TY - JOUR
T1 - Transient expansion of TP53 mutated clones in polycythemia vera patients treated with idasanutlin
AU - Marcellino, Bridget K.
AU - Farnoud, Noushin
AU - Cassinat, Bruno
AU - Lu, Min
AU - Verger, Emanuelle
AU - McGovern, Erin
AU - Patel, Minal
AU - Medina-Martinez, Juan
AU - Levine, Max Fine
AU - Arango Ossa, Juanes E.
AU - Zhou, Yangyu
AU - Kosiorek, Heidi
AU - Mehrotra, Meenakshi
AU - Houldsworth, Jane
AU - Dueck, Amylou
AU - Rossi, Michael
AU - Mascarenhas, John
AU - Kiladjian, Jean Jacques
AU - Rampal, Raajit K.
AU - Hoffman, Ronald
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/11/24
Y1 - 2020/11/24
N2 - Activation of the P53 pathway through inhibition of MDM2 using nutlins has shown clinical promise in the treatment of solid tumors and hematologic malignancies. There is concern, however, that nutlin therapy might stimulate the emergence or expansion of TP53-mutated subclones. We recently published the results of a phase 1 trial of idasanutlin in patients with polycythemia vera (PV) that revealed tolerability and clinical activity. Here, we present data indicating that idasanutlin therapy is associated with expansion of TP53 mutant subclones. End-of-study sequencing of patients found that 5 patients in this trial harbored 12 TP53 mutations; however, only 1 patient had been previously identified as having a TP53 mutation at baseline. To identify the origin of these mutations, further analysis of raw sequencing data of baseline samples was performed and revealed that a subset of these mutations was present at baseline and expanded during treatment with idasanutlin. Follow-up samples were obtained from 4 of 5 patients in this cohort, and we observed that after cessation of idasanutlin, the variant allele frequency (VAF) of 8 of 9 TP53 mutations decreased. Furthermore, disease progression to myelofibrosis or myeloproliferative neoplasm blast phase was not observed in any of these patients after 19- to 32-month observation. These data suggest that idasanutlin treatment may promote transient TP53 mutant clonal expansion. A larger study geared toward high-resolution detection of low VAF mutations is required to explore whether patients acquire de novo TP53 mutations after idasanutlin therapy.
AB - Activation of the P53 pathway through inhibition of MDM2 using nutlins has shown clinical promise in the treatment of solid tumors and hematologic malignancies. There is concern, however, that nutlin therapy might stimulate the emergence or expansion of TP53-mutated subclones. We recently published the results of a phase 1 trial of idasanutlin in patients with polycythemia vera (PV) that revealed tolerability and clinical activity. Here, we present data indicating that idasanutlin therapy is associated with expansion of TP53 mutant subclones. End-of-study sequencing of patients found that 5 patients in this trial harbored 12 TP53 mutations; however, only 1 patient had been previously identified as having a TP53 mutation at baseline. To identify the origin of these mutations, further analysis of raw sequencing data of baseline samples was performed and revealed that a subset of these mutations was present at baseline and expanded during treatment with idasanutlin. Follow-up samples were obtained from 4 of 5 patients in this cohort, and we observed that after cessation of idasanutlin, the variant allele frequency (VAF) of 8 of 9 TP53 mutations decreased. Furthermore, disease progression to myelofibrosis or myeloproliferative neoplasm blast phase was not observed in any of these patients after 19- to 32-month observation. These data suggest that idasanutlin treatment may promote transient TP53 mutant clonal expansion. A larger study geared toward high-resolution detection of low VAF mutations is required to explore whether patients acquire de novo TP53 mutations after idasanutlin therapy.
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U2 - 10.1182/bloodadvances.2020002379
DO - 10.1182/bloodadvances.2020002379
M3 - Article
C2 - 33216890
AN - SCOPUS:85097217708
SN - 2473-9529
VL - 4
SP - 5735
EP - 5744
JO - Blood Advances
JF - Blood Advances
IS - 22
ER -