Yang and Wang Journal of Hematology & Oncology (2018) 11:3

DOI 10.1186/s13045-017-0543-7

REVIEW Open Access

Precision therapy for acute myeloid

leukemia
Xue Yang and Jianxiang Wang*

Abstract
Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Despite advances in understanding
the pathogenesis of AML, the standard therapy remained nearly unchanged over the past three decades. With the poor
survival for older patients and high relapse rate, multiple studies are ongoing to address this important issue.
Novel therapies for AML, including the refinements of conventional cytotoxic chemotherapies and genetic and
epigenetic targeted drugs, as well as immunotherapies, have been developed in recent years. Here, we present a
mechanism-based review of some promising new drugs with clinical efficacy, focus on targeted drugs that are
most potential to pave the road to success, and put forward the major challenges in promoting the precision
therapy for AML.
Keywords: Acute myeloid leukemia, Precision therapy, Conventional chemotherapies, Molecular targeted inhibitors,
Epigenetic mutations, Immunotherapy

Background (> 60 years), the best chemotherapy remains to be identi-

Acute myeloid leukemia (AML) represents a heteroge- fied. Most of them recommended the same remission
neous malignancy characterized by a clonal proliferation induction regimen except those with unfavorable risk or
and impaired differentiation of myeloid precursors with di- severe commodity who are too fragile to tolerate inten-
verse outcomes. Despite the advances in understanding the sive chemotherapy. When it comes to post-remission
molecular heterogeneity and pathogenesis of AML, there treatment including consolidation and maintenance
has been little progress in the standard therapy for AML therapy, risk stratification should be taken into consider-
over the past four decades. The classic treatment ranges ation. AML patients are categorized based on cytogen-
from cytarabine-based chemotherapy to hematopoietic etic, molecular, and clinical characteristics that are
stem cell transplantation (HSCT), with a 5-year overall prognostic important. For younger patients, high-dose
survival (OS) of 40% for patients younger than 60 years. cytarabine are recommended in patients with favorable
For those older than 60 years, who made up of the majority cytogenesis. While for those with adverse prognosis,
of AML cases, the 5-year OS was only 10~20% [1, 2]. Few allogeneic HSCT (allo-HSCT) should be performed in
of patients who relapsed after complete remission (CR) the first remission. For elder patients who fit for chemo-
could survive for more than 5 years [3]. therapy in the first complete remission (CR), consolida-
Briefly, the treatment of AML consists mainly of tion therapy could contain anthracycline and cytarabine
remission induction and post-remission therapy which or intermediate-dose cytarabine alone. Likewise, those
contains chemotherapy, targeted therapies, and HSCT. with unfavorable risk should be considered for nonmye-
In terms of induction therapy, for adult patients with loablative HCT. Of note, for relapsed or refractory (R/R)
newly diagnosed AML, a combination of anthracycline AML population, allo-HSCT provides the highest likeli-
for 3 days and standard-dose cytarabine for 7 to 10 days hood of cure.
(“7 + 3” therapy) are recommended. For elder patients Among all AML subtypes, acute promyelocytic
leukemia (APL) contributes the highest proportion of cure
rate for patients undergoing targeted therapy such as all-
* Correspondence: [email protected]
State Key Laboratory of Experimental Hematology, Institute of Hematology transretinoic acid (ATRA) and arsenic trioxide, which
and Blood Diseases Hospital, Chinese Academy of Medical Sciences and implies a strong need for individualized medicine. With
Peking Union Medical College, Tianjin, China

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Yang and Wang Journal of Hematology & Oncology (2018) 11:3 Page 2 of 11

