The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia

Abstract

Recurrent mutations affecting cellular metabolism and epigenetic regulation are implicated in the pathogenesis of acute myeloid leukemia (AML). Isocitrate dehydrogenase 2 (IDH2) gene mutations are described in 12% of patients with AML and 5% of patients with myelodysplastic syndromes. IDH2 enzyme is involved in the Krebs cycle, catalyzing α-ketoglutarate from isocitrate. Mutant IDH2 enzymes acquire a neomorphic enzymatic activity with the ability to produce 2-hydroxyglutarate from α-ketoglutarate, inhibiting multiple α-ketoglutarate-dependent dioxygenase reactions; leading to aberrant DNA hypermethylation and differentiation block in myeloid precursors and ultimately promoting leukemogenesis. Enasidenib (formerly AG-221) is an oral small molecule selective targeted inhibitor of the mutant IDH2 enzyme, approved in August 2017 by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory (R/R) IDH2-mutated AML. Preclinical studies showed the effectiveness of enasidenib in inhibiting the production of 2-hydroxyglutarate with high potency, and alleviating the mutant IDH2-induced differentiation block. In the original AG221-001 phase I/II trial, patients with R/R AML were treated with enasidenib single agent therapy at escalating doses up to 650 mg daily, with the 100 mg dose level identified to be safe and effective for further evaluation. Overall, 113 patients were treated in the dose-escalation and 126 in the dose-expansion cohorts. The overall response rate for R/R patients was 40%, including a complete remission of 19%. At a median follow up of 7.7 months, the median overall survival was 9.3 months, and reached 19.7 months in responders. Enasidenib was well tolerated, although adverse events of clinical interest include indirect hyperbilirubinemia and IDH-inhibitor-induced differentiation syndrome, which can be life threatening if not identified and treated promptly. Ongoing clinical trials evaluating enasidenib in combination with intensive chemotherapy and hypomethylating agents in newly diagnosed AML, and in rational combinations for R/R AML patients are underway.

Keywords

acute myeloid leukemia enasidenib isocitrate dehydrogenase 2 refractory relapsed

Introduction

Acute myeloid leukemia (AML) is a malignant disorder of immature hematopoietic cells, characterized by differentiation arrest and rapid proliferation of abnormal myeloid precursors. These abnormal cells accumulate in the bone marrow and interfere with the production of normal blood cells.¹ Recent advances in the understanding of the pathophysiology of AML have resulted in a better awareness and comprehensive prognostic classification of different AML subtypes.² This newly identified genomic landscape of AML creates the opportunity for more targeted and individualized treatment strategies. Approximately 10 years ago, recurrent somatic IDH1 and IDH2 gene mutations were identified within cytogenetically normal AML.^3–5

The isocitrate dehydrogenase (IDH) enzymes function within the tricarboxylic acid, or Krebs cycle, and are responsible for the production of nicotinamide adenine dinucleotide phosphate (NADPH) from NADP+ by catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). The IDH1 (located in the cytoplasm) and IDH2 (located in the mitochondria) protein isoforms play an important role in cellular metabolism and differentiation, and α-KG is a required cofactor for multiple critical dioxygenase reactions.⁶ Recurrent hot-spot mutations in the IDH1 and IDH2 genes are now described in multiple cancers, including gliomas, chondrosarcomas, and cholangiocarcinomas, and are most frequent in hematologic malignancies including angioimmunoblastic T-cell lymphoma and myeloid malignancies.^7–10 Mutations in IDH2 occur in around 12% of patients with AML and 5% of patients with myelodysplastic syndromes (MDS).¹¹ Additionally, frequencies of IDH2 mutations approach 10–15% at the time of progression or transformation from MDS or myeloproliferative neoplasms (MPNs) to AML.^12,13 Heterozygous IDH2 mutations result from one of two amino acid alterations occurring at the highly conserved arginine residues within the active site of the enzyme, specifically IDH2-R140 or IDH2-R172. In AML, IDH2-R140 mutations occur more frequently than IDH2-R172 mutations, and they are considered two distinct subgroups with different prognosis and co-occurring mutations.^3,14–16

