New drugs in acute myeloid leukemia
New drugs in acute myeloid leukemia
T. M. Kadia 0
F. Ravandi 0
J. Cortes 0
H. Kantarjian 0
0 Department of Leukemia, University of Texas MD Anderson Cancer Center , Houston , USA
The standard therapy for acute myeloid leukemia (AML) has not changed meaningfully for the past four decades. Improvements in supportive care and modifications to the dose and schedule of existing agents have led to steady improvements in outcomes. However, developing new therapies for AML has been challenging. Although there have been advances in understanding the biology of AML, translating this knowledge to viable treatments has been slow. Active research is currently ongoing to address this important need and several promising drug candidates are currently in the pipeline. Here, we review some of the most advanced and promising compounds that are currently in clinical trials and may have the potential to be part of our future armamentarium. These drug candidates range from cytotoxic chemotherapies, targeted small-molecule inhibitors, and monoclonal antibodies.
Acute myeloid leukemia (AML) is the most common acute
leukemia in adults and among the most lethal. In the United States,
the annual incidence of AML is 19 000 new cases, and the
incidence of AML-associated deaths is 10 000. Classification
systems based on pretreatment karyotype and mutations allow
stratification of patients by risk . There have been significant
research efforts aimed at improving outcomes in AML, but the
standard therapy for most subtypes of newly diagnosed AML is
still unchanged for the past four decades. Outside the setting of a
clinical trial, most patients with newly diagnosed AML are offered
the combination of standard-dose cytarabine with an
anthracycline (daunorubicin or idarubicin), the so-called 7 + 3 regimen.
Favorable-risk patients are offered high-dose cytarabine (HiDAC)
consolidation, whereas those with adverse-risk disease are offered
allogeneic stem-cell transplant (SCT) in first remission. Other
than all-trans-retinoic acid in 1995 and arsenic trioxide in 2001
for the treatment of acute promyelocytic leukemia, the last drug
Food and Drug Administration (FDA)-approved for AML was
idarubicin in 1990. Gemtuzumab ozogamicin (GO), a CD33
monoclonal antibody bound to the toxin calicheamicin, was
approved for AML salvage in 2000 and withdrawn from the
market in 2010 [2, 3].
Despite advances in understanding the pathophysiology of
AML and recognizing its molecular heterogeneity, developing
viable therapeutics for patients with AML has proved a daunting
challenge. With improvements in supportive care, long-term
survival has improved in younger patients with AML, with
5year overall survival (OS) in the range of 40%–50%. However,
among patients over the age of 60 years, who make up the bulk
of AML cases, the long-term outlook is dismal, with a 5-year OS
of 10%–20% [4, 5]. There remains a clear need for newer
therapies and a more individualized approach for the treatment of
AML. In parallel with newer therapies, newer end points beyond
morphologic complete remission (CR) such as progression-free
survival and minimal residual disease-negative CR must also be
Several new agents are currently in advanced development to
help address this need. These agents, which span several
mechanisms of action, have undergone years of preclinical and
early clinical testing, building on the successes and failures of
prior approaches. Here we review some of the most promising
new drugs for the treatment of AML, divided into categories
based on their mechanisms of action: cytotoxic agents,
smallmolecule inhibitors, and targeted therapies (Table 1).
Vosaroxin is a first-in-class anticancer quinolone derivative that
intercalates into DNA and, similar to anthracyclines, potently
inhibits DNA topoisomerase II and induces double-stranded
(ds) DNA breaks. It may have several advantages over
traditional anthracyclines. First, vosaroxin is not associated with the
formation of free radicals, reactive oxygen species, or toxic
metabolites, potentially limiting its cardiotoxicity [7–9]. Second,
vosaroxin is not a substrate of P-glycoprotein and can induce
Mechanism of action
Vosaroxin Cytotoxic; DNA-intercalating agent CPX-351
Cytotoxic; liposomal formulation of cytarabine
and daunorubicin in 5:1 molar ratio
Cytotoxic; orally bioavailable novel nucleoside
Cytotoxic; longer acting hypomethylating agent
Small-molecule inhibitor of Polo-like kinase
Small-molecule inhibitor of isocitrate
dehydrogenase (IDH)-2 enzyme
Small-molecule inhibitor of IDH-1 enzyme
Small-molecule BH3 mimetic, inhibitor of BCL-2
Small-molecule multikinase inhibitor with activity
against mutant FLT3 (FLT3-ITD) in AML
Small-molecule multikinase inhibitor with activity
against mutant FLT (FLT-ITD) in AML
Small-molecule multikinase inhibitor with potent
activity against FLT3-ITD
Small-molecule kinase inhibitor with activity
against mutant FLT3 (both FLT3-ITD and
Small molecule both FLT3 and AXL kinases
Small-molecule inhibitor of both FLT3 kinase and
Monoclonal antibody-drug conjugate directed at
CD33, carrying a pyrrolobenzodiazepine dimer
Monoclonal bispecific antibody directed at CD33
Multicenter randomized phase III trial in combination with
cytarabine did not meet primary end point, but demonstrated
improved outcomes in older patients. Lower intensity trials
Randomized trial of CPX-351 versus 7 + 3 demonstrated improved
outcomes in patients with secondary AML.
