MDS patients with mutated IDH2 benefit from enasidenib

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.

Eytan Stein, MD

Photo courtesy of ASH

SAN DIEGO—Daily treatment with enasidenib monotherapy in patients with mutated IDH2-positive myelodysplastic syndromes (MDS) induced responses in the majority of patients treated, according to a presentation at the 2016 ASH Annual Meeting.

The study was a portion of a larger phase 1/2 trial of the agent in patients with acute myeloid leukemia (AML) and other hematologic malignancies, so the subset was relatively small, numbering 17 patients.

Nevertheless, enasidenib was well tolerated and induced responses in these predominantly higher-risk patients.

Enasidenib (AG-221/CC-9007) is a selective, oral, potent inhibitor of mutant IDH2 (mIDH2), which produces 2-HG and thus alters DNA methylation and blocks cellular differentiation of hematopoietic progenitor cells.

Approximately 15% of AML patients and 5% of MDS patients have mIDH2. So investigators undertook the study to evaluate the safety and efficacy of enasidenib monotherapy in these diseases.

Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, presented the analysis of enasidenib in mIDH2-positive MDS patients as abstract 343.*

Study design

MDS patients were allowed to enroll during the dose-escalation and expansion phase of the study, Dr Stein explained.

Patients had to be 18 or older and have an advanced hematologic malignancy with mutated IDH2—relapsed or refractory AML, relapsed or refractory MDS, untreated AML, or other hematologic malignancy with mIDH2.

MDS patients could not be candidates for other therapies, had to be IPSS-R high risk, and had to have relapsed or refractory RAEB-1/RAEB-2 disease.

Investigators also performed co-molecular profiling using next-generation sequencing with a FoundationOne® Heme Panel.

All patients received daily oral enasidenib at 100 mg daily in 28-day cycles.

Patient characteristics

The study accrued a total of 239 patients—176 with relapsed or refractory AML, 37 with untreated AML, 9 with another hematologic malignancy, and 17 with MDS.

The median age of the MDS patients was 67 (range, 45-78), and 71% were male. All had the IDH2 mutation, 88% had R140 mutations, and 12% had R172.

Thirteen patients (76%) had an ECOG performance status of 0-1, and 4 (24%) had a performance status of 2.

A little more than a third (35%) of patients had 2 or more prior anti-cancer regimens.

Two patients (12%) received prior lenalidomide therapy, 8 (47%) received other treatments, including sorafenib (n=2) and vosaroxin, epoetin alfa, pracinostat, cytarabine plus clofarabine, ruxolitinib, and rigosertib (n=1 each). Four patients (24%) were untreated.

“I want to make the point,” Dr Stein said, “that, of those patients, three quarters of them, 76% [n=13], had received a prior hypomethylating agent, really understanding that this is a very poor-risk group of patients that we are studying here.”

About half of patients (47%) had intermediate-2/high IPSS risk status, good MDS cytogenetic risk, and high/very high IPSS-R risk status.

Adverse events

Grade 3-4 treatment-emergent adverse events (AEs) occurring in 2 or more patients were hyperbilirubinemia (n=5), pneumonia (n=4), thrombocytopenia (n=4), anemia (n=3), hypokalemia (n=3), dyspnea (n=2), and tumor lysis syndrome (n=2).

“As I’ve said in a number of meetings where I’ve talked about IDH2 inhibitors, and specifically enasidenib, the hyperbilirubinemia that is seen with this drug is an indirect hyperbilirubinemia,” Dr Stein said.

“A known off-target effect of this drug is inhibition of the UGT1a1 enzyme, which conjugates bilirubin, and this indirect hyperbilirubinemia, which is typically relatively mild [and] does not appear to have any clinical sequelae.”

Investigators considered 9 of the AEs reported for 6 patients to be drug-related.

Four serious enasidenib-related AEs included tumor lysis syndrome (n=2), increased blood bilirubin (n=1), and transaminitis (n=1).

There were no treatment-related deaths.

Response and survival

Ten of 17 patients (59%) achieved an overall response, defined as complete response (CR) plus partial response, plus marrow CR, plus hematologic improvement (HI).

One patient achieved CR, 1 had a partial response, 3 had marrow CR, and 5 had HI.

Dr Stein noted that, of the 13 patients who had received prior hypomethylating agent therapy, 7 (54%) had a response with enasidenib.

Of the patients who attained HI, 2 had trilineage and 2 had bilineage improvement.

The median time to response was 21 days (range, 10-87), and the median number of treatment cycles was 3.0.

Patients remained on study for up to 24 months. Four patients in hematologic remission are still on study, and 3 patients proceeded to stem cell or bone marrow transplant, Dr Stein said.

Two patients discontinued because of investigator decision, and 8 discontinued therapy due to death or disease progression.

The limitation of the study regarding overall survival, Dr Stein said, is that the number is very small.

At a median follow-up of 7.5 months, the median overall survival was not reached.

“So I’m not arguing that this is the end word of this,” he said. “This is going to be dynamic as more patients come on these studies. But I think it’s a nice indication that this treatment appears to be well-tolerated and doing good for a large subset of patients.”

Co-occurring mutations

The investigators also analyzed co-occurring mutations in 13 MDS patients.

The small patient population prevented the investigators from making definitive conclusions regarding potential correlations between response and co-mutations.

Nevertheless, Dr Stein said the analysis revealed something “very, very intriguing.”

He noted that 7 patients had ASXL1 mutations, and “those are typically patients who are bad actors.”

“Five of those 7 patients had a response,” Dr Stein said. “And of those 5, 3 of them had received a prior hypomethylating agent. I think it’s at least food for thought that you can salvage a patient who has failed a hypomethylating agent, with poor risk disease. I think this is very, very exciting.”

Celgene Corporation and its collaborator, Agios Pharmaceuticals, sponsored the trial.

*Information in the abstract differs from the presentation.