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Molecular targeting in acute myeloid leukemia

Journal of Translational Medicine volume 15, Article number: 183 (2017) Cite this article

Abstract

Acute myeloid leukemia (AML) is a heterogenous disease associated with distinct genetic and molecular abnormalities. Somatic mutations result in dysregulation of intracellular signaling pathways, epigenetics, and apoptosis of the leukemia cells. Understanding the basis for the dysregulated processes provides the platform for the design of novel targeted therapy for AML patients. The effort to devise new targeted therapy has been helped by recent advances in methods for high-throughput genomic screening and the availability of computer-assisted techniques for the design of novel agents that are predicted to specifically inhibit the mutant molecules involved in these intracellular events. In this review, we will provide the scientific basis for targeting the dysregulated molecular mechanisms and discuss the agents currently being investigated, alone or in combination with chemotherapy, for treating patients with AML. Successes in molecular targeting will ultimately change the treatment paradigm for the disease.

Background

Despite the advance of modern chemotherapy, the prognosis of patients with acute myeloid leukemia (AML) has remained poor and little progress has been made that improves long term outcome of these patients. For more than four decades since the combination of an anthracycline and cytarabine was first used for induction therapy, the “3 + 7” regimen has remained the standard therapy for AML. The long term disease-free survival of AML patients under age 60 remains around 40% [1], with minimal improvement over the past several decades, suggesting that the gains from conventional chemotherapy may have been maximized. New approaches are, therefore, needed if further improvement in the outcome for AML patients is desired.

AML is a clonal malignancy associated with a wide-spectrum of genetic alterations. In addition to well-described chromosomal abnormalities, a multitude of mutations occur and they contribute to AML pathogenesis, either due to their effects of tumor suppressor genes or as drivers of intracellular oncologic signaling pathways or modifiers of epigenetics. The magnitude and frequency of these abnormalities, and their pathologic implications, were not fully appreciated until the last decade as novel techniques for the analysis of whole genome sequencing have become available.

The molecular events associated with AML have long been used to predict prognosis [2]. With an expanding understanding of the molecular genetic alterations underlying AML pathogenesis, recent efforts have concentrated on specific targeting of intracellular events driven by these abnormal proteins. Molecular targeting is a particularly attractive therapeutic approach for several reasons. First, the therapeutic efficacy of molecular targeting may complement the benefits provided by conventional chemotherapy. Second, the approach may be more specific to each patient’s molecular landscape and minimize systemic toxicity. Third, it may offer an increased likelihood of eradication of the malignant clones that drive the disease and often being responsible for disease relapse.

Here we will review the intracellular mechanisms and pathways that provide the platforms for molecular targeting in AML. Specifically, we will discuss therapies targeting FMS-like tyrosine kinase 3 (FLT3) and pathways associated with DNA methyltransferase (DNMT)3A, ten-eleven-translocation (TET)2, and IDH (isocitrate dehydrogenase) 1/2. We will also summarize the current status of utilizing histone deacetylase (HDAC), bromodomain and extra terminal (BET), and disruptor of telomeric silencing 1-like (DOT1L) inhibitors in AML. Finally, we will discuss the role of therapies targeting the anti-apoptotic protein, BCL (B-cell lymphoma)-2, as it has recently been shown that IDH1/2 mutation status may identify patients who are most likely to respond to therapeutic inhibition of BCL-2 [3]. Since molecular therapy of the promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα) in acute promyelocytic leukemia (APL) is well-established, we will limit our review to novel agents for non-APL AML. This review is not meant to be an exhaustive discussion of all emerging agents. Instead we will summarize the results of some of the clinical studies carried out so far.

Main text

Targeting FLT3 signaling pathway

FLT3 mutations

FLT3 is a surface receptor that consists of an extracellular ligand-binding domain, a transmembrane domain, a juxtamembrane domain, and two tyrosine kinase domains. Engagement of the wildtype receptor with the FLT3 ligand triggers a cascade of downstream events that signal cell proliferation [4, 5]. This is achieved first through autophosphorylation of the tyrosine residues on the receptor and then by the consequent phosphorylation and activation of the RAS, Src/JAK (Janus kinase), and PI3K pathways (Fig. 1). High levels of the downstream effector of the RAS pathway, ETS2, have recently been found to predict for poorer prognosis [6].

Fig. 1
figure 1

FLT3 kinase signaling pathway and sites blocked by FLT3 inhibitors. Sorafenib and quizartinib inhibit only FLT3–ITD mutations, while midostaurin, crenolanib, and gilteritinib inhibit both FLT3–ITD and FLT3 TKD mutations

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Mutations of the FLT3 receptor occur in nearly one-third of patients with AML and are one of the most frequent mutations encountered in this disease [7]. The mutations occur either as internal tandem duplications (FLT3/ITD mutations) in or near the juxtamembrane domain, or as point mutations that result in single amino acid substitutions within the activation loop of the tyrosine kinase domain (FLT3/TKD mutations). FLT3/ITD mutations occur in 24% [8] and FLT3/TKD mutations in 7% of AML [9]. Patients with FLT3/ITD mutations typically have high white cell counts at disease presentation and have normal or intermediate risk karyotypes. Although the likelihood of attaining a complete remission (CR) of the disease is similar to other AML patients, the duration of remission is usually short and the relapse rate high. FLT3/TKD mutations tend to confer slightly better prognosis. Interestingly, FLT3 phosphorylation has also been observed in a large proportion of AML patients, even in the absence of FLT3 mutations [9, 10].

FLT3 mutations result in a constitutively active kinase [10]. It addition to mediating the intracellular signaling events observed when wild type FLT3 receptor interacts with its ligand, FLT3/ITD activates the Stat 5 pathway [11,12,13,14] and upregulates the serine threonine kinase, Pim-1/2 [13, 15]. Both these processes promote leukemia cell proliferation and mediate anti-apoptotic effects. FLT3/ITD mutations also promote genomic instability by inducing the production of reactive oxygen species (ROS) that enhance DNA double-strand breaks and repair errors [16].

