# Predictive capacity of peritransplant measurable residual disease thresholds in NPM1-mutant acute myeloid leukemia

## TL;DR

This study shows that measuring residual disease levels around the time of a bone marrow transplant can better predict outcomes in a specific type of leukemia.

## Contribution

The study introduces peritransplant NPM1-MRD thresholds as more accurate outcome predictors than traditional methods in NPM1-mutant AML.

## Key findings

- Pretransplant MRD negativity strongly predicts favorable long-term survival in NPM1-mutant AML patients.
- Combining MRD measurements before and after HCT improves prediction of patient outcomes compared to conventional methods.
- Two MRD risk scores derived from longitudinal data effectively stratified patient survival outcomes.

## Abstract

•NPM1-MRD thresholds distinguish MRD-high patients with poor prognosis from MRD-low and MRD-negative patients with favorable outcomes.•Peritransplant NPM1-MRD thresholds are more accurate predictors of outcome than traditional binary or log-change–based MRD interpretation.

NPM1-MRD thresholds distinguish MRD-high patients with poor prognosis from MRD-low and MRD-negative patients with favorable outcomes.

Peritransplant NPM1-MRD thresholds are more accurate predictors of outcome than traditional binary or log-change–based MRD interpretation.

Measurable residual disease (MRD) monitoring for mutated NPM1 is increasingly used to guide treatment decisions in patients with acute myeloid leukemia (AML) carrying this mutation. NPM1-MRD positivity after induction has been shown to identify patients who may benefit from allogeneic hematopoietic cell transplantation (allo-HCT), and NPM1-MRD monitoring after allo-HCT can detect early relapse, enabling the prompt initiation of salvage therapy. However, recommendations for clinical decision-making based on peritransplant NPM1-MRD levels are missing. In this study, we retrospectively analyzed 172 patients with NPM1-mutant AML treated at 2 German centers to explore the predictive values of NPM1-MRD measured before and after allo-HCT. We found that pretransplant MRD negativity was a strong predictor of favorable long-term overall survival (OS). In contrast, patients with positive and negative NPM1-MRD status at day 30 after HCT showed comparable OS. Finally, statistically derived NPM1-MRD thresholds effectively stratified MRD-high and MRD-low patient groups with differential outcome, with 2 peritransplant MRD risk scores obtained by longitudinal integration. First, a combined score using MRD measurements before HCT and at day 30 HCT was used to guide early reduction of immunosuppression (concordance index [C-index], 0.737). Second, a combined score using MRD measurements before HCT and at day 30 and day 100 after HCT was used to guide later post-HCT interventions (C-index, 0.841; stratified 2-year OS groups, 100%, 90.1%, 57.1%, and 25.7%; P < .0001). This approach predicted OS better than age, FLT3-ITD status, or morphological remission status. We propose that in the peritransplant setting, NPM1-MRD thresholds are superior to conventional MRD analysis based on binary or log-step change data.