the advent in next-generation sequencing technologies, to leukemia initiating cells occurs at different stages
novel therapies have emerged, including multiple molecu- within primitive multipotent cells [7, 8]. Consequently,
lar target inhibitors and immunotherapies [Table 1]. the heterogeneity of AML brings about varied response
to treatment, as well as drug resistance and disease
Heterogeneity of AML relapse, posing a challenge to personalized therapeutic
Tumor heterogeneity refers to distinct morphological regimens, likewise, known as precision medicine.
and phenotypic features in tumors mainly arising from
gene alterations, which has been observed in all types of Refinements of conventional cytotoxic
tumors including leukemia. The heterogeneity of AML chemotherapies
involves both genomic and epigenomic changes, includ- Conventional intensive chemotherapy has a cure rate of
ing distinct sets of cytogenetic abnormalities and som- only 30–50%, and the majority of patients aged 70 years
atic mutations [4], resulting in a range of morphological, or older could not benefit from it due to poor tolerance
immunophenotypic, cytogenetic, biomolecular, and clin- and high mortality [9]. Despite 40–80% patients achieving
ical features [5]. Moreover, in the course of the disease, CR, the median survival in elderly patients receiving in-
the leukemic clone may change from diagnosis to tensive chemotherapy is 4.6 months with a 1-year survival
relapse due to the heterogeneity of leukemia cells [6], rate of only 28% [10]. Besides, a high frequency of subse-
and transformation of hematopoietic stem cells (HSCs) quent relapse remains the major obstacle to overcome. In
the past decades, studies have driven the improvements in
Table 1 Examples of targeted drugs for AML OS by novel formulations and refinements of conventional
Target Drug Phase of development chemotherapy.
PLKs Volasertib 3
FLT3 Sorafenib 2 Intensification of the standard induction therapy
Midostaurin (PKC412) 3 The 7 + 3 regimen, consisting of 7 days continuous infu-
Quizartinib (AC220) 3
sion of cytarabine along with a short infusion or bolus of
an anthracycline given on days 1 through 3, has been
Crenolanib (CP868596) 2
known as standard induction therapy in AML in the
Gilteritinib (ASP2215) 3 past decades. Recently, the escalation of daunorubicin or
Lestaurtinib (CEP-701) 3 cytarabine dose have shown benefit in the induction
DNMTs Azacitidine (5-Aza) Approved therapy. In adults under 60 years of age, previous trials
Decitabine Approved have suggested that a daunorubicin dose of 90 mg is su-
Guadecitabine (SGI-110) 3
perior to 45 mg, with the former showing an improved
remission rate and survival benefit [11]. In older patients
Sapacitabine (CYC682) 3
(> 60 years), a Korea trial showed a significant benefit of
IDH2 AG-221 3 90 mg/m2 both in remission rate and OS [12], which
IDH1 AG-120 2 was particularly prominent in intermediate-risk patients
HDACs Vorinostat 3 in the ECOG1900 trial. In a randomized AML17 trail
Entinostat 2 comparing 90 mg/m2 with 60 mg/m2, no significant dif-
BET OTX015 1
ference was seen in remission rate or OS in any cytogen-
etic subgroup, with the 60-day mortality rate
DOT1L Pinometostat (EPZ-2676) 1
significantly higher in the high-dose (HD) daunorubicin
LSD1 GSK2879552 1 group (90 mg/m2) (10 vs 5%, P = 0.001). However, it still
CD33 GO 3 remains necessary to take notice of molecular subgroups
SGN-33A 3 when it comes to longer follow-up, since in a recent
CD33 CART Preclinical E1900 trial with a median follow-up of 80 months,
CD123 CSL362 Preclinical
patients with Fms-like tyrosine kinase 3 (FLT3), nucleo-
phosmin (NPM1), and DNA methyltransferase
SL-401 Preclinical
(DNMT)3A all benefited from HD daunorubicin [13].
CD123 CART Preclinical In addition to daunorubicin, the administration of
PD-1 Nivolumab 2 cytarabine at a daily dose of 100 to 200 mg/m2 for 7 to
CTLA4 Ipilimumab 2 10 days is also an important part in the standard induc-
PLKs polo-like kinases, FLT3 Fms-like tyrosine kinase 3, DNMTs DNA methyl- tion therapy. In the EORTC-GIMEMA AML-12 trial
transferases, IDH isocitrate dehydrogenase, HDACs histone deacetylases, BET with a median follow-up of 6 years in patients aged 15
bromodomain and extra-terminal motif, DOT1L disruptor of telomeric silencing
1-like, LSD1 lysine-specific histone demethylase 1A, PD-1 programmed cell
to 60 years, higher remission and survival rate were
death protein 1, CTLA4 cytotoxic T-lymphocyte-associated protein 4 observed in high-dose cytarabine (3000 mg/m2 per 12 h
Yang and Wang Journal of Hematology & Oncology (2018) 11:3 Page 3 of 11

