AG-221 Achieved Excellent Responses in Relapsed, Refractory Leukemia, Myelodysplastic Syndrome

May 2014, Vol 5, No 4

San Diego, CA—Preliminary data suggest that a novel agent called AG-221 can induce complete remissions (CRs) in patients with relapsed, refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who harbor mutated IDH2. These exciting results were achieved in patients with an ominous prognosis who have few or no other treatment options. The data were presented at the 2014 American Association for Cancer Research (AACR) annual meeting.

AG-221 achieved CR in 5 of 7 respondents in a cohort of patients with AML/MDS in a phase 1 trial.

“This is the first clinical trial of an inhibitor of mutated IDH, and while the primary objectives of this study are to determine the safety and tolerability of AG-221, we were also able to demonstrate promising clinical activity, including multiple complete remissions, in patients whose blood cancers carried an IDH2 mutation, even at the lowest tested dose,” said lead investigator Eytan M. Stein, MD, Assistant Attending Physician, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York.

In a separate interview, Dr Stein explained that patients like those in the study typically receive chemotherapy, even though it is extremely toxic and does not provide much benefit. AG-221 is far less toxic and does not compromise the immune system, he explained.

AG-221 (developed by Agios) is an orally available, selective potent inhibitor of the gene mutation in the IDH metabolic enzyme. “Our study validates the concept of blocking mutated IDH2. The drug blocks mutated IDH2, dramatically decreasing the oncometabolite 2HG, an abnormal substance produced by mutated IDH2, allowing leukemia cells to mature into healthy infection-fighting cells,” Dr Stein explained.

The phase 1 dose-escalation study enrolled 22 patients with AML or MDS whose cancers harbored mutated IDH2. Patient cohorts were treated with AG-221 administered in 28-day cycles as 30 mg twice daily, 50 mg twice daily, 75 mg twice daily, or 100 mg daily.

The cutoff date for data presentation was March 2014. The doses of 75 mg twice daily and 100 mg daily are still being evaluated and will continue to be escalated until a maximum tolerated dose is identified, Dr Stein said.

The data presented at AACR were based on 10 patients from the 30-mg and 50-mg cohorts. Patients had progressive or refractory disease after 1 to 4 previous therapies; 1 patient had undergone bone marrow transplantation. The median age was 62.5 years, and all patients had documented IDH2 mutations. Of the 10 patients, 7 were evaluable for efficacy.

Of 7 patients, 6 had objective responses as assessed by the investigator, including 3 CRs and 2 CRs with an incomplete platelet recovery. Responding patients are continuing to receive the drug.

Thus far, the treatment has been well-tolerated. In all, 2 patients had severe adverse events: 1 patient had an elevated white blood cell count, and 1 had confusion and respiratory failure resulting from disease-related infection. A total of 4 patients died within 30 days of study drug termination, all as a result of disease-related sepsis occurring in cycle 1.

Laboratory tests showed a >90% reduction in plasma 2HG levels with treatment, as well as evidence of cellular differentiation and normalization of cell counts in bone marrow and blood.

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