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Emerging Treatments and Clinical Challenges in Myelodysplastic Syndromes: ASCO 2021 and EHA 2021 Updates
Volume 1
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Enasidenib Elicits Clinical Efficacy in High-Risk, IDH2-Mutated MDS


The IDH2 inhibitor enasidenib demonstrated promising efficacy in combination with azacitidine and as a single agent in patients with high-risk, IDH2-mutated myelodysplastic syndrome.

Sangeetha Venugopal, MD

Sangeetha Venugopal, MD

The IDH2 inhibitor enasidenib (Idhifa) demonstrated promising efficacy in combination with azacitidine and as a single agent in patients with high-risk, IDH2-mutated myelodysplastic syndrome (MDS), according to findings from a phase 2 study (NCT03383575) that were presented during the 2021 ASCO Annual Meeting and subsequently published in the Journal of Clinical Oncology.1

Enasidenib in combination with azacitidine induced an overall response rate (ORR) of 84% in patients with hypomethylating agent (HMA)–naïve, high-risk MDS (n = 25). Of these responses, 24% (n = 6) were complete responses (CRs), 8% (n = 2) were partial responses (PRs), 44% (n = 11) were bone marrow CRs, and 8% (n = 2) were hematological improvements.

When used as a single agent, enasidenib induced an ORR of 43% in patients who previously failed an HMA (n = 21). Of these responses, 24% (n = 5) were CRs, 5% (n = 1) were PRs, 5% (n = 1) were marrow CRs, and 10% (n = 2) were hematological improvements.

IDH2 mutations are present in 5% to 10% of patients with MDS.

“[The IDH2-mutant] phenotype is characterized by normal karyotype, increased bone marrow blast count, [and] neutropenia, but with sustained platelet count,” said lead study author Sangeetha Venugopal, MD, a clinical fellow in leukemia in the MD Anderson Cancer Center Leukemia Fellowship Program at The University of Texas MD Anderson Cancer Center, in a virtual presentation of the data.

Enasidenib is a selective, oral, IDH2 inhibitor that is FDA approved to treat patients with relapsed/refractory IDH2-mutated acute myeloid leukemia (AML).

Findings from the phase 1 AG221-C-001 study (NCT01915498) demonstrated a 53% response rate and a median overall survival (OS) of 16.9 months with enasidenib among patients with relapsed/refractory IDH2-mutant MDS.

In the ongoing, multicenter, open-label phase 2 trial, patients with HMA-naïve, high-risk MDS (arm A) received 75 mg/m2 of intravenous azacitidine daily or subcutaneous azacitidine on days 1 through 7 of 28-day cycles plus 100 mg of daily, oral enasidenib on days 1 through 14. Patients who previously failed HMA treatment (arm B) received single-agent, continuous enasidenib at 100 mg daily.

High-risk MDS was defined by high- or very high–risk per Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes Risk Assessment criteria or the presence of high-risk mutations, such as TP53, ASXL1, EZH2, or RUNX1, explained Venugopal.

“The median survival in patients with higher-risk MDS treated with standard-of-care [HMAs] is less than 2 years, which decreases to less than 6 months in the setting of HMA failure where no standard-of-care treatment options are available,” Venugopal said.

In the overall population (n = 46), the median patient age was 73 (range, 46-83) and 77% (n = 36) of patients were 65 years of age or older.

Per the World Health Organization 2017 criteria, 30% (n = 14) of patients had a diagnosis of MDS with multilineage dysplasia (MDS-MLD)/MDS-myeloproliferative neoplasm, unclassifiable (MDS-MPN-U), 59% (n = 27) had a diagnosis of MDS with excessive blasts (MDS-EB)/AML with myelodysplasia-related changed (AML-MRC), and 11% (n = 5) had a diagnosis of chronic myelomonocytic leukemia (CMML).

The majority of patients (50%; n = 23) had good cytogenetics. ASXL1, SRSF2, and RUNX1 mutations, which confer poor prognosis, were identified in 37% (n = 17), 43% (n = 20), and 17% (n = 8) of patients, respectively, Venugopal said.

Finally, per IPSS-R classification, 59% (n = 27) of patients had high- or very high–risk disease and 39% (n = 18) had low- or intermediate-risk disease.

In the overall population, the ORR was 68% and was comprised of CRs (24%; n = 11), PRs (7%; n = 3), marrow CRs (26%; n = 12), and hematologic improvement only responses (9%; n = 4). The median time to first response was 1 month (range, 0.9-3.7) and the time to best response was 3.1 months (range, 0.9-7.6). Moreover, 35% (n = 16) of patients had no response to treatment, 30% (n = 14) achieved stable disease (SD), and 4% (n = 2) developed progressive disease.

In arm A, the median time to first response was 0.9 months (range, 0.9-3.4) and the median time to best response was 1.6 months (range, 0.9-3.7). In this cohort, 16% of patients (n = 4) did not respond to enasidenib/azacitidine, 16% (n = 4) achieved SD, and no patients developed progressive disease.

In arm B, the median time to first response was 1 month (range, 0.9-3.7) and the median time to best response was 4.6 months (range, 2.8-7.6). In this cohort, 57% of patients (n = 12) did not respond to single-agent enasidenib, 48% (n = 10) achieved SD, and 10% (n = 2) developed progressive disease.

With a median follow-up of 12.6 months, the median OS was 32.2 months in Arm A and 21.3 months in Arm B.

“[The survival data reported] are much better than the reported OS in single-agent HMA or post-HMA failure settings,” added Venogopal.

Regarding safety, any-grade adverse effects (AEs) included infection (26%; n = 12), pneumonia (26%; n = 12), neutropenic fever (17%; n = 8), nausea (46%; n = 21), constipation (44%; n = 20), diarrhea (15%; n = 7), differentiation syndrome (17%; n = 8), fatigue (35%; n = 16), hyperbilirubinemia (20%; n = 9), liver function test abnormalities (15%; n = 7), electrolyte/metabolic abnormalities (28%; n = 13), and intracranial bleeding (6%; n = 3).

Grade 3 or 4 AEs included infection (13%; n = 6), pneumonia (13%; n = 6), neutropenic fever (17%; n = 8), nausea (2%; n = 1), diarrhea (2%; n = 1), differentiation syndrome (13%; n = 6), fatigue (7%; n = 3), hyperbilirubinemia (9%; n = 4), liver function test abnormalities (2%; n = 1), and electrolyte/metabolic abnormalities (2%; n = 1).

Regarding differentiation syndrome, the median time to onset was 1.4 months (range, 1.2-1.8) in arm A and 1.2 months (range, 1.0-8.4 months) in arm B. One patient with grade 2 differentiation syndrome did not require treatment, whereas 5 patients with grade 3 differentiation syndrome were successfully treated with dexamethasone. One patient with grade 3 differentiation syndrome was treated with hydroxyurea but progressed to AML.

Grade 5 AEs included infection (2%; n = 1), pneumonia (13%; n = 6), and intracranial bleeding (2%; n = 1).

“This study continues to accrue patients and, hopefully, with longer follow-up in a larger dataset, we will confirm these promising results of enasidenib in IDH2-mutated HR-MDS,” concluded Venugopal.


  1. Venugopal S, DiNardo CD, Takahashi K, et al. Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndrome (MDS). J Clin Oncol. 2021;39(suppl 15):7010. doi:10.1200/JCO.2021.39.15_suppl.7010
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