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Acute myeloid leukemia (AML) is a heterogenous disease arising from genetic mutations and epigenetic aberrations that prevent normal hematopoietic precursors from developing and differentiating in the normal way. There have been limited therapeutic advances in the field of AML over the past four decades, with standard-of-care (SOC) treatment being myeloablative cytotoxic chemotherapy and hematopoietic stem cell transplant (HSCT). However, many patients are ineligible for this treatment course due to older age or comorbidities. In recent years though, an increased understanding of the leukemic epigenome has led to the clinical development of several epigenetic modifying agents. These, and other advances in field, bring hope that the outcome of patients with AML can be improved.
On April 21, 2020, communities will unite on AML World Awareness Day (WAD), with a shared goal of raising awareness of AML. This collective goal will be achieved by sharing knowledge and advances in the prevention, management, and treatment of AML, worldwide. The AML Hub are proud to support AML WAD and have written a series of articles on key themes in AML to be shared in the lead-up to AML WAD. This article discusses novel epigenetic modifying agents in clinical development for AML, and is based on a publication by Darren Pan, Raajit Rampal, and John Mascarenhas, recently published in Blood Advances.1
Epigenetic alterations are heritable, but modifiable, molecular changes that modulate gene expression, without discrete mutations in the genes themselves. The accumulation of epigenetic alterations in addition to genetic mutations lead to an impairment of the normal maturation process and can lead to cells evading apoptosis and replicating indefinitely.
Epigenetic modifying agents are a low-intensity therapeutic approach offering an alternative to traditional SOC therapy. They are typically more tolerable than intensive chemotherapy (IC) while being moderately effective. Currently, few are approved by regulatory authorities like the United States Food & Drug Administration (FDA) or European Medicines Agency (EMA), but extensive clinical development is ongoing.
Rationale: DNMT methylates cytoside residues in cytosine guanine dinucleotide islands. This prevents transcription factors from binding to promoter regions and therefore silences gene expression. This is pertinent to AML cases, where the affected genes are involved in differentiation, DNA repair, and apoptosis.
Therapeutic agents: hypomethylating agents (HMAs) reverse the dysregulated DNA methylation caused by DNMT. The two most notable HMAs are azacitidine (AZA) and decitabine (DEC), which are cytosine analogues. Both agents lead to the hypomethylation of DNA, promoting the reactivation of tumor suppressor genes, which in turn is believed to lead to cellular differentiation and apoptosis. HMAs also have a second mechanism of action: they exhibit direct cytotoxicity at high doses.
Both AZA and DEC have proven particularly successful in elderly patients with newly diagnosed (ND) AML and some high-risk subsets, such as patients with chromosome 5 and 7 abnormalities. Additionally, AZA has shown some efficacy as a post-remission maintenance treatment. Results from the phase III QUAZAR-AML-001 study of CC-486, an oral formulation of AZA, as maintenance therapy showed CC-486 provided a clinically significant improvement in overall survival (OS) and relapse-free survival (RFS) in patients with AML in first remission following induction chemotherapy. CC-486 was therefore proposed by the authors as a new therapeutic maintenance standard for patients aged 55 or over with AML in first remission who are not eligible for HSCT. The full results are available here.
Next generation HMAs: Guadecitabine was designed to resist degradation by cytidine deaminase in order to increase the exposure window and improve marrow penetration. However, in the ASTRAL-1 study, guadecitabine failed to lead to an improvement in complete remission (CR) or overall survival (OS) when compared to physician’s choice of AZA, DEC, or low-dose cytarabine (LDAC). Ongoing studies seek to evaluate guadecitabine further: a phase III (NCT02920008) study is comparing guadecitabine vs treatment choice in patients with relapsed/refractory (R/R) AML and a phase II (NCT02096055) study is evaluating guadecitabine, with or without idarubicin or cladribine, in older patients with ND AML.
Key take-home messages from the ASTRAL-1 study
Administration: Currently, AZA or DEC treatment requires clinic visits for 5–7 days per month for subcutaneous (SC) or intravenous (IV) administration. Therefore, oral HMAs are being developed to increase adherence to treatment schedules, optimize drug exposure, and improve convenience. As mentioned above, CC-486 is an oral formulation of AZA, whilst ASTX727 is a novel combination of cedazuridine and oral DEC.
Combinations: HMAs require 3–4 cycles to achieve best response; interrupting treatment leads to a rapid loss of response. If a patient fails HMA therapy, the outcome is poor. Therefore, HMAs are being investigated in combination with other agents to improve responses and ensure they are durable. Combinations under investigation include
Can hypomethylating agents plus venetoclax replace chemotherapy induction for patients with AML?
