TY - JOUR
T1 - Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML
T2 - a phase 1 study
AU - Stein, Eytan M.
AU - DiNardo, Courtney D.
AU - Fathi, Amir T.
AU - Mims, Alice S.
AU - Pratz, Keith W.
AU - Savona, Michael R.
AU - Stein, Anthony S.
AU - Stone, Richard M.
AU - Winer, Eric S.
AU - Seet, Christopher S.
AU - Döhner, Hartmut
AU - Pollyea, Daniel A.
AU - McCloskey, James K.
AU - Odenike, Olatoyosi
AU - Löwenberg, Bob
AU - Ossenkoppele, Gert J.
AU - Patel, Prapti A.
AU - Roshal, Mikhail
AU - Frattini, Mark G.
AU - Lersch, Frederik
AU - Franovic, Aleksandra
AU - Nabhan, Salah
AU - Fan, Bin
AU - Choe, Sung
AU - Wang, Hongfang
AU - Wu, Bin
AU - Hua, Lei
AU - Almon, Caroline
AU - Cooper, Michael
AU - Kantarjian, Hagop M.
AU - Tallman, Martin S.
N1 - Acknowledgments:
Editorial assistance was provided to the authors by Helen Varley, CMPP,
Excel Medical Affairs, Horsham, United Kingdom, and supported by
Agios.
This work was supported by Agios Pharmaceuticals, Inc., in collaboration
with Bristol-Myers Squibb. Agios provided financial support for the study
and participated in the design, study conduct, and analysis and in-
terpretation of data, as well as the writing, review, and approval of the
manuscript.
Publisher Copyright: © 2021 American Society of Hematology
PY - 2021/4/1
Y1 - 2021/4/1
N2 - Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
AB - Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
UR - http://www.scopus.com/inward/record.url?scp=85096648504&partnerID=8YFLogxK
U2 - 10.1182/blood.2020007233
DO - 10.1182/blood.2020007233
M3 - Article
C2 - 33024987
AN - SCOPUS:85096648504
SN - 0006-4971
VL - 137
SP - 1792
EP - 1803
JO - Blood
JF - Blood
IS - 13
ER -