Can Next-Generation Sequencing Detect Mutant NPM1 Measurable Residual Disease in AML?

A study from Erasmus Medical Center in Rotterdam, Netherlands, investigated the benefits of next-generation sequencing (NGS)-based detection of mutant NPM1 (mNPM1) measurable residual disease (MRD) among patients with acute myeloid leukemia (AML). The findings were presented at the Society of Hematologic Oncology 2024 Annual Meeting.

Currently, mNPM1 MRD is detected via quantitative reverse transcription polymerase chain reaction (RT-qPCR). “However, RT-qPCR requires cDNA, which can influence outcome due to variations in gene expression levels of mNPM1 in AML patients, and different assays are needed for each specific mutation,” the authors noted. NGS may be advantageous compared with RT-qPCR because it uses DNA, “a more stable input source not dependent on gene expression levels,” and can detect all NPM1 variants using a single assay, according to the authors.

For this study, the researchers used RT-qPCR to evaluate 119 patients with mNPM1 AML in complete remission after induction therapy, and they used NGS in 310 patients. The investigators compared detection of mNPM1 MRD, along with the influence of concomitant FMS‐like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations on efficacy.

RT-qPCR and NGS were highly correlated (r=0.97 and 0.98, respectively). The study found that >2% mNPM1/ABL1 according to RT-qPCR was the best predictor of relapse (P=0.016), and this was comparable to variant allele frequency >0.01% by NGS (P=0.002).

“Applying this novel MRD threshold, additional mNPM1 AML cases were identified with similarly high relapse rates,” the investigators noted. Additionally, mNPM1 MRD was found to have an enhanced prognostic significance in patients with a FLT3-ITD mutation (P=0.001).

“NGS-based detection of mNPM1 MRD on DNA is an attractive alternative to RT-qPCR,” the authors concluded. “Furthermore, the prognostic significance of mNPM1 MRD is greatest in AML patients with concomitant FLT3-ITD.”

Reference

Vonk CM, Grob T, Rijken M, et al. Advantages and prognostic value of next-generation sequencing–based mutant NPM1 measurable residual disease detection in AML. Abstract #AML-464. Society of Hematologic Oncology 2024 Annual Meeting; Sept. 4-7, 2024; Houston, Texas.