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Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.
The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).
The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.
About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.
In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.
Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.
Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.
With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.
Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.
“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”
They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.
In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.
Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.
In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.
Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.
“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.
“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”
Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.
Stein et al. provide for the first time answers to the questions of whether IDH inhibitors are tolerated in patients and whether these compounds induce clinical responses and, excitingly, both answers are positive.
Data from the phase 1/2 trial are encouraging, given that the population studied has a notoriously dismal prognosis when treated with conventional modalities.
Findings from the companion translational study suggest heterogeneity in the dynamics of response to enasidenib, with some responding patients retaining mutant alleles in mature cells, and a smaller group of responding patients clearing the mutation.
These findings raise the important question of whether enasidenib can target leukemic stem cells, the holy grail of AML therapy. Additional questions arising from the research pertain to the long-term effects of the drug, whether it will induce clonal selection, and how it affects leukemic cells that lack an IDH2 mutation.
Together, the results of these studies argue for the further clinical exploration of IDH inhibitors. It is expected that for more powerful responses, differentiation-based IDH2 inhibition will need to be combined with orthogonal treatment modalities, such as standard chemotherapy or other types of mechanism-based targeted therapy. Obviously, in the next phase, enasidenib-based regimens should be compared head to head to standard regimens in a randomized controlled fashion. Such studies, and studies with other IDH2 and IDH1 inhibitors, will address the full role of IDH inhibition in AML treatment.
Bas J. Wouters, MD, PhD, a hematologist at Erasmus University Medical Center, Rotterdam, the Netherlands, made his remarks in a related commentary ( Blood. 2017;130:693-4 ). Dr. Wouters reported no competing financial interests.
Stein et al. provide for the first time answers to the questions of whether IDH inhibitors are tolerated in patients and whether these compounds induce clinical responses and, excitingly, both answers are positive.
Data from the phase 1/2 trial are encouraging, given that the population studied has a notoriously dismal prognosis when treated with conventional modalities.
Findings from the companion translational study suggest heterogeneity in the dynamics of response to enasidenib, with some responding patients retaining mutant alleles in mature cells, and a smaller group of responding patients clearing the mutation.
These findings raise the important question of whether enasidenib can target leukemic stem cells, the holy grail of AML therapy. Additional questions arising from the research pertain to the long-term effects of the drug, whether it will induce clonal selection, and how it affects leukemic cells that lack an IDH2 mutation.
Together, the results of these studies argue for the further clinical exploration of IDH inhibitors. It is expected that for more powerful responses, differentiation-based IDH2 inhibition will need to be combined with orthogonal treatment modalities, such as standard chemotherapy or other types of mechanism-based targeted therapy. Obviously, in the next phase, enasidenib-based regimens should be compared head to head to standard regimens in a randomized controlled fashion. Such studies, and studies with other IDH2 and IDH1 inhibitors, will address the full role of IDH inhibition in AML treatment.
Bas J. Wouters, MD, PhD, a hematologist at Erasmus University Medical Center, Rotterdam, the Netherlands, made his remarks in a related commentary ( Blood. 2017;130:693-4 ). Dr. Wouters reported no competing financial interests.
Stein et al. provide for the first time answers to the questions of whether IDH inhibitors are tolerated in patients and whether these compounds induce clinical responses and, excitingly, both answers are positive.
Data from the phase 1/2 trial are encouraging, given that the population studied has a notoriously dismal prognosis when treated with conventional modalities.
Findings from the companion translational study suggest heterogeneity in the dynamics of response to enasidenib, with some responding patients retaining mutant alleles in mature cells, and a smaller group of responding patients clearing the mutation.
These findings raise the important question of whether enasidenib can target leukemic stem cells, the holy grail of AML therapy. Additional questions arising from the research pertain to the long-term effects of the drug, whether it will induce clonal selection, and how it affects leukemic cells that lack an IDH2 mutation.
Together, the results of these studies argue for the further clinical exploration of IDH inhibitors. It is expected that for more powerful responses, differentiation-based IDH2 inhibition will need to be combined with orthogonal treatment modalities, such as standard chemotherapy or other types of mechanism-based targeted therapy. Obviously, in the next phase, enasidenib-based regimens should be compared head to head to standard regimens in a randomized controlled fashion. Such studies, and studies with other IDH2 and IDH1 inhibitors, will address the full role of IDH inhibition in AML treatment.
Bas J. Wouters, MD, PhD, a hematologist at Erasmus University Medical Center, Rotterdam, the Netherlands, made his remarks in a related commentary ( Blood. 2017;130:693-4 ). Dr. Wouters reported no competing financial interests.
Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.
The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).
The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.
About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.
In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.
Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.
Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.
With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.
Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.
“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”
They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.
In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.
Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.
In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.
Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.
“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.
“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”
Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.
Enasidenib was a well-tolerated, efficacious alternative to cytotoxic chemotherapy for patients with IDH2-mutated relapsed or refractory acute myeloid leukemia (AML), the results of a phase 1/2 study showed.
