TP53 is the most commonly mutated gene in human cancers. It encodes the p53 protein, an essential regulator of cell cycle progression, apoptosis, and DNA repair. A central role for TP53 as a tumor suppressor gene is clear: Disruption of p53 function through a loss-of-function mutation, gene deletion, or down-regulation of expression leads to uncontrolled cell growth, genome instability, and aneuploidy.1 In many hematologic cancers, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), TP53 mutations (TP53mut) are associated with resistance to conventional therapies and adverse clinical outcomes, including after allogeneic hematopoietic cell transplantation (HCT).2 Although TP53 mutations are also known to confer an adverse prognosis in patients with myelofibrosis,3 their impact on outcomes following HCT in myelofibrosis has not been specifically studied, and this was addressed by Gagelmann and colleagues in a recent Blood article.
The authors performed a retrospective analysis of 349 patients from a multicenter, international cohort with primary or secondary (post-essential thrombocythemia/polycythemia vera) myelofibrosis undergoing first HCT. Of these, 49 patients (14%) harbored TP53mut and 30 patients (8.6%) showed a multi-hit configuration. Multi-hit configuration was defined as having at least two mutations in TP53 with variant allele frequencies (VAF) of ≥10%, one mutation plus a deletion involving the TP53 locus at 17p, one mutation with a VAF ≥50%, or one mutation in association with a complex karyotype.
Following HCT, a clear and significant decrease in median overall survival (OS) was detected in TP53mut versus TP53wt patients (1.5 years vs. 13.5 years; p<0.001). The incidence of myelofibrosis relapse and leukemic transformation after HCT was also higher in patients with TP53mut, with myelofibrosis relapse occurring in almost 40% of patients and leukemic transformation occurring in 20% (versus 2% in patients with TP53wt).
A key finding of this study was that each of the adverse outcomes seen in patients with TP53mut (shorter OS, increased relapse risk, and leukemic transformation) was driven purely by multi-hit TP53mut configurations, while patients with single-hit TP53mut had similar outcomes to those observed in patients with TP53wt. The lack of predictive value of the non-transplant-specific myelofibrosis risk scores (DIPPS and MIPSS70) was also notable. Only the myelofibrosis transplant scoring system (MTSS) was found to have significant prognostic utility.5
The negative impact of biallelic TP53 hits on HCT outcomes in this cohort of patients with myelofibrosis is in accordance with data from transplanted patients with AML, where a recent study showed that a TP53 mutation only confers an adverse prognosis when accompanied by chromosome 17p loss (17p-) and/or a complex karyotype.6
In Brief
This analysis of a large retrospective cohort of patients with myelofibrosis undergoing HCT found that patients with multi-hit TP53mut represent a very high-risk group with a high incidence of relapse, leukemic transformation, and reduced OS. The striking difference in outcomes between single-hit and multi-hit TP53mut cases has important clinical implications for the selection and counseling of patients considering HCT for myelofibrosis. These data suggest that screening for TP53 mutations and careful distinction between single- and double-hit states is highly informative for risk stratification. Further studies are required to determine whether patients with multi-hit TP53mut can benefit from chemotherapy prior to transplant (e.g., with venetoclax plus hypomethylating agents) and the optimal management strategy for patients with single-hit TP53mut, who would ideally benefit from preventative strategies to reduce the likelihood of evolution to multi-hit disease.
Competing Interests
Drs. Sweeney and Psaila indicated no relevant conflicts of interest.