Predicting response: Being able to predict response to HMAs is another area of interest. Factors found to indicate favorable responses include mutations in p53, IDH, TET2, DNMT3A, normal lactate dehydrogenase (LDH) level, and elevated fetal hemoglobin levels. Factors associated with poor responses are male sex, older age, and lower performance score.
Rationale: The removal of acetyl groups by HDAC means DNA is less available to transcription factors. This contributes to the repression of genes involved in normal cellular development and therefore promotes leukemogenesis.
Therapeutic agents: HDAC inhibitors are designed to restore histone acetylation patterns, inducing the expression of genes involved in the arrest of proliferation, differentiation, and apoptosis. HDAC inhibitors also disrupt oncogenic signaling pathways and directly induce double-strand breaks and oxidative damage to DNA in leukemic cells.
Combinations
Next generation HDAC inhibitors: Next-generation HDAC inhibitors, such as pracinostat (granted orphan drug designation by the EMA), entinostat, and romidepsin are under investigation in AML. For example, a phase III trial of pracinostat + AZA in patients with ND AML who are unfit for IC is ongoing (NCT03151408). Early experience has shown promise in combination with AZA, but RCTs are required.
Rationale: IDH1 and IDH2 enzymes are required for maintaining the normal energy balance. IDH mutations lead to an increase in histone and DNA methylation, and blockage of normal myeloid differentiation. IDH mutations are present in around 16% of patients with AML, though this is higher in secondary AML (sAML).
Therapeutic agents: Ivosidenib and enasidenib are selective inhibitors of mutant IDH1 and IDH2, respectively. Enasidenib is approved as monotherapy for patients with R/R IDH2-mutated AML. Ivosidenib is approved as monotherapy for patients with R/R IDH1-mutated AML, and for patients with ND IDH1-mutated AML who are older than 75 years or who are ineligible for IC.
Read more about IDH inhibitors in AML here.
Combinations: Both ivosidenib and enasidenib are being investigated in combination with HMAs for upfront treatment of patients with IDH-mutated AML:
Ivosidenib in IDH1 AML
Rationale: Bromodomain inhibitors are a new class of epigenetic modifiers. Bromodomain and extraterminal (BET) proteins initiate transcriptional complexes through binding to acetylated lysine residues on histones. Whilst not solely responsible for transcription activation, BET proteins add a level of regulation.
Therapeutic agents: OTX015 (MK-8268) is a novel oral agent that binds to BET proteins and consequently induces cell cycle arrest and apoptosis in AML cell lines. A phase I dose-escalation study in patients with R/R AML found Grade 1–2 diarrhea and rashes hampered compliance at a dose of 120 mg daily, leading investigators to lower this to 80 mg for an ongoing phase II study.
Combinations: Preclinical findings indicate that bromodomain inhibitors have enhanced activity in combination with HDAC inhibitors, HMAs, and BCL-2 and MCL-1 inhibitors.
Epigenetic therapies to target enzymes that methylate and demethylate histone lysine and arginine residues are also in clinical development and are summarized in Table 1.
Table 1. Other targets for epigenetic therapies and summary of clinical development1
AML, acute myeloid leukemia; DOT1L, disruptor of telomeric silencing 1-like; EZH, enhancer of zeste homolog; HMA, hypomethylating agent; LSD1, lysine-specific demethylase 1; PRMT, protein arginine methyltransferase | ||
Target |
Type of target |
Clinical work |
---|---|---|
EZH1 |
Histone lysine methyltransferase |
A dual EZH1 and EZH2 inhibitor, DS-3201b, is in clinical trials in AML (NCT03110354), since EZH2 inhibitors alone failed to show significant activity as single agents in preclinical studies |
EZH2 |
Histone lysine methyltransferase |
|
DOT1L |
Histone lysine methyltransferase |
Phase I study of pinometostat, a DOT1L inhibitor, in 51 adult patients with acute leukemias showed modest clinical activity (NCT01684150) |
LSD1 |
Lysine demethylase |
Phase I studies of LSD1 inhibitors, like INCB059872, IMG-7289, and trancylpromine, are underway in AML, both as monotherapy and in combination with all-trans retinoic acid or HMAs |
PRMT5 |
Protein arginine methyltransferase |
Phase I study of PRMT5 inhibitor, GSK3326595, is underway in patients with AML (NCT03614728) |
Incremental improvements in the outcomes of patients with AML have become possible with an increased understanding of the importance of the leukemic epigenome. These epigenetic therapies have begun to offer viable treatment options to patients who are ineligible for IC and current SOC. Searching for synergistic pairings and reducing toxicity will provide additional improvements in the field, with the identification of biomarkers to response further finessing the selection of appropriate treatment for each patient.
To read more about novel combinations involving targeted agents, click here.
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