FLT3 inhibitors for AML

Based on the frequent occurrence of FLT3 mutations and the poor clinical outcome in patients harboring the mutations, molecular targeting of FLT3 kinase is an attractive therapeutic option for AML. Since the identification of FLT3 mutations, several molecular agents have been developed to target the FLT3 kinase. These include sorafenib and quizartinib that inhibit FLT3/ITD mutant receptor and midostaurin, crenolanib, and gilteritinib that inhibit both FLT3/ITD and FLT3/TKD mutant receptors (Fig. 1). Most of these agents are multi-kinase inhibitors.

Sorafenib

Sorafenib has been used off-label in the treatment of relapsed/refractory AML. It is an oral agent that is 1000–3000 times more potent in inducing growth inhibition and apoptosis in AML cells that harbor FLT3/ITD or D835G mutations than in those that harbor D385Y mutation or wildtype FLT3 kinase [17]. It is a multi-kinase inhibitor that also has activity against KIT, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR). In a phase I study, 16 patients with relapsed/refractory AML were randomly assigned to receive sorafenib in 21-day cycles of 5 days per week (n = 7 patients) or of 14 days (n = 9 patients). In both arms, the starting dose level was 200 mg twice daily. Subsequent dose levels were 600, 800, and 1200 mg daily in cohorts of three subjects at each dose level. Leukemic burden was reduced in patients with FLT3/ITD mutations but not those without the mutations [17].

Early successes with sorafenib were observed in patients with relapsed/refractory FLT3–ITD positive AML before and in those whose disease relapsed following allogeneic stem cell transplant (SCT) [18]. In this report, six patients received sorafenib on compassionate use. The initial dose was 400 mg twice a day and the dose was adjusted in case of cytopenia, suspected toxicity, or resistance. All three patients whose disease relapsed following allogeneic SCT attained CR. Another three patients who had refractory AML achieved CR, facilitating allogeneic SCT in two of the three patients. Since then, two phase I studies have been carried out using sorafenib as maintenance therapy following allogeneic SCT for AML with the FLT3–ITD mutation [19, 20]. Sorafenib was found to be well-tolerated and produced very favorable progression-free survival at 1 year.

Sorafenib has also been studied in combination with chemotherapy for AML patients. When sorafenib (400 mg twice a day) was used in a phase II study with azacytidine (75 mg/m2/day × 7 days) in 43 patients with relapsed/refractory AML (40 with FLT3–ITD mutations) [21], an overall response rate (ORR) of 46% was observed. In a phase I/II study of idarubicin (12 mg/m2/day × 3) and cytarabine (1.5 g/m2/day × 4) induction chemotherapy with sorafenib (400 mg twice a day) as frontline therapy for younger AML patients [22] the CR rate was 75%. With a median follow-up of 54 weeks, the probability of survival at 1 year was 74%. Three subsequent studies have also involved a combination of patients with and without FLT3 mutations. A phase II randomized placebo-controlled study of sorafenib (400 mg twice a day) with daunorubicin (60 mg/m2/day × 3) and cytarabine (100 mg/m2/day × 7) found that, although CR rates were comparable (60% vs 59%) and adverse events were higher in those who received sorafenib, the median event-free survival (EFS) was significantly longer in the sorafenib arm (21 months vs 9 months) [23]. However, such survival benefit was not observed when a similar regimen was used in elderly AML patients [24], or when sorafenib was used in combination with low-dose cytarabine [25].

The clinical results described above suggest that sorafenib might be effective in reducing leukemic burden and improving progression-free survival (PFS) for patients with relapsed/refractory AML with FLT3–ITD mutations, and may also have a role in combination with chemotherapy in certain patient populations. Further investigation is needed to define the role of sorafenib as frontline therapy, in combination with chemotherapy, for AML with FLT3 mutations, although with the recent Food and Drug Administration (FDA) approval of midostaurin, there may not be as much interest in investigating sorafenib. Since sorafenib is a multi-kinase inhibitor, its role in AML without FLT3 mutations would also be of great interest.

Midostaurin

Midostaurin is another oral multi-kinase inhibitor, with activity against not only FLT3 kinase, but also KIT, VEGFR, PDGFR, and protein kinase C. It is currently the only FLT3 inhibitor that is approved by the FDA for use in AML. When used with azacytidine in a phase I/II study for patients with relapsed/refractory AML [26], an ORR of 26% was obtained. The ORR was 33% in those with FLT3–ITD mutations.

In a phase IIb study of midostaurin monotherapy for relapsed/refractory AML assigning patients to either 50 or 100 mg twice a day, an ORR of 71% in the 35 patients with FLT3–ITD mutation and 42% in those without the mutation [27]. A higher midostaurin dose did not improve the outcome. Grade 3/4 non-hematological toxicities included infections, reduction in the ventricular ejection fraction, and diarrhea or nausea/vomiting. A phase Ib study combined midostaurin with daunorubicin (60 mg/m2/day × 3) and cytarabine (200 mg/m2/day × 7) induction therapy for younger patients with newly diagnosed AML [28]. The initial dose of midostaurin in this study was 100 mg twice a day but the dose had to be reduced to 50 mg twice a day due to toxicities. The combination produced a high CR rate and overall survival (OS). Based on this phase Ib study, a large phase III randomized placebo-controlled RATIFY trial was carried out. In this phase III study, midostaurin (50 mg twice a day) was used in combination with the “3 + 7” regimen as upfront therapy for young AML patients with FLT3 mutations (either ITD or TKD) [29]. Although the CR rates were comparable, patients in the midostaurin arm demonstrated a longer median disease-free survival (DFS) (26.7 months vs 15.5 months) and OS (74.7 months vs 25.6 months). The improved survival benefits were observed even in the patients who subsequently underwent allogeneic SCT, without increased adverse reactions.

The clinical results described above suggest that the addition of midostaurin to the standard “3 + 7” induction regimen as first line therapy might be beneficial for younger AML patients with FLT3 mutations. Since midostaurin is a multi-kinase inhibitor, it would also be interesting to determine its role in combination of chemotherapy for AML without FLT3 mutations.