on days 1, 3, 5, and 7) without significant toxicity. Par- randomized phase III trial with 711 patients named
ticularly, for patients under 46 years old, the CR rate, VALOR demonstrated that the addition of vosaroxin to
event-free survival (EFS), and OS in high-dose cytara- cytarabine resulted in a significant improvement in CR
bine arm were significantly higher than standard dose (30.1 vs 16.3%, P < 0.0001) and OS (6.7 vs 5.3 months, P
cytarabine arm (100 mg/m2 per day continuously for = 0.024) when censored for HSCT in R/R AML patients
10 days) [14]. ≥ 60 years [25]. With favorable efficacy and tolerability
An alternative method to intensify standard induction among older patients as well as notable survival benefits
regimen is the addition of a purine analog such as flu- in subsets, vosaroxin stands a nice choice for novel com-
darabine or cladribine. One study demonstrated that the binatorial regimens, which will be further confirmed by
DAC regimen (DA plus cladribine), rather than DAF future trials.
regimen (DA plus fludarabine), is associated with im-
proved OS and CR in patients younger than 60 years Molecular targeted inhibitors
with newly diagnosed AML. It is worth mentioning that Volasertib
both DAF and DAC increased CR rate in AML patients Volasertib (also known as BI 6727), which was awarded or-
with adverse karyotype. Thus, further trials focusing on phan drug status for AML in 2014, is a small-molecular in-
particular subgroups are needed [15]. Clofarabine is a hibitor of polo-like kinases (PLKs), particularly PLK-1
second-generation purine analog, which has shown (which was listed on Table 1). Inhibition of PLK1 overex-
effectiveness in both R/R AML patients and newly diag- pression in AML cell lines can bring about disorganized
nosed older patients [16, 17]. A phase III study in newly centrosome maturation, spindle assembly and cytokinesis
diagnosed AML patients aged 18 to 65 years old con- during mitosis [20], and then cellular apoptosis subse-
firmed the potent efficacy of clofarabine integrated in quently. A phase II study made a comparison between the
standard induction treatment, which showed reduced re- combination of volasertib with low-dose cytarabine (LDAC)
lapse probability without survival improvement. The and LDAC alone. The result confirmed greater clinical effi-
study only found the survival benefit of clofarabine in cacy in the combination arm, statistically significant in CR
subgroups of intermediate-risk AML and AML genotype (30 vs 13.3%, P = 0.052), median EFS (5.6 vs 2.3 months, P
without NPM1 and FLT3-ITD mutations [18]. = 0.021), and median OS (8 vs 5.2 months, P = 0.047) [26].
Meanwhile, there is also an ongoing phase III trial
CPX-351 (NCT01721876) and a phase II trial of intensive chemo-
CPX-351 is designed as a liposomal formulation of 7 + 3 therapy with or without volasertib (NCT02198482).
combination in a 5:1 ratio of cytarabine and daunorubi-
cin, which was proved to be an optimal combination, FLT3 inhibitors
with the highest level of synergy and the lowest level of FLT3 is a class III tyrosine kinase receptor that stimu-
antagonism [19, 20]. Two phase II randomized studies lates normal hematopoiesis and cell proliferation in
in 127 and 125 patients both confirmed a higher rate of primitive hematopoietic stem and progenitor cells [27].
CR (66.7 vs 51.2%, and 49.3 vs 40.9%, respectively) for Although activating mutations in FLT3 are reported in
patients treated with CPX-315 compared with those re- only 30% of AML adults [28], FLT3 is constitutively
ceiving 7 + 3 regimen, and no difference in EFS or OS expressed by autocrine signaling on leukemic cells in
has been found in both phase II trials [21, 22]. However, 70–100% of AML patients [29]. There are two types of
it is worth mentioning that a phase III study, in which FLT3 mutations, including approximately 20% of
the studying group was not strictly limited, demon- internal tandem duplications (FLT3/ITD) and 5~10% of
strated an increased OS with daunorubicin in AML point mutations in activating loop of tyrosine kinase
patients between the age of 60 and 65 years [23]. An- domain (FLT3/TKD), constitutively activating cell prolif-
other phase III study to confirm the efficacy of CPX-351 eration and survival of leukemia blasts. Both mutations
as first-line therapy in elderly patients (60–75 years) with are associated with poor prognosis and outcome, par-
high-risk (secondary) AML is ongoing (NCT01696084), ticularly FLT3/ITD, with an estimation of 2-year disease-
which may make CPX-351 a better induction therapy for free survival (DFS) rates of 20% and 4-year OS of 20%
elderly patients who are not suitable for chemotherapy. [30]. Of note, ITD mutations are associated with a poor
prognosis due to a high relapse rate, and higher allelic
Vosaroxin ratios of mutated/wild-type variants confer a worse
Vosaroxin is a quinolone derivative that intercalates prognosis [31], suggesting a greater clinical response to
DNA and inhibits topoisomerase II without producing selective FLT3-inhibitors [32]. Recent years have wit-
oxygen free radicals, which has been confirmed to have nessed a growing development of several FLT3 inhibitors
better efficacy and lower cardiac toxicity than traditional tested in clinical trials as either single agent or in com-
anthracyclines [24]. Most recently, a large multicenter bination with conventional chemotherapies, with the
Yang and Wang Journal of Hematology & Oncology (2018) 11:3 Page 4 of 11

