PHASE II STUDY OF THE IDH2-INHIBITOR ENASIDENIB IN PATIENTS WITH HIGH-RISK IDH2-MUTATED MYELODYSPLASTIC SYNDROMES (MDS)
Author(s): ,
Sangeetha Venugopal
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States;Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Courtney DiNardo
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Koichi Takahashi
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Marina Konopleva
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Sanam Loghavi
Affiliations:
Hematopathology,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Gautam Borthakur
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Amy DeZern
Affiliations:
Hematology,Johns Hopkins Sidney Kimmel Comprehensive Cancer Center,Baltimore,United States
,
Lucia Masarova
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Naval Daver
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Nicholas. J. Short
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Yesid Alvarado
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Farhad Ravandi
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Guillermo Montalban-Bravo
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Koji Sasaki
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Ricardo Delumpa
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
,
Mikkael A. Sekeres
Affiliations:
Hematology,Sylvester Comprehensive Cancer Center,Miami,United States
,
Bhumika Patel
Affiliations:
Hematology,Cleveland Clinic Taussig Cancer Institute,Cleveland,United States
,
Gail J. Roboz
Affiliations:
Division of Hematology & Oncology,Weill Cornell Medical Center,New York,United States
,
Hagop Kantarjian
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
Guillermo Garcia-Manero
Affiliations:
Leukemia,The University of Texas, MD Anderson Cancer Center,Houston,United States
EHA Library. Venugopal S. 06/09/21; 324575; S167
Sangeetha Venugopal
Sangeetha Venugopal
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S167

Type: Oral Presentation

Session title: Novel targets in MDS

Background
Isocitrate dehydrogenase 2 (IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML).

Aims
An open label phase II study designed to evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA) in pts with higher-risk IDH2-mutated MDS. (NCT03383575)

Methods
Pts with higher-risk [Revised International Prognostic Scoring System risk > 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and  pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI)]. Other endpoints include safety, and survival outcomes.

Results
48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46-83). Most pts (72%) had HMR: ASXL1 (39%), and RUNX1 (17%). Median number Tx cycles was 4 (2–32) in the ENA+AZA, and 7 (1–23) in the ENA arm. Common Tx-related grade 3–4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%); these occurred in 10%, 0%, and 5%, in the ENA arm. Grade 3–4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA and 21.3 mo in the ENA arm.



















 

Response


Evaluable
(N = 46)



Arm A (Untreated)


 ENA+AZA


(N = 25)



Arm B (HMA-failure)


ENA


(N = 21)



Overall response rate (ORR), n (%)



30 (68)



21 (84)



9 (43)



Complete remission (CR)



11 (24)



6 (24)



5 (24)



Partial remission (PR)



3 (7)



2 (8)



1 (5)



Marrow CR (mCR)



12 (26)



11 (44)



1 (5)



Hematological improvement (HI) only



4 (9)



2 (8)



2 (10)



No response (NR), n (%)



16 (35)



4 (16)



12 (57)



Stable disease (SD)



14 (30)



4 (16)



10 (48)



Progressive disease (PD)



2 (4)



0 (0)



2 (10)


Conclusion
ENA is well tolerated and shows promising efficacy in IDH2-mutated higher risk MDS. Follow up and accrual is ongoing to better define duration and biomarkers of response.

Keyword(s): AG-221, Azacitidine, MDS, Targeted therapy

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S167

Type: Oral Presentation

Session title: Novel targets in MDS

Background
Isocitrate dehydrogenase 2 (IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML).

Aims
An open label phase II study designed to evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA) in pts with higher-risk IDH2-mutated MDS. (NCT03383575)

Methods
Pts with higher-risk [Revised International Prognostic Scoring System risk > 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and  pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI)]. Other endpoints include safety, and survival outcomes.

Results
48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46-83). Most pts (72%) had HMR: ASXL1 (39%), and RUNX1 (17%). Median number Tx cycles was 4 (2–32) in the ENA+AZA, and 7 (1–23) in the ENA arm. Common Tx-related grade 3–4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%); these occurred in 10%, 0%, and 5%, in the ENA arm. Grade 3–4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA and 21.3 mo in the ENA arm.



















 

Response


Evaluable
(N = 46)



Arm A (Untreated)


 ENA+AZA


(N = 25)



Arm B (HMA-failure)


ENA


(N = 21)



Overall response rate (ORR), n (%)



30 (68)



21 (84)



9 (43)



Complete remission (CR)



11 (24)



6 (24)



5 (24)



Partial remission (PR)



3 (7)



2 (8)



1 (5)



Marrow CR (mCR)



12 (26)



11 (44)



1 (5)



Hematological improvement (HI) only



4 (9)



2 (8)



2 (10)



No response (NR), n (%)



16 (35)



4 (16)



12 (57)



Stable disease (SD)



14 (30)



4 (16)



10 (48)



Progressive disease (PD)



2 (4)



0 (0)



2 (10)


Conclusion
ENA is well tolerated and shows promising efficacy in IDH2-mutated higher risk MDS. Follow up and accrual is ongoing to better define duration and biomarkers of response.

Keyword(s): AG-221, Azacitidine, MDS, Targeted therapy

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