Quizartinib

Quizartinib is an oral kinase inhibitor that is highly selective for FLT3. In a phase I dose escalation study (from 12 to 450 mg/day) in 76 patients with relapsed/refractory AML [30], quizartinib produced an ORR of 17%, but 53% in those with FLT3–ITD mutations. The most common drug-related adverse events were nausea, prolonged QT interval, vomiting, and dysgeusia, most were Grade 2 or lower. Subsequent phase II studies of quizartinib monotherapy in similar groups of patients with FLT3–ITD mutations [31, 32] yielded CR rates of 44–54% and ORRs of 61–72%. These results are extremely compelling, although the duration of remissions in all the cases were short, with the median remission of only 3 months, suggesting the frequent development of resistance to quizartinib. Up to 22% of patients treated with FLT3 inhibitors developed a TKD mutation during FLT3 inhibitor therapy [33].

Quizartinib has also been used in combination with azacytidine or low dose cytarabine in a phase I/II study for relapsed/refractory AML [34]. Among the patients with FLT3–ITD mutations, ORR was high at 73%. Quizartinib has also been used in AML patients with FLT3–ITD mutations whose disease relapsed following allogeneic SCT [35]. The median survival was much improved, compared to historical controls.

Future studies may involve comparing quizartinib with midostaurin to determine if the outcome benefits of midostaurin could be attained with less side effects using a more selective FLT3 inhibitor like quizartinib.

Gilteritinib

Gilteritinib is a potent FLT3/AXL inhibitor that shows activities against both FLT3–ITD and FLT3–TKD mutants. In the large phase I/II dose-escalation, dose-expansion Chrysalis trial of gilteritinib monotherapy for relapsed/refractory AML [36], 252 patients, 77% of them with confirmed FLT3 mutations, were assigned to one of seven dose-escalation (20–450 mg/day) cohorts or dose-expansion cohorts. The ORR was 49% in those with FLT3 mutations, but only 12% in those without the mutations. The ORR was higher, at 52%, in those who received ≥80 mg/day of the inhibitor. In this group of patients, the median OS was 31 weeks and the median duration of response was 20 weeks. Gilteritinib was generally well tolerated, with diarrhea and fatigue being the most common adverse reactions.

Preclinical data of gilteritinib combined with azacytidine in AML cells harboring FLT3–ITD mutations showed that the kinase inhibitor augment the apoptosis induced by azacytidine [37], providing the rationale for testing of this combination in the clinic.

Crenolanib

Crenolanib is a selective FLT3 inhibitor that is active against both ITD and TKD mutations. It is also uniquely active against leukemic clones that have developed quizartinib resistance [38]. In an open-label phase II study in relapsed/refractory AML with a FLT3 mutation [39]. The ORR was 62% in patients who were FLT3 inhibitor-naïve and 38% in those with a prior history of FLT3 inhibitor therapy. Gastrointestinal toxicity and transaminitis were the most common adverse reactions observed in this study.

Crenolanib has also been used in combination with standard chemotherapy. In a phase II study of idarubicin (12 mg/m2/day × 3) and high dose cytarabine (1.5 g/m2/day × 4) plus escalating doses of crenolanib (60–100 mg three times a day) in relapsed/refractory AML patients with FLT3 mutations [40], four of the six patients who had failed ≤2 lines of therapy attained CR of their disease. In contrast, none of the five patients who had failed three or more lines of therapy achieved CR.

When crenolanib (100 mg three times a day) was used in combination with the “3 + 7” regimen for newly diagnosed AML patients with FLT3 mutations [41], the overall CR rate was 96%. With a median follow up of 6.2 months, disease relapse was observed in only three of 24 patients.

Ongoing clinical trials utilizing FLT3 inhibitors in AML

Based on the availability of an increasing number of FLT3 inhibitors and the encouraging early clinical results obtained using these small molecules, there are currently many clinical trials ongoing internationally to determine the precise role of these inhibitors in the management of AML. A selection of these clinical trials is summarized in Table 1.

Table 1 A selection of active studies evaluating FLT3 inhibitors in AML
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Targeting epigenetics

Epigenetics in AML

Epigenetics refers to the study of mechanisms underlying stable and ideally heritable changes in gene expression or cellular phenotype without changes in the underlying DNA sequences. Various laboratory studies have implicated dysregulation of epigenetic mechanisms in the pathogenesis of AML. In addition, many of the mutations that occur in AML are localized to genes involved in transcriptional regulation [42]. Changes in the genome-wide pattern of methylation are also known to be epigenetic modifiers [43]. Depending on the specific type and site of methylation, the effects on gene expression can differ significantly.

Epigenetic mechanisms

Transcriptional regulation is accomplished through a network of molecular mechanisms (Fig. 2). These include histone acetylation, histone methylation, DNA methylation, and DNA hydroxymethylation. Here, we will limit our discussion to the mechanisms relevant to epigenetic targeting using the currently available small molecules.

Fig. 2
figure 2

Epigenetic mechanisms of gene regulation through histone acetylation and histone and DNA methylation by various epigenetic modifiers. These epigenetic mechanisms can be blocked by inhibitors at various specified sites

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Histone acetylation and methylation

The first step of gene transcription involves acetylation of the histone tails, causing a change in the chromatin conformation so that the distance between DNA and histone is increased, rendering the DNA more accessible to transcription factors. In contrast, deacetylation induces the opposite effects. Acetylation is catalyzed by histone lysine acetyltransferases (KATs) and deacetylation by HDACs. The acetylated lysine residues are then recognized by bromodomain-containing reader proteins such as the BET proteins [44]. BET proteins include BRD2, BRD3, BRD4, and BRDt.

Transcriptional activation is further modified by histone lysine methylation. Histone lysine methylation is mediated by lysine methyltransferases (KMTs). Histone methylation modulates the affinity of the reader proteins to the histone. Unlike acetylation, histone methylation either activates or represses gene transcription. Molecular abnormalities of the mixed-lineage leukemia (MLL) protein occur recurrently in AML [45]. MLL potentially has more than 70 fusion partners. The MLL protein upregulates Hox expression and results in a block of hematopoietic differentiation [46]. The abnormal fusion proteins arise due to gene translocation or duplication. The abnormal MLL arising from translocation also frequently contains the DOT1L protein [47], a KMT targeting H3K79.

