The prognostic impact of multiple RUNX1 mutations and RUNX1 wild-type loss in patients with RUNX1-mutated AML

On 28^th July 2017, in an article published in Leukemia, Anna Stengel from the MLL Munich Leukemia Laboratory, Munich, Germany, and colleagues reported results of their study, which aimed to characterize the associated genetic alterations and the prognostic significance of multiple Runt-related Transcription Factor 1 (RUNX1)  mutations (mut) and RUNX1 Wild-Type (WT) loss in patients with RUNX1 mutated Acute Myeloid Leukemia (AML).

In this study, the authors analyzed Bone Marrow (BM) or Peripheral Blood (PB) samples from 467 AML patients (median age = 72 years) harboring a RUNX1 mutation using Chromosome Banding Analysis (CBA) and next-generation amplicon sequencing of RUNX1. Patients were split into subgroups including cases with RUNX1 WT loss (53/467), > 1 RUNX1mut (93/467), or 1 RUNX1mut and conservation of the WT allele (321/467).

The key results of the study were:

• Trisomy 8 was more abundant in cases with 1 RUNX1mut compared to cases with RUNX1 WT loss; 66% vs 31%; P = 0.022
• Compared to cases with 1 RUNX1mut, trisomy 13 was more abundant in cases with RUNX1 WT loss; 15% vs 62%; P < 0.001
• The median number of additional mutations in 1 RUNX1mut & > 1 RUNX1mut and RUNX1 WT loss were 2 and 3, respectively
• The most frequent additionally mutated genes observed in 163 RUNX1mut patients included: SRSF2 (39%), ASXL1 (36%), DNMT3A (19%), IDH2 (17%), SF3B1 (17%), TET2 (17%), and BCOR (16%)
• Cases with RUNX1 WT loss showed a significantly higher frequency of ASXL1 mutations compared to the other cases (1 RUNX1mut and > 1 RUNX1mut); 50% vs 29%, P = 0.009
• Compared to 1 RUNX1mut, median Overall Survival (OS) was significantly lower in patients with RUNX1 WT loss (P = 0.002) and > 1 RUNX1mut (P = 0.048); 22 vs 5 vs 14 months
• OS was negatively impacted by RUNX1 WT loss (HR = 1.6, P = 0.024), ≥ 2 additional mutations (HR = 1.9, P = 0.019) and ASXL1 mutations (HR = 1.6, P = 0.030)

Stengel et al. concluded by noting that “the number of RUNX1 mutations, the number of accompanying mutations and the type of accompanying mutations is biologically and clinically relevant” in patients with RUNX1 mutated AML.

Abstract

RUNX1-mutated acute myeloid leukemia (AML) show a distinct pattern of genetic abnormalities and an adverse prognosis. We analyzed the impact of multiple RUNX1 mutations and RUNX1 wild-type (WT) loss in 467 AML with RUNX1 mutations (mut): (1) RUNX1 WT loss (n=53), (2) >1 RUNX1mut (n=94) and (3) 1 RUNX1mut (n=323). In 1 RUNX1mut, +8 was most frequent, whereas in WT loss +13 was the most abundant trisomy (+8: 66% vs 31%, P=0.022; +13: 15% vs 62%, P<0.001). Analyses of 28 genes in 163 selected cases revealed SRSF2 (39%), ASXL1 (36%), DNMT3A (19%), IDH2 (17%) and SF3B1 (17%) as most frequently mutated genes. RUNX1 WT loss showed a higher frequency of ASXL1mut compared with the other cases (50% vs 29%, P=0.009). Median overall survival (OS) in the total cohort was 14 months. WT loss (OS: 5 months) and >1 RUNX1mut (14 months) showed an adverse impact on prognosis compared with 1 RUNX1mut (22 months; P=0.002 and 0.048, respectively). Mutations in ASXL1 and greater than or equal to2 additional mutations correlated with shorter OS (10 vs 18 months, P=0.028; 12 vs 20 months, P=0.017). Thus, the number of RUNX1mut, RUNX1 WT loss and the number and type of additional mutations is biologically and clinically relevant.