RUNX1 Mutation Is Associated with Poor Outcome in Patients with Acute Myeloid Leukemia Receiving Allogeneic Stem Cell Transplantation

Background: Runt-related transcription factor 1 (RUNX1) is a key regulator of hematopoiesis, and aberrant expression of this gene can facilitate leukemogenesis. RUNX1 mutations (RUNX1^mut) are thought to carry a poor prognosis and have been recently incorporated into the risk stratification systems for acute myeloid leukemia (AML) by European LeukemiaNet (ELN) (Dohner et al. 2017) and National Comprehensive Cancer Network (NCCN et al. 2019). However, the clinical significance of this mutation after allogeneic stem cell transplantation (allo-SCT) is controversial with a recent study suggesting that allo-SCT may reverse the unfavorable influence of RUNX1^mut(Qin et al. 2017). In this study, we describe the prognostic impact of RUNX1^mutin patients with AML undergoing allo-SCT and compare the outcomes to ELN-defined adverse risk, RUNX1^wtAML patients and patients with intermediate risk AML.

Methods: We retrospectively reviewed our database of 407 patients who received allo-SCT at the Moffitt Cancer Center between 2013 and 2018. Only AML patients undergoing allo-SCT during first complete remission that had molecular information prior to transplant were included. This cohort was divided into three subgroups: 1) RUNX1^mutAML 2) ELN-defined adverse risk, RUNX1^wtAML and 3) ELN-defined intermediate risk AML. We utilized clinical data captured by BMT Research and Analysis Information Network (BRAIN). Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Cumulative incidence function was performed as defined by the Fine and Gray model. Kaplan-Meier analysis with log-rank test was used to estimate median overall survival (mOS) from the time of diagnosis.

Results: Among 407 AML patients reviewed, we identified 28 patients with RUNX1^mut, 71 adverse risk RUNX1^wtpatients, and 69 intermediate risk patients. Of the 28 patients (18 males/10 females) with RUNX1^mut, 53.6% were under age 60, two-thirds had de novo AML (dAML), and 92.9% had intermediate risk cytogenetics as defined by ELN 2017 at diagnosis. Baseline characteristics are described in Table 1.

Univariate analysis identified RUNX1^mutto be predictive of inferior OS compared to the intermediate risk cohort (HR 2.29, 95% CI 1.12-4.64, p=0.022). Subsequent multivariate regression using covariates of age, sex, AML type, lines of therapy prior to allo-SCT, and conditioning regimen confirmed RUNX1^mutas an independent covariate for reduced OS (HR 2.51, 95% CI: 1.18-5.33, p=0.016). At a median follow-up of 29.3 months for the entire cohort, Kaplan-Meier analysis confirmed an inferior mOS in patients with RUNX1^mutcompared to the intermediate risk group (25.7 months vs. 59.8 months, p=0.029) and was not different from RUNX1^wtadverse risk group (25.7 months vs. 45.7 months, p=0.872) (Figure 1A).

Cumulative incidence of relapse after allo-SCT for patients with RUNX1^mutis significantly higher than intermediate risk patients (p=0.005, Figure 1B); however, there was no difference compared to RUNX^wtadverse risk AML (p=0.295). There was no difference in non-relapse mortality (NRM) between RUNX1^mutand intermediate risk patients (p=0.789, Figure 1B) or RUNX1^mutand RUNX1^wtadverse risk AML (p=0.323).

When impact of concomitant somatic mutations on disease recurrence in RUNX1^mutcohort was assessed, no discernible trends were identified. RUNX1^mutwas mutually exclusive with NPM1 and frequently co-occurred with DNMT3A (21.4%), IDH2 (17.9%), and SRSF2 (17.9%) (Figure 2). Interestingly, 92.9% of the patients with RUNX1^muthad ELN-defined intermediate risk cytogenetics and only 7.1% of the cohort had ELN-defined adverse risk cytogenetics.

Conclusions: Our findings indicate that allo-SCT AML patients with RUNX1^muthave poor outcomes analogous to RUNX1^wtadverse risk AML.

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