Outcomes of decitabine and venetoclax treatment in mutant TP53 AML vs wild-type TP53 AML

TP53 is a tumor suppressor gene which protects cells against stress and is seen as the guardian of the genome as it preserves genomic integrity. TP53 is also known to be one of the most frequently mutated genes in human cancers.¹ In de novo acute myeloid leukemia (AML), TP53 has been found to be mutated in 5–10% of patients, though this is increased in older patients and again in patients with therapy-related AML. TP53 mutations (TP53^mut) in AML are associated with a complex karyotype, poor response to chemotherapy, and poor outcomes.

In older patients with TP53^mut AML the use of hypomethylating agents, such as decitabine (DEC) may offer a slight advantage over chemotherapy. Currently, a combination of venetoclax with low-intensity HMA regimens is the standard of care in older or unfit patients with AML. A phase 2 study (NCT03404193) of a 10-day decitabine + venetoclax regimen (DEC10-VEN) in older or unfit patients with newly diagnosed AML, secondary AML or relapsed/refractory AML was published last year² (our summary of the paper is here). A post hoc analysis investigating the outcomes of those patients who had TP53^mut AML was originally presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition³ (briefly summarized here), and has now been published in Cancer.¹ Here we provide an in-depth summary of the results.

Study design and patient characteristics

Detailed information on the study design can be found here. Briefly, patients with newly diagnosed AML, secondary AML, or relapsed/refractory AML, who were aged ≥60 years were enrolled. They received

• Induction therapy: decitabine (20 mg/m²) for 10 days every 4–6 weeks 
• Maintenance therapy after complete response (CR) or incomplete hematologic recovery (CRi): decitabine (20mg/m²) for 5 days
• Concurrent venetoclax: 100 mg Day 1, 200 mg Day 2, then 400 mg daily

Outcomes in these patients were compared with those from another study (NCT01786343) in which newly diagnosed patients with TP53^mut AML were treated with DEC10 only.

TP53 next generation sequencing (NGS) was performed on bone marrow aspirates. Either the entire coding region, hot-spot regions of 81 genes, or TP53 alone were sequenced. Measurable residual disease was also assessed in bone marrow aspirate, using flow cytometry.

Outcomes assessed included overall response rate (including CR, CRi, and morphologic leukemia-free state), relapse-free survival, and overall survival.

There were a total of 118 patients enrolled who received DEC10-VEN, of which 30% had TP53^mutAML. The median age was 72 years, and patients who had TP53^mutAML were more likely to have therapy-related AML (46%), but less likely to have co-mutations compared with patients carrying a wild-type TP53 gene (TP53^wt)—see Table 1 for baseline patient characteristics.

Table 1. Baseline characteristics of patients with TP53^mutAML and TP53^wt AML treated with DEC10-VEN*

Results

Patients harboring TP53^mut had lower response rates than those with TP53^wt, with an overall response rate of 66% vs 89%, respectively (p = 0.02), and lower rates of measurable residual disease negativity (29% vs 59%; p = 0.012). In addition, patients with TP53^mut had a higher 60-day mortality than those with TP53^wt (26% vs 4%; p < 0.001) and all the TP53^mut patients who died within that time had refractory disease (Table 2). TP53^mut was associated with a lower overall survival (5.2 vs 19.4 months; hazard ratio [HR], 4.67; 95% confidence interval [CI], 2.44–8.93; p < 0.0001) and relapse-free survival (3.4 vs 18.9 months; HR, 4.80; 95% CI, 1.97–11.69; p < 0.0001).

Table 2. Outcomes of patients with TP53^mutAML and TP53^wt AML treated with DEC10-VEN*

On multivariate analysis, patients with TP53^mut AML had lower odds of achieving CR and CR/CRi than patients with TP53^wt AML (odds ratios [OR], 0.17; p < 0.001 [Table 3] vs OR, 0.22; p = 0.003). Studying the mutations more closely, Kim, et al. did not find an association between multi-hit alterations and overall survival compared with those patients who had just a single mutation (HR, 1.24; 95% CI, 0.50–3.05; p = 0.643). They did note that there were multi-hit TP53 alterations in 57% of those patients who responded without relapse vs 81% of patients who had a relapse after responding vs 100% of patients who had refractory AML (p = 0.049). Further, the group found associations between ASXL1 mutations and CR, and between TP53^mut AML, secondary AML, KRAS/NRAS mutations, and overall survival (Table 3).

Table 3. Multivariate analysis of the outcomes of complete remission and overall survival*

Following the first cycle of treatment, 25 patients (76%) had NGS testing and responding patients (n = 20) had significant reductions in TP53^mut variant allele frequency (VAF; mean change, −28.5%; 95% CI, −15.4% to −41.6%; p < 0.001), whereas in the patients with refractory disease (n = 5) the VAF change was not significant (mean change, −21.4%; 95% CI, −9.5% to 52.2%; p = 0.126). Further NGS analysis of patients who relapsed following an initial response to treatment, at progression, found that there was a significant increase in TP53^mut VAF compared with VAF after completion of the first treatment cycle (mean change, +22.6%; 95% CI, 4.8%–40.5%; p = 0.018). The study group found a higher incidence of primary refractory disease (34%) in patients with TP53^mut AML than in patients with TP53^wt AML (11%; p = 0.002), and that TP53^mut was associated with a high risk of relapse in patients who achieved CR/CRi (HR, 5.52; 95% CI, 2.70–11.28; p < 0.001).

When comparing TP53^mut AML patients treated with DEC10-VEN (n = 20) and those treated with DEC10 only (n = 7) from another trial, there was no significant difference in overall survival or relapse-free survival between the two treatment regimens.

Conclusion

The group highlighted that although the study had limitations due to small sample sizes, particularly in subgroup analyses, and it being a post hoc analysis, this represents the largest series of TP53^mut AML patients treated prospectively with DEC10-VEN. The study found that this group of patients experienced lower response and survival rates compared with TP53^wt AML patients when treated with DEC10-VEN. These results underscore the importance of identifying novel therapies for patients with TP53^mut AML.