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

Orca-T vs allogeneic hematopoietic stem cell transplantation (Precision-T): a multicenter, randomized phase 3 trial Open Access

This is an impressive advance in allo transplant, Orca-T cutting moderate–severe cGVHD dramatically (≈13% vs 44%) and nearly doubling cGVHD-free survival at 1 year (78% vs 38%) while also lowering NRM and serious infections is hard to ignore. Overall survival (OS) isn’t statistically different yet, but the combination of better disease control, less toxicity, and preserved immune reconstitution makes this feel like a meaningful step toward safer, more “engineered” transplants rather than just better immunosuppression.

Asciminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4FIRST trial Open Access

This is starting to look like a real frontline disruptor in chronic myeloid leukemia (CML), asciminib showing a pretty striking ~22% absolute improvement in MMR at 96 weeks vs investigator-selected TKIs (and nearly 30% over imatinib) with a cleaner tolerability profile makes a strong case for moving beyond ATP-competitive tyrosine kinase inhibitors (TKIs) upfront. The efficacy signal is consistent across depths of response and durability looks excellent, with fewer discontinuations, overall survival (OS) will take time, but this feels very competitive as a new standard option.

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia

CLL17 shows that fixed‑duration venetoclax–obinutuzumab or venetoclax–ibrutinib is noninferior to continuous ibrutinib upfront, with 3‑year PFS ≈80% across all arms. The big difference is depth of response, undetectable MRD was 73% with venetoclax–obinutuzumab, 47% with venetoclax–ibrutinib, and 0% with ibrutinib. Toxicities tracked with mechanism (more cytopenias/infusion reactions with ven‑obinutuzumab, more cardiac events with ibrutinib). Overall, this strongly supports time‑limited therapy as a frontline standard for many chronic lymphocytic leukemia (CLL) patients.

BRUIN CLL-313: Randomized Phase III Trial of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Pirtobrutinib demonstrated superiority over bendamustine rituximab in IRC assessed progression free survival (PFS) in treatment naïve CLL/SLL, with a 24 month PFS rate of 93.4% versus 70.7%. Overall survival trends favored pirtobrutinib, despite the study design allowing for crossover. Who would have thought this was coming????

Acalabrutinib treatment for older (aged ≥80 years) and/or frail patients with CLL: primary end point analysis of the CLL-Frail trial Open Access

Acalabrutinib in patients aged ≥80 years demonstrated 12-month progression-free (PFS) and overall survival (OS) rates of 93.3% and 95.7%, respectively, after a median follow-up of 19 months. Adverse events were severe but rarely included major bleeding or atrial fibrillation. Patient-reported quality of life improved, including amerlioration of frailty.