Early Success Reported With Two New Agents for High-Risk Myelodysplastic Syndromes

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At the 2016 American Society for Hematology (ASH) Annual Meeting & Exposition, researchers reported early success with two new experimental agents for high-risk myelodysplastic syndromes—enasidenib (also known as AG-221), a potent oral inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme, and guadecitabine (also known as SGI-110), a novel subcutaneous hypomethylating agent.

The speakers emphasized the need for new agents in this disease. Response rates to current hypomethylating agents (azacitidine and decitabine) are 30% to 40%, with complete responses obtained by only 10% to 15% of patients. Once patients fail to respond to hypomethylating agents, outcomes are poor.

Oral Enasidenib

Daily treatment with oral enasidenib monotherapy induced responses in the majority of myelodysplastic syndrome patients with mutations in IDH2, most of whom had high-risk disease and three-fourths of whom had failed prior hypomethylating agents.
— Eytan M. Stein, MD

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“Daily treatment with oral enasidenib monotherapy induced responses in the majority of myelodysplastic syndrome patients with mutations in IDH2, most of whom had high-risk disease and three-fourths of whom had failed prior hypomethylating agents,” reported Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.1 “Notably, more than one-half of patients who had failed prior hypomethylating agents had a response with enasidenib, and only two patients had disease progression during treatment.”

IDH2 mutations occur in approximately 5% of patients with myelodysplastic syndromes and about 15% of patients with acute myeloid leukemia. Mutant IDH2 proteins have neomorphic enzymatic activity and are associated with DNA and histone hypermethylation, altered gene expression, and blocked differentiation of hematopoietic progenitor cells.

Enasidenib is a small-molecule allosteric inhibitor of mutated IDH2 protein that induces hematologic responses in IDH2-mutation–positive patients with acute myeloid leukemia. The current study is the first to evaluate its safety and efficacy in IDH2-mutation–positive patients with myelodysplastic syndromes.

Key Study Findings

The multicenter study included 17 patients with myelodysplastic syndromes and mutated IDH2 who were part of a larger 239-patient trial, which also included patients with acute myeloid leukemia. Patients had relapsed or refractory disease or were not candidates for standard therapies. Patients received oral enasidenib at 60 to 100 mg daily in 28-day cycles. They were assessed for overall response rate, which includes complete remission, partial remission, marrow complete remission, and any hematologic improvement.

Forty-one percent of patients had received one prior treatment, and 35% had received two or more prior treatments; for 76% of patients, prior treatment included a hypomethylating agent. By the Revised International Prognostic Scoring System (IPSS-R), 47% of patients were at high or very high risk for disease progression. In this “very poor–risk population,” as Dr. Stein called these patients, the overall response rate was 59%.

Patients remained on the study for up to 24 months. Three subsequently underwent allogeneic bone marrow transplant.

Fourteen patients (82%) experienced a grade 3/4 treatment-emergent adverse event (from any cause). These events included hyperbilirubinemia (30%), pneumonia (24%), thrombocytopenia (24%), anemia (18%), hypokalemia (18%), dyspnea (12%), and tumor-lysis syndrome (12%). Enasidenib-related serious adverse events included tumor-lysis syndrome in two patients and blood bilirubin increase and transaminitis in one patient each. “The hyperbilirubinemia with this drug is indirect and a known off-target effect,” he added. “It is typically mild and has no clinical sequelae.”

At a median follow-up of 7.5 months, median overall survival was not reached. “This is not the final word; the study will be dynamic as more patients come on it. But it’s a nice indication that this treatment appears to be well tolerated and is doing good things for a large subset of patients,” Dr. Stein commented.

Molecular Profiling

Molecular profiling by next-generation sequencing has proved interesting. Due to the small sample size, the findings are only descriptive, cautioned Dr. Stein, “but one thing is intriguing: Typically, patients with ASXL1 mutations are bad actors, but five of seven patients with this mutation had responses, and three of these five patients had received prior treatment with a hypomethylating agent…. This is food for thought; you might be able to use this drug to salvage a patient who has failed a hypomethylating agent.”

Co-occurring mutations were identified in a number of patients. Trends were observed between response and co-occurring ASXL1 and/or SRSF2 mutations, he added.

Subcutaneous Guadecitabine

Findings for guadecitabine were encouraging in previously untreated patients.2 It is formulated as a dinucleotide of decitabine and deoxyguanosine and generates prolonged exposure as compared with decitabine.

We found that guadecitabine was active in higher-risk [myelodysplastic syndromes] and [chronic myelomonocytic leukemia], producing a 71% overall response rate and a 32% complete response rate.
— Guillermo Montalban-Bravo, MD

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“Improving the current response and survival outcomes of patients with higher-risk [myelodysplastic syndromes] and [chronic myelomonocytic leukemia], particularly in the presence of very high–risk biologic features, is fundamental. In the current clinical trial, we assessed the activity of guadecitabine in such patients, as front-line therapy,” said Guillermo Montalban-Bravo, MD, of The University of Texas MD Anderson Cancer Center, Houston.

“We found that guadecitabine was active in higher-risk [myelodysplastic syndromes] and [chronic myelomonocytic leukemia], producing a 71% overall response rate and a 32% complete response rate,” he said. “The drug was active in the presence of high-risk features.”