IDH2 mutation and leukemogenesis

IDH2 mutations are typically early mutational events and are described as the founding or initiating clonal mutation in approximately a third of patients with IDH2-mutant myeloid malignancy.⁶ IDH2 mutations commonly co-occur with other ‘epigenetically active’ mutations such as DNMT3A, ASXL1, SRSF2, and STAG2 mutations, and which are also described to occur in older individuals with clonal hematopoiesis, known as CHIP mutations.^6,15,17,18 NPM1 and FLT3 mutations also co-occur frequently in patients with IDH2-mutated AML. IDH2 and TET2 mutations, however, are mostly mutually exclusive due to functional redundancy, acting on the same downstream cellular pathways.^6,19

The mutant IDH2 enzyme acquires a neomorphic enzymatic activity that is capable of converting NADPH and α-KG to NADP⁺ and producing the ‘oncometabolite’ D-2-hydroxyglutarate (2-HG).^20,21 2-HG competitively inhibits multiple α-KG-dependent dioxygenases and is thought to exert pathogenicity through its effects on multiple pathways: through a differentiation block via inhibition of histone demethylases and TET family enzymes, and through alterations in cellular respiration, apoptotic pathways, and altered hypoxic response via inhibition of cytochrome C oxidase and dysregulation of hypoxia-inducible factor 1-alpha (HIF-1α).^19,22–25

IDH2 protein and targeted inhibitor

The discovery of recurrent IDH mutations leading to dysregulation of cellular metabolism and differentiation arrest prompted the development of targeted agents to inhibit the mutant enzyme.

The first in class oral selective inhibitor of the mutant IDH2 protein is enasidenib (IDHIFA, formerly AG-221). Enasidenib was recently approved in August 2017 by the United States Food and Drug Administration (FDA) for the treatment of patients with relapsed or refractory AML (R/R AML) with an IDH2 mutation, based on the results of a phase I/II dose escalation and expansion trial (Figure 1).

Figure 1.

Mechanism of action of enasidenib. By inhibiting the mutant isocitrate dehydrogenase 2 (IDH2) enzyme, 2-hydroxyglutarate levels decrease, alleviating the differentiation block exerted by 2-hydroxyglutarate (2HG)-induced competitive inhibition of multiple α-ketoglutarate-dependent dioxygenases.

This review will summarize the available preclinical and clinical data of enasidenib in AML.

Enasidenib and preclinical data

Enasidenib is a first-generation oral small molecule selective inhibitor of mutant IDH2 proteins, with inhibition of both R140 and R172 IDH2 isoforms. Slow tight binding to the allosteric site of the mutant enzyme prevents its conformational structural change, thus inhibiting the conversion of α-KG to 2-HG with high potency, leading to a time-dependent reduction in the production of 2-HG by the IDH2-R140Q homodimer (half-maximal inhibitory concentration [IC50] = 0.10 μmol/liter at 16 h), the IDH2-R140Q/WT heterodimer (IC50 = 0.03 μmol/liter), and the IDH2-R172K/WT heterodimer (IC50 = 0.01 μmol/liter).²⁶

Preclinical studies identified enasidenib was effective at inhibiting the production of 2-HG in TF1 erythroleukemia cell lines, and was able to induce differentiation of cells in a dose-dependent manner.^26,27 These observations were consistent with ex vivo fluorescence-activated cell sorting (FACS)-sorted primary blasts from patients with IDH2-mutant AML. In xenograft models, intracellular 2-HG concentrations in peripheral blood, bone marrow, and spleen were dramatically reduced to near normal levels after enasidenib treatment. With enasidenib treatment, AML cells displayed multiple surface antigens associated with myeloid differentiation, including CD11b, CD14, CD15, and CD24, indicating the apparent effectiveness of enasidenib treatment in alleviating the mutant IDH2-induced differentiation block.²⁶

Moreover, in an aggressive human AML xenograft mouse model, enasidenib was identified to confer a dose-dependent survival advantage. Xenografts were randomly treated either with single agent enasidenib at various doses including 5, 15, or 45 mg/kg, or cytarabine 2 mg/kg daily for 5 days. They found a statistically superior survival with enasidenib at a dose of 45 mg/kg compared with placebo or cytarabine.²⁶ Upon enasidenib continuous treatment, they observed a decrease in the number of bone marrow blasts, and an increase in number of CD15-expressing differentiated cells. Of interest, these differentiated cells retained the same mutant IDH2 allele frequency, and supported the hypothesis of enasidenib-induced differentiation of cells, without apoptosis or loss of the malignant clone as expected with cytotoxic therapy.²⁶

Enasidenib in a phase I/II trial

Based on the favorable preclinical data suggesting efficacy and good tolerability, enasidenib was next evaluated in the first-in-human AG221-001 phase I dose escalation and expansion trial [ClinicalTrials.gov identifier: NCT01915498] (Table 1). Trial eligibility included adult patients aged above 18 years with advanced hematologic malignancies and the presence of an IDH2 mutation. The first patient was treated with enasidenib in September 2013.

