Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: Results from the AMLSG 09-09 trial

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1^mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1^mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1^mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1^mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1^mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1^mut TL log₁₀ reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1^mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P 5.01). The better reduction in NPM1^mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P 5.009). In conclusion, the addition of GO to intensive chemotherapy in NPM1^mut AML resulted in a significantly better reduction in NPM1^mut TLs across all treatment cycles, leading to a significantly lower relapse rate.