MRD assessed byWT1andNPM1transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin

Abstract

We analysed the prognostic significance of minimal residual disease (MRD) level in adult patients with acute myeloid leukemia (AML) treated in the randomized gemtuzumab ozogamicin (GO) ALFA-0701 trial.Levels of WT1 and NPM1 gene transcripts were assessed using cDNA-based real-time quantitative PCR in 183 patients with WT1 overexpression and in 77 patients with NMP1 mutation (NPM1mut) at diagnosis.Positive WT1 MRD (defined as > 0.5% in the peripheral blood) after induction and at the end of treatment were both significantly associated with a higher risk of relapse and a shorter overall survival (OS). Positive NPM1mut MRD (defined as > 0.1% in the bone marrow) after induction and at the end of treatment also predicted a higher risk of relapse, but did not influence OS. Interestingly, the achievement of a negative NPM1mut MRD was significantly more frequent in patients treated in the GO arm compared to those treated in control arm (39% versus 7% (p=0.006) after induction and 91% versus 61% (p=0.028) at the end of treatment). However, GO did not influence WT1 MRD levels.Our study supports the prognostic significance of MRD assessed by WT1 and NPM1mut transcript levels and show that NPM1 MRD is decreased by GO treatment.

Minimal Residual Disease in Acute Myeloid Leukemia of Adults: Determination, Prognostic Impact and Clinical Applications.

“…Outcomes of these groups differed significantly in terms of OS (59±4%, 59±4%, 72±5%), leukemia free survival (24±7%, 46±4%, 65±5%) and relapse probability (CIR 72±4%, 45±4%,25±5%). In line with these data, the RQ-PCR positivity of WT1-MRD (defined as >0.5% in peripheral blood) after induction, was associated with a higher risk of relapse and a shorter OS in a further series of 183 AML patients with WT1 overexpression 38. The post induction time-point was confirmed in 45 AML patients, in whom a post-inductionWT1 log clearance < 1.96 predicted disease recurrence 39.…”

Prognostic significance of diagnosed WT1 level in acute myeloid leukemia: a meta-analysis

“…More cohort studies concerning diagnosed WT1 H are needed in an effort to further modify the pooled estimates to a certain extent, especially for the patients with non-M3 AML or CN-AML. Moreover, it is also meaningful for us to clarify the relationship between the prognosis and WT1 levels after induction and consolidation chemotherapy [31][32][33][34]. Further studies investigating WT1-specific vaccine and the biologic role of WT1 function in leukemia are greatly needed as well.…”

Assessment of Minimal Residual Disease in Standard-Risk AML

“…3,13,14 In addition, the risk of relapse may be better defined with the use of leukemia-specific molecular markers (e.g., mutated NPM1) as targets for detection of submicroscopic levels of leukemia, so-called minimal residual disease, after therapy. 15 Although the presence of minimal residual disease can provide prognostic information, [16][17][18][19][20][21][22] it is unclear whether such identification is useful in the context of systematic molecular profiling. Moreover, questions have been raised about the assessment of minimal residual disease in routine practice, given the clonal complexity of AML.…”