We interviewed acute myeloid leukemia (AML) thought-leader Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center to learn more about recent and ongoing clinical trials studying epigenetic modifiers.
What is the role of epigenetic regulation and modification in AML?
For years, we have known that genetic mutations are involved in the pathogenesis of AML. And for many years, the accepted hypothesis for AML development was that two different types of genetic mutations were required for malignant transformation of a myeloid precursor. Class I mutations were believed to result in uncontrolled cellular proliferation and evasions of apoptosis. These mutations included those that conferred constitutive activity to tyrosine kinases or dysregulation of downstream signaling molecules. Class II mutations were associated with inhibition of cellular differentiation, including key transcription factor and proteins involved in transcriptional regulation.4-6 However, more recent research has been focused on the presence of epigenetic modifications to the AML genome, which suggests the Class I and II mutations alone present an incomplete picture of AML genetics.4,6,7 Unique mutations in genes related to epigenetic control of the genome, encompassing DNA methylation and histone modification, have now been identified in a substantial number of patients with AML.4,6
As an example, we can look at the genes for isocitrate dehydrogenase (IDH). Mutations in IDH1 and IDH2 have been discovered to occur in patients with AML. Some of these mutations, including IDH1-R132, IDH2-R172, and IDH2-R140, lead to loss of the normal Krebs Cycle conversion of isocitrate to alpha-ketoglutarate, while reducing alpha-ketoglutarate to the onco-metabolite 2-hydroxyglutarate (2HG).8,9 The accumulation of 2HG has been suggested to block cellular differentiation and promote tumorigenesis.9,10 Additional evidence has delineated that IDH mutations in AML are characterized by a distinctive hypermethylated DNA signature leading to impaired differentiation, which can potentially be reversed with small molecule IDH inibition.9,11
What are some of the key clinical trials surrounding pharmacological agents targeting IDH mutations in AML?
One of the prominent drugs in this category is enasidenib. This drug is a selective mutant IDH2 (mIDH2) inhibitor that results in leukemic cell differentiation and the emergence of functional mIDH2 neutrophils in patients with relapsed/refractory AML (RRAML).12 A phase 1/2 study of enasidenib assessed the maximum-tolerated dose (MTD), pharmacokinetic/pharmacodynamic profiles, clinical activity, and safety of enasidenib in patients with mIDH2 advanced myeloid malignancies, the largest subgroup being patients with RRAML. The 100 mg daily oral dose that had been previously selected in dose escalation/expansion analyses was used for this study.12,13
In the phase 1/2 analysis, patients with RRAML had an overall response rate (ORR) of 40.3%, and their median response duration was 5.8 months. These responses were associated with cellular differentiation and maturation, usually with no evidence for cellular aplasia. Median overall survival (OS) among this cohort was 9.3 months, with a median OS of 19.7 months for the 19.3% of patients who achieved a complete remission (CR). Median survival for those who had received ≥2 prior therapy regimens for their AML was 8.0 months. Overall median event-free survival (EFS) was 6.4 months.12
A companion translational analysis of enasidenib by Amantangelo, et al., measured 2HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the phase 1/2 study, and correlated these with clinical response. This trial found potent 2HG suppression in both the R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. It should be noted that that 2HG suppression alone did not predict response, considering that most patients who were non-responders also showed 2HG suppression in their samples. The study also demonstrated CR with mIDH2 persistence and normalization of hematopoietic stem and progenitor compartments, along with emergence of functional mIDH2 neutrophils. In a subgroup of patients achieving CR, the mIDH2 allele burden was found to be reduced and remained undetectable with response.14 Based on the phase 1/2 data, enasidenib was approved by the United States Food and Drug Administration for treatment of patients with RRAML who exhibit mutations in IDH2. The RealTime IDH2 Assay, used to detect specific mutations in the IDH2 gene in patients with AML, was also approved as a companion diagnostic.15
Another emerging agent is ivosidenib (AG-120), a selective oral inhibitor of IDH1. A phase 1 study was performed, reporting IDH1 mutation clearance assessed by variant allele frequency (VAF) analysis using next-generation sequencing in patients with advanced mIDH1-positive hematologic malignancies who completed the dose escalation phase. Patients received the agent once or twice daily continuously in 28-day cycles. Determination of mIDH1 VAF was performed using the FoundationOne®Heme test on mononuclear cells from the bone marrow or peripheral blood at screening and subsequent times during the study. Primary objectives for this study included safety, determination of MTD, and selection of dose cohorts for future trials. Results demonstrated that ivosidenib was well-tolerated, an MTD was not reached, and the dosing analysis supported once-daily dosing in phase 2. The CR rate was 17.9% with a ORR of 38.5%. In patients for whom longitudinal mIDH1 VAF data were available, 22% achieved a CR.16
[Update 01/15/18: At ASH 2017, results were reported from a phase 1 trial in which patients with newly diagnosed AML with an IDH1 or IDH 2 mutation were treated with either ivosidenib or enasidenib, respectively, in combination with standard induction chemotherapy. The median time to ANC recovery ≥500/µL was 28 days for patients receiving ivosidenib and 34 days for those receiving enasidenib. The median time to platelet recovery ≥50,000/ µL was 28 days in patients receiving ivosidenib and 33 days in patients receiving enasidenib. Interestingly, patients with secondary AML (sAML) who received enasidenib had a prolonged median time to platelet recovery of 50 days. Among patients with de novo AML receiving ivosidenib, the overall response rate (CR/CRp/CRi) was 86% while the overall response rate was only 44% among those with sAML. Finally, the overall response rate was 67% among patients with de novo AML treated with enasidenib and 58% for those with sAML.17
Also at ASH, preliminary data was presented from a phase 1b/2 study of azacitidine combined with either enasidenib or ivosidenib in patients with newly diagnosed AML and IDH mutations. At the data cutoff date, the overall response rate (ORR) was 50% among of patients who received enasidenib in combination with azacitidine, and 60% among those receiving ivosidenib plus azacitidine.18]
[Update 07/25/18: On July 20, 2018 the FDA approved ivosidenib tablets for the treatment of adult patients with relapsed or refractory AML who have a mutation of the isocitrate dehydrogenase-1 (IDH1) gene as detected by an FDA-approved test.]