Table 1.

Ongoing clinical trials of enasidenib.

ClinicalTrials.gov identifier	Title	Status	Phase
NCT02677922	A Safety and Efficacy Study of Oral AG-120 Plus Subcutaneous Azacitidine and Oral AG-221 Plus Subcutaneous Azacitidine in Subjects with Newly Diagnosed Acute Myeloid Leukemia (AML)	Recruiting	II
NCT02577406	An Efficacy and Safety Study of AG-221 (CC-90007) versus Conventional Care Regimens in Older Subjects with Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation (IDHENTIFY)	Recruiting	III
NCT02632708	Safety Study of AG-120 or AG-221 in Combination with Induction and Consolidation Therapy in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 and/or IDH2 Mutation	Recruiting	I
NCT03013998	Study of Biomarker-Based Treatment of Acute Myeloid Leukemia	Recruiting	I/II
NCT03383575	Targeted Therapy with the IDH2-inhibitor Enasidenib (AG221) for High-Risk IDH2-Mutant Myelodysplastic Syndrome	Recruiting	II

The primary endpoint of the phase I dose escalation portion of the trial was establishing the safety, the maximum tolerated dose (MTD), and the recommended phase II dose level. Secondary endpoints included pharmacokinetic (PK) and pharmacodynamic (PD) evaluation, as well as treatment efficacy. Efficacy outcomes included rate of complete remission, complete remission with partial hematologic recovery in accordance with modified 2003 International Working Group criteria for AML,²⁸ the duration of response, and the rate of conversion from transfusion dependence to transfusion independence.

Patients were treated initially with enasidenib at different escalating doses either once or twice daily on continuous 28-day cycles. Pharmacokinetic studies supported once daily dosing, based on the high plasma exposure and long half life of the drug.²⁹ The MTD was not identified at doses up to 650 mg daily, and based on PK profiling, safety and efficacy (further detailed below) the 100 mg dose level was selected as the recommended phase II level for ongoing clinical development. The subsequent expansion trial was performed in four cohorts of patients with IDH2 mutation, including patients aged over 60 years old with R/R AML, or any age if relapsed after stem cell transplantation; patients younger than 60 years old with R/R AML and no prior transplantation; and patients aged above 60 years with newly diagnosed AML, but unfit for conventional chemotherapy. A fourth cohort included patients with IDH2-mutated myeloid malignancies ineligible for the other expansion arms. Patients in the expansion cohort were treated with enasidenib single agent at 100 mg orally daily.

Patients were enrolled from September 2013 to April 2016 and a total of 239 patients were treated, 113 in the escalation cohort, and 126 in the expansion cohort. Overall, the median age was 70 years (range 19–100); 57% of them were men. The majority, 176 patients (74%), were diagnosed with R/R AML, and of these, 66% had intermediate risk cytogenetic status, 34% had poor risk cytogenetic status, 17% had a history of myelodysplastic syndrome, and 14% had prior stem cell transplantation. Ninety-four patients (53%) had received two or more prior AML directed therapies.

Enasidenib was generally well tolerated. The median number of cycles of enasidenib received was 5 cycles, and ranged from 1 to 25 cycles. One hundred and ninety-five patients (82%) experienced at least one treatment-related adverse event of any grade according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0). The most common reported adverse events were indirect hyperbilirubinemia (38%) and nausea (23%). Grade 3 or 4 adverse events were reported in 41% of patients, and notably included indirect hyperbilirubinemia in 12% of patients, and IDH inhibitor associated differentiation syndrome (IDH-DS) in 6% of patients. Enasidenib-induced indirect hyperbilirubinemia is similar to that occurring in Gilbert’s syndrome due to an off-target inhibition of UGT1A1 enzyme in the liver, and is generally not clinically significant. Dose reductions are not required and hyperbilirubinemia typically resolves with continuous treatment, without directed intervention.³⁰

Serious adverse events (SAEs), defined as life-threatening events leading to death, hospitalization or prolonged incapacity, regardless of attribution, were observed in 24% of patients. SAEs of interest include IDH-DS (8%), leukocytosis (4%), and tumor lysis syndrome (3%).

