The Prognostic Significance of TP53 Mutations for Overall Outcome in Lower-Risk MDS Patients

BACKGROUND AND AIMS

Recent results have indicated that the TP53 mutations had a negative prognostic relevance for lower-risk myelodysplastic syndrome (MDS) patients but the relations between the presence of mutations and treatment has not been clarified yet. Therefore, we analyzed the prevalence of TP53 mutations in lower-risk MDS patients and determined the proportion of TP53 mutated bone marrow cells during the disease. We further observed mutual relation of treatment and mutated clones and defined impact of mutations on survival of patients.

METHODS

TP53 mutations were analyzed in DNA from bone marrow of 141 low risk or intermediate-1 risk MDS patients included into the cohort according to the International Prognostic Scoring System using primers designed within the IRON-II study research consortium (Roche Applied Science) on the GS Junior system. If mutations were detected, we searched for mutations at different timepoints of the disease and overall 210 samples were examined for mutations. Ten of the 16 patients with TP53 mutation received lenalidomide and/or 5-azacytidine. Mean coverage of sequenced exons was about 800-fold allowing an approximate detection sensitivity of 2% mutational burden.

RESULTS

The overall incidence of TP53 mutations was 11.3 % (16/141), three patients harbored two mutated clones. The mutation frequency in patients with and without del(5q) was 21% (13/62) and 3.8% (3/79), respectively. During the observation period, 37 patients (26.2%) died, the data obtained from remaining patients were censored either at the last date they were known to be alive (94 patients - 66.7%) or at the time of stem cell transplantation (HSCT) (10 patients - 7.1%). The median overall survival was 164.2 months in TP53 unmutated group and 84.5 in mutated group respectively calculated by Kaplan-Meier Survival Curves and the Log-Rank Test (P=0.18). Mutations were detectable in eight of the sixteen available patients (50%) at the time of diagnosis and remaining patients (50 %) displayed mutations in an average 35.1 months (range 12-69 months) from diagnosis.

Three patients with mutational burden below 5% are alive more than 3 years without signs of disease progression and three patients with clone size above 40% died. The mutated clone disappeared after bone marrow transplantation in one patient. The proportion of TP53 mutated cells decreased radically after successful treatment with azacytidine in two patients. The clone size increased in four patients treated with lenalidomide and all of them died. Two patients with mutated clone sizes below 20% are still under observation.

CONCLUSIONS

We confirmed the higher frequency of TP53 mutations in lower- risk MDS with del(5q) in a large cohort of patients. Patients with the TP53 mutations had shorter survival compared to those without mutation. The mutations were detected in a half of the patients at the time of diagnosis and approximately three years after diagnosis in remaining patients. The presence of TP53 mutation as an adverse prognostic factor should be routinely investigated in lower risk MDS patients at the time of the diagnosis as well as repeatedly in the course of the disease.

Supported by grant (NT/13899, NT/14377, NT/14539) and the project for conceptual development of research organization (00023736) from the Ministry of Health of the Czech Republic.