Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax.

Abstract

BACKGROUND:

TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193).

METHODS:

Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.

RESULTS:

Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone.

CONCLUSIONS:

Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

• Authors: Kunhwa Kim, Abhishek Maiti, Sanam Loghavi, Rasoul Pourebrahim, Tapan M Kadia, Caitlin R Rausch, Ken Furudate, Naval G Daver, Yesid Alvarado, Maro Ohanian, Koji Sasaki, Nicholas J Short, Koichi Takahashi, Musa Yilmaz, Guilin Tang, Farhad Ravandi, Hagop M Kantarjian, Courtney D DiNardo, Marina Y Konopleva
• Journal: Cancer (Cancer) Vol. 127 Issue 20 Pg. 3772-3781 (10 15 2021) ISSN: 1097-0142 [Electronic] United States
• PMID: 34255353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Cancer Society.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Sulfonamides
• TP53 protein, human
• Tumor Suppressor Protein p53
• Decitabine
• venetoclax

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (therapeutic use)
• Decitabine (adverse effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Middle Aged
• Sulfonamides
• Tumor Suppressor Protein p53 (genetics)