Differentiation syndrome (DS) has been previously described with other differentiating agents such as all-trans retinoic acid and arsenic trioxide, standard treatment for acute promyelocytic leukemia (APL).^31,32 DS occurs in around 25% of patients with APL during induction treatment. Differentiation of promyelocytes is associated with increased production of inflammatory vasoactive cytokines, leading to the migration, adhesion, and infiltration of differentiated cells into the lungs and other tissues. This systemic hyperinflammatory state is characterized by capillary leak, fever, edema, rash, hypotension, pulmonary infiltrates, and renal dysfunction.³³ It can be life threatening with an increased risk of early mortality if not treated promptly. Preemptive initiation of dexamethasone with suspected DS at the earliest manifestation had reduced risk of morbidity and mortality³⁴ (Figure 2).

Figure 2.

Algorithm for the management of differentiation syndrome (IDH-DS) associated with enasidenib.

An independent review committee retrospectively evaluated potential cases of IDH-DS among patients with R/R AML enrolled in the phase I/II trial.³⁵ Possible or probable IDH-DS based on reported symptoms and signs occurred in 33 patients (11.7%). The median age of onset was 70 years (range 38–80 years). The median time from initiation of treatment and occurrence of DS was 30 days (range 7–129 days). The main reported symptoms were shortness of breath, unexplained fever, lung infiltrates, and hypoxia. Leukocytosis was identified concurrently in 13 patients (39.4%). Manifestations are similar to those observed in patients treated with all trans-retinoic acid and arsenic trioxide for APL. Patients who developed IDH-DS were more likely to have higher bone marrow blast burden above 20% and fewer previous therapies for AML. Systemic corticosteroid therapy was used in 20 patients (84.8%). Interruption of enasidenib treatment was required in 15 patients (45.5%), but none required permanent discontinuation of the drug. No reported deaths were attributed to IDH-DS. With the recent FDA approval of enasidenib treatment for patients with R/R mIDH2 AML, clinicians should be aware of the early symptoms and signs of DS, which have been reported any time from 7 days to 5 months after initiation of enasidenib treatment. It can also occur upon drug reinitiation after treatment interruption. Although IDH-DS can be life threatening, early recognition and initiation of treatment are key for DS management (Figure 2). Oral or intravenous dexamethasone 10 mg twice daily should be given until clinical improvement. Tapering of corticosteroids should not be attempted before resolution of symptoms. If respiratory failure or renal dysfunction happens and persists for more than 48 h after initiation of corticosteroids, enasidenib should be interrupted until resolution of severe symptoms. It is important to recognize that withholding enasidenib will not improve symptoms immediately given its prolonged terminal half life of 137 h. When leukocytosis co-occurs with IDH-DS, hydroxyurea can be initiated for cytoreduction.³⁵

Isolated noninfectious leukocytosis can occur, without clinical DS, as a result of a rapid myeloid maturation and proliferation. Leukocytosis of any grade was reported in 17% of patients; of these 36% required intervention. Most cases were reported in the first 2 months of treatment. Initiation of hydroxyurea with a transient interruption of enasidenib was successful in controlling leukocytosis in most cases.³⁰

Efficacy outcomes have now been reported for patients with R/R AML. An overall response rate (ORR) of 40.3% [95% confidence interval (CI) 33.0–48.0%], including complete remission (CR), complete remission with incomplete hematologic recovery (CRi), partial remission (PR), and morphologic leukemia free state (MLFS) occurred in 34 (19.3%), 12 (6.8%), 11 (6.3%), and 14 (8%) patients respectively. An objective response was attained in 35.4% of patients with IDH2-R140 mutations and in 53.3% of patients with IDH2-R172 mutations. Patients treated in the expansion cohort using 100 mg daily of enasidenib experienced an ORR of 38.5%.

