TP53 Mutated MDS Patients Respond Equally to Hypomethylating Agents but Have Significantly Shorter Response Duration Compared to Patients with Wild Type TP53

Background: Prognostic impact of TP53 mutations has been well described in MDS. However little is known about predictive impact on response to hypomethylating agents (HMA).

Aim: To determine predictive impact of TP53 mutation on response to frontline HMA therapy in MDS.

Methods: Bone marrow samples from 168 patients with untreated MDS were screened for TP53 mutation by next generation sequencing platform. All patients were treated with upfront 5-azacitidine or decitabine based HMA therapy. 13 of them had longitudinal follow up of TP53 mutation after HMA therapy.

Results: 38 patients (23%) had TP53 mutations. At baseline, TP53 mutated patients were significantly more neutropenic (P = 0.02), thrombocytopenic (P = 0.008), and had higher bone marrow blast (P = 0.006). TP53 mutation was significantly associated with complex karyotype (P < 0.001), monosomal karyotype (P < 0.001), and del 17p/-17 (P < 0.001). There was a trend toward mutual exclusivity between splicing pathway gene mutations and TP53 mutation (P = 0.07). Complete response (CR) and overall response (OR) to HMA therapy was observed in 34% and 45% of TP53 mutated patients, respectively, and there was no statistical difference from wild type patients (P = 0.38 and P = 0.13). Time to achieve response was also similar between TP53 mutated and wild type patients (P = 0.2). However, TP53 mutated patients had significantly shorter CR duration compared to wild type patients (6.3 months versus 28.5 months, P = 0.001). 11 out of 13 patients who had longitudinal follow up of TP53 mutation were found to have the same persistent TP53 mutation when they lost response to HMA therapy. TP53 mutated patients had worse overall survival (P <0.001) and prognostic impact of TP53 mutation was significant after adjusting for complex karyotype or IPSS-R risk.

Conclusion: MDS patients with TP53 mutations equally respond well to HMA therapy compared to WT patients. However, duration of response is significantly shorter than WT patients, which translates into worse overall survival. Longitudinal follow up showed persistence of the same TP53 clone after HMA therapy. Novel therapeutic strategy to improve duration of response in TP53 mutated MDS is urgently needed.