Enasidenib

Enasidenib for the treatment of acute myeloid leukemia
James Dugan & Daniel Pollyea

Abstract:

Introduction: In August 2017 the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous leukemia (AML) with an IDH2 mutation. Enasidenib targets cells with mutant copies of isocitrate dehydrogenase-2 (IDH2), inhibiting the oncometabolite 2-hydroxyglutarte (2-HG) formed by the mutant IDH2.
Areas covered: We review the studies leading to enasidenib’s approval, as well as common side effects and safety issues experienced during the clinical trials. There is a focus on the diagnosis and treatment of these side effects including differentiation syndrome.
Expert commentary: We are experiencing a revolution in the understanding of the mechanism of AML. A majority of the effort has been concentrated on targeting gene mutations or pathway activations with precision therapeutics. Enasidenib is beneficial in a patient population that previously had limited treatment options. However, given the fact that enasidenib is a highly specific inhibitor of an early stable mutation, it is questionable whether a strategy of targeting a

single mutation or pathway in relapsed AML will allow for better than the 20% complete remission (CR) rate observed with this therapy. The proper role for single mutation targeting in AML needs to be carefully considered.
Keywords: IDH2, AML, enasidenib, leukemia, differentiation syndrome

1.0 Introduction:

In August 2017 the United States Federal Drug Administration (FDA) approved enasidenib (Idhifa, Celgene/Agios) for adults with relapsed and refractory acute myelogenous leukemia (AML) with an IDH2 mutation. Enasidenib targets cells with mutant copies of isocitrate dehydrogenase-2 (IDH2), inhibiting the oncometabolite 2-hydroxyglutarte (2-HG) formed by the mutant IDH2.
Areas covered: We review the studies leading to enasidenib’s approval, as well as common side effects and safety issues experienced during the clinical trials. There is a focus on the diagnosis and treatment of these side effects including differentiation syndrome.
Expert commentary: We are experiencing a renaissance in the understanding of the mechanism of AML. A majority of the effort has been concentrated on targeting gene mutations or pathway activations with precision therapeutics. Enasidenib is beneficial in a patient population that previously had limited treatment options. However, given the fact that enasidenib is a highly specific inhibitor of an early stable mutation, it is questionable whether a strategy of targeting a single mutation or pathway in relapsed AML will allow for better than the 20% complete remission (CR) rate observed with this therapy. The proper role for single mutation targeting in AML needs to be carefully considered.
2.0 Overview of acute myelogenous leukemia:

AML is the most common acute leukemia affecting adults. There were an estimated 21,380 new cases of AML in the United States in 2017, and the 5-year overall survival was 26.9%1. Advances in AML over the past four decades have been limited. Induction therapy with cytotoxic chemotherapy has remained the standard treatment approach since the 1970s. After factoring in post-remission therapies, 40% of patients aged less than 60 years will experience a five-year overall survival (OS) with traditional induction chemotherapy2,3. These data overestimate outcomes for the average AML patient because the median age at diagnosis is 66 years1. For this group outcomes are considerably worse. Complete remission (CR) rates after induction chemotherapy average about 45% and induction mortality rates can be as high as 30%6. One-year OS rates vary based on comorbidities, adverse cytogenetics, and age, but are estimated to be around 10-50%6,7. Elderly patients diagnosed with AML often present with multiple comorbid conditions putting them at risk for pronounced cytopenias, prolonged hospital admissions, infections, and increased rates of treatment specific mortality after receiving chemotherapy8,9. This patient population represents an unmet need for effective therapies that confer less toxicity.
By way of decades of research, we have a new understanding of the molecular disturbances and clonal diversity that drives AML. One of these molecular derangements thought to be driving AML is isocitrate dehydrogenase (IDH). The IDH enzymes are homodimeric and catalyze the conversion of isocitrate to alpha-ketoglutarate (-KG) within the tricaboxylic acid (also known as citric acid or Krebs) cycle. IDH is involved in diverse enzymatic cellular processes including histone demethylation and DNA modification14, and is most commonly mutated in patients with cytogenetically normal AML15. Roughly 20% of newly diagnosed adult AML patients will harbor an IDH1 or IDH2 mutation; IDH2 is more common than IDH1 (8-19% vs. 7-14%,

