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.
Highlights
Minimal residual disease (MRD) is an important tool for assessment of response to therapy and disease follow-up in hematological malignancies
We report correlation between MRD levels www.impactjournals.com/oncotarget and patient outcome, using sensitive cDNA – based RQ-PCR assays of two molecular MRD markers, Wilms’ Tumor 1 gene (WT1) overexpression and NPM1 mutations in a homogeneous population of acute myeloid leukemia (AML) patients aged 50 to 70 years treated in the multicentric randomized ALFA-0701 trial, which tested the addition of gemtuzumab ozogamicin (GO) to conventional chemotherapy
Our results showed that WT1 MRD was associated with an increase cause specific hazard of relapse and with a shorter overall survival (OS) from complete remission (CR)
Summary
Minimal residual disease (MRD) is an important tool for assessment of response to therapy and disease follow-up in hematological malignancies. MRD monitoring is used for European LeukemiaNet www.impactjournals.com/oncotarget. Real-time quantitative PCR (RQ-PCR) and multiparameter flow cytometry (MFC), can be used to monitor MRD in www.impactjournals.com/oncotarget. Chimeric fusion genes, such as PMLRARA, RUNX1-RUNXT1 or CBFβ-MYH11, are reliable markers for MRD evaluation by RQ-PCR. These markers are present in only 20-25% of AML cases. As nucleophosmin 1 gene mutations (NPM1mut) is a frequent marker, present in 30% of all AML patients and in 50% of those with normal karyotype, mutation-specific RQ-PCR assays have been developed for MRD monitoring [6,7,8,9,10]. We report on the correlation between MRD response and patient’s outcome and the effect of GO on MRD levels
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