 mo.

In all, 66 pts (14.1%) had FLT3-ITD (n = 46) and/or FLT3-TKD^mut (n = 24) at AML Dx; NPM1 and FLT3-ITD status was NPM1^mut + FLT3-ITD^– in 107 pts, NPM1^mut + FLT3-ITD⁺ in 30 pts, and NPM1^wt + FLT3-ITD⁺ in 16 pts. In the Oral-AZA arm, median OS in pts with FLT3^mut was not meaningfully different from that in pts with FLT3^wt (28.2 and 24.7 mo, respectively), but FLT3^mut conferred a negative prognosis in the PBO arm (median OS 9.7 mo, vs 15.2 mo for FLT3^wt pts). Risk of death was reduced 46% with Oral-AZA vs PBO in pts with FLT3^mut (HR 0.54 [95%CI 0.25, 1.14]). When considering MRD status, median OS in FLT3^mut/MRD- pts was 28.2 vs. 15.9 mo in the Oral-AZA (n = 14) and PBO (n = 17) arms, respectively, and was 24.0 vs 8.0 mo in FLT3^mut/MRD+ pts (Oral-AZA, n = 16; PBO, n = 18).

In MV analyses, Oral-AZA significantly improved OS vs PBO when adjusted for other variables (P = 0.035); NPM1 status (P = 0.001), FLT3 status (P = 0.035), and cytogenetic risk at Dx (P < 0.001) were each also significantly predictive of OS, as was post-IC MRD status (P < 0.001). All except FLT3 status (P = 0.737) were significantly predictive of RFS.

CONCLUSIONS: Oral-AZA prolonged OS and RFS vs PBO in pts with NPM1^mut, with improvements beyond the prognostic benefit conferred by MRD-, suggesting that pts with NPM1^mut and MRD- can attain substantial OS benefit with Oral-AZA maintenance. An OS benefit was also observed with Oral-AZA vs PBO in pts in FLT3^mut at Dx, but outcomes may be confounded by co-occurring NPM1^mut, so further investigation is needed. MV analyses confirmed the independent prognostic influence of Oral-AZA, NPM1 and FLT3 mutations at Dx, cytogenetic risk at Dx, and post-IC MRD status on OS.