In addition to these studies, we are now analyzing the combination of IDH inhibitors with standard of care chemotherapy and induction chemotherapy, which provides the dual effect of epigenetic modifiers and cytotoxic therapy. In addition, some studies are evaluating a combination of IDH inhibitors with 5-methyl transferase inhibitors (5-azacytadine). We look forward to results on these analyses in the near future.19
What other key agents and clinical trials are of particular interest surrounding epigenetic modifiers?
Another oral histone deacetylase (HDAC) inhibitor, pracinostat, was studied in a phase 2 trial combined with azacitidine in patients with AML 65 years of age and older who were not considered eligible for induction chemotherapy. Treatment consisted of pracinostat 60 mg orally 3 days per week on alternate days for 3 weeks (with azacitidine administered subcutaneously or intravenously daily for 7 days). Cycles repeated every 28 days until there was evidence for disease progression, lack of response, or poor treatment tolerability. Composite complete response rate (cCR), consisting of CR plus CR with incomplete blood count recovery (CRi) plus morphologic leukemia-free state (MLFS), was the primary endpoint. Results showed that CR was achieved in 42% of patients, with a CRi in 4%, and MLFS in 6%, combining for a cCR rate of 52%. The median duration of cCR was 13.2 months. The median OS was 19.1 months with a median follow-up of 21 months, and one-year and two-year OS were 62% and 45%, respectively.20
Not every drug or trial in this arena has produced promising results. One study evaluated using the HDAC inhibitor vorinostat in combination with idarubicin and high-dose cytarabine; or using high-dose cytarabine during induction instead of standard-dose cytarabine, vs standard 7+3 chemotherapy in younger patients with AML. Patients were randomized 1:1:1 to either 7+3, idarubicin plus high-dose cytarabine, or idarubicin plus high-dose cytarabine plus vorinostat. Results demonstrated no significant differences in EFS, relapse-free survival (RFS), or OS between the three cohorts. The CR rate and CR with incomplete marrow recovery rates were 75% for the 7+3 arm, 79% with ID idarubicin plus cytarabine, and 77% for the vorinostat cohort.21
Another class of agents undergoing investigation are DOT1-like (DOT1L) inhibitors. Both AML and acute lymphocytic leukemia (ALL) may exhibit a mixed lineage leukemia (MLL), characterized by the presence of MLL fusion proteins created by chromosomal translocations affecting the MLL gene at the 11q23 chromosome locus.22 Aberrant fusion proteins involving the MLL histone methyltransferase (HMT) lead to recruitment of another HMT – DOT1L – to a multi-protein complex. Pinometostat is a small molecule inhibitor of DOT1L with affinity and high selectivity against non-MLL HMTs. Pinometostat therapy can reduce histone H3K79 methylation, decrease MLL target gene expression, and selectively target and kill leukemic cells. A dose expansion study involved patients with AML, ALL, MLL, myelodysplastic syndrome (MDS) myeloproliferative neoplasm, or chronic myeloid leukemia (CML). Early results demonstrated a morphologic CR in one patient, cytogenetic CR (MLL-negative) in one patient, a partial response in one patient, and resolution of leukemia cutis in three patients. The overall safety profile of pinometostat was acceptable, and clinical activity was demonstrated by both marrow responses and resolution of leukemia cutis.23 At this time, research is concentrating on elucidating why there were so few CRs in this study and also working on combining this drug with other agents, including 5-azacytidine.
Finally, lysine-specific demethylase 1 (LDS1) is another target for leukemia therapy. LDS1 is a histone demethylase expressed in leukemic cells, and it functions to regulate the differentiation block in AML.24,25 Inhibitors of LDS1 are currently being studied in multiple phase 1/2 clinical trials for treatment of adults with RRAML or MDS.19,25
As a result of the research on these new and emerging therapies, what would you consider to be the key takeaways for oncologists?
