NPM1-Mutated Myeloid Neoplasms: Updated Outcomes with High-Intensive Chemotherapy Regardless of the Blast Percentage
Authors: Gener-Ricos Georgina , Bataller Alex , Almanza-Huante Emmanuel , Chien Kelly S. , Hammond Danielle E. , Sasaki Koji , DiNardo Courtney D. , Kadia Tapan M. , Daver Naval , Borthakur Gautam , Issa Ghayas C. , Short Nicholas J. , Garcia-Manero Guillermo , Montalban-Bravo Guillermo 
Published: December 2023

Background: The most recent World Health Organization (WHO) classification has stablished NPM1-mutated myeloid neoplasms (MNs) to be acute myeloid leukemia (AML) regardless of bone marrow (BM) blast percentage. In contrast, the new International Consensus Classification (ICC) considers NPM1-mutant MNs as AML only in the presence of ≥10% BM blasts. Previous studies from our group and others have reported favorable outcomes of NPM1-mutant MNs with &lt;20% blasts when treated with intensive chemotherapy. Here we seek to further evaluate clinical outcomes of this group of pts.
Methods: We retrospectively re-evaluated the patient's characteristics, disease features and outcomes in patients with NPM1-mutated oligoblastic AML (&lt;20% blasts) (oligo-AML). In addition, we also evaluated the clinicopathological characteristics in a cohort of patients with secondary NPM1-mutated AML (sAML), the majority of which had received treatment before progressing to AML. The Kaplan-Meier method was used to estimate the overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS).
Results: We identified 54 patients with NPM1-mutated oligo-AML. Median age was 62 years (range, 19-87) and most of them were female (59%). Median bone marrow (BM) blasts was 10%. Most patients could have been classified as CMML-2 (7/54, 13%), MDS-EB1 (7/54, 13%) and MDS-EB2 (24/54, 44%), based on the 2016 WHO classification. Median NPM1 variant allele frequency (VAF) was 0.38 (range, 0.05-0.52) and 38 patients (70%) had normal karyotype. These patients harbored a median of 1 co-mutation (range, 0-5), predominantly DNA methylation pathway, such as DNMT3A (31%) or TET2 (23.5%), or RAS pathway, mainly NRAS (25.5%), but rarely exhibited mutations in other functional pathways (Figure 1). Twenty-three patients (43%) progressed to AML with &gt;20% BM blasts within a median of 10.7 months. Of 54 patients, 46 patients (82%) received chemotherapy-based regimens [61% low-intensity chemotherapy (LI-Chemo) based on hypomethylating agents or low-dose cytarabine and 21% high-intensity chemotherapy (HI-Chemo)] and 21 patients (39%) received a stem cell transplant (SCT). With a median follow up of 67.6 months (LI-Chemo of 48.3 months; HI-Chemo of 71.4 months), the median OS, EFS and RFS was 30.4 months, 30.4 months and 14.7 months for the LI-Chemo group, respectively, but median OS, EFS and RFS were not reached (NR) for HI-Chemo group. However, when compared by age, patients with &lt;60 years had trends to have better OS with LI-Chemo or HI-Chemo than patients aged ≥60 years (Figure 2). In addition, 5 patients received chemotherapy-based regimens with venetoclax, however improved OS was only seen when combined with HI-Chemo and SCT (n=2, with a median OS NR without deaths, likely related to younger people).
In parallel, we identified 31 patients with NPM1-mutated sAML progressed from oligo-AML. Median age was 67 years (range, 31-83) and female were 58%. Median BM blasts was 40%. Median NPM1 VAF was 0.38 (range, 0.02-0.56). Most patients did not exhibit clonal cytogenetic evolution and remained with a diploid karyotype (65%). Seventy-four percent of patients (17 out of 23 tested) had known prior NPM1-mutated oligo-AML, and in 6 patients NPM1 mutation was acquired at progression. Median number of co-mutations were 3 (range, 0-7). DNTM3A (65%) or TET2 (33.3%) mainly co-occurred with RAS pathway mutations, and in particular FLT3-ITD (26.7%) or FLT3-TKD (13.3%) (Figure 1). Eleven of 31 patients (36%) received LI-Chemo regimens, whereas 15 of 31 patients (48%) had HI-Chemo regimens. Nine patients (29%) underwent SCT. With a median follow up of 39.6 months (LI-Chemo of 55.5 months; HI-Chemo of 39.4 months), the median OS, EFS and RFS was 11.4 months, 12.4 months and NR for LI-Chemo, respectively; and 13.2 months, 6.5 months and NR for HI-Chemo, respectively. No significant differences were seen depending on the number of therapies received for previous oligo-AML. Previously untreated patients who received a venetoclax-based regimen with SCT had prolonged survival (n=4, median OS NR, with median follow up of 41 months).
Conclusions: NPM1-mutated acute myeloid leukemia can be treated as such irrespective of blasts burden. For these cases, especially young patients, should be treated with intensive chemotherapy and subsequent allogeneic stem cell transplant as a clear curative approach.