High Hopes for AG-221 in Advanced Leukemia

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Eytan Stein, MD

Encouraging Preliminary Results With AG-221

AG-221’s unique mechanism targeting a specific mutation is the way of the future and represents a highly specific oral therapy that may transform the treatment of a devastating group of blood disorders.

—Eytan Stein, MD

Although the data are preliminary, single-agent AG-221 therapy targeted to the IDH2 (isocitrate dehydrogenase 2) mutation holds great promise as a nonchemotherapy approach to the treatment of advanced hematologic malignancies, including relapsed/refractory acute myelogenous leukemia (AML) and untreated AML.

In an updated analysis of a dose-ecalation phase I trial that now includes 73 patients with advanced hematologic cancer, AG-221 was well tolerated and achieved more than 90% inhibition of its target (ie, 2-HG [2-hydroxyglutarate]) in patients with an IDH2 mutation.1

In 45 evaluable patients with the IDH2 mutation, the overall response rate was 56%; 15 patients achieved a complete response (9 with incomplete platelet recovery), and 10 had a partial response; 17 patients had stable disease throughout the treatment period. Moreover, responses were durable, lasting as long as 9 months on study. No patient in complete remission has relapsed. An estimated 90% of responses are 3 months or longer, and four responders are beyond 6 months of treatment.

“These findings are remarkable and were achieved in patients unlikely to respond to other chemotherapies,” noted lead author Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These data provide continued validation of mutant IDH2 as a therapeutic target in AML and myelodysplastic syndromes. What we have learned with additional experience is that responses have been durable. It’s only an interim analysis and it’s very early, but my dream is that this becomes a treatment for IDH2 mutation–positive patients. This treatment has minimal toxicity and could be an alternative to chemotherapy,” Dr. Stein said.

About 15% to 20% of AML patients harbor the IDH2 mutation, which leads to overproduction of 2-HG, thereby preventing immature white blood cells from maturing into normal white blood cells. AG-221 is a first-in-class, potent oral inhibitor of the IDH2 mutant enzyme; this novel agent “takes the brakes off” of undifferentiated white blood cells and allows them to mature as normal cells, acting in a similar manner as all-trans-retinoic acid and arsenic trioxide (Trisenox) in acute promyelocytic leukemia (APL), he explained. 

Early Responses

The updated analysis Dr. Stein presented at the 2014 Annual Meeting of the American Society of Hematology was based on 73 patients and 4 additional dose-expansion cohorts. 

The cohort of 73 patients included 55 with relapsed/refractory AML, 5 with untreated AML, 6 with myelodysplastic syndrome, and 6 with other hematologic malignancies. The median age of all patients was 67 years (range, 33–90 years). At the time of the 2014 ASH Annual Meeting, 45 patients were evaluable for response. Twelve patients had initiated therapy too recently and were not evaluable for response, and 16 patients discontinued therapy without an evaluable 28-day assessment. The maximal tolerated dose had not yet been reached.

Toxicity Update

AG-221 was well tolerated. Cancer-related symptoms, not attributable to this drug, were mild to moderate and included nausea, fever, diarrhea, and fatigue. One case of dose-related grade 5 hypoxia was reported in a patient with unrelated fungal pneumonia and sepsis. The 60-day all cause mortality rate was 13.7%.

Most of the serious adverse events were mild to moderate and considered disease-related. Serious adverse events possibly drug-related were reported in 13 patients. 

Eleven deaths were reported, nine of them unrelated to treatment; two deaths due to sepsis/hypoxia and atrial flutter, respectively, were possibly treatment-related, he said.

“I believe that AG-221’s unique mechanism targeting a specific mutation is the way of the future and represents a highly specific oral therapy that may transform the treatment of a devastating group of blood disorders,” Dr. Stein commented. ■

Disclosure: Dr. Stein is a consultant for Janssen Pharmaceuticals and Agios Pharmaceuticals.


1. Stein EM, Altman JK, Collins R, et al: AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase I study in patients with IDH2 mutation positive advanced hematologic malignancies. 2014 ASH Annual Meeting. Abstract 115. Presented December 7, 2014.


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