respectively)16,17. IDH mutations are acquired early in leukemogenesis18. The mutations are stable and may be undetectable when a patient achieves a CR, but the same mutations recur when the disease relapses18. Mutant IDH enzymes lack the ability to convert isocitrate to -KG
19. Pathogenic IDH mutations are heterozygous, with subjects retaining one wild-type allele, and IDH1 and IDH2 are almost always mutually exclusive. These data argue against IDH involvement in AML as simple loss of function20. The enzymatic disruption of -KG metabolism leads to an increase in the oncometabolite R-2-hydroxyglutarte (2-HG), which is thought to induce a block in cellular differentiation and prevent normal maturation of the myelogenous cell line20-22. Enasidenib is an oral mutant IDH2 inhibitor and received approval for treatment of adults with relapsed or refractory AML with an IDH2 mutation on August 1st, 2017. This review will focus on the pharmacology, efficacy, and safety of enasidenib, as well as the trials leading to its approval.
3.0 Mechanism of Action:

The oncometabolite 2-HG, formed after metabolism of isocitrate by the mutated IDH2 enzyme, leads to DNA hypermethylation23 and increased repressive histone methylation24 (see figure 1). This altered methylation has been implicated in the inhibition of myeloid maturation in vitro25,26 and in vivo27. Additionally, 2-HG has been shown to affect the expression of prolyl hydroxylases encoded by the EGLN family of genes. These alpha-ketoglutarate-dependent hydroxylases target hypoxia inducible factor (HIF) for degradation. The expression of HIF has been implicated in leukemogenesis, although the exact mechanisms behind the EGLN hydroxylases, HIF, and the evolution of leukemia is still a subject of scientific debate22,28,29.
Enasidenib, which targets IDH2 mutant variants R140Q, R172K, and R172S at approximately 40-fold lower concentrations than the wild-type enzyme in vitro30, has been

shown to reduce serum 2-HG, DNA hypermethylation, repressive histone methylation, and promote myeloid differentiation in mutant IDH2 models 31-33. In a phase 1/2 study looking at 125 patients with relapsed/refractory AML, enasidenib decreased total 2-HG levels by 90.6%.
Enasidenib was therapeutically active in these patients regardless of the type of IDH2 mutation. Notably, 2-HG suppression alone did not predict response, as non-responders also had significant 2-HG suppression, and 2 of 5 patients with increased 2-HG levels achieved a PR. There was no significant difference in baseline 2-HG levels between patients achieving a CR and those obtaining any response (CR + CR with incomplete hematologic recovery [CRi], CR with incomplete platelet recovery [CRp], morphologic leukemia free state [MLFS] and partial response [PR]). The kinetics of clinical response did correlate to the timing of 2-HG inhibition, but this had no bearing on the response obtained34.
The mutant IDH2 allele burden is extremely heterogenous among patients, ranging from low-level positivity to fully clonal with a 50% allele burden. There was no association between allele burden and clinical response obtained. Only half of the total patients treated exhibited a change in allele frequency by more than 5%. There was no significant difference in event-free survival in those patients that achieved a CR with an undetectable allele burden (i.e. molecular remission) and those patients achieving a CR without molecular remission. Many patients had a marked decrease in blast percentage, many near 0%, with a concomitant mutant IDH2 allele frequency greater than 10%. Given these results the authors concluded that mutant IDH2 cells persist despite CR and that a reduction in allele burden is neither necessary nor sufficient for clinical response to enasidenib. Furthermore, the allele frequency of other AML associated mutations remained unchanged in neutrophils at CR, consistent with differentiation of a transformed leukemic clone. These differentiated neutrophils demonstrated intact phagocytic

activity consistent with maturation of normal granulocyte function. This post-treatment analysis published by Amatangelo et al. supports enasidenib as a promoter of myeloid differentiation rather than an agent that confers direct cytotoxicity34.
3.1 Pharmacokinetics:

Enasidenib has an extended half-life (~137 hours) and reaches a steady state at 29 days.

