Measurable Residual Mutated NPM1 before Allogeneic Transplant for Acute Myeloid Leukemia
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".