former usually associated with modest anti-tumor activ- demonstrated a significant improvement in OS and EFS
ity, transient reduction of blasts, and increased toxicity among AML patients with FLT3 mutation, when adding
[33]. Though more tolerated than traditional cytotoxic midostaurin to standard induction therapy. In particular,
agents, drug resistance has still posed a major challenge the benefit of midostaurin was observed in patients
to patients treated with single FLT3 inhibitor, including undergoing transplantation during the first remission
F691, N676, and D835 mutation with kinase domain of [53]. Thus, the combination regimen could be consid-
FLT3-ITD [34]. ered as first-line treatment in younger AML patient,
while it is still uncertain whether the combination regi-
Sorafenib men might benefit older patients or those with wild-type
Sorafenib is a potent first-generation multikinase inhibi- FLT3. As is reported, combination with histone deacety-
tor with activity against FLT3/ITD receptor, which has lase (HDAC) inhibitors is also associated with a higher
been evaluated as either single agent [35–41] or in com- CR [54–56], and most recently, whether midostaurin
bination with chemotherapies [42–45]. SORAML is a improves RFS after transplant is under investigation
placebo-controlled randomized study of adding sorafenib (NCT01883362).
to daunorubicin and cytarabine (7 + 3) in 267 newly
diagnosed patients aged 18–60 years. The addition of so- Quizartinib (AC220)
rafenib resulted in a significantly prolonged 3-year EFS Quizartinib selectively inhibits FLT3/STK1, CSF1R/FMS,
(40 vs 22%, P = 0.013) and RFS (56 vs 38%, P = 0.017) SCFR/KIT, and PDGFRs. A phase I trial in R/R AML pa-
without improvement in OS and CR [46]. In contrast to tients determined the maximum tolerated dose (MTD)
this study, a second randomized study in 201 older pa- of 200 mg per day with the dose-limiting toxicity (DLT)
tients aged 61–80 years showed no improvement in EFS, of grade 3 QTc prolongation [57]. Subsequently, several
CR, and OS, with a higher early mortality (17 versus 7%, phase II trials studying with lower doses demonstrated
P = 0.052) compared with placebo [44]. It can be seen prominent composite CR (CRc) rate ranging from 44 to
from the difference of two studies that the combination 54% and ORR (CRc + PR) ranging from 61 to 72% in
of sorafenib with intensive chemotherapy may be too FLT3-ITD-positive patients [58–60]. Combination stud-
toxic for older patients, who have a poor prognosis ies are ongoing (NCT01892371). As mentioned, single
mainly due to more resistance and less tolerance. Thus, agent is proved to have limited efficacy due to drug
for older patients, combining multikinase inhibitors with resistance. Though active against FLT3-ITD mutation,
lower intensity therapies like hypomethylating agents most of tyrosine kinase inhibitors (TKIs) including qui-
(HMAs) may be an alternative choice [47]. Recent stud- zartinib had no activity against FLT3-TKD mutation
ies also suggest potential benefit of post-HSCT sorafenib [34], the effect of which on the outcome remains
in patients with FLT3-ITD [48]. unsettled.

Midostaurin (PKC412) Crenolanib (CP868596)

Midostaurin is a first-generation multi-target agent that To maximize tolerability and response duration, novel
inhibits FLT3, c-kit, platelet-derived growth factor recep- FLT3 inhibitors like crenolanib, which is potent, select-
tor (PDGFR), vascular endothelial growth factor receptor ive, and invulnerable to resistance-conferring kinase do-
(VEGFR), and protein kinase C [3]. As a well-tolerated main mutation, are developed [61]. In addition to FLT3-
and orally bioavailable agent, it enhances the response to ITD mutation in nearly one third of AML patients [62],
induction chemotherapy and represents the potential to nowadays with the progress of more powerful FLT3
bridge mutant and wild-type (WT)-FLT3 AML patients inhibitors being tested in many clinical trials, resistance-
to transplantation [49]. In two phase IIB studies of conferring point mutations like D835 and F691 have
single-agent midostaurin administered in FLT3-mutated emerged during disease progression [63]. Crenolanib is a
and FLT3-WT AML patients, there is a blast decrease ≥ selective pan inhibitor active against both FLT3-ITD and
50% in the majority of R/R or vulnerable/frail patients, FLT3-TKD D835 mutations, whereas most agents only
especially those with FLT3 mutation, but CRs are rare have limited activity against the former. Crenolanib is a
and transient [50, 51]. When it comes to combination, a benzamidine quinolone derivative and currently a repre-
phase IB trail adding midostaurin of two doses during sentative of the potent next-generation FLT3 TKIs.
(concomitant) or after (sequential) standard induction
therapy confirmed a higher CR and lower toxicity in the Gilteritinib (ASP2215)
lower-dose group (50 mg daily), as well as a higher CR As potent as crenolanib, gilteritinib is also a selective
rate in FLT3-mutated patients (92 vs 74%) [52]. In the next-generation FLT3 inhibitor with activity against both
meantime, there was a multicenter, randomized phase FLT3-ITD and FLT3-TKD mutations. A preclinical study
III trial (RATIFY) in 717 younger adult patients, which compared gilteritinib with four other FLT3 inhibitors
Yang and Wang Journal of Hematology & Oncology (2018) 11:3 Page 5 of 11

