Influence of Nucleophosmin (NPM1) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration

Author(s): Claudia Tregnago, PhD¹, Maddalena Benetton, PhD¹, Rhonda E. Ries, MS², Jack H. Peplinski, MS², Todd A. Alonzo, PhD³, Derek Stirewalt, MD², Megan Othus, PhD⁴, Nicolas Duployez, MD⁵, Edwin Sonneveld, PhD⁶, Jonas Abrahamsson, MD⁷, Linda Fogelstrand, MD, PhD^8,9, Nils von Neuhoff, PhD¹⁰, Henrik Hasle, MD, PhD¹¹, Dirk Reinhardt, MD, PhD¹⁰, Soheil Meshinchi, MD, PhD², Franco Locatelli, MD, PhD¹², Martina Pigazzi, PhD^1,13;

Source: https://doi.org/10.1200/JCO-24-01715

Dr. Anjan Patel's Thoughts

It does not seem that all NPM1 mutations are created equally. Type A and B mutations had favorable outcomes and type D mutations do much worse, something to consider when risk stratifying in patients with AML.

PURPOSE

Several genomic subsets of NPM1 mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity, NPM1 mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of NPM1 genotypes on patient’s outcomes and interrogated the underlying biology of the different subtypes.

MATERIALS AND METHODS

Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known NPM1 genotype and available outcome were selected for this study. Diverse NPM1 variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the NPM1 variants was studied.

RESULTS

Evaluation of clinical outcome on the basis of NPM1 genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D v 86% for type non-D, P = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3; P = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed NPM1-D mRNA and protein, mediating peculiar mitochondrial gene expression.

CONCLUSION

The evaluation of specific NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.

Author Affiliations

¹ Department of Women’s and Children’s Health, Onco-hematology Lab and Clinic, University of Padova, Padova, Italy; ² Translational Sciences and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA; ³ University of Southern California, Los Angeles, CA; ⁴ SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Center, Seattle, WA; ⁵ Laboratory of Hematology, Lille University Hospital, Lille, France; ⁶ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; ⁷ Institution for Clinical Sciences, Department of Pediatrics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; ⁸ Department of Laboratory Medicine, Sahlgrenska Academy University of Gothenburg, Gothenburg, Sweden; ⁹ Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden; ¹⁰ Department of Pediatric Hematology and Oncology, University Hospital Essen, Essen, Germany; ¹¹ Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark; ¹² Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Catholic University of the Sacred Heart, Rome, Italy; ¹³ Foundation Istituto Ricerca Pediatrica (IRP), Padova, Italy

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