All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit Know AML

The AML Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

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

Aug 26, 2021
Share:

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 (TP53mut) in AML are associated with a complex karyotype, poor response to chemotherapy, and poor outcomes.

In older patients with TP53mut 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 TP53mut 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 TP53mut 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 TP53mutAML. The median age was 72 years, and patients who had TP53mutAML 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 (TP53wt)—see Table 1 for baseline patient characteristics.

Table 1. Baseline characteristics of patients with TP53mutAML and TP53wt AML treated with DEC10-VEN*

Characteristic, % (unless otherwise stated)

TP53mutAML
n = 35

TP53wtAML
n = 83

p value

Median age (range), years

74 (69–78)

71 (68–77)

0.583

Male

51

55

0.691

ECOG performance status

 

 

 

              0–1

71

73

0.818

              ≥2

29

27

Diagnosis

 

 

 

              De novo AML

31

53

0.032

              sAML with AHD

34

39

0.661

              Therapy-related AML

46

11

<0.001

ELN 2017 risk group

 

 

 

              Favorable

0

31

              Intermediate

0

17

<0.001

              Adverse

100

52

ELN 2017 cytogenetic risk

 

 

 

              Favorable

0

0

              Intermediate

6

70

              Adverse

94

30

<0.001

              Complex cytogenetics

89

10

<0.001

Co-mutations

 

 

 

              NPM1

3

33

0.001

              FLT1-ITD/TKD

0

22

0.001

              IDH1/IDH2

11

25

0.092

              RUNX1

6

22

0.035

              ASXL1

3

23

0.008

              KRAS/NRAS

11

28

0.005

AHD, antecedent hematologic disorder; AML, acute myeloid leukemia; DEC10-VEN, 10-day decitabine with venetoclax treatment regimen; ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet; sAML, secondary acute myeloid leukemia; TP53mut, mutant TP53; TP53wt, wild-type TP53.
Bold font indicates statistically significant p values
*Adapted from Kim, et al.1

Results

Patients harboring TP53mut had lower response rates than those with TP53wt, 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 TP53mut had a higher 60-day mortality than those with TP53wt (26% vs 4%; p < 0.001) and all the TP53mut patients who died within that time had refractory disease (Table 2). TP53mut 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 TP53mutAML and TP53wt AML treated with DEC10-VEN*

Outcome, %

TP53mutAML
n = 35

TP53wtAML

n = 83

p value

Overall response rate

66

89

0.002

              CR

37

58

0.040

              CRi

20

19

0.928

              CR/CRi

57

77

0.029

              Morphologic leukemia-free state

9

12

0.582

              MRD-negative by flow cytometry

29

59

0.012

              No response

29

11

0.017

              Inevaluable

6

0

0.028

30-day mortality

3

1

0.525

60-day mortality

26

4

<0.001

AML, acute myeloid leukemia; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; DEC10-VEN, 10-day decitabine with venetoclax treatment regimen; ELN, European LeukemiaNet; MRD, minimal residual disease; TP53mut, mutant TP53; TP53wt, wild-type TP53.
Bold font indicates statistically significant p values
*Adapted from Kim, et al.1

On multivariate analysis, patients with TP53mut AML had lower odds of achieving CR and CR/CRi than patients with TP53wt 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 TP53mut AML, secondary AML, KRAS/NRAS mutations, and overall survival (Table 3).

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

Outcome

OR (95% CI)

P value

Achievement of CR

 

 

              TP53mut vs TP53wt

0.17 (0.06–0.47)

<0.001

              ECOG PS ≥2 vs 0–1

0.24 (0.08–0.71)

0.010

              Prior HMA for AHD vs none

0.15 (0.01–0.24)

0.002

              RUNX1mut vs RUNX1wt

0.23 (0.06–0.88)

0.031

              ASXL1mut vs ASXL1wt

0.05 (0.12–0.24)

<0.001

Overall survival

 

 

              TP53mut vs TP53wt

6.96 (3.76–12.88)

<0.001

              sAML with AHD vs de novo AML

2.97 (1.78–4.94)

<0.001

              DNMT3Amut vs DNMT3Awt

0.44 (0.24–0.81)

0.009

              KRAS/NRASmut vs KRAS/NRASwt

2.82 (1.58–5.02)

<0.001

AHD, antecedent hematologic disorder; AML, acute myeloid leukemia; CI, confidence interval; CR, complete remission; ECOG PS, Eastern Cooperative Oncology Group performance status; HMA, hypomethylating agent; HR, hazard ratio; OR, odds ratio; sAML, secondary acute myeloid leukemia; TP53mut, mutant TP53; TP53wt, wild-type TP53.
Bold font indicates statistically significant p values
*Adapted from Kim, et al.1

Following the first cycle of treatment, 25 patients (76%) had NGS testing and responding patients (n = 20) had significant reductions in TP53mut 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 TP53mut 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 TP53mut AML than in patients with TP53wt AML (11%; p = 0.002), and that TP53mut 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 TP53mut 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 TP53mut AML patients treated prospectively with DEC10-VEN. The study found that this group of patients experienced lower response and survival rates compared with TP53wt AML patients when treated with DEC10-VEN. These results underscore the importance of identifying novel therapies for patients with TP53mut AML.

  1. Kim K, Maiti A, Loghavi S, et al. Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax. Cancer. 2021. Online ahead of print. DOI: 10.1002/cncr.33689
  2. DiNardo C, Maiti A, Rausch C, et al. 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. Lancet Haematol. 2020;7(10):e724-e736. DOI:1016/S2352-3026(20)30210-6
  3. Kim K, Maiti A, Kadia TM, et al. Outcomes of TP53-mutant acute myeloid leukemia with venetoclax and decitabine. Oral abstract #693. 62nd American Society of Hematology Annual Meeting and Exposition; Dec 7, 2020; Virtual.

Share: