High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) with mutated NPM1 is a newly recognized separate entity in the revised 2016 WHO classification, and is associated with a favorable prognosis. While previous studies have evaluated NPM1 in a binary fashion, we recently demonstrated a significant independent negative prognostic effect of high NPM1 mutant allele burden (VAF) at diagnosis in a cohort of de novo AML patients. Although the importance of minimal residual disease (MRD) monitoring in NPM1‐mutated AML has been well characterized, the potential relationship between diagnostic allele burden and MRD is unknown. We retrospectively evaluated for MRD at first remission (CR1). We used either next‐generation sequencing (NGS) [n = 71], and/or immunohistochemistry (IHC) for mutant NPM1 (NPM1c) [n = 60], in a subset of patients from our recently examined cohort. We identified a statistically significant positive correlation between the VAF at diagnosis, and at CR1 (Spearman r = 0.4, P = .006), and enrichment for MRD in high diagnostic VAF patients (P = .05), as previously defined. IHC‐positivity also correlated significantly with a higher median diagnostic NPM1 VAF (0.42 vs 0.39, P = .02), and with the VAF at CR1 (Spearman r = 0.7, P = .003). In multivariable analyses, both high diagnostic VAF (P = .003) and MRD (P = .02) were independent predictors of shorter event‐free survival (EFS). Our findings suggest a relationship between the NPM1 mutant allele burden at diagnosis, and the presence of MRD at first remission. Our findings support IHC as a potentially useful adjunctive tool for disease monitoring.

High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG)

“…We also verified if the allelic burden calculated for NPM1 mutations (variant allelic fraction, VAF ≤ 0.4 or > 0.4) could have an impact on outcome as recently reported [ 17 ] but we did not observe any correlation between NPM1 VAF and clinical outcome in our cohort of patients. By multivariate analysis ( Table 3 ), the positive effect on survival of an aberrant NPM1 and a double mutated CEBPA was confirmed.…”

Nucleophosmin mutations confer an independent favorable prognostic impact in 869 pediatric patients with acute myeloid leukemia

“…Moreover, their study showed that FLT3/ITD mutations in combination with the type-A mutation have much poorer prognosis when compared to FLT3/ITD mutations with type B and D cases. Recently, Patel et al 31,32 have reported that high variant allele frequency of NPM1 predict poor outcomes in de novo AML and the effect is not affected by FLT/ITD. Murine model studies have showed that mutant NPM1 and FLT3/ITD exhibit a marked and potent molecular synergy toward driving AML pathogenesis 33,34 .…”

Next‐generation sequencing for measurable residual disease detection in acute myeloid leukaemia

“…Recent studies utilizing NGS for the detection of MRD in AML vary greatly in their design and technical aspects. Cohorts studied have included AML patients undergoing allogeneic haematopoietic cell transplantation (alloHCT) (Getta et al , ; Kim et al , ; Thol et al , ; Zhou et al , ; Press et al , ), receiving standard induction chemotherapy (Klco et al , ; Gaksch et al , ; Jongen‐Lavrencic et al , ; Morita et al , ; Onecha et al , ; Rothenberg‐Thurley et al , ; Thol et al , ; Wong et al , ), receiving novel therapies in clinical trials (Levis et al , ), or having only specific mutations (Thol et al , ; Kohlmann et al , ; Salipante et al , ; Levis et al , ; Patkar et al , ; Zhou et al , ; Patel et al , ). Also, since most studies to date have had access to diagnostic samples, de novo leukaemia‐associated mutation discovery using remission samples alone remains an important unmet challenge.…”