Histone methylation is further modulated by lysine demethylases (KDMs). Lysine-specific histone demethylase 1A (LSD1) is one of the KDMs and has specificity for H3K4 and H3K9. It can function either as a transcriptional activator or repressor.

DNA methylation and hydroxymethylation

DNA methylation is catalyzed by DNMTs and converts cytosine residues to 5-methylcytosine. This reaction usually occurs at the CpG islands within the gene and/or at its distant enhancer. DNA methylation usually results in silencing of the specific gene. Mutations in DNMT3A gene occur in more than 20% of AML patients [48]. The frequency increases with age and is associated with poorer clinical outcome.

DNA hydroxymethylation occurs as an intermediary step in the demethylation pathway, oxidizing 5-methylcytosine to 5-hydroxymethylcytosine. This process is catalyzed by TET2 which is mutated in up to 20% of AML cases [43]. DNA hydroxymethylation is dependent on α-ketoglutarate; its conversion from isocitrate is mediated by IDH1 and IDH2. Mutations of IDH1 and IDH2 result in the production of 2-hydroxyglutarate that competitively inhibit TET2 activity [49].

Epigenetic modifiers for AML

Based on the major role epigenetics plays in the disease process, targeting epigenetic modifiers represents an attractive option for treating AML (Fig. 2).

Histone deacetylase (HDAC) inhibitors

Since HDAC expression is often dysregulated in AML cells [42], targeting HDAC using specific inhibitors has been attempted. However, the clinical response of AML to HDAC inhibitor monotherapy has so far been uniformly disappointing [50, 51], but when combined with chemotherapy, improved response rates were observed. In a phase I study of vorinostat (400 mg/day) used either sequentially or concurrently with decitabine (20 mg/m2/day × 5) [52], 2 of 13 AML patients with relapsed/refractory disease treated concurrently attained complete remission but none of the 15 patients treated on the sequentially protocol responded.

A phase II study randomized 149 patients with AML or myelodysplastic syndrome, most treatment-naïve, to receive either azacytidine (50 mg/m2/day × 10) monotherapy or azacytidine with entinostat (4 mg/m2/day days 3 and 10) [53]. Unfortunately, the addition of entinostat did not improve the hematologic response rate. In contrast, when pracinostat was combined with azacytidine in a phase II study for older AML patients [54], the combination produced a CR and CR with incomplete hematologic recovery (CRi) rate of 42 and 4% respectively. A phase Ib/II study of azacytidine (75 mg/m2/day × 5) combined with escalating doses of panobinostat (10–40 mg/day) in intensive chemotherapy-naïve AML and myelodysplastic syndrome (MDS) patients also produced an ORR of 31% for AML and 50% for MDS [55].

HDAC inhibitors have also been used with intensive combination chemotherapy in newly diagnosed AML. A phase Ib/II study combined panobinostat with intensive induction chemotherapy for older patients with newly diagnosed AML [56]. In this study, patients received the standard idarubicin (8 mg/m2/day × 3) and cytarabine (100 mg/m2/day × 7) regimen plus panobinostat at escalating doses (10–40 mg/day). Patients who attained CR received a consolidation cycle with the same combination, followed by panobinostat maintenance until progression. CR was observed in 64% of the patients, with a time to relapse of 17 months.

When vorinostat was used in combination with idarubicin and cytarabine as induction therapy for AML patients 65 years or younger [57], the ORR was 85% in the group and 100% in those with FLT3–ITD mutations. However, when the identical regimen was used in a phase III randomized study of idarubicin and cytarabine with or without vorinostat [58], no significant clinical benefits were observed in the vorinostat arm.

Based on these results, it is expected that any role HDAC inhibitor may have in the future development of therapeutics for AML will involve combination with chemotherapy.

BET inhibitors

BET proteins are crucial in regulating gene transcription and they do so through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. BET inhibition has been shown to repress the transcriptional network driven by c-myc [59]. So far, there has only been one reported study of a BET inhibitor for patients with AML. In a phase I dose-escalation study of monotherapy with the bromodomain OTX015 in adult acute leukemia patients (36 with AML) who had failed or were unable to receive standard induction chemotherapy [60], three patients attained a CR or CRi and two other patients had partial blast clearance. Diarrhea and fatigue were common adverse reactions, and two of the patients developed hyperbilirubinemia.

DOT1L inhibitors

The DOT1L inhibitor, pinometostat, has shown activity in animal models of acute leukemia [61]. It also increased the in vitro sensitivity of MLL-rearranged AML to chemotherapy [62]. In a phase I study of pinometostat monotherapy in patients with relapsed/refractory acute leukemia [63], clinical response was observed in six of the 49 patients, with two patients attaining CR, one PR, and three resolution of leukemia cutis. Adverse events included nausea, constipation, vomiting, abdominal pain, diarrhea, hypocalcemia, hypokalemia, hypomagnesemia, fatigue, fever, peripheral edema, mucositis, febrile neutropenia, leukocytosis, anemia, cough, dyspnea, and pneumonia. Interestingly, nine patients showed evidence of differentiation syndrome.

LSD1 inhibitors

Leukemia cells, including those with complex cytogenetics have so far been consistently demonstrated in vitro to be highly sensitive to LSD1 inhibitors [64,65,66,67]. The LSD1 inhibitor T-3775440 has been shown to disrupt the transcription factor, growth factor-independent 1B (GFI1B) complex and impede leukemia cell growth [65]. The LSD1 inhibitors NCD25 and NCD38 hindered the oncogenic potentials of leukemia cell lines [67]. Although human studies are ongoing, no clinical results are currently available.

DNMT inhibitors

Azacytidine and decitabine are two DNMT inhibitors that have been used alone or in combination with low dose cytarabine for treating AML in patients who are not suitable candidates for intensive induction chemotherapy. They both produced CR and CRi rates around 20% [68,69,70,71]. Since the DNMT inhibitors azacytidine and decitabine have already been used in the clinic extensively to treat AML and MDS, we will limit our discussion of DNMT inhibitors in the review to the second generation DNMT inhibitor, guadecitabine.

