Prospective study on the impact of TP53 mutations in patients with AML treated with azacitidine

Despite many medical advances over the last decade, the prognosis of patients over 65 years with acute myeloid leukemia (AML) remains dismal. The current standard therapies in AML are distinguished between intensive vs low-intensity treatment options, with the foremost involving intensive chemotherapy, while the latter includes hypomethylating agents, such as azacitidine. TP53 gene mutations have been reported as possible predictive biomarkers of greater treatment response with decitabine; however, the impact of the functional classification of TP53 mutations in patients treated with an azacitidine regimen remains unclear.

Pierre Bories and colleagues carried out a prospective study to determine the impact of TP53 mutations in AML patients, and to assess the usefulness of the TP53 mutation classification as a biomarker to identify a subgroup of patients who might specifically benefit from azacitidine. Below is a summary of their findings, which were recently published in PLoS ONE.¹

Study design

• The study enrolled AML patients treated with azacitidine from the Regional Cancer Network ONCOMIP registry between 2007 and 2016
• Genomic DNA was extracted from bone marrow samples of patients, and the TP53 status was derived from exome sequencing (49 patients) or from next-generation sequencing and multiplex PCR (179 patients)
• Statistical analysis: Duration of response was evaluated by complete remission (CR), or complete remission with incomplete hematologic recovery (CRi). Overall survival (OS) was defined as the time from the date of diagnosis to the date of death from any cause, and patients alive were censored at the last follow-up. Both were estimated using the Kaplan-Meier method.

Results

Between January 2007 and December 2016, 279 AML patients who received a median of six cycles of azacitidine were enrolled in the study. Their characteristics were broadly similar, except for a significant difference in median platelet count, with the highest counts observed in TP53WT and lowest in TP53MUT (74 vs 46g/L; p = 0.001).

The study found an overall prevalence of TP53 mutations equal to 24.6% (55 patients) with a variant allele frequency higher than 10%, including 96.4% (53 out of 55) patients harboring high-risk cytogenetics.

Prognosis factors for OS under azacitidine therapy

The factors affecting OS were identified among the 224 patients with available TP53 status at baseline. In both univariate and multivariate analyses, age, lactate dehydrogenase (LDH), and adverse karyotyping were found to be significantly associated with OS. TP53 status was only significant in the univariate analysis (see Table 1).

Table 1. Significant prognostic factors in univariate and multivariate analyses¹

LDH, lactate dehydrogenase; OS, overall survival; TP53ALT, TP53 alteration; TP53MUT, TP53 mutation.
Factor	6-month OS (%)	Univariate HR [95% CI]	p value	Multivariate HR [95% CI]	p value
Age	—	1.02 [1.00; 1.04]	0.04	1.03 [1.01; 1.06]	0.016
LDH	—	1.08 [1.04; 1.11]	< 0.001	1.07 [1.03; 1.11]	< 0.001
Adverse karyotype	57	1.79 [1.35; 2.37]	< 0.001	1.58 [1.06; 2.34]	0.024
Non-adverse karyotype	82	1		1
TP53MUT	53	2.22 [1.60; 3.08]	< 0.001	1.49 [0.95; 2.34]	0.081
TP53ALT	49	2.53 [1.85; 3.45]	< 0.001	—

Patient outcomes according to the TP53 status

Patients with TP53 mutations had a significantly lower OS compared with those with wild type TP53. In addition, patients with a TP53 alteration had poorer OS compared with patients without. Within the group of 109 patients with adverse karyotype, TP53 mutations and TP53 alterations (including mutation and/or deletion) remained significantly associated with a poorer OS compared with patients with unaltered TP53 (Table 2).

Table 2. OS and HR by genotype¹

OS, overall survival; TP53ALT, TP53 alteration; TP53MUT, TP53 mutation; TP53WT, TP53 wild type.
Genotype	OS (months)	HR in the total population [95% CI]	p value	OS in the adverse cytogenetics population (months)	HR in the adverse cytogenetics population [95% CI]	p value
TP53MUT	7.9	2.22; [1.60; 3.08]	< 0.001	7.9	1.61; 95% [1.08; 2.41]	0.019
TP53WT	12.6	—		9.6	—
TP53ALT	5.4	2.53 [1.85; 3.45]	0.001	5.4	2.03 [1.33;3.09]	< 0.001

The CR/CRi azacitidine response rates did not differ significantly in patients with TP53 mutations (21.8% vs 17.8%; p = 0.502) or alterations (19.1% vs 18.6%; p = 0.926) when compared with the wild type. This was also the finding in the subgroup of patients with adverse karyotype.

Discussion

According to recent bodies of evidence, not all TP53 mutations are functionally equivalent. In this study of elderly patients with AML, the authors found no association between TP53 alterations (including mutation and/or deletion) and response to azacitidine, but a significant association with a shorter OS. As recent data on molecular predictors of response to venetoclax combinations in older patients with AML indicate that TP53 loss promotes resistance to both venetoclax and chemotherapy, patients treated with venetoclax combinations will inevitably have to undergo genetic analysis. Finally, the authors claim that their cohort is a reference in the ongoing non-randomized phase II trial, testing TP53-activating compounds that may be useful in the emerging field of targeted therapy against the TP53 pathway genes.