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Enasidenib is effective in inducing remission in patients with relapsed or treatment-resistant acute myeloid leukemia (AML), and an isocitrate dehydrogenase-2 (IDH2) gene mutation, according to early trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology (ASCO).

Enasidenib is a selective inhibitor of mutant-IDH2 enzymes, which occurs in up to 20% of patients with AML. These mutations in IDH2 can contribute to leukemia by blocking hematopoietic cell differentiation.

Of the patients with IDH2 mutations included in this trial, 40.3% responded to the treatment, while 19.3% achieved complete remission. The results of the trial, presented by of Memorial Sloan Kettering Cancer Center, at ASCO 2017, were also published in the journal .

In this first-in-human, Phase I/II study, the investigators' primary objective was to determine the safety and maximum tolerated dose of enasidenib. The secondary objectives included characterizing the pharmacokinetic-pharmacodynamic profile and clinical activity of the drug.

Between September 2013 and April 2016, 239 patients with advanced hematologic malignancies and IDH2 mutation were enrolled in the study. Of those 239 patients, 176 had relapsed or refractory AML.

Stein and his colleagues found that overall 71 (40.3%) patients with relapsed/refractory AML had a hematologic response during treatment. Thirty-four patients with relapsed/refractory AML (19.3%) achieved complete remission, while 11 patients achieved partial remission.

The median duration of response with enasidenib was 5.8 months. The investigators also noted that 11% of patients proceeded to transplant, "suggesting enasidenib may provide a bridge to potentially curative treatment."

Median overall survival with enasidenib was 9.3 months among all patients with relapsed/refractory AML and 19.7 months for those patients who attained complete remission. The investigators also determined that the median overall survival in patients who had received 2 or more prior anti-cancer regimens was 8.0 months.

Stein and his colleagues wrote that these overall survival results were "especially promising" and compared them to those from a randomized in which patients with relapsed/refractory AML were treated with a choice of seven salvage treatments and achieved a median overall survival of 3.3 months.

As far as the safety of the drug is concerned, Stein and his colleagues found that enasidenib was "generally well tolerated." In this trial patients received enasidenib doses of between 50 mg and 650 mg daily in the dose-escalation arm of the study, and 100 mg daily in the expansion arm of the study. They found that a maximum tolerated dose was not reached.

Overall, 24% of patients had treatment-related serious adverse events, including IDH differentiation syndrome (8%), leukocytosis (4%), tumor lysis syndrome (3%) and hyperbilirubinemia (2%).

"Because enasidenib is not myeloblative, patients with mutant-IDH2 hematological malignancies may be spared the degree of toxicity associated with intensive treatment," the investigators wrote, adding that enasidenib-related treatment-emergent adverse events (TEAE) led to dose modification, interruption, or discontinuation in only 7%, 22%, and 5% of patients respectively.

They also noted that since Enasidenib is not associated with bone marrow aplasia or susceptibility to severe infection that can be experienced with standard cytotoxic agents, rates of enasidenib-related grade 3-4 hematologic TEAEs (10%) and infections (1%) were low in this study when compared to other AML treatments.

Stein and his colleagues reported that nearly all (238 of the 239 patients) experienced a TEAE, while 195 (82%) experienced a treatment-related TEAE. The most common of these were indirect hyperbilirubinemia (38%), and nausea (23%).

"This therapy was almost always administered as an outpatient, and resulted in durable remissions not only in patients who responded to therapy with CR (complete remission) or CRIs (complete remission with incomplete hematologic recovery) , but also in patients, who had stable disease," said , D. Warren Brown chair of Leukemia Research, and professor of medicine and medicinal chemistry at the Ohio State University Wexner Medical Center, in commenting about the study to 番茄社区 Medical Today.

"This contrasts to therapy we've given before to AML patients, including IDH2 mutation-positive individuals where responses were similar to this, but the therapy required them to receive very toxic chemotherapy, resulting in them being hospitalized for more than a month," he noted.

A multicenter, randomized comparing enasidenib with conventional care regimens in older patients with relapsed/refractory AML is now taking place.

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