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.
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.
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.
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.
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.
Triple therapy for CLL, AVO, is highly active and has very high MRD-negative rates compared to other studies using Ven+Obi or BTKi therapy alone. The battle between indefinite BTKi therapy vs more intense combination therapy will continue as we don’t know if one paradigm is better from a bigger picture.
This study was done with and without obinutuzumab, both arms beat obinutuzumab and chlorambucil. There were more deaths in the obinutuzumab arm even though it was superior because of COVID, so it is immunosuppressive.
Ibrutinib delays disease progression for asymptomatic patients but has no overall survival (OS) benefit; hence, still watch and wait in those patients.
This study compared double induction vs. standard induction and a reduced dose of daunorubicin 90mg/m2 vs. 60mg/m2. The reduced dose was just as efficacious and double inductions do not seem to be beneficial. Probably less is more in this setting and once you get the CR, one can move forward with consolidation and start planning for transplant.
Compelling study showing Asciminib vs. investigator’s choice TKi. Asciminib was better tolerated and with deeper molecular responses. This may become a preferred option for many new chronic myeloid leukemia (CML) patients. Cost may be an issue.
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