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

  • J Clin Oncol. 2021 May 10;39(14):1584-1594. doi: 10.1200/JCO.20.02341.
David A Sallman  1 ,  Amy E DeZern  2 ,  Guillermo Garcia-Manero  3 ,  David P Steensma  4 ,  Gail J Roboz  5 ,  Mikkael A Sekeres  6 ,  Thomas Cluzeau  7 ,  Kendra L Sweet  1 ,  Amy McLemore  1 ,  Kathy L McGraw  1 ,  John Puskas  1 ,  Ling Zhang  1 ,  Jiqiang Yao  8 ,  Qianxing Mo  8 ,  Lisa Nardelli  1 ,  Najla H Al Ali  1 ,  Eric Padron  1 ,  Greg Korbel  9 ,  Eyal C Attar  9 ,  Hagop M Kantarjian  3 ,  Jeffrey E Lancet  1 ,  Pierre Fenaux  10 ,  Alan F List  1 ,  Rami S Komrokji  1
Affiliations
  • 1. Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • 2. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
  • 3. Department of Leukemia, MD Anderson Cancer Center, Houston, TX.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
  • 5. Weill Cornell Medicine and The New York Presbyterian Hospital, New York, NY.
  • 6. Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH.
  • 7. Cote D'Azur University, Nice Sophia Antipolis University, Hematology Department, CHU Nice, Nice, France.
  • 8. Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • 9. Aprea Therapeutics, Boston, MA.
  • 10. Hospital St Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
PMID: 33449813 DOI: 10.1200/JCO.20.02341
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.

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