TP53 Mutations and Outcome in Patients with Myelodysplastic Syndromes (MDS)

Objectives:

TP53, a tumor suppressor gene, is frequently mutated in myeloid malignancies. The negative impact of TP53 mutations in myelodysplastic syndromes (MDS) has been described previously but there is controversy regarding the prognostic impact of the mutation's characteristics (location, type, passenger vs. driver, and others).

Methods:

We sequenced DNA samples from 732 patients (pts) with MDS and related myeloid malignancies for the presence of TP53 mutations and 61 other genes that have been described as recurrently mutated in MDS. Overall survival (OS) was measured from the time of diagnosis to time of death or last follows up. Variant allele frequencies (VAFs) adjusted by zygosity were used to define clonal architecture of driver clones.

Results:

Of 80 mutations detected in 73 (10%) pts, 66 (88%) were missense, 7 (9%) were nonsense, and 7 (9%) were frame shift deletions/insertions. Pts with TP53 mutations had a higher WBC (4.6 vs. 3.9 X 10⁹/L, p = .04), higher bone marrow blast % (median 9 vs. 3, p =0.1), and a higher risk category by revised International prognostic Scoring System (56% vs. 27%, p =.01) compared to pts with TP53 wild type. TP53 mutations were commonly occurred with TET2 (16%), PRPF8 (13%), ASXL1 (11%), DDX54 (8%), DNMT3A (8%), and IDH2 (8%). The mean VAF for TP53 was 41.9 (5-100). TP53 mutations were defined as drivers in 20% of samples, passengers in 40%, and mosaic in 40%. Mutation positions included: 19 (24%) in the DNA binding domain, 2 (3%) in the transactivation domain, 1 (1%) in the tetramerization domain and 58 (72%) other. With a median follow up of 16.4 months, the median OS for the entire group was 8.24 months. Patients with TP53 as driver mutations had a worse OS compared with patients with TP53 as passenger mutations (median, 2.2 vs. 13.0 months, respectively, p =.02). Similarly, OS by TP53 VAF categorized as low (<25%), intermediate (25-50%), and high (>50%) was 12.4, 8.5, and 3.4 months, respectively. Among patients with available treatment data, 29 patients were treated with the hypomethylating agents, azacitidine or decitabine, 17% responded (60% CR, and 40% PR), and OS was similar compared to patients treated with other therapies. Patients treated with Hematopoietic stem cell transplant (HCT) had superior OS compared to pts not receiving HCT (median, 14.9 vs. 8.9 months, respectively, p =.05).

Conclusions:

TP53 mutations are associated with poor outcome in MDS, but the outcome varies depending on the type of mutation and VAF. Treatment with HCT remains a valid treatment option in a subset of patients but novel treatment strategies are desperately needed.