Single-agent sapacitabine had outcomes similar to LDAC, but
sequential combination study with decitabine showed promising
results. A randomized study of this approach is ongoing.
Single-agent activity in AML and myelodysplastic syndrome seems
promising. A randomized study versus conventional care is
ongoing, as are combination studies.
A phase II study of volasertib combined with LDAC demonstrated
improved outcomes over LDAC. A randomized phase III study
is underway to confirm these results.
Single-agent studies have reported significant activity in patients
with IDH2-mutated AML. Combination studies with
conventional chemotherapy have been planned.
Single-agent study has demonstrated activity in patients with
IDH1-mutated AML. Combination studies are planned.
Single-agent ABT-199 demonstrated a signal of response in
patients with AML, particularly in patients with IDH mutations.
Combination studies are now underway.
Following several single-arm studies, a phase III randomized study
of 7 + 3 with or without sorafenib demonstrated improved
outcomes (but not improved OS) with sorafenib in younger
patients with AML. A randomized study in older patients did not
show a benefit. Lower intensity therapy such as hypomethylating
agents are being studied in combination with sorafenib.
Results from a large phase III randomized double-blind study of
7 + 3 with our without midostaurin in newly diagnosed patients
with FLT3-mutated AML were recently presented. Among
younger patients (median age 48 years), the midostaurin arm
was associated with a significant improvement in event-free- and
Single-agent dose-finding studies have demonstrated efficacy, but
DLT is QT prolongation. Lower doses of quizartinib have
demonstrated similar activity but less toxicity. These are now
being studied in combination studies.
Single-agent studies have demonstrated activity in heavily
pretreated patients; combination studies are now being
Single-agent studies are just underway, with preliminary data
Single-agent studies are just underway, with preliminary data
Single-agent and combination studies are underway in several
clinical settings. Preliminary experience is positive,
demonstrating good safety profile and efficacy in clearing bone
Single-agent studies are just getting underway.
p53-independent apoptosis [8, 10]. Based on preclinical activity
in leukemia cell lines and evidence of safety in a phase I trial in
leukemia, several phase II trials have been completed,
demonstrating efficacy as a single agent and in combination with cytarabine
[11–14]. In a phase Ib/II study of vosaroxin (10–90 mg/m2 on D1
and 4) combined with cytarabine (400–1000 mg/m2 on D 1–5) in
patients with relapsed or refractory (R/R) AML, the recommended
phase II dose was 90 mg/m2 of vosaroxin on D1 and 4 combined
with cytarabine 1000 mg/m2 on D1–5 . Among 69 patients
with primary refractory AML, or those in first relapse, the
CR/CR with incomplete blood count recovery (CRi) rate was
28%. The 30-day all-cause mortality was 2.5% and the
doselimiting toxicity (DLT) was stomatitis . Based on these
encouraging results, a phase III randomized, placebo-controlled
study of cytarabine with or without vosaroxin in patients with
first-relapsed or refractory AML was conducted . A total of
711 patients were randomized to receive either cytarabine (1000
mg/m2 i.v. on D1–5) plus placebo or cytarabine plus vosaroxin
(90 mg/m2 i.v. on D1 and 4 of cycle 1 and 70 mg/m2 in
subsequent cycles). The vosaroxin arm was associated with a
significantly higher rate of CR (30% versus 16%, P < 0.0001) and an
improvement in OS (7.5 versus 6.1 months, P = 0.061). Although
the study did not achieve its primary end point, in prespecified
subgroup analyses, vosaroxin was associated with a significant
improvement in OS for patients ≥60 years (7.1 versus 5 months,
P = 0.003) and when censoring for allogeneic SCT (6.7 versus 5.3
months, P = 0.024). Importantly, the combination was not
associated with increased early mortality (30-day mortality with
vosaroxin 8% versus 7%; 60-day mortality 20% versus 19%,
respectively). There were more adverse events in the vosaroxin arm,
including higher rates of febrile neutropenia and stomatitis, but
the regimen was tolerable. Vosaroxin is also being studied in a
lower intensity combination with decitabine in older patients
with newly diagnosed AML (NCT01893320).
