NPM1 MRD Status Is a Dominant Predictor of AML Relapse After AlloHCT

Disease relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains the leading cause of treatment failure for patients with acute myeloid leukemia (AML), but measurable residual disease (MRD) testing after first complete remission can be a powerful predictor of relapse, according to an analysis published in Bone Marrow Transplantation.1

Pretransplant NPM1 MRD testing significantly predicts relapse risk in acute myeloid leukemia.

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NPM1 mutations are one of the most common genetic mutations in AML, occurring in about 30% of adult cases.2 While current clinical guidelines for NPM1 MRD testing often rely on measuring mutant RNA transcript levels,3 there is a continuous effort to improve the sensitivity and accuracy of testing, particularly using DNA-based next-generation sequencing (NGS) assays. Identifying patients with high-risk MRD before transplant is crucial for personalizing the conditioning regimen and posttransplant monitoring.

Pretransplant MRD Defines High-Risk AML

The researchers investigated the prognostic value of a highly sensitive DNA-based NGS assay to detect mutated NPM1 in the blood of patients with AML after their first complete remission (CR1) immediately before undergoing alloHCT. A total of 190 adults from the Pre-MEASURE study who received alloHCT for NPM1-mutated AML during CR1 between 2013 and 2019 were included. The researchers used a commercially available research testing kit.

Of the patients who had successful NPM1 NGS MRD testing, 26% relapsed and 34% died after receiving alloHCT.

Pretransplant MRD positivity for the NPM1 mutation was associated with a significantly increased rate of relapse and decreased overall survival (OS) compared with those who tested negative. The 3-year relapse rate was 52% for MRD-positive patients vs 20% for MRD-negative patients (HR, 4.3; P < .001). The 3-year OS rate was 34% for MRD-positive patients vs 71% for MRD-negative patients (HR, 3.6; P < .001).

“Some of this risk could be mitigated by conditioning regimen, with higher intensity regimens being associated with decreased relapse and improved survival in NPM1 MRD positive patients,” the authors noted.

In addition, the risk of relapse and death was dose-dependent, with the risk increasing along with the proportion of NPM1-mutant DNA.

Prognostic Dominance: NPM1 vs FLT3-ITD Comutation

Because NPM1 mutations often co-occur with FLT3 internal tandem duplication (FLT3-ITD), the researchers also divided patients based on whether they were commutated for FLT3-ITD at baseline (n = 123; 66%). The increased risk of relapse for patients with NPM1-mutant who were MRD positive, regardless of their baseline FLT3-ITD status. At 3 years, patients who tested MRD positive for NPM1 had an increased cumulative incidence of relapse (CIR) regardless of FLT3-ITD status at baseline.

CIR was equivalent between patients with NPM1 present and with NPM1 and/or FTL3-ITD present (45% vs 44%, respectively), and so was OS (45% vs 46%) at 3 years. MRD-negative patients also had similar CIR and OS.

NPM1 MRD testing identified 6 relapse events, while FLT3-ITD MRD testing only identified 1 relapse event.

“…Our results support findings that validate the prognostic value of pre-transplant NPM1 MRD and support prioritizing it over FLT3-ITD when only one test is available,” the researchers concluded.

References

1. Al-Ali RW, Gui G, Ravindra N, et al. Measurable residual mutated NPM1 before allogeneic transplant for acute myeloid leukemia. Bone Marrow Transplant. Published online November 4, 2025. doi:10.1038/s41409-025-02757-1

2. Diamantidis MD, Vlachou MS, Katsikavela A, Kalomoiri S, Bartzi V, Ikonomou G. NPM1-mutated AML: deciphering the molecular and clinical puzzle in the era of novel treatment strategies. Cancers (Basel). 2025;17(13):2095. doi:10.3390/cancers17132095

3. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377. doi:10.1182/blood.2022016867