using immunoblotting and drew a conclusion that its in DNMT inhibitors

vitro efficacy is equal to or greater than the other TKIs DNA methylation is catalyzed by DNMTs. Recurrent
(midostaurin, sorafenib, quizartinib, and crenolanib) and mutations in DNMT3A are found in 6 to 36% of AML
may be the most useful FLT3 inhibitor to date [64]. patients, which is hypothesized to act as dominant nega-
Worth mentioning, due to less activity against c-kit than tives in leukemogenesis [74]. HMAs inhibiting DNMTs
quizartinib, gilteritinib has little myelosuppression. are options for older patients who cannot tolerate inten-
sive chemotherapy with lower toxicities and equal effi-
cacy. As known, azacitidine (5-Aza) and decitabine are
Lestaurtinib two HMAs currently approved for clinical use, both
Lestaurtinib (CEP-701) is an orally bioavailable first- of which have shown clinical benefit in clinical trials
generation FLT3 inhibitor, as well as a potent inhibitor [75–78]. A phase II study of older patients who were
of JAK2 [65, 66]. Recently, a randomized assessment unfit for intensive chemotherapy treated with 10-day
from UK AML 15 and AML 17 trials confirmed no sta- schedule of decitabine yielded a CR rate of 47%, with-
tistically significant benefit observed in the combination out certain benefit observed in the combination of
of lestaurtinib with standard chemotherapy for newly di- decitabine with HDAC valproic acid. Interestingly,
agnosed AML patients mostly younger than 60 years. patients harboring monosomy 7 or del(7q) had a
higher response rate of 91% [79]. This study also pro-
posed that higher pretreatment levels of miR-29b
NPM1 mutation were associated with response (P = 0.02) to decitabine,
NPM1 mutations represent the most frequent genetic al- allowing it to be a predictive marker and stratification
teration in AML, which are found in approximately 25% tool in selection of older AML patients for this regi-
of patients with de novo AML. It is associated with im- men. Further multicenter studied should be per-
proved outcomes, and the mechanisms have not been formed. Another single-institution trail suggested
clearly elucidated. NPM1 is a promising therapeutic patients with unfavorable risk or TP53 mutations had
target for AML, since NPM1 mutations represent significantly higher response rates to 10-day decita-
founder genetic lesions in leukemogenesis. Some recent bine therapy despite their poor prognosis after cyto-
studies have shown conflicting results on the association toxic chemotherapy [80]. In addition to this, the OS
between NPM1 mutation and the response to ATRA or rate was similar among patients with unfavorable-risk
arsenic trioxide (ATO) adjunct to standard chemother- and intermediate-risk cytogenetic profiles. It is worth
apy [67–69]. Interestingly, it has also been suggested mentioning that patients with TP53 mutations may
that ATRA and arsenic trioxide combination can select- not always be sensitive to single-agent decitabine
ively induce apoptosis and differentiation in NPM1- treatment owing to the emergence of resistant sub-
mutated cells, as well as promote leukemia regression in clones and incomplete mutation clearance. Still, deci-
elderly patients unfit for induction chemotherapy [70, tabine should be considered as an important agent in
71]. Furthermore, since NPM1-mutated leukemia cells the treatment of AML patients with TP53 mutations
are associated with increased CD33 expression [72], unfit for cytotoxic chemotherapy. To date, there are
CD33 antibodies like gemtuzumab ozogamicin (GO) no therapies specifically targeting against DNMT3A.
could be a targeted therapy for those NPM1-mutated Guadecitabine (SGI-110), as a second-generation
patients with high CD33 expression. Finally, recent evi- HMA, is a dinucleotide of decitabine and deoxyguano-
dence has emerged that drugs such as dactinomycin, sine resistant to cytidine deaminase and can prolong the
triggering a nucleolar stress response, may target exposure to decitabine in vivo. A phase I study assessed
NPM1-mutated AML [73]. three treatment schedules of guadecitabine: daily sched-
ule for 5 days continuously, weekly, and twice-weekly
schedule. It was identified that the maximum demethyla-
Epigenetic mutations and alterations tion was achieved with a dose of 60 mg/m2 per day for
Lately, epigenetic alterations that are heritable and re- 5 days consecutively [81]. Likewise, a multicenter ran-
versible in contrast to genetic changes represent a focus domized phase I/II study accessing the safety and activ-
of interest with respect to therapeutic targets in AML. ity of two doses and schedules of guadecitabine in older
With a rapid advance in all kinds of sequencing, recur- AML patients also recommended the 60 mg/m2 guade-
rent mutated genes involved in epigenetic regulation citabine in a 5-day regimen. A phase II study randomiz-
have been identified, including TET2, IDH1, IDH2, ing among 5-day regimen, 10-day regimen, and a
DNMT3A, and EZH2. Abnormal DNA methylation and combination of the 5-day schedule with idarubicin or
histone modification are two main modes of epigenetic cladribine is ongoing (NCT02096055), as well as a phase
dysregulation. III study in progress to compare this 5-day schedule of
Yang and Wang Journal of Hematology & Oncology (2018) 11:3 Page 6 of 11