While the ‘7 + 3’ regimen has been the standard induction
regimen for AML for decades, several attempts have been made
to modify the treatment program to improve outcomes.
Intensifying the dose of cytarabine [16, 17] or daunorubicin
[18, 19] or even changing the anthracycline [20, 21] has led to
improved response rates but only modest improvements in
long-term outcome. One innovation, aimed to reduce
extramedullary toxicity and increase exposure of leukemic cells to the
doublet, involves packaging the ‘7 + 3’ combination in a
liposome. CPX-351 is nano-scale liposome which includes within it,
a fixed molar ratio of ara-C and daunorubicin of 5:1 . This
molar ratio was studied and found to be an optimal
combination, maximizing synergy, and avoiding antagonism. A
firstin-man phase I dose-escalation study in patients with relapsed
and refractory AML confirmed safety and efficacy and produced
a CR/CR with incomplete platelet recovery (CRp) rate of 23%
. A multicenter phase II study randomized (2:1) 125 patients
with relapsed AML to CPX-351 versus physician’s choice of
intensive chemotherapy for first salvage . CPX-351 was
associated with a higher rate of CR/CRi compared with the control
arm (49.3% versus 40.9%), but there was no difference in
median OS (8.5 versus 6.3 months, P = 0.19). In a prespecified
subgroup analysis of poor risk patients, CPX-351 was associated
with a significant improvement in median OS (6.6 versus 4.2
months, P = 0.02) and median event-free survival (EFS; 1.9
versus 1.2 months, P = 0.08) . The drug was well tolerated in
this population and was associated with a lower 60-day
mortality (16.1% versus 24.1%) compared with the control arm. A
second randomized phase II trial was conducted in frontline
AML patients aged ≥60 years . A total of 127 patients were
| Kadia et al.
randomized (2:1) to CPX-351 (100 U/m2 on D1,3,5) or
conventional ‘7 + 3’(cytarabine 100 mg/m2 i.v. on D1–7 with
daunorubicin 60 mg/m2 i.v. on D1–3). Overall response rate (ORR)
was the primary end point. CPX-351 produced a higher
response rate (66.7% versus 51.2%, P = 0.07) . In a predefined
cohort of patients with secondary AML, CPX-351 demonstrated
a higher response rate (58% versus 32%, P = 0.06) and
prolongation of EFS [hazard ratio (HR) = 0.59, P = 0.08] and OS
[HR = 0.46, P = 0.01]. Prolonged myelosuppression was noted
with CPX-351 compared with 7 + 3, but this did not translate
into increased infection-related deaths. CPX-351 was associated
with a lower 60-day mortality compared with ‘7 + 3’ (4.7%
versus 14.6%). A phase III registration trial in patients with
newly diagnosed secondary AML is ongoing (NCT01696084).
Sapacitabine is an N4-palmitoyl derivative of
20-C-cyano-20deoxy-β-D-arabino-pentofuranosylcytosine (CNDAC) which is
orally bioavailable and resistant to deamination and inactivation
[25–27]. CNDAC, the active component of sapacitabine, is a
deoxycytidine analog similar to cytarabine with a unique
mechanism of action. Upon phosphorylation to the nucleotide and
incorporation into actively synthesized DNA, replication is not
immediately inhibited in a cytotoxic manner like cytarabine or
clofarabine [25–27]. Instead, the cyano group within the ring
triggers rearrangement of the nucleotide while it is incorporated
in the DNA, creating a single-strand (ss) DNA break. This is
then converted to a ds-DNA break after a round of DNA
replication, which leads to cell death. This may explain the effect it
has on actively dividing hematopoietic cells and the observation
that responses and myelosuppression are more profound with
successive courses of therapy.