Following a dose of 100 mg, the absolute bioavailability is 57%. The mean volume of distribution is 55.8L. In vitro, enasidenib metabolism is mediated by multiple CYP enzymes (e.g. CYP1A2, 2C9, 2C19, 2D6, 3A4), as well as UGTs (e.g. UGT1A1, 2B7, 2B15). Enasidenib is eliminated mainly in the feces, with only 11% eliminated by the kidneys. Age, bodyweight, body surface area, ethnicity, gender, mild hepatic impairment, and renal impairment (creatinine clearance > 30 mL/min) are not thought to alter the pharmacokinetics of enasidenib30.
4.0 Clinical trials:

4.1 Phase I and II trials:

The FDA granted approval for Enasidenib based on the dose-escalation and expansion study published in Blood in August of 2017 (NCT01915498)35. In the phase 1 dose-escalation portion of the study, patients received oral enasidenib 30-150 mg twice daily or 50-650 mg once daily. Escalation was based on 3+3 dose escalation paradigm. The phase 1 expansion component of the study was comprised of four cohorts with IDH2 mutations: 1) age 60 years or older with relapsed/refractory AML, or any age of relapse after hematopoietic stem cell transplant; 2) age younger than 60 years with relapsed/refractory AML and no prior transplant; 3) age 60 years or older with untreated AML and ineligible for induction chemotherapy; and 4) patients ineligible for other expansion arms35. The maximum tolerated dose was not reached at 650 mg per day so it

was felt that the pharmacokinetic profile, 2-HG reductions, and clinical efficacy warranted further investigation of the 100-mg dose. 113 patients in the dose-escalation phase and 126 in the 4-arm expansion phase comprised the intention-to-treat population who received enasidenib.
Response rates were measured after a minimum of 6 months of treatment. Thirty-four patients (19.3%) with relapsed or refractory AML attained CR for a median of 8.8 months. Twelve patients (6.8%) experienced a CRi, 11 (6.3%) had a PR, and 14 (8.0%) achieved a MLFS. The overall response rate for patients with relapsed/refractory AML was 40.3%. The median followup duration was 7.7 months. The median OS for patients with relapsed/refractory AML was 9.3 months and the estimated 1-year survival was 39%. Patient who attained a CR had a median OS of 19.7 months35.
4.2 Ongoing Clinical Trials:

In October 2015 a randomized, open-label, multinational phase 3 trial comparing the efficacy of enasidenib versus conventional care regimens (CCRs) in older patients (aged > 59 years) with relapsed or refractory IDH2-mutated AML after two or three treatment regimens30 opened to accrual (NCT02577406). These data have not yet been reported.
Two other clinical trials are looking at enasidenib in the upfront setting. Enasidenib is being paired with azacitadine in a phase 1b/2, randomized study for patients ineligible for standard induction therapy. The study started enrolling on June 3, 2016 and has an anticipated completion date of January 28th, 2019 (NCT02677922 )36 . The second is a phase 1, multicenter trial looking at the safety of enasidenib in conjunction with induction and consolidation chemotherapy (NCT02632708). The study started enrolling in December of 2015 and has an anticipated completion date of September 202037. Preliminary data for these two trials was presented at the American Society of Hematology meeting in 2017. For enasidenib paired with azacitadine four

of six patients responded to therapy. One of the four achieved a CRi and proceeded to bone marrow transplant highlighting that even those patients not thought fit for induction chemotherapy can attain an improved performance status while being treated for AML and use enasidenib as a bridge to transplant. The ORR for enasidenib given with induction chemotherapy is estimated at 62%, which includes those patients achieving CR without hematologic recovery, but not patients with a PR (0%) or MLFS (20%). The presenters concluded that this combination is safe and the results warrant a phase 3 trial examining standard induction versus standard induction with IDH inhibition.
The ”BEAT AML” trial (NCT03013998), is a multi-sub-study phase 1b/2 trial focused on establishing a method for genomic screening followed by assigning and accruing to a multi-study “Master Protocol (BMAL-16-001-M1)”, which includes an experimental arm for patients with IDH2 mutations (BMAL-16-001-S3). This is a phase 2 study using the 100-mg dose in patients older than 60 years of age with previously untreated AML. Please refer to table 1 for a listing of the aforementioned clinical trials.
There are additional abstracts and investigator-initiated trials looking at the combination of enasidenib and other chemotherapeutics and targeted therapy. Work is underway to design clinical trials using multiple small molecule inhibitors. Enasidenib paired with FLT3 inhibitors may start in phase I investigation this year.
5.0 Tolerability and Safety:

