Measurable Residual Mutated NPM1 before Allogeneic Transplant for Acute Myeloid Leukemia

Introduction NPM1 mutations, seen in ∼30% of adult acute myeloid leukemia (AML) cases, often co-occur with FLT3 internal tandem duplication ( FLT3 -ITD). Measurable residual disease (MRD) testing before allogeneic hematopoietic cell transplant (alloHCT) for persistence of mutated NPM1 or FLT3 -ITD in AML patients in complete remission (CR) can identify those at highest risk of relapse and death. Quantitative RT-PCR assays are currently recommended for NPM1 MRD testing, while FLT3 -ITD is DNA-based next generation sequencing (NGS). Objectives DNA-based NGS assays for NPM1 MRD testing may have several advantages but require validation. This study aimed to evaluate these assays in blood from patients with AML in CR1 before alloHCT. Methods 190 of 531 patients from the Pre-MEASURE study (PMID: 36881031), aged ³18, with NPM1 -mutated AML who underwent alloHCT in CR1 at a CIBMTR reporting site in the USA between 2013-2019, were randomly selected for MRD testing using a commercially available NGS assay (Invivoscribe, San Diego, CA), validated to detect NPM1 MRD down to a variant allele fraction (VAF) of 0.005%. The results were compared with an anchored multiplex PCR-based (AMP) targeted NGS assay and, where available, FLT3 -ITD MRD results. Results NPM1 NGS MRD testing was successful in 186/190 patients, detecting NPM1 insertion variants in 71 (38%) patients with a median VAF of 0.003% (range: 0.0002-2.1%). The presence of NPM1 MRD pre-alloHCT was associated with significantly increased rate of relapse (40% vs 15% at 3 years; HR=3.4; P<0.001) and decreased overall survival (OS) (50% vs 75% at 3 years; HR=2.9; P<0.001). In multivariable analysis, residual NPM1 MRD burden pre-alloHCT was associated with risk of relapse and mortality in a dose-dependent manner ( Figure 1 ). 123 (66%) patients were co-mutated for FLT3 -ITD at baseline and had undergone prior testing for FLT3 -ITD MRD (PMID: 38696205). When MRD was defined by the presence of NPM1 alone vs NPM1 and/or FLT3 -ITD, relapse and OS at 3 years were similar ( Figure 2 ). These findings were confirmed in the full Pre-MEASURE cohort (n=317) using the AMP assay. NPM1 MRD positive patients who received nonmyeloablative or reduced-intensity conditioning (RIC) without melphalan (mel) had increased risk of relapse or mortality compared to patients who received myeloablative conditioning or RIC with mel, independent of FLT3 -ITD co-mutational status ( Figure 3). Conclusions In patients with NPM1 -mutated AML, the detection of residual NPM1 variants in pre-alloHCT blood during CR1 using a highly sensitive DNA-based assay is associated in a dose-dependent manner with a significantly increased risk of relapse and mortality post-alloHCT. This risk can be partly mitigated by conditioning regimen. For patients with both NPM1 and FLT3 -ITD mutations at diagnosis, NPM1 should be prioritized as the primary target for MRD assessment if only one test is feasible.

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