guadecitabine with standard care. Also, another phase comparison was drawn between the effects of preventing
III randomized study of guadecitabine versus treatment DNA hypermethylation induced by genetic loss of TET2
choice in R/R AML has been initiated (NCT02920008). and restoring TET2 activity by inhibiting mutant IDH2
Anyway, therapeutic efficacy of guadecitabine will ultim- in AML [87]. Both AG-221 and 5-Aza induced differen-
ately rely on a demonstrable improvement in OS; only tiation of leukemic cells, but neither significantly killed
then SGI-110 can be expected to become an alternative mutant cells. Therefore, targeting epigenetic dysregula-
choice for patients ineligible for traditional induction tion could be an effective therapeutic strategy in AML,
chemotherapy due to old age, comorbidities, etc. [82]. while dual-pronged therapies such as combining epigen-
Sapacitabine (CYC682) is a novel oral nucleoside ana- etic inhibitors with kinase-targeted therapies may be a
log. It is metabolized into the active metabolite CNDAC better choice [88]. Nowadays, both AG-120 and AG-221
and incorporated into cellular DNA to exert anticancer are being investigated in newly diagnosed AML patients
activity by interfering with DNA synthesis and inducing with IDH mutations, in combination with induction and
cell cycle arrest. In a phase II trial, sapacitabine was ad- consolidation chemotherapy (NCT02632708) and azaci-
ministered to 60 AML patients aged 70 years or older tidine (NCT02677922).
from 12 centers in the USA, studying three dose sched-
ules of sapacitabine: (A) 200 mg bid for 7 days, (B) HDAC inhibitors
300 mg bid for 7 days, and (C) 400 mg bid on days 1–3 Histone modifications include acetylation and methylation
for 2 weeks. One-year OS was 35, 10, and 30% in three which are reversibly mediated by histone acetyltransfer-
groups, respectively. The 30-day mortality was 13% and ases, HDACs, HMTs, and histone demethylases, respect-
the 60-day mortality doubled [83]. In addition, SEAM- ively. Histone acetylation increases the accessibility of
LESS, a multicenter, randomized, phase III study of com- transcription factors to gene regions and consequently
paring sapacitabine alternating with decitabine to single promotes gene expression. Conversely, deacetylation leads
agent decitabine in approximately 485 elderly patients to transcriptional repression and impaired hematopoietic
aged 70 years or older, is ongoing (NCT01303796). differentiation, which can be inhibited by HDAC inhibi-
tors (HDACIs). When used as a single agent in MDS and
IDH inhibitors AML, HDACIs seem to be modest [89]. Considering the
IDH is one kind of enzyme that catalyzes the oxidative de- disappointing results of combined clinical trials recently
carboxylation of isocitrate to alpha-ketoglutarate (α-KG), [55, 90–93], it remains a challenge to find an optimal
and the enzyme TET2 co-works with a-KG to convert 5- combination regimen of HDACIs with other agents. Other
methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmc), histone modifiers like BET inhibitors (OTX015), DOT1L
which promotes DNA demethylation. Mutant IDH inhibitors (EPZ-2676), and LSD1 inhibitors (GSK2879552)
(mIDH) enzymes convert α-KG to (R)-2-HG, which com- are being investigated as monotherapy in clinical trials
petitively inhibits a-KG-dependent enzymes including and still need further exploration.
TET2. Besides, inactivating mutation in TET2 can lead to
loss of function. Thus, both IDH and TET2 mutations can Immunotherapy for AML
result in accumulation of 5mc and DNA hypermethylation Cancer immunotherapy aims to stimulate the immune
and consequently promote AML. system to destroy tumors. Novel immunotherapies for
Though prognostic impact of IDH gene mutations AML mainly consist of monoclonal antibodies (mAbs),
remains controversial, inhibitors targeted mIDH have chimeric antigen receptor-engineered T cells (CAR T
been developed these days. Small-molecule mIDH inhib- cells), and checkpoint inhibitors.
itors include AG-221, AG-120, AG-881, and IDH305,
among which AG-221 and AG-120 have shown evidence Monoclonal antibodies
of efficacy and are being tested in clinical trials. The first Currently, the most encouraging therapeutic targets for
IDH2 inhibitor AG-221 is developed to inhibit mutant AML are CD33 and CD123, which are both expressed in
IDH2, reduce 2HG levels, and restore TET2 activity, leukemic cells and normal hematopoietic cells. Due to
thereby reversing 5mC accumulation in mouse mIDH off-tumor effects of aplasia and neutropenia, it is rela-
AML models [84]. In ASH 2015, a phase I dose escal- tively more difficult to find an ideal target for AML than
ation and expansion study of AG-221 demonstrated an ALL. It was wildly known that GO, the first anti-CD33
ORR of 41% and a true CR of 18% in patients with R/R mAb approved by the FDA in 2000, was withdrawn from
AML [85]. AG-120 monotherapy was associated with an market in 2010 due to early toxicity and little clinical
ORR of 35% in a similar study [86]. Additionally, methy- benefit. Nevertheless, recent studies have demonstrated
lation inhibitors like 5-Aza can inhibit the conversion of an improved survival in populations with favorable/
cytosine to 5mC in TET2-mutant AML in mice, thereby intermediate-risk cytogenetics [94–97]. Since older AML
preventing 5mC from accumulation. In a study, a patients are not suited to cytotoxic chemotherapy, best
Yang and Wang Journal of Hematology & Oncology (2018) 11:3 Page 7 of 11