Guadecitabine is also known as SGI-110 and is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine. Unlike azacytidine and decitabine, it is resistant to degradation by cytidine deaminase. A phase I multicenter, dose-escalation randomized study assigned 35 patients with AML and nine patients with myelodysplastic syndrome (MDS) in the daily ×5 dose-escalation cohorts, 28 patients with AML and six patients with MDS in the once-weekly dose-escalation cohorts, and 11 patients with AML and four patients with MDS in the twice-weekly dose-escalation cohorts [72]. Six of the 74 patients with AML and six of the 19 patients with MDS had a clinical response to treatment. The most common Grade 3 or higher adverse events were febrile neutropenia, pneumonia, thrombocytopenia, anemia, and sepsis.

IDH inhibitors

IDH1 and IDH2 mutations occur in around 5–10 and 10–15% of adult AML respectively [73]. Interestingly, IDH mutations predict for response to therapeutic BCL-2 inhibition [3]. Several IDH inhibitors are currently being investigated clinically. IDH305 suppresses mutant IDH1-dependent 2-hydroxyglutarate production and was tested as monotherapy in a phase I study that included 21 patients with relapsed/refractory AML [74]. CR was observed in 2, CRi 1, and PR 4 patients. Another phase I study used a different IDH1 inhibitor, AG-120, as monotherapy in 78 patients with mutant IDH1, 63 of these patients had relapsed/refractory AML [75]. ORR was observed in 38% and CR 18%. The median duration of response was 10.2 months for all responders and 6.5 months for the R/R AML responding patients. The majority of adverse events observed in these two studies were Grade 1/2, including diarrhea, fatigue, nausea, fever, and IDH inhibitor-associated differentiation syndrome.

Enasidenib is an IDH2 inhibitor. In a multicenter phase I/II study of 239 patients [76], ORR of 40.3% was observed among the 176 patients evaluable for efficacy when it was given as monotherapy, with a median duration of response of 5.8 months. The median OS among the relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained CR was 19.7 months. Grade 3/4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH inhibitor-associated differentiation syndrome (7%), which is characterized by fever, edema, hypotension, malaise, and pleural and/or pericardial effusions, in addition to marked neutrophil-predominant leukocytosis.

Ongoing clinical trials utilizing epigenetic modifiers in AML

Based on the availability of an increasing number of epigenetic modifiers and the encouraging early clinical results obtained using these small molecules, there are currently many clinical trials ongoing internationally to determine the precise role of these inhibitors in the management of AML. A selection of these clinical trials is summarized in Table 2.

Table 2 A selection of active studies evaluating epigenetic modifiers in AML
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Targeting BCL-2 and JAK/STAT pathway

BCL-2 is an anti-apoptotic protein that has been demonstrated to induce chemoresistance, and overexpression has been implicated in AML [77] (Fig. 3). Venetoclax is an oral BCL-2 inhibitor currently being investigated for AML. It appears to be particularly effective in patients with IDH1/2 mutations [3]. When used as monotherapy in a phase II study of patients with relapsed/refractory AML [78], 19% overall response rate was observed, with another 19% showing antileukemic activity not meeting the IWG criteria for response. Three of the twelve patients with IDH1/2 mutations achieved CR or CRi. Common adverse events included nausea, diarrhea and vomiting, and febrile neutropenia and hypokalemia (Grade 3/4). Hox expression also predicts response to venetoclax [79].

Fig. 3
figure 3

BCL-2 and JAK/STAT pathways showing how BCL-2 inhibitors affect leukemia cell apoptosis and JAK/STAT inhibitors affect the proliferation of leukemia cells

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In two phase I studies of venetoclax combined with low dose chemotherapy for chemotherapy-naïve AML patients aged 65 years or older, high response rates were obtained. In the study that combined venetoclax with either azacytidine or decitabine [80], responses were obtained in 26 (76%) of the 34 evaluable patients, with 13 CR and 11 CRi. Eleven patients had IDH1/2 mutations, of whom nine (82%) responded. In a trial that combined venetoclax with low dose cytarabine [81], a 44% ORR was observed in the 18 patients treated, with four patients attaining CR and another four CRi.

Targeting the JAK/STAT pathway is another molecular therapeutic option since JAK mutation has been implicated in some patients with AML [82]. In a phase I/II study of pacritinib, a JAK/STAT inhibitor, in patients with advanced myeloid malignancies [83], three of the seven patients treated for AML were reported to show clinical benefits. Pacritinib was well tolerated and the most frequent adverse reactions were diarrhea, nausea, vomiting, and fatigue, most were Grade 1/2, with Grade 3 side effects reported in 22.6%, four of whom had diarrhea. Being an inhibitor of the JAK/STAT pathway, pacritinib may also be effective in AML with FLT3 mutations. Further investigations are, therefore, merited.

Ongoing clinical trials targeting BCL-2 and JAK/STAT pathway in AML

There are currently many clinical trials ongoing internationally to determine the precise role of these inhibitors in the management of AML. A selection of these clinical trials is summarized in Table 3.

Table 3 A selection of active studies evaluating BCL-2 and JAK/STAT inhibitors in AML
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Conclusions

The lack of improvement in the outcome of AML with standard chemotherapeutic agents suggests the need to explore other therapeutic approaches. Molecular targeting holds great promise. The molecular mechanisms most intensely targeted are the FLT3 signaling pathway, epigenetics, and the BCL-2 and JAK/STAT pathways. The inhibitors discussed in this review have all shown significant activity against AML. However, there remain many questions to be answered before these agents can provide the next leap in the prognosis of AML patients. These questions include what the exact role these compounds should be in clinical practice, whether they should be used in combination with chemotherapy, the timing of the targeted therapy, and the role of maintenance therapy following either consolidation therapy or allogeneic SCT. Furthermore, the multiple co-active intracellular pathways and the genomic instability in AML provide the opportunity for the AML cells to develop additional mutations, rendering them resistant to the inhibitors. The heterogeneity of the disease among AML patients is also another potential obstacle. With advances in the understanding of the molecular events associated with AML and the inclusion of genome-wide sequencing in the routine investigations in AML patients, it is likely that personalized medicine will herald a new era in AML therapy. This is especially so with the increasing number of compound being made available. Not only will these compounds be routinely combined with conventional chemotherapy during induction or consolidation therapy, sequential application of different molecular inhibitors may also be used in individual AML patients, according to changes in the genomic landscape of the leukemia cells. AML therapy will no longer be “one size fits all”.

