MUTANT IDH (MIDH) INHIBITORS, IVOSIDENIB OR ENASIDENIB, WITH AZACITIDINE (AZA) IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML)
Author(s): ,
Courtney D. DiNardo
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Anthony S. Stein
Affiliations:
City of Hope Comprehensive Cancer Center,Duarte,United States
,
Eytan M. Stein
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States;Weill Cornell Medical College,New York,United States
,
Amir T. Fathi
Affiliations:
Massachusetts General Hospital Cancer Center,Boston,United States;Harvard Medical School,Boston,United States
,
Andre C. Schuh
Affiliations:
Princess Margaret Cancer Centre,Toronto,Canada
,
Pau Montesinos
Affiliations:
Hospital Universitari i Politecnic La Fe,Valencia,Spain
,
Olatoyosi Odenike
Affiliations:
University of Chicago Medicine and the University of Chicago Comprehensive Cancer Center,Chicago,United States
,
Hagop M. Kantarjian
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Richard M. Stone
Affiliations:
Harvard Medical School,Boston,United States;Dana-Farber Cancer Institute,Boston,United States
,
Robert Collins
Affiliations:
University of Texas Southwestern Medical Center,Dallas,United States
,
Giovanni Martinelli
Affiliations:
University of Bologna,Bologna,Italy;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS,Meldola,Italy
,
Montserrat Arnan Sangerman
Affiliations:
ICO-Hospital Duran i Reynals,Barcelona,Spain
,
Bin Wu
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Daniel O. Koralek
Affiliations:
Agios Pharmaceuticals, Inc.,Cambridge,United States
,
Jason Van Oostendorp
Affiliations:
Celgene Corporation,Summit,United States
,
Jing Gong
Affiliations:
Celgene Corporation,Summit,United States
,
Kyle J. MacBeth
Affiliations:
Celgene Corporation,Summit,United States
Paresh Vyas
Affiliations:
MRC Molecular Haematology Unit and Oxford Biomedical Research Centre; University of Oxford and Oxford University Hospitals,Oxford,United Kingdom
EHA Library. D. DiNardo C. Jun 17, 2018; 214481; S1562
Courtney D. DiNardo
Courtney D. DiNardo
Contributions
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Abstract

Abstract: S1562

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:30 - 08:45

Location: Victoria Hall

Background
IDH1 and IDH2 mutations occur in approximately 20% of patients with AML, with increasing frequency in older patients. Ivosidenib (AG-120) and enasidenib (AG-221) are oral small-molecule inhibitors of mIDH1 and mIDH2 proteins, respectively, both shown to promote myeloid differentiation. As monotherapies, enasidenib and ivosidenib induced clinical responses in patients (pts) with mIDH relapsed/refractory AML. AZA monotherapy prolonged survival vs conventional care in older pts with newly diagnosed (ND) AML. AZA reduces DNA methylation by inhibiting DNA methyltransferases, and mIDH inhibitors indirectly reduce DNA methylation by suppressing the oncometabolite, 2-HG, and restoring function to α-ketoglutarate-dependent TET family enzymes. In vitro, mIDH inhibitor + AZA combinations enhanced cell differentiation and apoptosis.

Aims
Evaluate clinical outcomes with combination mIDH inhibitors + AZA in older pts with ND-AML in an ongoing phase 1b/2 study (NCT02677922).

Methods
Adult pts with mIDH ND-AML ineligible for intensive treatment (Tx) and ECOG PS scores ≤2 were eligible. Pts received ivosidenib (mIDH1) 500 mg QD or enasidenib (mIDH2) 100 or 200 mg QD, plus SC AZA 75 mg/m2 x 7d, in continuous 28d cycles. Response was defined by modified IWG 2003 AML criteria; overall response rate (ORR) included complete remission (CR), CR with incomplete count recovery (CRi/CRp), partial remission (PR), and morphologic leukemia-free state (MLFS).


Results
At data cutoff (Sep 1, 2017) 17 pts had received ivosidenib 500 mg (n=11) or enasidenib 100 mg (n=3) or 200 mg (n=3) + AZA in the phase 1b portion of the study; 11 pts were ongoing.

Ivosidenib: Median age was 76 yrs (range 74-82) and 82% of pts had an ECOG PS score of 1. Median number of Tx cycles was 3 (range 1-13). Three pts discontinued Tx, 2 due to progressive disease (PD). AEs in ≥4 pts (any grade) were nausea (n=8), constipation (6), fatigue (5) and diarrhea (4). Grade 3-4 hematological AEs (Table) occurred at similar frequency to what has been reported for AZA alone. Serious AEs in >1 pt were pneumonia and febrile neutropenia (n=2 each). Eight of 11 pts responded: 4 pts attained CR, 1 CRi, 1 PR, and 2 MLFS.

Enasidenib: Median age was 68 yrs (range 65-76) and 83% of pts had an ECOG PS score of 1. Median number of Tx cycles was 9 (1-13). Three pts discontinued Tx, 2 due to PD. Most common AEs (any grade) were nausea and hyperbilirubinemia (n=4 each). Serious AEs in >1 pt were pyrexia, bilirubin increase, pneumonia (n=2 each). Four of 6 pts responded: 2 pts achieved CR, 1 PR, and 1 MLFS.

Conclusion
mIDH inhibitor + AZA regimens were generally well tolerated in these older pts with ND-AML;  65% of pts remained on-study at data cutoff. The most common AEs were grade 1-2 gastrointestinal events and enasidenib-related indirect bilirubin elevations, likely due to off-target inhibition of the UGT1A1 enzyme. Response rates are encouraging. Phase 1b enrollment completed in late 2017; updated data for all 23 ivosidenib and 6 enasidenib pts will be presented, as well as longitudinal changes in mIDH variant allele frequencies. Enrollment continues in the phase 2 portion of this study (enasidenib + AZA) and in the phase 3 AGILE study of ivosidenib+ AZA (NCT03173248).

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Acute Myeloid Leukemia, Azacitidine, Enasidenib, Ivosidenib

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