The median time to attain a first response was 1.9 months (range 0.5–9.4 months). Most patients attained first response by cycle 5. The median time to achieve complete remission was 3.8 months (range 0.5–11.2 months), with a median duration of response of 8.8 months. Seventeen patients (10%) discontinued enasidenib therapy to proceed to stem cell transplantation. Unlike cytotoxic agents, patients on enasidenib may respond later, with time to first responses requiring more than 9 months on therapy, and thus it is reasonable to continue enasidenib treatment unless patients develop significant adverse effects or obvious progressive disease.

Flow cytometry studies were performed on five samples of responding patients, showing a complete eradication of leukemic myeloid precursors after enasidenib treatment. However, the mutant IDH2 variant allele frequency (VAF) remained stable in four of five patients. Further investigations by measuring the mutant IDH2 VAF in peripheral blood mature neutrophils in seven additional responding patients demonstrated the persistence of mutant IDH2 allele burden between immature leukemic clone and mature neutrophils after treatment, consistent with the concept of differentiation induction of leukemic myeloid precursors exerted by enasidenib.³⁶

Samples from patients with R/R AML were analyzed in order to determine the exact mechanism of action of the drug as well as possible biomarkers for responses.³⁶ The total level of 2-HG in blood was measured in 125 patients with R/R AML. The measurement of total 2-HG was done within 28 days of the first dose and every cycle during enasidenib therapy. The median 2-HG suppression in all patients was 90.6%. It was observed that the median 2-HG suppression was higher in patients with mutant IDH2-R140 compared with mutant IDH2-R172 (94.9% versus 70.9% respectively). There was no statistical difference in 2-HG suppression in patients with mutant IDH2-R140 treated with an enasidenib daily dosage of less than 100 mg, 100 mg, or greater than 100 mg. There was a statistical difference in 2-HG suppression in patients with mutant IDH2-R172 treated with an enasidenib daily dosage of 100 mg or greater than 100 mg, however the response rate was not statistically significant between the two dosages (44% versus 59%, p = 0.53). The time to maximal 2-HG suppression was also not different between a daily dosage of less than 100 mg, 100 mg, or greater than 100 mg. Most importantly, 2-HG baseline levels did not correlate with the treatment response, nor did the degree and kinetics of suppression.³⁶ Mutant IDH2 VAF was tested as a biomarker of response in patients treated with enasidenib. The mutant IDH2 VAF was evaluated in 17 patient samples using both digital polymerase chain reaction and next-generation sequencing (NGS) techniques, and no association between the mutant IDH2 allele burden and the clinical response was identified. Patients who achieved CR had both low and high baseline VAF levels of mutant IDH2. A reduction in mutant IDH2 allele burden was mainly observed among responders, and interestingly, undetectable levels were observed in 9 out of 29 CR patients (31%), and all patients had R140 mutation. However, mutant IDH2 clone can persist in patients achieving CR, and a reduction in allele burden does not correlate with clinical response.³⁶

Co-occurring mutations beside the IDH2 mutation were detected in 98% of patients with R/R AML in the phase I/II study, and most frequently included SRSF2 in 45% of patients, DNMT3A in 42% of patients, ASXL1 in 27% of patients, and RUNX1 in 24% of patients. According the European Leukemia Network classification in 2017, 56% of patients are classified as the adverse prognostic group.²

The number of co-occurring mutations as well as the diversity of mutations were higher in patients harboring the IDH2-R140 mutation in comparison with the IDH2-R172 mutation. In relation to clinical response, patients who achieved complete or partial response were found to have a significantly lower number of co-occurring mutations. Higher mutational burden (six or more co-occurring mutations) was also associated with poor response to enasidenib. Patients with more than six co-occurring mutations had a significant lower response rate of 21.9% compared with 70.4% in patients with less than three co-occurring mutations. Furthermore, it was observed that the presence of an NRAS mutation was associated with lower responses. The poor response to enasidenib monotherapy also appears to extend to other RAS pathway genes, including PTPN11 and KRAS mutations. Mitogen-activated protein kinase (MAPK) pathway activation is considered one of the mechanisms of primary resistance to enasidenib and warrants further investigations and analysis of rational combinations in order to overcome resistance.³⁶

At a median follow up of 7.7 months (range 0.4–26.7 months), the overall survival in all patients with R/R AML was 9.3 months (95% CI 8.2–10.9). Thirty-day and 60-day mortality rates were 5.1% and 13.1%, respectively. Patients who achieved complete remission lived longer with a median overall survival of 19.7 months. Patients who had previously received more than two prior therapies for refractory AML experienced a median survival of 8 months. Median event-free survival was 6.4 months (95% CI 5.4–7.5).³⁰

The phase II portion of the original AG221-001 trial is completed. A total of 106 patients were treated with single agent enasidenib at 100 mg orally daily dosing. Results of the phase II trial portion are not presented yet.

