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Experimental targeted therapy improves survival in acute myeloid leukemia

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June 28, 2017

Enasidenib, an experimental inhibitor of IDH2, nearly tripled OS compared with historical data in patients with relapsed or treatment-resistant acute myeloid leukemia, according to early trial data published in Blood.

“Patients with relapsed or refractory AML have a really dismal prognosis, so the need for treatments in that patient population is extraordinarily high,” Eytan M. Stein, MD, internist and hematologic oncologist at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “The discovery that this IDH2 mutation can be treated with minimal side effects made this study come together and move forward.”

Eytan M. Stein

The FDA received a new drug application for enasidenib (AG-221/CC-90007; Agios, Celgene) earlier this year and is expected to rule on its approval in late August, according to Stein.

Advances in the treatment of AML have been limited over the past 40 years. Five-year OS in younger adults with AML is between 40% and 50%, and those with relapsed or refractory disease exhibit a 5-year OS between 5% and 10%.

About 15% of patients with AML have recurrent mutations in IDH1 and IDH2 genes, which prevent white blood cells from maturing into neutrophils.

Standard AML therapies aggressively target all white blood cells. Researchers examined whether enasidenib would inhibit the IDH2 gene and allow immature white blood cells to mature into neutrophils instead of becoming leukemia cells.

“The mechanism of action is differentiation rather than cytotoxicity,” Stein said. “It is not like chemotherapy in that it does not cause cytopenia, therefore patients don’t go through this period of having very low blood counts, being susceptible to infections and needing frequent transfusions.”

The safety and maximum tolerated dose of enasidenib served as the primary endpoint of the study. The pharmacokinetic and pharmacodynamic profiles of enasidenib served as the secondary endpoints.

Researchers collected data from 239 patients (median age 70; 57% men) with IDH2 mutations. Seventy-four percent (n = 176) had treatment-resistant disease with few or no remaining treatment options available.

In the dose-escalation phase, researchers administered five dose levels of enasidenib (30 mg, 50 mg, 75 mg, 100 mg, 150 mg) twice daily for 28 days, and eight dose levels (50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 300 mg, 450 mg, 650 mg) once daily for 28 days.

Researchers reported efficacy outcomes from the subgroup of patients with relapsed/refractory AML.

At median follow-up of 7.7 months (range 0.4-26.7 months), 40.3% (n = 71) of patients with treatment-resistant AML responded to enasidenib and 19.3% (n = 34) achieved complete remission.


Researchers reported median OS of 14.4 months in patients who achieved a partial response and 19.7 months in those who achieved complete response.

Compared with previous studies evaluating other treatments, OS improved from 3.3 months to 9.3 months in patients who received enasidenib.

“The OS we presented in the overall population and in the patients who achieved complete remission is extraordinarily promising for this patient population and not what you would expect with other therapies,” Stein said. “To see a subset of this patient population take a pill at home and go into remission without side effects from the drug is something we have not really seen before with this disease.”

The maximum tolerated dose was not reached at the highest dosage of 650 mg daily. However, patients did not tolerate prolonged dosing at 650 mg daily. Five of seven patients in the 650-mg dosing group required dose reduction or modification due to treatment-emergent adverse effects that did not qualify under dose-limiting treatment.

The most common treatment-emergent adverse effects included hyperbilirubinemia (38%), nausea (23%), and IDH inhibitor–associated differentiation syndrome (6%). Two participants who experienced IDH inhibitor–associated differentiation syndrome died in the course of treatment.

Additional trials to assess enasidenib in combination with standard treatment in older patients with relapsed or refractory AML are ongoing, researchers noted.

“We need to understand why some patients did not respond to the drug and why some who responded relapsed,” Stein said. “We would like to see which combinations might be put together to get the overall response rate up from 40% to 60% or 70%.” – by Chuck Gormley

For more information:

Eytan M. Stein, MD, can be reached at Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email:

Disclosure: Stein reports grants and personal fees from Celgene Corporation and Agios Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures.


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Mikkael Sekeres

We have finally, formally, entered the molecular era of therapeutics for patients with acute myeloid leukemia. This year has seen the approval of midostaurin (Rydapt, Novartis) combined with traditional chemotherapy for the upfront treatment of patients with AML whose leukemia expresses the FLT3 molecular mutation, and now we have solid evidence of activity of enasidenib (AG-221/CC-90007; Agios, Celgene) in patients with relapsed or refractory disease whose leukemia expresses an IDH2 mutation. Responses to this single agent were much higher than those seen when midostaurin was first used as monotherapy and at least comparable to what is seen for traditional cytotoxic approaches to relapsed or refractory AML, as was response duration. The logical next step would be to combine enasidenib with other antileukemic agents, and to move it to the upfront setting, for patients with IDH2 mutations.

Mikkael Sekeres, MD, MS

Cleveland Clinic Taussig Cancer Institute

Disclosure: Sekeres reports an advisory board role with Celgene.