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Acute myeloid leukemia

The prognostic potential of monitoring disease dynamics in NPM1-positive acute myeloid leukemia

Leukemia volume 33, pages 1531–1534 (2019)Cite this article

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Highly sensitive quantitative real-time PCR (qPCR) measurements of leukemia-specific alterations, such as reciprocal translocations (e.g. RUNX1-RUNX1T1) or mutations (e.g. NPM1), enables monitoring of treatment response and measurable residual disease (MRD) levels in acute myeloid leukemia (AML) [1]. Because of its high prevalence (>30% of all AML patients), mutated NPM1 (NPM1mut) is of particular importance. The NPM1mut cell burden was found to correlate with relapse risk and survival in AML [2, 3]. However, such approaches are widely limited to static analyses at pre-defined time points, not explicitly analyzing the dynamics of treatment response, remission, and relapse. Based on time course data from 340 NPM1 mutant-AML patients we investigated, whether response dynamics yield additional prognostic information, specifically whether slope and depth of initial MRD decrease correlates with long-term outcome. Herein, our focus was the identification of prognostic factors to improve relapse risk assessment of individual patients.

First, we analyzed the pairwise correlations (Supplementary Table S1) of typical treatment response dynamic characteristics, namely the elimination slope (α), the minimal NPM1 level after primary treatment (induction + consolidation) within 6 months after treatment start (n), the maximum slope during relapse phase (β), the time until molecular relapse (d), and the overall survival time (s). The frequency distributions of these five characteristics within the patient population are visualized in Supplementary Figure S2. We demonstrate that time until relapse (d) and survival time (s) are positively correlated with correlation coefficient ρ = 0.73 (95% confidence interval: [0.51; 0.86]) and that these two parameters themselves anti-correlate with the relapse slope (β) with correlation coefficients ρ = −0.64 [−0.76; −0.50] and ρ = −0.56 [−0.76; −0.27], respectively (Supplementary Figure S3A and B). This indicates that a rapidly evolving relapse usually occurs earlier after therapy start than a slower one, and that this leads to shorter survival. Furthermore, we identified a moderate negative correlation ρ = −0.48 [−0.65; −0.26] between the NPM1 level after primary treatment (n) and the time until relapse (d), pointing toward the already known prognostic value of NPM1 levels for relapse incidence [3,4,5,6] (Supplementary Figure S3C).

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Acknowledgements

This work has been supported by the German Federal Ministry of Education and Research (www.bmbf.de/en/), Grant number 031A424 “HaematoOpt”.

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Authors and Affiliations

  1. Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, TU Dresden, Dresden, Germany

    H. Hoffmann, I. Glauche & I. Roeder

  2. Medical Clinic and Polyclinic I, University Hospital Dresden Carl Gustav Carus, TU Dresden, Dresden, Germany

    C. Thiede, M. Kramer, C. Röllig, G. Ehninger & M. Bornhäuser

  3. National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany

    M. Bornhäuser & I. Roeder

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  1. H. Hoffmann
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  2. C. Thiede
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Correspondence to I. Roeder.

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CT is CEO and co-owner of AgenDix GmbH, a company performing molecular diagnostics. Other authors declare that they have no conflict of interest.

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Hoffmann, H., Thiede, C., Glauche, I. et al. The prognostic potential of monitoring disease dynamics in NPM1-positive acute myeloid leukemia. Leukemia 33, 1531–1534 (2019). https://doi.org/10.1038/s41375-018-0371-y

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