TY - JOUR
T1 - Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome
AU - DiNardo, Courtney D.
AU - Venugopal, Sangeetha
AU - Lachowiez, Curtis
AU - Takahashi, Koichi
AU - Loghavi, Sanam
AU - Montalban-Bravo, Guillermo
AU - Wang, Xuemei
AU - Carraway, Hetty
AU - Sekeres, Mikkael
AU - Sukkur, Ameenah
AU - Hammond, Danielle
AU - Chien, Kelly
AU - Maiti, Abhishek
AU - Masarova, Lucia
AU - Sasaki, Koji
AU - Alvarado, Yesid
AU - Kadia, Tapan
AU - Short, Nicholas J.
AU - Daver, Naval
AU - Borthakur, Gautam
AU - Ravandi, Farhad
AU - Kantarjian, Hagop M.
AU - Patel, Bhumika
AU - Dezern, Amy
AU - Roboz, Gail
AU - Garcia-Manero, Guillermo
N1 - Publisher Copyright:
© 2023 by The American Society of Hematology.
PY - 2023/6/13
Y1 - 2023/6/13
N2 - The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ~5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior hypomethylating agent (HMA) therapy. Fifty patients with mIDH2 MDS enrolled: 27 in arm A and 23 in arm B. Median age of patients was 73 years. The most common adverse events were neutropenia (40%), nausea (36%), constipation (32%), and fatigue (26%). Hyperbilirubinemia from off-target UGT1A1 inhibition occurred in 14% of patients (8%; grades 3 and 4), and IDH-inhibitor–associated differentiation syndrome (IDH-DS) in 8 patients (16%). In the combination arm, the overall response rate (ORR: complete remission [CR] + marrow CR [mCR] + partial remission) was 74%, including 70% composite CR (CRc: CR + mCR). Median time to best response was 1 month (range, 1-4), and a median of 4 cycles was received (1-32). The median overall survival (OS) was 26 months (range, 14 to not reached). In the enasidenib monotherapy cohort after HMA failure, ORR and CRc were both 35% (n = 8), with 22% CR (n = 5). Median time to first response was 27 days, and time to best response was 4.6 months (2.7-7.6 months). A median of 7 cycles was received (range, 1-29), and the median OS was 20 months (range, 11 to not reached). Enasidenib is an effective treatment option for mIDH2 MDS, both in combination with azacitidine for treatment-naïve high-risk MDS, and as a single agent after prior HMA therapy. This trial is registered at www.clinicaltrials.gov as #NCT03383575.
AB - The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ~5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior hypomethylating agent (HMA) therapy. Fifty patients with mIDH2 MDS enrolled: 27 in arm A and 23 in arm B. Median age of patients was 73 years. The most common adverse events were neutropenia (40%), nausea (36%), constipation (32%), and fatigue (26%). Hyperbilirubinemia from off-target UGT1A1 inhibition occurred in 14% of patients (8%; grades 3 and 4), and IDH-inhibitor–associated differentiation syndrome (IDH-DS) in 8 patients (16%). In the combination arm, the overall response rate (ORR: complete remission [CR] + marrow CR [mCR] + partial remission) was 74%, including 70% composite CR (CRc: CR + mCR). Median time to best response was 1 month (range, 1-4), and a median of 4 cycles was received (1-32). The median overall survival (OS) was 26 months (range, 14 to not reached). In the enasidenib monotherapy cohort after HMA failure, ORR and CRc were both 35% (n = 8), with 22% CR (n = 5). Median time to first response was 27 days, and time to best response was 4.6 months (2.7-7.6 months). A median of 7 cycles was received (range, 1-29), and the median OS was 20 months (range, 11 to not reached). Enasidenib is an effective treatment option for mIDH2 MDS, both in combination with azacitidine for treatment-naïve high-risk MDS, and as a single agent after prior HMA therapy. This trial is registered at www.clinicaltrials.gov as #NCT03383575.
KW - Durable responses occurred with enasidenib after prior
KW - Enasidenib
KW - HMA therapy
KW - IDH2 MDS
KW - IDH2 enzyme
KW - a selective inhibitor of mutant
KW - in combination with azacitidine in treatment-naïve patients
KW - is an effective treatment option in patients with
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U2 - 10.1182/bloodadvances.2022008378
DO - 10.1182/bloodadvances.2022008378
M3 - Article
C2 - 35973199
AN - SCOPUS:85139913143
SN - 2473-9529
VL - 7
SP - 2378
EP - 2387
JO - Blood Advances
JF - Blood Advances
IS - 11
ER -