TP53 Mutation Associated With Poor, But Varied, Outcomes in Myelodysplastic Syndromes

The TP53 mutation, a common molecular abnormality in myeloid malignancies such as myelodysplastic syndromes (MDS), is associated with poor outcomes; however, it is unclear whether specific characteristics of the mutation can affect prognosis.

At the 2016 ASH Meeting on Hematologic Malignancies, Karam Al-Issa, MD, of the Leukemia Program at the Cleveland Clinic in Cleveland, Ohio, presented results of a DNA sequencing study that confirmed the poor prognosis associated with TP53 mutations and that outcomes varied depending on the type of mutation and variant allele frequency (VAF).

Dr. Al-Issa and colleagues sequenced DNA samples from 732 patients with MDS and related myeloid malignancies (median age = 70 years; range = 24-89 years) to detect the presence of TP53 mutations, as well as 61 other genes that have been described as recurrently mutated in MDS.

A total of 80 mutations were detected in 73 patients (10%): 66 were missense (88%), seven were nonsense (9%), and seven were frame shift deletions/insertions (9%).

Compared with a control group of 659 patients with wild-type TP53, patients with mutated TP53 had higher:

  • white blood cell count (3.9×109/L vs. 4.6×109/L; p=0.04)
  • bone marrow blast percentage (median = 3 vs. 9; p=0.1)
  • risk category by revised International Prognostic Scoring System (27% vs. 56%; p=0.01)

TP53 mutations were identified as driver mutations in 20 percent of samples, as passengers in 40 percent, and as mosaic in the remaining 40 percent.

Mutation positions included: 19 (24%) in the DNA binding domain, two in the transactivation domain (3%), one in the tetramerization domain (1%), and 58 in an “other” locations (72%).

The authors also found that the TP53 mutation commonly occurred with the following genes:

  • TET2 (16%)
  • PRPF8 (13%)
  • ASL1 (11%)
  • DDX54 (8%)
  • DNMT3A (8%)
  • IDH2 (8%)

After a median follow-up of 16.4 months, the median overall survival (OS), measured from the time of MDS diagnosis to time of death or last follow-up, was 8.24 months in the entire patient group.

The type of mutation (passenger or driver) affected the length of OS: Patients with TP53 as driver mutations had a shorter OS compared with those with TP53 as passenger mutations (median = 2.2 vs. 13 months; p=0.02). Similarly, lower TP53 VAF was associated with longer OS (TABLE).

Among the 54 patients with available therapy data, 34 were treated with the hypomethylating agents (HMAs) azacitidine or decitabine as first-line therapies. Eight of these patients responded (7 complete remissions and 1 partial remission), and 19 had stable disease. Overall, rates of OS were similar among patients treated with HMAs and other therapies (including chemotherapy). The investigators observed that patients who received hematopoietic cell transplantation (HCT) had superior OS, compared with patients who did not receive HCT (median OS=14.9 vs. 8.9 months; p=0.05).

“HCT remains the best available option, but the outcome remains poor,” Dr. Al-Issa said. “Treatment with HCT remains a valid treatment option in a subset of patients, but novel treatment strategies are desperately needed.” He also noted that a larger study is required to confirm these results.


Reference

Al-Issa K, Sekeres MA, Nielsen A, et al. TP53 mutations and outcome in patients with myelodysplastic syndromes (MDS). Abstract #89258. Presented at the ASH Meeting on Hematologic Malignancies, September 16-17, 2016; Chicago, IL.

TABLE. Overall Survival, According to VAF of TP53 Mutation
Variant Allele Frequency Median Overall Survival, months
Low (<25%) 12.4
Intermediate (25-50%) 8.5
High (>50%) 3.4

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