After demonstrating broad preclinical activity in multiple
human tumor cells, including leukemia cell lines, a phase I
study was conducted in advanced leukemias . Forty-seven
patients were treated with sapacitabine on two different
schedules: (A) orally ( p.o.) twice daily (b.i.d.) for 7 days every 3–4
weeks, or (B) p.o. b.i.d. on days 1–3 and 8–10 every 3–4 weeks.
The DLTs on both schedules were gastrointestinal in nature,
including diarrhea, abdominal pain, neutropenic colitis, and
small bowel obstruction. The maximum tolerated dose (MTD)
for schedule A was 325 mg b.i.d.; the MTD for schedule B was
425 mg b.i.d. Grade 3 or 4 myelosuppression was common and
30% had febrile episodes associated with myelosuppression.
Thirteen patients (28%) achieve an objective response, including
4 CR (9%), 2 CRp (4%), and 7 CRi (15%). The estimated 30-day
mortality was 4% . The encouraging safety and efficacy
profile prompted further development in AML. A randomized
phase II study in older patients with newly diagnosed AML
studied three schedules of sapacitabine : (A) 200 mg b.i.
d. × 7 days, (B) 300 mg b.i.d. × 7 days, and (C) 400 mg b.i.d. on
D1–3 and 8–10. Among the 60 patients who were randomized
to the three schedules, the 1-year OS rate was 35% for cohort A,
10% for B, and 30% for C . The most common adverse
events were myelosuppression and the 60-day mortality was
26%. A second randomized phase II trial compared sapacitabine
(300 mg b.i.d. on D1–3 and 8–10) in a ‘pick-the-winner’ design
to standard low-dose cytarabine (LDAC, 20 mg s.c. b.i.d. × 10
days) in 143 older patients with AML . At the planned
interim analysis, there was no difference in response (CR/CRi,
27% versus 16%, P = 0.09), 2-year relapse-free survival (10%
versus 14%, P = 0.4), or 2-year OS (12% versus 11%, P = 0.2) for
sapacitabine compared with LDAC . The trial was stopped
early for insufficient evidence of benefit. It was clear from these
earlier studies that, although active, sapacitabine as a single
agent was inadequate therapy. In a pooled analysis of patients in
a lead-in phase of a randomized phase III trial, 46 patients were
treated with sapacitabine alternating with decitabine . The
approach was well tolerated, yielded a response rate of 37%
(22% CR), 35% 1-year survival, and 13% 60-day mortality .
A randomized phase III trial comparing this approach to
singleagent decitabine is ongoing (NCT01303796).
Hypomethylating agents (HMAs) such as 5-azacytidine and
decitabine have improved outcomes in patients with AML and
have become important low-intensity options for older patients
and those unfit for intensive therapy. In these select subgroups,
HMAs produce outcomes similar to those obtained with
intensive chemotherapy, with lower toxicity . Both 5-azacytidine
and decitabine have also been shown to be effective in older
patients with higher blast count AML and associated with a
survival benefit when compared with conventional therapy
[32, 33]. Resistance to these agents and the development of HMA
failure is a major limitation. Although the exact mechanism of
resistance is not known, altered metabolism of the nucleoside
analog or modification of the drug target have been proposed.