Abbreviations

AML:

acute myeloid leukemia

FLT3:

FMS-like tyrosine kinase 3

DNMT:

DNA methyltransferase

TET:

ten-eleven-translocation

IDH:

isocitrate dehydrogenase

HDAC:

histone deacetylase

BET:

bromodomain and extra terminal

DOT1L:

disruptor of telomeric silencing 1-like

BCL-2:

B cell lymphoma-2

PML-RARα:

promyelocytic leukemia-retinoic acid receptor alpha

APL:

acute promyelocytic leukemia

JAK:

Janus kinase

ITD:

internal tandem duplication

TKD:

tyrosine kinase domain

CR:

complete remission

ROS:

reactive oxygen species

VEGFR:

vascular endothelial growth factor receptor

PDGFR:

platelet-derived growth factor receptor

SCT:

stem cell transplant

ORR:

overall response rate

EFS:

event-free survival

PFS:

progression-free survival

FDA:

Food and Drug Administration

OS:

overall survival

DFS:

disease-free survival

KAT:

histone lysine acetyltransferase

KMT:

lysine methyltransferase

KDM:

lysine demethylase

MLL:

mixed-lineage leukemia

LSD1:

lysine-specific histone demethylase

MDS:

myelodysplastic syndrome

CRi:

complete remission with incomplete blood count recovery

References

  1. Hann IM, Stevens RF, Goldstone AH, Rees JKH, Wheatley K, Gray RG, et al. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia. Results of the Medical Research Council’s 10th AML Trial (MRC AML10). Blood. 1997;89:2311–8.

    CAS  PubMed  Google Scholar 

  2. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65.

    CAS  PubMed  Google Scholar 

  3. Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21:178–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Takahashi S. Inhibition of the MEK/MAPK signal transduction pathway strongly impairs the growth of Flt3-ITD cells. Am J Hematol. 2006;81:154–5.

    PubMed  Google Scholar 

  5. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H, et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene. 2000;19:624–31.

    CAS  PubMed  Google Scholar 

  6. Fu L, Fu H, Wu Q, Pang Y, Xu K, Zhou L, et al. High expression of ETS2 predicts poor prognosis in acute myeloid leukemia and may guide treatment decisions. J Transl Med. 2017;15:159.

    PubMed  PubMed Central  Google Scholar 

  7. Levis M, Small D. FLT3: ITDoes matter in leukemia. Leukemia. 2003;17:1738–52.

    CAS  PubMed  Google Scholar 

  8. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002;100:1605–9.

    Google Scholar 

  9. Yamamoto Y, Kiyoi H, Nakano Y, Suzuki R, Kodera Y, Miyawaki S, et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood. 2001;97:2434–9.

    CAS  PubMed  Google Scholar 

  10. Zheng R, Levis M, Piloto O, Brown P, Baldwin BR, Gorin NC, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004;103:267–74.

    CAS  PubMed  Google Scholar 

  11. Ozeki K, Kiyoi H, Hirose Y, Iwai M, Ninomiya M, Kodera Y, et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood. 2004;103:1901–8.

    CAS  PubMed  Google Scholar 

  12. Choudhary C, Schwable J, Brandts C, Tickenbrock L, Sargin B, Kindler T, et al. AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood. 2005;106:265–73.

    CAS  PubMed  Google Scholar 

  13. Mizuki M, Schwable J, Steur C, Choudhary C, Agrawal S, Sargin B, et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood. 2003;101:3164–73.

    CAS  PubMed  Google Scholar 

  14. Grundler R, Miething C, Thiede C, Peschel C, Duyster J. FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood. 2005;105:4792–9.

    CAS  PubMed  Google Scholar 

  15. Kim KT, Baird K, Ahn JY, Meltzer P, Lilly M, Levis M, et al. Pim-1 is upregulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. Blood. 2005;105:1759–67.

    CAS  PubMed  Google Scholar 

  16. Sallmyr A, Fan J, Datta K, Kim KT, Grosu D, Shapiro P, et al. Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML. Blood. 2008;111:3173–82.

    CAS  PubMed  Google Scholar 

  17. Zhang W, Konopleva M, Shi YX, McQueen T, Harris D, Ling X, et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J Natl Cancer Inst. 2008;100:184–98.

    CAS  PubMed  Google Scholar 

  18. Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, et al. Compassionate use of sorafenib in FLT3-ITD—positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood. 2009;113:6567–71.

    CAS  PubMed  Google Scholar 

  19. Chen Y-B, Shuli L, Andrew LA, Connolly C, Del Rio C, Valles B, et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for patients with FLT3-ITD AML. Blood. 2014;124:671.

    Google Scholar 

  20. Battipaglia G, Ruggeri A, Massoud R, El Cheikh J, Jestin M, Antar A, et al. Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3-mutated acute myeloid leukemia. Cancer. 2017. doi:10.1002/cncr.30680.

    Article  PubMed  Google Scholar 

  21. Ravandi F, Alattar ML, Grunwald MR, Rudek MA, Rajkhowa T, Richie MA, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121:4655–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ravandi F, Cortes JE, Jones D, Faderl S, Garcia-Manero G, Konopleva MY, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol. 2010;28:1856–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Röllig C, Serve H, Hüttmann A, Noppeney R, Müller-Tidow C, Krug U, Baldus CD, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16:1691–9.

    PubMed  Google Scholar 

  24. Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31:3110–8.

    CAS  PubMed  Google Scholar 

  25. MacDonald DA, Assouline AS, Brandwein J, Kamel-Reid S, Eisenhauer EA, Couban S, et al. A phase I/II study of sorafenib in combination with low dose cytarabine in elderly patients with acute myeloid leukemia or high-risk myelodysplastic syndrome from the National Cancer Institute of Canada Clinical Trials Group: trial IND.186. Leuk Lymphoma. 2013;54:760–6.

