Smoking and Its Prognostic Effect on Survival in Patients with TP53 Mutated MDS

INTRODUCTION: Smoking is an established risk factor for myelodysplastic syndrome (MDS). While smoking has been shown to be correlated with TP53 mutation in multiple solid malignancies, and TP53 mutated MDS has been shown to have poorer survival, there is a paucity of data on the prognostic effect of smoking on survival in patients with TP53 mutated MDS. To further characterize this, we performed a retrospective study to investigate the relationship between smoking and survival in patients with TP53 mutated MDS.

METHODS: After IRB approval, a total of 127 patients with MDS who were treated at Thomas Jefferson University Hospital from January 2016 to February 2020 were included in the study. All diagnoses were reviewed by a hematopathologist and TP53 mutation status was confirmed by in-house next generation sequencing. Patient data was collected from the date of MDS diagnosis until death or date of last follow up. Ever-smokers were defined as any patient with a history of tobacco smoking or current smokers, while non-smokers were defined as those with no history of tobacco smoking as documented in the electronic medical record. Data was also collected on revised international prognostic scoring system (R-IPSS) scores. Univariate associations were compared between variables of interest and smoking status. The Wilcoxon rank-sum test was used to assess difference between continuous variables and the chi-squared test was used to assess difference between categorical variables.

RESULTS: Median overall survival (mOS) for the entire study cohort was 2.63 years (95% CI 2.10-4.29). In patients with TP53 mutations (n=35) we saw no survival difference between ever-smokers (0.64 years; 95% CI 0.30-1.19) and non-smokers (0.79 years; 95% CI 0.49-not reached), p=0.96. Overall, smokers had a shortened mOS (2.22 years; 95% CI 1.31-3.06) compared to never-smokers (4.30 years; 95% CI 2.62-7.61), trending towards significance with p=0.053. After stratification by smoking status, Caucasian smokers showed significantly reduced mOS (2.22 years; 95% CI 1.19-3.38) compared to non-smokers (5.65 years; 95% CI 3.23-7.8; p<0.05). Analysis looking at patients with high/very high risk R-IPSS scores also showed reduced survival for ever-smokers (0.64 years; 95% CI 0.53-0.88) compared to non-smokers (0.97 years; 95% CI 0.49-not reached), trending towards significance with p=0.06. For the whole cohort, high and very high risk IPSS-R scores (mOS 0.64; 95% CI 0.56-0.97) showed significantly reduced mOS compared to low and intermediate scores (mOS 4.49; 95% CI 2.8-7.74) with p<0.001. TP53 mutated MDS also showed decreased survival with mOS 0.64 years (95% CI 0.5-0.97) compared to mOS 4.49 years (95% CI 2.8-7.74) for wild type TP53 with p<0.001.

CONCLUSION: We found no survival difference between ever-smokers and non-smokers in patient with TP53 mutated MDS. However, we did find a convincing trend towards poorer survival in ever-smokers compared to non-smokers in all patients, with a statistically significant reduction in survival in the Caucasian subgroup. Although there was no survival difference in the TP53 mutated cohort, the overall survival difference in the cohort as a whole suggests that smoking may play a role in more aggressive disease. Given the short survival time for TP53 mutated MDS, further studies with higher power may be required to distinguish survival differences. Future studies should also assess the impact of smoking on other cytogenetic and molecular subgroups of patients.

Palmisiano:Genentech: Research Funding; AbbVie: Research Funding.