Early Data for AG-221 Show Unprecedented Activity in Acute Myeloid Leukemia and Myelodysplastic Syndrome

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Eytan Stein, MD

Patricia LoRusso, DO

AG-221 in Hematologic Malignancies

These complete responses in refractory AML with a drug not nearly as toxic as chemotherapy—one in a patient who showed disease progression on bone marrow transplant—are exciting.

—Patricia LoRusso, DO

Although the data are preliminary, experts were impressed with responses to a novel IDH2 inhibitor called AG-221 in patients with hematologic malignancies. In the first clinical trial of AG-221, there were three complete remissions, two complete remissions with incomplete platelet count recovery (where platelets had not yet reached 100,000/μL), and one partial remission in patients with relapsed, refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) whose tumors harbored mutated isocitrate dehydrogenase (IDH2).1 These were all patients with limited treatment options and a very poor prognosis.

“This is kind of unheard of, but it is very early clinical data and it is an extremely exciting result. These data provide early validation of future directions. We plan to study mutant IDH2 further as a therapeutic target in AML and MDS,” said lead author Eytan Stein, MD, Memorial Sloan Kettering Cancer Center, New York. “These patients have no good treatment options. We give them chemotherapy, but it is not very effective and has substantial toxicity,” he noted.

“These complete responses in refractory AML with a drug not nearly as toxic as chemotherapy—one in a patient who showed disease progression on bone marrow transplant—are exciting,” commented Patricia LoRusso, DO, Karmanos Cancer Institute, Detroit. Dr. LoRusso moderated a press conference at the 2014 Annual Meeting of the American Association for Cancer Research (AACR), where these data were presented. “It is only a phase I trial, and we don’t yet know what these complete responses mean,” she added.

Novel Mechanism

In a separate interview, Dr. Stein explained that this study validates the concept that blocking mutant IDH2 dramatically reduces production of the oncometabolite 2-hydroxyglutarate (2-HG), which is an abnormal substance produced by mutant IGH2 that interferes with maturation of bone marrow cells. IDH2 mutations have been identified in several solid tumors and hematologic malignancies, including AML and MDS.

“We thought that if you blocked IDH2 this would allow the myeloblast to mature into a healthy infection-fighting neutrophil,” he explained.

AG-221 (developed by Agios) is an orally available, selective potent inhibitor of the mutated IDH protein. The phase I dose-escalation study enrolled 22 patients with AML or MDS whose cancers were positive for mutated IDH2. Patient cohorts were treated with AG-221 administered in 28-day cycles as follows: 30 mg twice daily, 50 mg twice daily, 75 mg twice daily, or 100 mg/d. The cutoff date for data presentation was March 2014. The regimens of 75 mg twice daily and 100 mg/d are still being evaluated and will continue to be escalated until a maximum tolerated dose is indentified, Dr. Stein said.

The data presented at the AACR meeting were based on 10 patients from the 30-mg and 50-mg cohorts. Patients had progressive or refractory disease after one to four prior therapies; one patient had undergone bone marrow transplantation. Median age was 62.5 years, and all patients had documented IDH2 mutations.

Of these 10 patients, 7 were evaluable for efficacy. Of these, six had objective responses as assessed by the investigator, including three complete responses and two complete responses with incomplete platelet recovery. Responding patients are continuing to receive the drug.

Toxicity Findings

Thus far, the treatment has been well tolerated. Two patients had severe adverse events, one with elevated white blood cell count and one with confusion and respiratory failure due to disease-related infection. Four patients died within 30 days of study drug termination, all due to disease-related sepsis occurring in cycle 1. Thus far, no dose-limiting toxicities have been identified.

Dose escalation is continuing in additional patient cohorts, and cohort expansion is planned for later in the year. ■

Disclosure: Drs. Stein and LoRusso reported no potential conflicts of interest.


1. Stein EM, Tallman M, Pollyea DA, et al. 2014 American Association for Cancer Research Annual Meeting. Abstract CT103. Presented April 6, 2014.

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