Patterns of leukemic transformation in patients with TP53-mutant myelodysplastic syndromes.

Abstract

7054 Background: TP53 is the most frequently mutated gene in human cancers, including 7-13% of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Although it is associated with transformation to AML in patients with MDS, the additional genomic events leading to transformation are poorly understood. Methods: We retrospectively evaluated 312 patients with TP53-mutated AML or MDS diagnosed between 2013-2016. Patient characteristics and bone marrow data, including cytogenetic and next generation sequencing information, were assessed at the time of diagnosis and progression to AML. Results: There were 151 TP53-mutated MDS patients and 161 TP53-mutated de novo AML patients with a median follow-up time of 34.1 months. Forty-one patients with TP53-mutated MDS transformed to AML. Sequencing data at transformation was available in 17 patients (41%). At diagnosis, median age was 67 with 2 patients with intermediate-risk, 7 patients with high-risk, and 32 patients with very high-risk MDS by IPSS-R. Complex karyotype was seen in 40 patients, and 12 patients had 1, 25 patients had 2, and 4 patients had 3 TP53 abnormalities. Predictors of transformation to AML include TP53 loss of heterozygosity (p = 0.008), 3 TP53 abnormalities (p = 0.049), complex cytogenetics (p = 0.023), and female gender (p = 0.002). Median time to transformation was 10.4 months. At transformation, an increase in TP53 variant allelic frequency was observed in 7 patients (41%), and new mutations, particularly NRAS, IDH1, TP53, MLL, KDM6A, TET2, and NOTCH1, were acquired by 10 patients (59%). Cytogenetic evaluation revealed identical clones in 5 patients, linear acquisition of cytogenetic abnormalities in 12 patients, and new clones in 8 patients. Patients with TP53-mutated AML from MDS also had worse median overall survival than patients with TP53-mutated de novo AML at 2.5 months vs. 5.7 months respectively (p < 0.001). Conclusions: TP53 mutations confer a worse prognosis, especially in the setting of AML transformed from MDS. This may be due to the acquisition of new mutations and cytogenetic abnormalities. Further exploration of the biological mechanisms leading to transformation in TP53-mutant MDS is warranted.