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3860 Frequency, Characteristics and Prognostic Significance of RUNX1 mutations in Patients with Acute Myeloid Leukemia, Not Otherwise Specified

Acute Myeloid Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis
Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Mi-Hyun Bae, MD, PhD1*, Young-Uk Cho, MD, PhD1, Bohyun Kim1*, Dong Hyun Lee1*, Seongsoo Jang, MD, PhD1, Eul-Ju Seo, MD, PhD1*, Chan-Jeoung Park, MD, PhD1, Dae-Young Kim, MD, PhD2, Jung-Hee Lee, MD, PhD3*, Je-Hwan Lee, MD, PhD2, Kyoo-Hyung Lee, MD, PhD2, Yoon Hwan Chang4* and In-Suk Kim5*

1Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, South Korea
2Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
3Department of Hematology, University of Ulsan College of Medicine and Asan Medical Center, Seoul, South Korea
4Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea
5Department of Laboratory Medicine, Pusan National University Yangsan Hospital, Pusan, South Korea

Background: Somatic mutations in RUNX1 gene have been identified in a substantial proportion of patients with de novo acute myeloid leukemia (AML). It is suggested as a new candidate molecular marker and, therefore, is suggested to be routinely performed at the diagnostic stage of AML. Despite its clinical importance, however, previous cohorts have been heterogeneous in terms of cytogenetic and molecular subtypes of AML. Here, the aim of this study was to evaluate the frequency, biologic characteristics, and prognostic significance of RUNX1 mutations focusing on patients with AML, not otherwise specified (NOS).

Methods: Diagnostic samples from 202 patients with AML were analyzed for RUNX1 mutations. We excluded AML with recurrent genetic abnormalities, AML with myelodysplasia-related changes, and therapy-related AML because these entities have prognostic relevances of their own. RUNX1 mutations were detected using standard PCR techniques and direct sequencing.

Results: RUNX1 mutations were found in 27 (13.4%) patients. The mutations were clustered in Runt homology domain (13, 48.1%) and transactivation domain (9, 33.3%). Frameshift mutations were most common (52.9%), followed by missense mutations (35.3%) and nonsense mutations (11.8%). As shown in Table 1, patients with RUNX1 mutations had a lower platelet count (P = 0.03), a higher rate of trisomy 8 (P = 0.02) and trisomy 13 (P = 0.039), and a trend toward older age (P = 0.063) than patients without mutations. Presence of RUNX1 mutations and NPM1 or CEBPA mutations were mutually exclusive. At the median follow-up of 12.1 months, RUNX1 mutations predicted for shorter overall survival (OS; P = 0.007) and relapse-free survival (RFS; P = 0.003). In the multivariate analysis, RUNX1 mutation was a significant marker for inferior OS (hazard ratio, 3.037; P = 0.014) and RFS (hazard ratio, 5.699; P = 0.001).

Conclusion: The findings of our study further strengthen the previous data about RUNX1 mutations in AML. Furthermore, AML NOS with RUNX1 mutations is characterized by distinct biology and is associated with adverse clinical outcome. Our study supports the notion that RUNX1 mutational status would be integrated into diagnostic workup of AML, particularly for AML, NOS subgroup.

Table 1. Clinical and biologic features of the cohort by RUNX1 mutations

RUNX1 mutations

P-value

Mutated, n (%)

Wild type, n (%)

Number

27 (13.4)

175 (86.6)

Male sex

17 (63.0)

94 (53.7)

0.489

Median age, years (range)

63 (14 - 80)

55 (1 - 83)

0.063

WBC count, •109/L (median, range)

7.9 (1.1 – 133.3)

14.0 (0.8 – 231.3)

0.636

Hemoglobin, g/dL (median, range)

8.6 (5.0 – 10.6)

8.8 (4.1 – 17.3)

0.376

Platelet count, •109/L (median, range)

35 (14 – 230)

59 (9 – 900)

0.03

Blood blasts, % (median, range)

29 (0 – 94)

38.5 (0 – 93)

0.312

FAB subtypes

  M0

3 (11.1)

11 (6.3)

0.609

  M1, M2

21 (77.8)

129 (73.7)

0.831

  M4, M5

3 (11.1)

27 (15.4)

0.767

  M6, M7

0

8 (4.6)

0.546

Cytogenetic abnormalities

  Normal karyotype (%)

11 (40.7)

104 (59.4)

0.106

  Trisomy 8 (%)

5 (18.5)

8 (4.6)

0.02

  Trisomy 11 (%)

1 (3.7)

4 (2.3)

0.823

  Trisomy 13 (%)

3 (11.1)

3 (1.7)

0.039

  Trisomy 21 (%)

1 (3.7)

2 (1.1)

0.866

Distribution of other mutations

  FLT3-ITD

5 (18.5)

50 (28.6)

0.39

  FLT3-TKD

1 (3.7)

4 (2.3)

0.823

  NPM1

0

55 (31.4)

0.002

  CEBPA

0

17 (9.7)

0.187

  MLL-PTD

1 (3.7)

14 (8.0)

0.691

Disclosures: No relevant conflicts of interest to declare.

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