Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes.

Abstract

PURPOSE:

Approximately 20% of patients with TP53-mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells.

METHODS:

This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with TP53-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043).

RESULTS:

Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one TP53 mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% v 25%; P = .006). Responding patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency < 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 v 7.5 months; P = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%).

CONCLUSION:

Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML.

• Authors: David A Sallman, Amy E DeZern, Guillermo Garcia-Manero, David P Steensma, Gail J Roboz, Mikkael A Sekeres, Thomas Cluzeau, Kendra L Sweet, Amy McLemore, Kathy L McGraw, John Puskas, Ling Zhang, Jiqiang Yao, Qianxing Mo, Lisa Nardelli, Najla H Al Ali, Eric Padron, Greg Korbel, Eyal C Attar, Hagop M Kantarjian, Jeffrey E Lancet, Pierre Fenaux, Alan F List, Rami S Komrokji
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 39 Issue 14 Pg. 1584-1594 (05 10 2021) ISSN: 1527-7755 [Electronic] United States
• PMID: 33449813 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Quinuclidines
• TP53 protein, human
• Tumor Suppressor Protein p53
• Azacitidine
• eprenetapopt

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Azacitidine (administration & dosage, adverse effects)
• Biomarkers, Tumor
• Female
• Humans
• Male
• Middle Aged
• Mutation
• Myelodysplastic Syndromes (drug therapy, genetics, mortality)
• Quinuclidines (administration & dosage, adverse effects)
• Tumor Suppressor Protein p53 (genetics)