    CAS  PubMed  Google Scholar 

  26. Strati P, Kantarjian H, Ravandi F, Nazha A, Borthakur G, Daver N, et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol. 2015;90:276–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Fischer T, Stone RM, Deangelo DJ, Galinsky I, Estey E, Lanza C, et al. Phase IIB trial of oral midostaurin, the FMS-like tyrosine kinase receptor and multi-targeted inhibitor in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wildtype or mutated FLT3. J Clin Oncol. 2010;28:4339–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Stone RM, Fischer T, Paquette R, Schiller G, Schiffer CA, Ehninger G, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26:2061–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Stone RM, Mandreka SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017. doi:10.1056/NEJMoa1614359.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Cortes JE, Kantarjian H, Foran JM, Ghirdaladze D, Zodelava M, Borthakur G, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31:3681–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Levis MJ, Perl A, Dombret H, Döhner M, Steffen B, Rousselot P, et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. Blood. 2012;120:673.

    Google Scholar 

  32. Cortes JE, Perl A, Dombret H, Kayser S, Steffen B, Rousselot P, et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. Blood. 2012;120:48.

    Google Scholar 

  33. Alvarado Y, Kantarjian HM, Luthra R, Ravandi F, Borthakur G, Garcia-Manero G, et al. Treatment with FLT3 inhibitor in patients with FLT3-mutated acute myeloid leukemia is associated with development of secondary FLT3-tyrosine kinase domain mutations. Cancer. 2014;120:2142–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Abdelall WKH, Borthakur G, Garcia-Manero G, Patel KP, Jabbour EJ, Daver NG, et al. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial. Blood. 2016;128:1642.

    Google Scholar 

  35. Hills RK, Gammon G, Trone D, Burnett AK. Quizartinib significantly improves overall survival in FLT3-ITD positive AML patients relapsed after stem cell transplantation or after failure of salvage chemotherapy: a comparison with historical AML database (UK NCRI data). Blood. 2015;126:2557.

    Google Scholar 

  36. Perl AE, Altman JK, Cortes JE, Smith CC, Litzow M, Baer MR, et al. Final results of the Chrysalis trial: a first-in-human phase 1/2 dose-escalation, dose-expansion study of gilteritinib (ASP2215) in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Blood. 2016;128:1069.

    Google Scholar 

  37. Ueno Y, Mori M, Kamiyama Y, Kaneko N, Isshiki E, Takeuchi M. Gilteritinib (ASP2215), a novel FLT3/AXL inhibitor: preclinical evaluation in combination with azacitidine in acute myeloid leukemia. Blood. 2016;128:2830.

    Google Scholar 

  38. Smith CC, Lasater EA, Lin KC, Wang Q, McCreery MQ, Stewart WK, et al. Crenolanib is a selective type I pan-FLT3 inhibitor. Proc Natl Acad Sci. 2014;111:5319–24.

    CAS  PubMed  Google Scholar 

  39. Randhawa JK, Kantarjian H, Borthakur G, Thompson PA, Konopleva M, Daver N, et al. Results of a phase II study of crenolanib in relapsed/refractory acute myeloid leukemia patients (Pts) with activating FLT3 mutations. Blood. 2014;124:389.

    Google Scholar 

  40. Ohanian M, Kantarjian HM, Borthakur G, Kadia TM, Konopleva M, Garcia-Manero G, et al. Efficacy of a type I FLT3 inhibitor, crenolanib, with idarubicin and high-dose ara-C in multiply relapsed/refractory FLT3+ AML. Blood. 2016;128:2744.

    Google Scholar 

  41. Wang ES, Stone RM, Tallman MS, Walter RB, Eckardt JR, Collins R. Crenolanib, a type I FLT3 TKI, can be safely combined with cytarabine and anthracycline induction chemotherapy and results in high response rates in patients with newly diagnosed FLT3 mutant acute myeloid leukemia (AML). Blood. 2016;128:1071.

    Google Scholar 

  42. Abdel-Wahab O, Levine RL. Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood. 2013;121:3563–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

    Google Scholar 

  44. Umehara T, Nakamura Y, Jang MK, Nakano K, Tanaka A, Ozato K, et al. Structural basis for acetylated histone H4 recognition by the human BRD2 bromodomain. J Biol Chem. 2010;285:7610–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sorensen PH, Chen CS, Smith FO, Arthur DC, Domer PH, Bernstein ID, et al. Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. J Clin Investig. 1994;93:429–37.

    CAS  PubMed  Google Scholar 

  46. Kawagoe H, Humphries RK, Blair A, Sutherland HJ, Hogge DE. Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. Leukemia. 1999;13:687–98.

    CAS  PubMed  Google Scholar 

  47. Okada Y, Feng Q, Lin Y, Jiang Q, Li Y, Coffield VM, et al. hDOT1L links histone methylation to leukemogenesis. Cell. 2005;121:167–78.

    CAS  PubMed  Google Scholar 

  48. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363:2424–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, 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;17:225–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111:1060–6.

    CAS  PubMed  Google Scholar 

  51. Gojo I, Jiemjit A, Trepel JB, Sparreboom A, Figg WD, Rollins S, et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood. 2007;109:2781–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kirschbaum M, Gojo I, Goldberg SL, Bredeson C, Kujawski LA, Yang A, et al. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Br J Haematol. 2014;167:185–93.

    CAS  PubMed  Google Scholar 

  53. Prebet T, Sun Z, Figueroa ME, Ketterling R, Melnick A, Greenberg PL, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup Trial E1905. J Clin Oncol. 2014;32:1242–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Garcia-Manero G, Othus M, Pagel JM, Radich JP, Fang M, Rizzieri DA, 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.

    Google Scholar 

  55. Tan P, Wei A, Mithraprabhu S, Cummings N, Liu HB, Perugini M, et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J. 2014;4:e170.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ocio EM, Herrera P, Olave M-T, Castro N, Pérez-Simón JA, Brunet S, et al. Panobinostat as part of induction and maintenance for elderly patients with newly diagnosed acute myeloid leukemia: phase Ib/II panobidara study. Haematologica. 2015;100:1294–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Garcia-Manero G, Tamboro FP, Bekele NB, Yang H, Ravandi F, Jabbour E, et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012;30:2204–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Garcia Manero G, Atallah E, Khaled SK, Arellano M, Patnaik MM, Odenike O, 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.

