Scientific programme

PS10  Plenary Session

05-May-2017 12:00 13:30

Background: IDH2 mutations (mIDH2) are recurrent in ~5% of patients with MDS. mIDH2 proteins have neomorphic activity that leads to DNA and histone hypermethylation, altered gene expression, and blocked hematopoietic differentiation. Enasidenib (AG-221) is an oral, small-molecule inhibitor of mIDH2 protein that induces clinical responses in patients with mIDH2-positive acute myeloid leukemia (Stein, Blood, 2015). Outcomes with enasidenib monotherapy in patients with mIDH2-positive MDS are reported here.

Methods: Adult patients with mIDH2-positive MDS who were relapsed/refractory to prior therapies or ineligible for standard treatment were included in this phase 1 dose-escalation and expansion study. Clinical responses were measured from serial peripheral blood (PB) and bone marrow (BM) samples and by objective investigator report. Overall response rate (ORR) was assessed per IWG 2006 MDS criteria. Next-generation sequencing identified co-mutations in BM/PB mononuclear cells.

Results: Of all 17 MDS patients, 4 continued to receive enasidenib at data-cutoff (15-April-2016). Median age was 67 years (range 45-78) (Table). At entry, 3 patients had relapsed post-transplant and 13 patients (76%) had failed prior hypomethylating agents (HMAs). Six patients (35%) had received ≥2 prior anti-MDS therapies. Patients in the dose-finding phase received enasidenib doses between 60-300mg daily; 10 patients (59%) received enasidenib 100mg QD. Median number of treatment cycles was 3 (range 1-25). Five patients received ≥6 enasidenib cycles and 4 received ≥12 cycles. Six patients (35%) had a grade 3-4 drug-related TEAE. ORR was 59% (Figure). Seven of 13 patients (54%) who had received prior HMAs responded. Two patients had progressive disease. Median overall survival was not reached at median follow-up of 7.5 months. The most frequently observed co-mutations were ASXL1 and SRSF2. Although trends were observed between response and these mutations, this small cohort prevents definitive conclusions.

Conclusions: Daily enasidenib therapy was well-tolerated and induced responses in more than one-half of these patients with mIDH2-positive MDS, most of whom had higher-risk disease and three-fourths of whom had failed prior HMA treatment. Mutational testing is becoming essential to diagnosis and prognostication in MDS and can identify patients who may benefit from targeted treatment with enasidenib.

E.M. Stein 1,2, A.T. Fathi 3,4, C.D. DiNardo 5, D.A. Pollyea 6, R.T. Swords 7, G.J. Roboz 2,8, R. Collins 9, M.A. Sekeres 10, R.M. Stone 11, E.C. Attar 12, A. Tosolini 13, Q. Xu 14, M. Amatangelo 15, I. Gupta 13, R.D. Knight 13, S. de Botton 16, M.S. Tallman 1,2, H.M. Kantarjian 5
1Memorial Sloan Kettering Cancer Center, Leukemia Service, New York, USA
2Weill Cornell Medical College, Department of Medicine, New York, USA
3Harvard Medical School, Department of Hematology/Oncology, Boston, USA
4Massachusetts General Hospital, Department of Hematology/Oncology, Boston, USA
5The University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, USA
6University of Colorado Cancer Center, Division of Hematology, Aurora, USA
7Sylvester Comprehensive Cancer Center- University of Miami, Department of Leukemia, Miami, USA
8New York Presbyterian Hospital, Clinical and Translational Leukemia, New York, USA
9University of Texas Southwestern Medical Center, Department of Hematologic Malignancies, Dallas, USA
10Cleveland Clinic Taussig Cancer Institute, Department of Hematology and Medical Oncology, Cleveland, USA
11Dana Farber Cancer Institute, Department of Medical Oncology, Boston, USA
12Agios Pharmaceuticals Inc., Medical, Cambridge, USA
13Celgene Corporation, Department of Hematology/Oncology, Summit, USA
14Celgene Corporation, Department of Biostatistics, Summit, USA
15Celgene Corporation, Department of Translational Development, Summit, USA
16Gustave Roussy, Clinical Hematology, Villejuif, France