Based on the favorable results of the phase I dose-finding and expansion trial, an ongoing phase III international open-label randomized confirmatory trial (IDHENTIFY) is underway, comparing the efficacy and safety of enasidenib as monotherapy versus conventional care regimens in patients 60 years or older with R/R AML after at least two lines of AML therapy and documented IDH2 mutation (Table 1). Patient are randomized in a 1:1 ratio to enasidenib 100 mg orally daily or to conventional care regimens of the physician’s choice, including best supportive care, 5-azacytidine 75 mg/m²/day for 7 days, low-dose cytarabine 20 mg twice daily for 10 days, or intermediate-dose cytarabine 0.5–1.5 g/m²/day for 3–6 days repeated every 28-day cycle. Randomization is stratified by receipt of prior intensive chemotherapy, primary refractory disease status, and prior allogeneic stem cell transplantation. The primary endpoint of the study is overall survival. Secondary endpoints include ORR, event-free survival, duration of response, time to response, treatment mortality at 30 and 60 days, and safety. Enrollment began in October 2015 and approximately 316 patients will participate in this study. Given that overall survival of older patients with R/R AML is approximately 3–5 months with any currently approved salvage regimen (i.e. cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, or best supportive care), an overall survival improvement similar to 8 months as reported in the phase I/II trial in patients receiving more than two lines of AML therapies will be considered a notable improvement.^37,38

Enasidenib in the frontline treatment

Enasidenib as monotherapy

Of 239 patients treated in the phase I/II dose escalation and expansion trial, 38 patients (15.9%) with newly diagnosed mutant IDH2 AML received enasidenib as frontline monotherapy, and outcomes of this patient cohort were recently presented.³⁹ These patients were not candidates for intensive chemotherapy and had a performance status of 0–2. Median age was 77 years (range 58–87); 62% of patients were aged 75 years and over. Thirty-two percent of patients had myelodysplastic-related changes at diagnosis. Median number of cycles on enasidenib treatment was 6.5 (range 1–35) and median follow up was 8.6 months. ORR was 32% (95% CI 22.5–55.2), of which seven patients(18%) achieved complete remission after a median of 5.6 months from initiation of treatment. Median overall survival was 11.3 months (95% CI 5.7–17.0) and median event-free survival was 5.7 months (95% CI 3.1–16.0). Patients who responded to enasidenib had prolonged survival, with a median overall survival of 19.8 months versus 5.4 months in nonresponders. Fifty percent of patients had at least one grade 3–4 treatment-related adverse event, with only 2 of the 38 patients discontinuing treatment due to such an event. Similar to the R/R AML cohort, the most frequent treatment-related adverse events of any grade were indirect hyperbilirubinemia (30%) and nausea (22%). SAEs included IDH-DS reported in four patients (11%) and tumor lysis syndrome in three patients (8%). These data suggest that in a patient population for whom standard therapy is not recommended, such as a frail or unfit population, enasidenib monotherapy is an appropriate option.

Enasidenib in combination

Given the efficacy and safety of enasidenib tested in patients with R/R mutant IDH2 AML, enasidenib is now under evaluation as part of combination strategies for newly diagnosed AML in younger/fit and older/unfit populations, in combination with the current standard of care in each group (Table 1).