Study Details

The findings were from a single-arm, nonrandomized phase II trial of 50 patients, including 43 with newly diagnosed myelodysplastic syndromes and 7 with chronic myelomonocytic leukemia classified as intermediate-2 or high risk by IPSS (by IPSS-R, approximately 44% of each cohort were classified as high risk and 42%, as very high risk). Complex karyotype was identified in 47% of the myelodysplastic syndromes cohort and 14% of the chronic myelomonocytic leukemia cohort. One-third of the patients had therapy-related disease. Sequencing revealed that TP53, ASXL1, and TET2 were mutated in more than 20% of patients, with a number of other genes mutated as well.

Treatment consisted of guadecitabine at 60 mg/m2 given subcutaneously daily for 5 days every 28 days. The primary endpoint was complete response.


Among 44 evaluable patients, the overall response rate was 71%, reflecting responses in 68% of patients with myelodysplastic syndromes and 83% of patients with chronic myelomonocytic leukemia. Complete responses were observed in 32% of patients, marrow complete remissions were noted in 32%, and hematologic improvement was seen in 7%. Among 33 patients evaluable for cytogenetic response, 24% achieved a complete cytogenetic response after a median of four cycles, he reported. Dr. Montalban-Bravo acknowledged that although hematologic improvement was infrequent, “most patients with a marrow complete response had some degree in at least one of the different cell lines.”

Novel Agents for High-Risk Myelodysplastic Syndromes

  • Oral enasidenib and subcutaneous guadecitabine were evaluated in
    phase II studies of patients with high-risk myelodysplastic syndromes.
  • In previously treated patients with mutations in IDH2, monotherapy
    with enasidenib induced responses in 59% of patients, with complete remissions in 8%.
  • As front-line therapy, guadecitabine induced responses in 71%,
    with complete remissions in 32%.

At a median of 6.3 months of follow-up, median event-free survival was 8.4 months and median overall survival was 14.1 months. In the univariate analysis for survival, the only significant factor was mutation of ASXL1, which carried a hazard ratio of 2.99 (P = .047). Patients with this mutation had a median survival of 7.8 months, while median survival was not reached in ASXL1 wild-type patients.

“Only the presence of ASXL1 mutation predicted for shorter overall survival. Of note, so far neither IPSS-R category nor presence of TP53 mutation has impacted survival,” he said.

For response, only the presence of the RUNX1 mutation predicted for a lower likelihood (odds ratio = 0.17,
P = .034).

Ten patients have proceeded to allogeneic stem cell transplant, of whom six remain in complete remission, he added.

The main adverse events associated with guadecitabine treatment were grade 1 or 2 fatigue (66%) and nausea (38%). The primary grade 3 toxicities were neutropenic fever (32%) and infection (26%). At 8 weeks, the mortality rate was 6%, reflecting three non–treatment-related deaths. Dose reductions were required for 34% of patients due to cytopenias and related complications, but the stopping rule for toxicity was not met, he reported.

Less robust responses to guadecitabine were reported from a phase II study by French investigators.3 This study included 56 higher-risk patients with myelodysplastic syndromes who relapsed after or were refractory to treatment with azacitidine. The overall response rate to guadecitabine was 26.6% among primary refractory patients and 12.2% among relapsing patients, including 1 complete response (3%). The median duration of response was 9 months.

“The response rates with guadecitabine, in this population of higher-risk [myelodysplastic syndromes], chronic myelomonocytic leukemia, or low blast count [acute myeloid leukemia] with failure to azacitidine (and often with International Working Group 2006 disease progression) were modest,” the authors concluded.

There is an ongoing phase III trial of guadecitabine in patients who have failed to respond to hypomethylating agents. ■

Disclosure: Dr. Stein has received research funding from Seattle Genetics, Agios Pharmaceuticals, and Celgene and has served as a consultant or advisor to Agios Pharmaceuticals, Celgene, and Novartis. Dr. Montalban-Bravo reported no potential conflicts of interest.


1. Stein EM, Fathi AT, DiNardo CD, et al: Enasidenib (AG-221), a potent oral inhibitor of mutant isocitrate dehydrogenase 2 enzyme, induces hematologic responses in patients with myelodysplastic syndromes. 2016 ASH Annual Meeting. Abstract 343. Presented December 4, 2016.

2. Montalban-Bravo G, Bose P, Alvarado Y, et al: Initial results of a phase 2 study of guadecitabine (SGI-110), a novel subcutaneous hypomethylating agent for patients with previously untreated intermediate-2 or high risk myelodysplastic syndromes or chronic myelomonocytic leukemia. 2016 ASH Annual Meeting. Abstract 346. Presented December 4, 2016.

3. Sebert M, Bally C, Peterlin P, et al: Results of a phase II study of guadecitabine (SGI-110) in higher risk MDS, CMML or low blast count AML patients refractory to or relapsing after azacitidine treatment. 2016 ASH Annual Meeting. Abstract 347. Presented December 4, 2016.

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Expert Point of View: Steven D. Gore, MD

Survival in previously untreated patients seems to be inferior to what we achieved with azacitidine and decitabine in the registration trials. Is this drug [guadecitabine] any different from azacitidine?
— Steven D. Gore, MD

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Steven D. Gore, MD,...