supportive care (BSC) including hydroxyurea or low- expressed more frequently than CD33, and CD123
dose cytarabine is considered despite dismal outcomes CART mediated potent in vivo antileukemic effect as
[98]. A randomized phase III EORTC-GIMEMA AML- well as increased survival of the majority of animals
19 trial demonstrated a significant improved OS in older [110]. Furthermore, it is worth mentioning that the
AML patients with single-agent low-dose GO (6 mg/m2 persistence of CAR T cells is associated with both
on day 1 and 3 mg/m2 on day 8), compared with BSC anti-tumor efficacy and prolonged myeloablation,
group (4.9 vs 3.6 months, P = 0.005). Subgroup analysis which suggests that a following rescue HSCT strategy
confirmed the prediction that GO would be most effect- is imperative. Future investigations in CAR T therapy
ive in patients with high CD33 expression [99]. Phase IV warrant more focus on selection of specific AML-
clinical trials for patients with relapsed AML are now related surface targets.
ongoing (NCT02312037). Given the above, GO mono-
therapy could embody a new choice for elderly patients.
Besides, the combination of azacitidine and GO in phase Checkpoint inhibitors
II studies also revealed encouraging remission and sur- In normal situations, immune checkpoints act as protect-
vival rates in elderly patients [100, 101]. ive mechanism against autoimmunity, while tumor cells
At ASH 2015, another CD33 antibody known as SGN- take advantage of them to evade immune system response
33A, presented promising results in a phase I study in and mediate immune resistance [113]. Thus, checkpoint
combination with hypomethylating drugs in older inhibitors work via unleashing suppressed immune
patients [102]. These encouraging results have promoted responses [114]. Two key checkpoint receptors are pro-
the phase III CASCADE study (NCT019002329) which grammed cell death protein 1 (PD1) and cytotoxic T-
attempts to evaluate SGN-33A combined with 5-Aza or lymphocyte-associated antigen 4 (CTLA4), both of which
decitabine for older adults with newly diagnosed AML. have been used in preclinical AML models [115]. One
In comparison with GO, vadastuximab seems to have group treated three relapsed AML patients after allo-
effective therapeutic results in poor-risk group in on- HSCT with the PD-1 inhibitor nivolumab. Among these
going studies [103]. Other drugs like CSL362 and SL- three patients, one achieved an ongoing CR, one experi-
401 that target CD123 are now being investigated in enced stabilization, and the third failed to respond. It sug-
various studies and have shown some promising data gested that targeting PD-1 might be an effective salvage
[104, 105]. therapy for relapsed AML after allo-HSCT, though the
optimal dose of nivolumab to restore GvL effects without
CAR T therapy leading to severe GvHD still remains studying [116].
Closely linked with graft-versus-host disease (GvHD), Phase II trials using single nivolumab or in combination
graft-versus-leukemic (GvL) effect appears after HSCT, with CTLA4 antibodies after allo-HSCT and chemo-
via which the donor T cell plays an important role in therapies are ongoing (NCT02532231, NCT02846376,
killing leukemia cells. Elderly patients are not suitable NCT02464657).
candidates for HSCT due to high toxicity and relapse
rate [106], and the efficacy of HSCT could be enhanced
by infusion of CAR T cells [107]. CARs targeting CD19 Conclusion
have demonstrated remarkable potency in B cell malig- The fundamental goal of precision medicine is to inte-
nancies such as B-ALL. The success of CD19 CAR T lies grate population-based molecular, clinical, and other
in two factors: (1) massive expansion and persistence of data to make individual-based clinical decisions for pa-
infused CAR T cells with costimulators and (2) tolerabil- tients [117]. It has been demonstrated that the new for-
ity of CD19 B cell aplasia due to its limited expression mulated chemotherapies, molecular targeted agents, and
on mature B cells [108]. As mentioned, it remains chal- immunotherapies all have clinical activity as single
lenging to find an ideal AML target owing to its pro- agents, but the activity seems limited. Recent studies
found and intolerable hematopoietic toxicity. Most of have confirmed that combining with chemotherapy or
the current antigens in AML treatment are just over- other new drugs may bring more benefit for AML pa-
expression antigens, rather than true AML-specific sur- tients. The treatment of AML remains a tough challenge
face antigens, which brings about fatal off-tumor toxicity despite advances in our understanding of molecular
[109]. Several studies have proved in mouse models that mechanism and prognostic impact. Therefore, many
targeting with anti-CD123 CAR T-cells (CD123 CART) questions are still unsolved in the use of these new
and anti-CD33 CAR T-cells (CD33 CART) had some drugs, which indicates that both patient and disease sta-
anti-AML potency but severe myeloablation was inevit- tus should be taken into consideration. Massive efforts
able [110–112]. Particularly, a preclinical study in a are required to pave the way for precision medicine in
mouse model using CD123 CART showed that CD123 the foreseeable future.
Yang and Wang Journal of Hematology & Oncology (2018) 11:3 Page 8 of 11

