P498: clinical and biological markers associated with long-term survival for patients with acute myeloid leukemia (aml) in remission after chemotherapy in the quazar aml-001 trial of oral azacitidine

Background: In the randomized, phase 3 QUAZAR AML-001 trial, oral azacitidine (Oral-AZA) significantly prolonged overall survival (OS) compared with placebo (PBO) (median OS 24.7 vs 14.8 months [mo], respectively) in older patients (pts) with AML in first remission after intensive chemotherapy (IC). At an updated data cutoff performed in Sep 2020, 34.9% of pts in the Oral-AZA arm and 24.4% of pts in the PBO arm remained alive at ≥3 y from randomization. Aims: Assess clinical and biological variables associated with long-term survival (LTS) in QUAZAR AML-001. Methods: In all, 472 pts were randomized 1:1 to receive Oral-AZA 300 mg or PBO QD ×14d/28d within 4 mo of achieving first complete remission (CR) or CR with incomplete blood count recovery (CRi) after IC. The primary endpoint was OS, time from randomization until death, withdrawal of consent, or loss to follow-up. The LTS cohort comprised pts who were alive ≥3 y from randomization as of Sep 2020 and the non-LTS cohort included pts who died or were censored before 3 y. Variables assessed for association with LTS were diagnostic (Dx [pre-IC]) features (AML subtype, cytogenetic risk, NPM1 and FLT3 mutations [mut]); pre-study treatment (Tx) variables (response to IC [CR/CRi], receipt of consolidation, number of consolidation cycles); baseline (BL) demographic and disease characteristics, hematologic parameters (red blood cells [RBCs], hemoglobin, platelets, and leukocyte subsets), and measurable residual disease (MRD) status; and post-BL variables (MRD response [conversion from MRD+ at BL to MRD– on study], timing of MRD– [MRD– response on-study vs BL MRD–], and receipt of transplant after Tx discontinuation [D/C]). Associations of LTS with bone marrow immune parameters (CD3, CD4, and CD8 T-cell counts, and expression of PD-1/TIM-3 T-cell exhaustion markers) were investigated in a subset of pts (n=108). Variables were compared within Tx arms (LTS vs non-LTS) in univariate analyses with P values corrected for multiple testing. A logistic multivariable regression analysis of the effects of prognostic BL covariates on LTS was performed. Results: The LTS cohort included 83/238 pts (34.9%) in the Oral-AZA arm and 57/234 pts (24.4%) in the PBO arm. Within both arms, factors significantly associated with LTS were intermediate (Int)-risk cytogenetics and NPM1mut at Dx, and MRD response (MRD+ to MRD–) on study (Figure). MRD response rate was 2-fold higher with Oral-AZA vs PBO (37% vs 19%, respectively), and while early attrition was more common in the PBO arm, most MRD responses occurred within 6 mo. Factors significantly associated with LTS only in the PBO arm were BL (post-IC) MRD– status and receipt of transplant after Tx D/C. No significant associations were observed between BL hematological or immune parameters and LTS. The multivariable analysis (MVA) confirmed Oral-AZA Tx as independently significantly predictive of LTS vs PBO. Other covariates significantly associated with LTS in MVA were Int-risk cytogenetics and NPM1mut at Dx, and MRD– status at BL. Image:Summary/Conclusion: Oral-AZA Tx was significantly associated with LTS vs PBO. In univariate analysis, Int-risk cytogenetics and NPM1mut at Dx, and MRD response on-study, were significantly prognostic of LTS in both arms, whereas MRD– status at BL (post-IC) was associated with LTS only in the PBO arm.