The Food and Drug Administration recently approved enasidenib (Idhifa, formerly AG-221; Celgene) for the treatment of adult patients with relapsed or refractory AML having an IDH2 mutation as detected by a companion diagnostic test (RealTime IDH2 Assay; Abbott Molecular Inc.). The drug was generally safe and well tolerated, according to reported trial results (Blood. 2017 Aug. 10;130[6]:722-31). The main grade 3-4 enasidenib-related adverse events were hyperbilirubinemia (12%) and IDH inhibitor–associated differentiation syndrome (6%).
The drug is an oral selective inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) enzymes that is not myeloablative. Although enasidenib appears to work by inducing myeloblast differentiation, predictors of response to the drug generally remain elusive, according to Eytan M. Stein, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and his coauthors.
About 12% of patients with AML have an IDH2 mutation. This genetic defect leads to accumulation of the metabolite 2-hydroxyglutarate (2-HG), causing DNA and histone hypermethylation. Hypermethylation, in turn, blocks hematopoietic cellular differentiation.
In a phase 1/2 trial sponsored by Celgene and Agios Pharmaceuticals, the investigators tested daily enasidenib monotherapy among 239 patients with IDH2-mutated advanced myeloid malignancies.
Among the 176 patients with relapsed or refractory AML (more than half of whom had already received at least two regimens directed against the disease), the overall response rate was 40.3%, and the complete response/remission rate was 19.3%. The median duration of response was 5.8 months.
Evaluation of serial bone marrow aspirates showed that responses were associated with myeloid cellular differentiation and maturation, generally without evidence of aplasia or hypoplasia.
With a median follow-up of 7.7 months, median overall survival was 9.3 months in the entire AML cohort and 19.7 months in the subset achieving complete response/remission. Ten percent of patients went on to allogeneic stem cell transplantation.
Although nearly all patients had a marked reduction in plasma levels of 2-HG, the extent of reduction did not predict response, suggesting that this metabolite is not a biomarker for benefit, and additional mechanisms are at play.
“Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed,” Dr. Stein and his coinvestigators wrote. “Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib.”
They noted that an ongoing multicenter, randomized phase 3 trial, called IDHENTIFY (NCT02577406), is testing enasidenib against conventional regimens in older adults with late-stage AML harboring an IDH2 mutation.
In a companion translational study, investigators led by Michael D. Amatangelo, PhD, a scientist with Celgene in Summit, N.J., further explored mechanisms of enasidenib response and sought to identify alternative biomarkers for benefit in the AML cohort. They measured 2-HG levels, mutant IDH2 allele burden, and co-occurring somatic mutations in samples serially collected during the trial, and used flow cytometry to assess inhibition of mutant IDH2 on hematopoietic differentiation.
Enasidenib therapy induced 2-HG suppression regardless of whether patients’ IDH2 mutation affected the R140 or the R172 residue, according to reported results (Blood. 2017 Aug. 10;130[6]:732-41). However, analyses confirmed that 2-HG suppression alone did not predict response, as most nonresponders also had suppression.
In some patients with complete remission, mutant IDH2 persisted, but there was normalization of hematopoietic stem and progenitor compartments, and emergence of functional neutrophils having the IDH2 mutation. And some patients saw a reduction in mutant IDH2 allele burden, with levels remaining undetectable during response.
Analyses failed to identify any single mutation predictive of response to enasidenib. However, patients who did not achieve a response more commonly had mutations in NRAS and other MAPK pathway effectors, suggesting that RAS signaling plays a role in primary resistance to the drug.
“Although this is only a subgroup analysis of a large single-arm experience, taken together, the clinical response and translational data demonstrate that single-agent [mutant IDH2] inhibition by enasidenib in [relapsed or refractory AML] represents a critical and novel differentiation therapy,” Dr. Amatangelo and his coinvestigators wrote.
“Although enasidenib responses are clinically durable, the genetic heterogeneity observed in our patients suggests that combination with other therapies may be required to achieve long-term disease remission in more patients,” they added. “Current clinical studies combining enasidenib with combination chemotherapy or azacitidine (NCT02677922 and NCT02632708) and future orthogonal targeted therapies will address this question.”
Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene.
FROM BLOOD
Key clinical point:
Major finding: The overall response rate was 40.3%; 2-HG levels and co-occurring mutations were not reliable predictors of response.
Data source: A phase 1/2 trial of enasidenib monotherapy including 176 patients with relapsed or refractory IDH2-mutated AML, and a companion translational study of mechanisms and biomarkers of response in the same patients.
Disclosures: Dr. Stein disclosed that he received grants and personal fees from Celgene and Agios Pharmaceuticals, the trial sponsors. Dr. Amatangelo disclosed that he is employed by and owns equity in Celgene. The study was supported by the National Institutes of Health, National Cancer Institute.