SGI-110 or guadecitabine is a second-generation HMA designed
to be resistant to degradation by cytidine deaminase, one of the
major enzymes responsible for decitabine degradation and
shortened half-life [34–36]. SGI-110
(20-deoxy-5-azacytidylyl(30 → 50)-20deoxyguanosine sodium salt) is a dinucleotide of
decitabine and deoxyguanosine linked by a phosphodiester bond
that gives it properties of longer half-life and more prolonged
in vivo exposure to decitabine. A first-in-human phase I
doseescalation study evaluated three different schedules of SGI-110
(3–125 mg/m2/day) in patients with R/R myelodysplastic
syndrome or AML: (A) s.c. daily on D1–5, (B) s.c. on 1, 8, 15 of
28-day cycle, and (C) s.c. twice weekly . The drug was well
tolerated, with the most common grade 3 or higher adverse events
being myelosuppression and infection. The recommended phase
II dose was 60 mg/m2 daily × 5. Six of 74 patients with R/R had an
objective response, with 5 of the 6 being treated at a dose of 60
mg/m2 or higher . Preliminary results from a phase II study
using a 10-day schedule of SGI-110 in R/R AML were recently
reported . Among 53 heavily pretreated patients (median
age 57 years), the response rate (CR + CRi + CRp) was 30%, with
30- and 60-day mortality rates of 1.9% and 11.3%, respectively
. The doses studied, 60 and 90 mg/m2/day, were both tolerable
with myelosuppression and febrile neutropenia being the most
common grade ≥3 adverse events. This signal of activity has
prompted several studies in newly diagnosed AML—both as
single agent in a randomized phase III study compared with
‘treatment choice’ (NCT02348489) and in a four-arm study
randomizing between the 5-day schedule, 10-day schedule, in
combination with idarubicin, or in combination with cladribine
(NCT02096055). Both studies are ongoing and preliminary data
small-molecule targeted therapies
Plk-1 belongs to the family of serine/threonine kinases and
plays an important role in centrosome maturation, spindle
formation, and cytokinesis during mitosis. Plk-1 is aberrantly
highly expressed in leukemia cell lines and in freshly isolated
leukemia cells from patients with AML relative to normal bone
marrow cells from healthy donors . Inhibition of Plk-1
using small-interfering RNA (siRNA) in leukemia cells has
been shown to inhibit their proliferation, suggesting important
therapeutic potential .
Volasertib is a small-molecule serine threonine kinase
inhibitor of the cell cycle kinase Plk1. It binds competitively to the
adenosine triphosphate binding pocket of this kinase and
inhibits its enzymatic activity at low nanomolar concentrations.
Volasertib is also an inhibitor of two related Polo-like kinase
family members, Plk2 (Polo-like kinase 2) and Plk3 (Polo-like
kinase 3), at low nanomolar concentrations. Treatment of cells
with volasertib leads to cell cycle arrest in early prometaphase
due to impaired spindle formation (leading to formation of a
monopolar spindle instead of a bipolar spindle), which is
followed by apoptotic cell death . A phase I dose-finding study
of volasertib in combination with low-dose araC (LDAC, 20 mg
s.c. b.i.d. × on D1–10) in AML provided evidence of clinical
efficacy and determined the MTD to be 350 mg i.v. on D1 and
15 . This led in to a randomized phase II study of LDAC
with or without volasertib in patients deemed unsuitable for
intensive induction therapy . Eighty-seven patients with a
median age of 75 years were randomized to either LDAC or
LDAC + volasertib at the above established doses. The response
rate (CR/CRi) was higher for the combination arm (30% versus
13.3%, P = 0.052) and associated with a significant improvement
in median EFS (5.6 versus 2.3 months, P = 0.021) and median
OS (8 versus 5.2 months, P = 0.047) . While there was an
increased frequency of adverse events associated with the
combination arm (myelosuppression, infections, gastrointestinal), there
was no difference in 30-day (9.5% versus 8.9%, respectively) or
60day (21.4% versus 17.8%, respectively) mortality between the two
arms. These data earned volasertib the FDA’s Breakthrough
Therapy Designation for AML to help expedite further
development of this drug. An ongoing multicenter phase III randomized
control trial of LDAC with or without volasertib in patients with
newly diagnosed AML ineligible for intensive chemotherapy may
help confirm these data (NCT01721876). Other studies
combining volasertib with intensive chemotherapy and with HMAs are
isocitrate dehydrogenase inhibitors
Newer techniques in whole-genome deep-sequencing have
uncovered novel mutations that may be involved the
pathogenesis of AML. Better understanding the biological significance of
these mutations can provide opportunities for biologically
targeted therapies. Mutations in isocitrate dehydrogenase (IDH)
1/2 have been identified in up to 20% of patients with normal
karyotype AML and have been shown to induce a neomorphic
enzyme activity in the IDH protein. This leads to the aberrant
production of the onco-metabolite 2-hydroxyglutarate (2-HG).
