Eprenetapopt (APR-246) and Azacitidine in TP53-Mutant Myelodysplastic Syndromes. Issue 14 (10th May 2021)

• Record Type: Journal Article
• Authors: Sallman, David A.; DeZern, Amy E.; Garcia-Manero, Guillermo; Steensma, David P.; Roboz, Gail J.; Sekeres, Mikkael A.; Cluzeau, Thomas; Sweet, Kendra L.; McLemore, Amy; McGraw, Kathy L.; Puskas, John; Zhang, Ling; Yao, Jiqiang; Mo, Qianxing; Nardelli, Lisa; Al Ali, Najla H.; Padron, Eric; Korbel, Greg; Attar, Eyal C.; Kantarjian, Hagop M.; Lancet, Jeffrey E.; Fenaux, Pierre; List, Alan F.; Komrokji, Alan F.
• Is Part Of: Journal of clinical oncology. Volume 39:Issue 14(2021)
• Page Start: 1584
• Page End: 1594
• Publication Date: 2021-05-10
• Subjects: Oncology -- Periodicals; Cancer -- Periodicals; Oncology; Medical Oncology; Cancérologie -- Périodiques; Cancer -- Périodiques; Cancérologie; Cancer; Oncology; Oncologia; Càncer; Periodicals; 616.994
• DOI: 10.1200/JCO.20.02341
• Languages: English
• ISSNs: 0732-183X

Abstract

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.