Treatment-related treatment emergent adverse events (TEAEs) were experienced in 82% of patients (195/239) enrolled in the dose-escalation and expansion study. The most common treatment-related TEAEs were indirect hyperbilirubinemia (38%) and nausea (23%). For patients who received enasidenib 100 mg/day (n=153) the most common side effects were increased

bilirubin (8%), IDH differentiation syndrome (IDH-DS, 7%), anemia (7%), thrombocytopenia (8%), and tumor lysis syndrome (5%). Grade 3-4 enasidenib-related adverse events occurred in 99 of the 239 patients (41%) and included indirect hyperbilirubinemia (12%) and IDH-DS (6%). Treatment-related TEAEs led to enasidenib dose interruptions for 75 patients (22%), dose reductions for 22 patients (6%), or discontinuations for 17 patients (5%)35.
Enasidenib inhibits the mutant IDH2 enzyme leading to the release of previously blocked myeloid differentiation. This release of normal differentiation leads to a differentiation syndrome likened to the differentiation syndrome seen in the treatment of acute promyelocytic leukemia (APL). IDH-DS leads to redistribution of intravascular fluid, which can cause pleural effusions, ascites, pericardial effusions, peripheral edema, and rapid weight gain. The rapid accumulation of fluid in the chest and abdomen can lead to respiratory failure and renal compromise. Patients are often monitored in an intensive care setting for close monitoring of vital signs and concern for rapid deterioration requiring mechanical ventilation. Typically, IDH-DS can be managed with steroids (see table 2 for recommendations on treatment) without need for interrupting enasidenib. If symptoms persist or worsen despite 48 hours of steroids enasidenib should be held. Once symptoms improve to grade 2 or less enasidenib can be restarted without a dose reduction.
. Median time to onset of symptoms was 30 days (range; 7-129 days), which distinguishes it from the differentiation syndrome seen with retinoic acid and arsenic trioxide used in APL where patients will often exhibit symptoms within one week of starting therapy38,39. IDH-DS occurred in 23 patients, or 11.7%, an incidence less than that seen in APL39. Eighteen of these patients were considered to have grade 3 or 4 IDH-DS. Sixteen of the 18 episodes resolved without serious consequences. Two patients died from IDH-DS related complications, one patient from

sepsis contracted while recovering from grade 3 IDH-DS and another from a pericardial effusion that was thought to have developed as a result of IDH-DS35.
Enasidenib may be associated with a burst of myeloid proliferation presenting as non-infectious leukocytosis26. Treatment related leukocytosis was reported for 15 patients (6%). Typically, this effect was seen within the first two cycles of treatment. One patient discontinued the study and 6 patients required dose interruption35.
Enasidenib-induced indirect hyperbilirubinemia occurred in 35% of the patients receiving 100 mg daily. The rise in bilirubin was not thought to be related to intrinsic liver injury since bilirubin levels did not coincide with rises in transaminases. Increases in bilirubin may be a result of off-target inhibition of UGT1A1, which is a known metabolizer of enasidenib in vitro.
6.0 Conclusions:

Patients with relapsed/refractory AML have few therapeutic options. Enasidenib is a relatively well tolerated therapy that results in beneficial clinical outcomes for those who respond. The data collected by Stein et al.35 suggests that daily oral therapy with enasidenib can induce normal myeloblast differentiation, even in a heavily pretreated population.
The authors suggest that because enasidenib induces myleoid differentiation as its mechanism of action against AML, rather than cytotoxicity, patients are spared the typical severe adverse events experienced during cytotoxic therapies. Indeed, the rates of grade 3 and 4 hematologic TEAEs (10%) and infections (1%) are less than the rates seen in other AML treatments.
IDH-DS was reported in 11.7% of the patients and is certainly the most dangerous complication associated with enasidenib. This incidence of differentiation syndrome is less than that typically ascribed to APL-related differentiation syndrome (15-26%)40,41. IDH-DS and the corresponding

leukocytosis are treatable; however, differentiation syndrome was also attributable to the only treatment-related deaths.
Roughly 20% of patients received a CR. Despite the relatively low number, those patients that did achieve CR had durable remissions, with a median OS of 19.7 months. The median OS of 9.3 months for all relapsed/refractory patients with AML receiving enasidenib was favorable compared to other similar studies42.
7.0 Expert commentary:

Enasidenib is a highly selective therapy against a molecular driver of AML; drugs such as this are the direct consequence of the increased understanding of the underpinnings of AML and represent a potential hopeful strategy in AML. However, some of the clinical results should temper optimism for strategies that target single mutations and pathways in this extremely heterogeneous disease. Enasidenib is inarguably a highly specific inhibitor of cells with mutant copies of IDH2; IDH2 is an early, stable mutation in AML. Therefore, it would be reasonable to hope that more than 20% of patients treated with an IDH2 inhibitor would experience a complete remission. When reminded of the fact that the 20% of responders only include the 20% of AML patients with an IDH2 mutation, the total numbers of patients who experience a CR, relative to all patients treated, is sobering. Furthermore, it is satisfying that the clinical results of some patients support the hypothesis that IDH2 mutations contribute to AML through an oncometabolite fueled arrest of differentiation, and enasidenib can interrupt this process by inducing differentiation and restoring remission. However, this clinical scenario is not the most common one; despite reducing 2-HG levels in almost all patients, only a minority have a clinical response35, calling into question whether we truly understand the mechanism of targeting IDH2. Perhaps these shortcomings can be mitigated by introducing enasidenib earlier in the course of

treatment, and results from studies with these designs are eagerly anticipated. Additionally, Stein et al. reported 10% of patients went on to bone marrow transplantation, and perhaps this will be the true value of enasidenib as a single agent in the relapsed setting, to serve as a bridge to a potentially curative therapy. Perhaps enasidenib should be paired with other mutational or pathway inhibitors like FLT3 inhibitors, but whether this is a viable strategy from a tolerability standpoint, or whether this is practical when considering the vast heterogeneity and complexity of this disease, remains to be seen.
Regardless of results from upcoming clinical trials, the work done to date with enasidenib is important in that it shows precision molecular targeting in AML is a viable method for impacting the pathogenesis of AML and improving clinical outcomes. It is incumbent on future investigations to refine the mechanism of the drug, better predict responders and delineate the ideal setting for enasidenib.
8.0 5 year view:

Enasidenib has provided a treatment option for a patient population that previously did not have good options. The role for enasidenib in mutant IDH2 relapsed/refractory AML will persist for years to come. Whether this is the optimal setting for enasidenib remains to be seen. Clinical trials are underway to answer questions about efficacy in the upfront setting, both in combination with traditional induction chemotherapy and the hypomethylators. Using enasidenib in combination with other small molecule inhibitors or other targeted therapy is a provocative idea, well positioned for early clinical trial development. Given what we know about enasidenib’s mechanism of action strategies directed against the epigenetic or molecular changes associated with mutant IDH2 will likely be explored. Drugs that inhibit EGLN expression or upregulate HIF resulting could result in improved efficacy compared to enasidenib alone. 2-HG inhibits the large

family of -KG-dependent enzymes which includes the ten-eleven translocation (TET) family, the Kdm4c family of histone lysine demethylases, enzymes involved in nucleic acid metabolism, and others with unknown function. It seems plausible that any drug effecting these pathways could be useful in mutant IDH2 AML. The success of these therapeutic strategies will be contingent on a more thorough understanding of the molecular mechanisms of IDH-associated leukemogenesis and enasidenib’s influence on these fundamental molecular pathways.
9.0 Key Issues:

• Enasidenib is FDA approved for adults with relapsed/refractory AML with an IDH2 mutation
• Typical dosing is 100 mg daily

• CR was 19.3%; ORR was 40.3%; Median OS was 9.3 months

• Those patients achieving CR had a median OS of 19.7 months

• 2-HG levels do not correspond to treatment response

• Enasidenib causes blast maturation and can precipitate differentiation syndrome

• Differentiation syndrome led to the only treatment related deaths

• Differentiation syndrome is treatable and enasidenib can be re-started after treatment

Funding

This manuscript was not funded.

Declaration of Interest

D Pollyea receives research funding from Agios and Pfizer and is an advisory board member for Celyad, Agios, Celgene, Abbvie, Argenx, Pfizer, Curis, Takeda and Servier. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Celgene Corporation provided a scientific accuracy review at the request of the journal editor.

References

Papers of special note have been highlighted as:

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