TY - JOUR
T1 - Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes
AU - Sallman, David A.
AU - DeZern, Amy E.
AU - Garcia-Manero, Guillermo
AU - Steensma, David P.
AU - Roboz, Gail J.
AU - Sekeres, Mikkael A.
AU - Cluzeau, Thomas
AU - Sweet, Kendra L.
AU - McLemore, Amy
AU - McGraw, Kathy L.
AU - Puskas, John
AU - Zhang, Ling
AU - Yao, Jiqiang
AU - Mo, Qianxing
AU - Nardelli, Lisa
AU - Al Ali, Najla H.
AU - Padron, Eric
AU - Korbel, Greg
AU - Attar, Eyal C.
AU - Kantarjian, Hagop M.
AU - Lancet, Jeffrey E.
AU - Fenaux, Pierre
AU - List, Alan F.
AU - Komrokji, Rami S.
N1 - Publisher Copyright:
© 2021 by American Society of Clinical Oncology Creative Commons Attribution Non-Commercial No Derivatives 4.0 License
PY - 2021/5/10
Y1 - 2021/5/10
N2 - 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.
AB - 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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U2 - 10.1200/JCO.20.02341
DO - 10.1200/JCO.20.02341
M3 - Article
C2 - 33449813
AN - SCOPUS:85100685894
SN - 0732-183X
VL - 39
SP - 1584
EP - 1594
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 14
ER -