Prognostic impact of 'multi-hit' <i>versus</i> 'single-hit' <i>TP53</i> alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases

Abstract

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation (TP53MT) compared to a single-hit (SH) mutation in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an in-depth analysis utilizing data from ten US academic institutions to study differences in molecular characteristics and outcomes of SH (N=139) versus MH (N=243) TP53MT AML. Complex cytogenetics were more common in MH than in SH TP53MT AML (P<0.001); whereas ASXL1 (P<0.001), RAS (P<0.001), splicing factor (P=0.003), IDH1/2 (P=0.001), FLT3 ITD (P<0.001) and NPM1 (P=0.005) mutations clustered significantly with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between patients with SH or MH disease (event-free survival: 3.0 vs. 2.20 months, respectively, P=0.22; overall survival: 8.50 vs. 7.53 months, respectively, P=0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation as a time-dependent covariate were associated with superior event-free survival (hazard ratio [HR]=0.44, 95% confidence interval [95% CI]: 0.19-1.01, P=0.05 and HR=0.34, 95% CI: 0.18-0.62, P<0.001) and overall survival (HR=0.24, 95% CI: 0.08-0.71, P=0.01 and HR=0.28, 95% CI: 0.16-0.47, P<0.001). Complex cytogenetics (HR=1.56, 95% CI: 1.01-2.40, P=0.04) retained an unfavorable significance for overall survival. Our analysis suggests that MH TP53MT is less relevant in independently predicting outcomes in patients with AML than in those with MDS.

Figure 1.

Overview of TP53 domains, structures, and distribution of TP53 variants detected, positioned on the TP53 protein. Variants from patients with mono-allelic TP53 are depicted at the top and those from patients with multiple TP53 hits at the bottom. Missense mutations are shown as gold circles and all other variants, including truncated mutations corresponding to splice site variants, nonsense, nonstop, and frameshift deletions or insertions, are shown as blue circles. NTD: N-terminal domain; TAD: transactivation domain; PRD: proline-rich domain; DBD: DNA-binding domain; TD: tetramerization domain; BD: basic domain; CTD: C-terminal domain.

Figure 2.

Patterns of the co-mutations identified in the TP53 cohort. Patients with single-hit TP53 are depicted at the Left (black) and patients with multi-hit TP53 at the right (red).

Figure 3.

Kaplan-Meier survival curves for patients with single-hit and multi-hit TP53-mutated acute myeloid leukemia. (A) Duration of response, (B) event-free survival and (C) overall survival (OS) in single-hit (SH) versus multi-hit (MH) TP53-mutated acute myeloid leukemia (AML). (D) Subset analysis showing the impact of complex cytogenetics on OS in SH and MH TP53-mutated AML. (E) Landmark analysis for OS among patients with complete remission receiving allogeneic hematopoietic stem cell transplantation in SH versus MH TP53 AML. (F) Landmark analysis for OS among patients with complete remission undergoing allogeneic hematopoietic stem cell transplantation with respect to the presence or absence of complex cytogenetics and TP53 allelic burden. CR: complete remission; CRi: complete remission with incomplete blood count recovery; CK: complex cytogenetics; allo-HCT: allogeneic stem cell transplantation; NR: not reached.