Abbreviations 9. Ravandi F, Burnett AK, Agura ED, Kantarjian HM. Progress in the treatment
5hmc: 5-Hydroxymethylcytosine; 5mC: 5-Methylcytosine; allo- of acute myeloid leukemia. Cancer. 2007;110:1900–10.
HSCT: Allogeneic HSCT; AML: Acute myeloid leukemia; APL: Acute 10. Kantarjian H, Ravandi F, O'Brien S, Cortes J, Faderl S, Garcia-Manero G, et al.
promyelocytic leukemia; ATO: Arsenic trioxide; ATRA: All-transretinoic acid; Intensive chemotherapy does not benefit most older patients (age 70 years
CAR T cells: Chimeric antigen receptor-engineered T cells; CR: Complete or older) with acute myeloid leukemia. Blood. 2010;116:4422–9.
remission; CTLA4: Cytotoxic T-lymphocyte-associated antigen 4; DLT: Dose- 11. Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, et al.
limiting toxicity; DNMTs: DNA methyltransferases; EFS: Event-free survival; Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med.
FLT3: Fms-like tyrosine kinase 3; GO: Gemtuzumab ozogamicin; GvHD: Graft- 2009;361:1249–59.
versus-host disease; GvL: Graft-versus-leukemic; HDAC: Histone deacetylase; 12. Lee J-H, Joo Y-D, Kim H, Bae SH, Kim MK, Zang DY, et al. A randomized trial
HMAs: Hypomethylating agents; HSCT: Hematopoietic stem cell comparing standard versus high-dose daunorubicin induction in patients
transplantation; ITD: Internal tandem duplications; LDAC: Low-dose with acute myeloid leukemia. Blood. 2011;118:3832–41.
cytarabine; mAbs: Monoclonal antibodies; mIDH: Mutant IDH; 13. Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling
MTD: Maximum tolerated dose; OS: Overall survival; PD1: Programmed cell RP, et al. Benefit of high-dose daunorubicin in AML induction extends
death protein 1; PDGFR: Platelet-derived growth factor receptor; PLKs: Polo- across cytogenetic and molecular groups. Blood. 2016;127:1551–8.
like kinases; R/R: Relapsed/refractory; TKD: Tyrosine kinase domain; 14. Willemze R, Suciu S, Meloni G, Labar B, Marie J-P, Halkes CJ, et al. High-dose
TKIs: Tyrosine kinase inhibitors; VEGFR: Vascular endothelial growth factor cytarabine in induction treatment improves the outcome of adult patients
receptor; WT: Wild type; α-KG: Alpha-ketoglutarate younger than age 46 years with acute myeloid leukemia: results of the
EORTC-GIMEMA AML-12 trial. J Clin Oncol. 2013;32:219–28.
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None et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine
during induction prolongs survival of patients with acute myeloid leukemia:
Funding a multicenter, randomized phase III study. J Clin Oncol. 2012;30:2441–8.
This work was supported by the National Natural Science Foundation of 16. Kantarjian H, Gandhi V, Cortes J, Verstovsek S, Du M, Garcia-Manero G, et al.
China (81430004), Tianjin Clinical Research Center for Blood Diseases Phase 2 clinical and pharmacologic study of clofarabine in patients with
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(2016-I2M-1-001). 17. Burnett AK, Russell NH, Hunter AE, Milligan D, Knapper S, Wheatley K, et al.
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Availability of data and materials leukemia but does not improve survival. Blood. 2013;122:1384–94.
Not applicable 18. Löwenberg B, Pabst T, Maertens J, van Norden Y, Biemond BJ, Schouten HC,
et al. Therapeutic value of clofarabine in younger and middle aged (18–65
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approved the final manuscript. Ratiometric dosing of anticancer drug combinations: controlling drug ratios
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Consent for publication 21. Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, et
Not applicable al. Phase 2 trial of CPX-351, a fixed 5: 1 molar ratio of cytarabine/
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Competing interests AML. Blood. 2014;123:3239–46.
The authors declare that they have no competing interests. 22. Cortes JE, Goldberg SL, Feldman EJ, Rizzeri DA, Hogge DE, Larson M, et al.
Phase II, multicenter, randomized trial of CPX-351 (cytarabine: daunorubicin)
Publisher’s Note liposome injection versus intensive salvage therapy in adults with first
Springer Nature remains neutral with regard to jurisdictional claims in relapse AML. Cancer. 2015;121:234–42.
published maps and institutional affiliations. 23. Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C,
Ferrant A, et al. High-dose daunorubicin in older patients with acute
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