Now that enasidenib is approved for clinical use, clinicians must keep in mind that the drug does not work overnight. The average median time to evidence of first response is 4 months, so they need to keep patients on the drug for at least this long. During the first therapy cycle, myeloid blasts may actually increase in the blood and bone marrow, called a proliferative burst. This is not a sign of disease progression and should not indicate to the clinician that treatment must be held. In addition, treatment with enasidenib may cause indirect hyperbilirubinemia, and again, this is a not a reason to hold therapy. Direct hyperbilirubinemia may occur, indicating liver issues, but this is not likely related to enasidenib, though it does warrant your attention. I would recommend you refer to the package insert for specific dose modification guidelines.
Importantly, clinicians must be vigilant for differentiation syndrome (DS), a process by which leukemic myeloblasts release cytokines as they differentiate to normal healthy adult neutrophils. DS can become apparent clinically in the form of neutrophils (or even monocytes) in the peripheral blood, and a patient complaining of swollen legs, shortness of breath, and dyspnea. If a chest x-ray or CT scan reveals absence of pneumonia and the presence of bilateral fluffy pulmonary infiltrates, or even pleural effusion or pericardial effusion, this is consistent with DS. In these cases, the patient can be treated with dexamethasone 10 mg/day until 3 to 4 days after symptom resolution, when steroid therapy can be tapered off. Overall, enasidenib has a long half-life, so the drug should not be held/discontinued unless a patient with DS has severe symptoms. If the agent does have to be held because of symptom severity, the patient will not lose treatment response because of the long half-life. I think these are the most important points for the practicing clinician who can order this drug now.
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- Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control. 2008;19(4):379-390.
- Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
- Shi AH, Abdel-Wahab O, Patel JP, Levine RL. The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer. 2012;12(9):599-612.
- Kelly LM, Gilliland DG. Genetics of myeloid leukemias. Annu Rev Genomics Hum Genet. 2002;2:179-198.
- O'Brien EC, Prideaux S, Chevassut T. The epigenetic landscape of myeloid leukemia. Adv Hematol. 2014;2014:103175.
- Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9(6):465-476.
- Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225-234.
- DiHardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2010;09(8):732-736.
- Lu C, Ward PS, Kapoor GS, et al. IDH Mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;283(7390):474-478.
- Kernitsky A, Wang F, Hansen E, et al. IHD2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibitors. Blood. 2015;125(20:296-303.
- Stein EM, DiNardo CD, Pollyear DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
- Fan B, Chen Y, Wang F, et al. Pharmacokinetic/pharmacodynamic (PK/PD) evaluation of AG-221, a potent mutant IDH2 inhibitor, from a phase 1 trial of patients with IDH2 mutation positive hematologic malignancies. Haematologica. 2015;100:Abstract 379.
- Amatangelo MD, Quek L, Shih A et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732-741.
- United Stated Food and Drug Administration. FDA approves new targeted treatment for relapsed or refractory acute myeloid leukemia. (August 1, 2017). Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm569421.htm.
- DiNardo C, deBotton S, Stein E, et al. Determination of IDH1 Mutational Burden and Clearance Via Next-Generation Sequencing in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Inhibitor of Mutant IDH1. Blood. 2016;128:1070.
- Stein EM, DiNardo CD, Mims AS, et al. Ivosidenib or enasidenib combined with standard induction chemotherapy is well tolerated and active in patients with newly diagnosed AML with an IDH1 or IDH2 mutation: Initial results from a phase 1 trial. Presented at: 59th Annual Meeting and Exposition of the American Society of Hematology; Atlanta, GA; December 9-12, 2017. Abstract 726.
- DiNardo CD, Stein AS, Fathi AT, et al. Mutant isocitrate dehydrogenase (mIHD) inhibitors, enasidenib and ivosidenib, in combination with azacitidine (AZA): preliminary results of a phase 1b/2 study in patients with newly diagnosed acute myeloid leukemia (AML). Presented at: 59th Annual Meeting and Exposition of the American Society of Hematology; Atlanta, GA; December 9-12, 2017. Abstract 639.
- ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/.
- Garcia-Manero G, Atallah E, Khaled SR, et al. A phase 2 study of pracinostat and azacitidine in elderly patients with acute myeloid leukemia (AML) not eligible for induction chemotherapy: response and long term survival benefit. Blood. 2016;128:100.
- Garcia-Manero G, Othus M, Patel JM, et al. SWOG S1203: a randomized phase III study of standard cytarabine plus daunorubicin (7+3) therapy versus idarubicin with high dose cytarabine (IA) with or without vorinostat (IA+V) in younger patients with previously untreated acute myeloid leukemia (AML). Blood. 2016;128:901.
- Slany RK. The molecular biology of mixed lineage leukemia. Haematologica. 2009;94(7):984-993.
- Stein EM, Garcia-Manero G, Rizzieri DA, et al. A Phase 1 study of the DOT1L inhibitor, pinometostat (EPZ-5676), in adults with relapsed or refractory leukemia: safety, clinical activity, exposure and target inhibition. Blood. 2015;126:2547.
- Song YWF, Wu J. Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives. J Hematol Oncol. 2016;9(1):49.
- Saygin C, Carraway HE. Emerging therapies for acute myeloid leukemia. J Hematol Oncol. 2017;10(1):93.