    Google Scholar 

  59. Coudé MM, Braun T, Berrou J, Dupont M, Bertrand S, Masse A, et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015;6:17698–712.

    PubMed  PubMed Central  Google Scholar 

  60. Berthon C, Raffoux E, Thomas X, Vey N, Gomez-Roca C, Yee K, et al. Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol. 2016;3:e186–95.

    PubMed  Google Scholar 

  61. Rau RE, Rodriguez B, Luo M, Jeong M, Rosen A, Rogers JH, et al. DOT1L as a therapeutic target for the treatment of DNMT3A-mutant acute myeloid leukemia. Blood. 2016;128:971–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu W, Deng L, Song Y, Redell M. DOT1L inhibition sensitizes MLL-rearranged AML to chemotherapy. PLoS ONE. 2014;9:e98270.

    PubMed  PubMed Central  Google Scholar 

  63. Stein EM, Garcia-Manero G, Rizzieri DA, Tibes R, Berdeja JG, Jongen-Lavrencic M, 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.

    Google Scholar 

  64. Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SG, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2017. doi:10.1038/leu.2017.77.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ishikawa Y, Gamo K, Yabuki M, Takagi S, Toyoshima K, Nakayama K, et al. A novel LSD1 inhibitor T-3775440 disrupts GFI1B-containing complex leading to transdifferentiation and impaired growth of AML cells. Mol Cancer Ther. 2017;16:273–84.

    CAS  PubMed  Google Scholar 

  66. Sugino N, Kawahara M, Tatsumi G, Kanai A, Matsui H, Yamamoto R, et al. A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers. Leukemia. 2017. doi:10.1038/leu.2017.59.

    Article  PubMed  Google Scholar 

  67. Fiskus W, Sharma S, Shah B, Portier BP, Devaraj SG, Liu K, et al. Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells. Leukemia. 2017. doi:10.1038/leu.2017.77.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Pleyer L, Burgstaller S, Girschikofsky M, Linkesch W, Stauder R, Pfeilstocker M, et al. Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol. 2014;93:1825–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28:562–9.

    CAS  PubMed  Google Scholar 

  70. Issa JP, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–40.

    CAS  PubMed  Google Scholar 

  71. Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556–61.

    CAS  PubMed  Google Scholar 

  72. Issa JP, Roboz G, Rizzieri D, Jabbour E, Stock W, O’Connell C, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16:1099–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Paschka P, Schlenk RF, Gaidzik VI, Habdank M, Krönke J, Bullinger L, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28:3636–43.

    CAS  PubMed  Google Scholar 

  74. DiNardo CD, Schimmer AD, Yee KWL, Hochhaus A, Kraemer A, Carvajal RD, et al. A phase I study of IDH305 in patients with advanced malignancies Including relapsed/refractory AML and MDS that harbor IDH1R132 mutations. Blood. 2016;128:1073.

    Google Scholar 

  75. DiNardo CD, de Botton S, Pollyea DA, Stein EM, Fathi AT, Roboz GJ, et al. Molecular profiling and relationship with clinical response in patients with IDH1 mutation-positive hematologic malignancies receiving AG-120, a first-in-class potent inhibitor of mutant IDH1, in addition to data from the completed dose escalation portion of the phase 1 study. Blood. 2015;126:1306.

    Google Scholar 

  76. Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017. doi:10.1182/blood-2017-04-779405.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Porwit-MacDonald A, Ivory K, Wilkinson S, Wheatley K, Wong L, Janossy G. Bcl-2 protein expression in normal human bone marrow precursors and in acute myelogenous leukemia. Leukemia. 1995;9:1191–8.

    CAS  PubMed  Google Scholar 

  78. Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kontro M, Kumar A, Majumder MM, Eldfors S, Parsons A, Pemovska T, et al. HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia. Leukemia. 2017;31:301–9.

    CAS  PubMed  Google Scholar 

  80. Pollyea DA, Dinardo CD, Thirman MJ, Letai A, Wei AH, Jonas BA, et al. Results of a phase 1b study venetoclax with decitabine or azacytidine in untreated acute myeloid leukemia patients ≥65 years ineligible for standard induction therapy. J Clin Oncol. 2016;34:7009.

    Google Scholar 

  81. Lin TL, Strickland SA, Fiedler W, Walter RB, Hou J-Z, Roboz GJ, et al. Phase 1b/2 study of venetoclax with low-dose cytarabine in treatment-naïve patients age ≥65 with acute myelogenous leukemia. J Clin Oncol. 2016;34:7007.

    Google Scholar 

  82. Furqan M, Mukhi N, Lee B, Liu D. Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res. 2013;1:5.

    PubMed  PubMed Central  Google Scholar 

  83. Verstovsek S, Odenike O, Singer JW, Granston T, Al-Fayoumi S, Deeg HJ. Phase 1/2 study of pacritinib, a next generation JAK2/FLT3 inhibitor, in myelofibrosis or other myeloid malignancies. J Hematol Oncol. 2016;9:137.

    PubMed  PubMed Central  Google Scholar 

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SHL, PMD, and VMR were responsible for conceiving the ideas, carrying out the research, and writing the manuscript. All authors read and approved the final manuscript.

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  1. Division of Hematology and Oncology, Brown University Warren Alpert Medical School, Rhode Island Hospital, 593 Eddy Street, Providence, RI, 02903, USA

    Seah H. Lim, Patrycja M. Dubielecka & Vikram M. Raghunathan

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Lim, S.H., Dubielecka, P.M. & Raghunathan, V.M. Molecular targeting in acute myeloid leukemia. J Transl Med 15, 183 (2017). https://doi.org/10.1186/s12967-017-1281-x

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Keywords

  • Acute Myeloid Leukemia (AML)
  • FLT3 Mutations
  • FLT3 Inhibitor
  • Fms-like Tyrosine Kinase 3 (FLT3)
  • Disruptor Of Telomeric Silencing 1-like (DOT1L)

Journal of Translational Medicine

ISSN: 1479-5876

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