Enasidenib with standard intensive chemotherapy

Adults aged 18 and above, diagnosed with untreated AML with a documented IDH2 mutation, are being enrolled in a phase I trial [ClinicalTrials.gov identifier: NCT02632708] to receive one to two cycles of induction chemotherapy consisting of enasidenib 100 mg orally daily in combination with standard 7+3 cytarabine and anthracycline chemotherapy.⁴⁰ Patients who achieve complete remission may continue up to four cycles of consolidation with high-dose cytarabine in combination with enasidenib 100 mg daily. In patients who do not receive hematopoietic stem cell transplantation in first remission, enasidenib can be continued as maintenance treatment for up to 2 years. Preliminary results from this ongoing trial, based on data through 1 August 2017, were recently presented. Fifty-six patients with an IDH2 mutation have been enrolled in this trial. The median age was 63 years (range 32–76 years); notably 62% of patients were 60 years of age or older. Fifty-seven percent of patients had de novo AML and 43% had a diagnosis of secondary AML. Thirty-nine patients (70%) had IDH2-R140 mutation and 17 patients (30%) had IDH2-R172 mutation. Thirty-six percent of patients had adverse prognostic risk based on cytogenetics or molecular abnormalities. Fifty-one of 56 patients (91%) experienced grade 3 or 4 treatment-related adverse events, most commonly febrile neutropenia (63%), hypertension (11%), colitis (8%), and maculopapular rash (8%). Thirty-day and 60-day mortality rates were consistent with intensive chemotherapy: 5% and 8% respectively; and no treatment-related deaths were reported. One patient with prolonged grade 4 thrombocytopenia, without residual leukemia, was considered to have a dose-limiting toxicity (DLT) of the combination of enasidenib with standard chemotherapy. Median time to absolute neutrophil count recovery was 34 days (range 29–35), and the median time to platelet recovery was 33 days (range 29–50). ORR was achieved in 41 patients (82%), of which 25 (61%) experienced complete remission. This ongoing phase I trial supports the feasibility of combining enasidenib with chemotherapy in frontline treatment in the young/fit population. This ongoing trial is evaluating additional dosing schedules to identify the optimal combination dosing strategy.

Enasidenib with hypomethylating agent therapy

Enasidenib is also under evaluation in combination with the hypomethylating agent 5-azacytidine in newly diagnosed patients with AML who are unfit for standard intensive chemotherapy.⁴¹ Since the IDH2 mutation is epigenetically active and associated with aberrant hypermethylation, it was hypothesized that the combination with hypomethylating agents would be complementary. Preclinical models demonstrated a synergistic effect of enasidenib combined with 5-azacytidine.⁴² In a phase Ib/II trial, adult patients with untreated AML, not candidates for intensive chemotherapy, were given 5-azacytidine treatment in combination with enasidenib. At data cutoff on 1 September 2017, six patients with IDH2 mutations were treated in the phase 1b portion of this trial, three patients received 100 mg and three receiving 200 mg daily enasidenib. The median number of combination cycles received was 9 (range 1–13). The most common treatment-related adverse events were nausea and indirect hyperbilirubinemia (four patients each). One case of IDH-DS was reported with enasidenib 200 mg daily dosing. ORR including CR, CRi, PR, or MLFS was achieved in four out of six patients, and the 100 mg enasidenib dose was selected for a further combination study. These preliminary data are encouraging and support the ongoing phase II expansion portion of the trial, in which a planned 99 patients will be randomized 2:1 to the combination versus 5-azacytidine alone.

Conclusion

Enasidenib is an oral, potent, small molecule selective inhibitor of mutant IDH2 proteins which functions through induction of differentiation. Enasidenib was approved by the FDA in August 2017 for R/R AML harboring an IDH2 mutation, based on favorable results of the original phase I/II dose-escalation and expansion trial. The overall response in patients with R/R AML treated with enasidenib monotherapy included a CR rate of 19% and ORR of 40%, with a median overall survival of 9.3 months, reaching 19.7 months in patients attaining complete remission. A randomized phase III confirmatory study is ongoing. Enasidenib is well tolerated; side effects of special interest include indirect hyperbilirubinemia and IDH-inhibitor-related differentiation syndrome. Awareness of IDH-DS and timely systemic corticosteroid therapy is essential management when IDH-DS is suspected. No definite clinical biomarkers of response or resistance have yet been identified; patients with both IDH2 isoforms (R140 and R172) appear to respond equally to enasidenib despite an apparent lack of full 2-HG suppression in patients with IDH2-R172 mutations. Ongoing evaluation of enasidenib in combination with intensive chemotherapy and hypomethylating agents in the frontline treatment of AML, as well as future rational combinations for R/R IDH2-mutated populations to prevent relapse or primary resistance, will hopefully lead to further improvements for this patient population.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

CD has served in an advisory role for AbbVie, Agios, Bayer, and Celgene Pharmaceuticals.

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