2-HG has been shown to dysregulate enzymes involved in
epigenetic function, promote hypermethylation, and may be
sufficient in causing leukemia [43–45]. Strategies to target IDH
mutant AML are being investigated with promising early
results. AG221, an orally bioavailable small-molecule inhibitor
of IDH2, has demonstrated inhibition of 2-HG production and
objective clinical responses . In a phase I study, 158 patients
with IDH2-mutated AML have been treated once or twice daily
with doses ranging from 30 to 200 mg. The ORR was 40%,
including 16.5% CR (updated data from presentation) . The
drug was very well tolerated, with the most common adverse
events being nausea, fever, diarrhea, and fatigue. Similarly,
IDH1 inhibitors are being developed. Preliminary results from a
phase I trial of the IDH1 inhibitor AG-120 in R/R
IDH1mutated AML were recently presented including 52 treated
patients . Investigators reported responses in 16 of 52 (31%)
patients, including 8 (16%) CR (updated data from
presentation) . Unlike traditional cytotoxic chemotherapy, responses
with these agents have occurred progressively over several
cycles, were durable and were associated with differentiation or
maturation of the leukemic blasts. Both studies are ongoing with
dose escalation and no MTD has been reached. These signals of
clinical activity with IDH inhibitors in a molecularly defined
subset of AML have generated excitement about individualizing
the treatment of AML.
Another approach to targeting AML involves activating the
intrinsic or mitochondrial pathway of apoptosis. This pathway
of apoptosis is regulated by the BCL-2 family of proteins,
involving a dynamic balance of proapoptotic effectors (Bak, Bax) and
antiapoptotic proteins (BCL-2, BCL-XL, and MCL-1). In the
balanced state, the antiapoptotic proteins bind to and sequester
the proapoptotic proteins, preventing them from triggering
mitochondrial outer membrane permeabilization, release of
cytochrome c, and apoptosis. Small-molecule ‘BH3-mimetics’
have been developed that bind to the antiapoptotic proteins in
the BH3 domain and liberate the proapoptotic proteins to
trigger apoptosis. Earlier investigational BH3 mimetics were
found to bind efficiently to multiple antiapoptotic proteins,
including BCL-2, BCL-XL, and MCL-1 and were consequently
associated with on-target toxicity, including thrombocytopenia.
ABT-199, a more advanced clinical candidate BH3 mimetic,
was specifically designed to retain specificity for BCL-2, but lack
affinity for BCL-XL. ABT-199 has demonstrated significant
activity in lymphoid neoplasms including chronic lymphocytic
leukemia. Since AML blasts and AML stem cells are dependent
on BCL-2 for survival, while normal hematopoietic cells are
dependent on MCL-1, ABT-199 was tested in AML. In preclinical
studies, Pan et al.  tested the activity of ABT-199 in leukemia
cell lines, murine primary xenografts, and primary samples of
patients with AML. Their studies demonstrated significant
activity of ABT-199 in all three AML model systems, correlating
with dependence on mitochondrial apoptosis and predicted by
BH3 profiling. Interestingly, they also demonstrated activity
| Kadia et al.
against AML stem and progenitor cells in the primary samples,
immunophenotypically defined as CD34(+), CD38(−), and
CD123(+) cells . These data prompted a clinical trial of
single-agent ABT199 in AML . Among 32 patients with R/R
AML, ABT-199 (20 mg escalated to 800 mg daily) therapy
demonstrated a CR/CRi rate of 15.5%. Importantly, 19% of
patients had a reduction of blasts by at least 50% from baseline,
suggesting antileukemic activity . The responses were
particularly enriched in patients with IDH mutations, with three of
the four CR/CRi occurring in patients with IDH mutations.
Several other patients with IDH mutations had significant blast
count reduction that did not meet IWG response criteria. These
clinical observations confirm laboratory observations that
suggest BCL-2 as a synthetic lethal partner for IDH2-mutated
AML . If these observations are confirmed, IDH mutations
could be utilized as a predictive biomarker for response.
Promising clinical activity as a single agent has led to ongoing
studies of combination of ABT-199 with HMAs (NCT02203773)
and LDAC (NCT02287233).
Activating mutations in FMS-like tyrosine kinase 3 (FLT3)
receptor tyrosine kinase are present in about a third of patients
with AML and are associated with a high risk of relapse and an
overall adverse prognosis. Recognized activating mutations are
in the form of internal tandem duplications (ITD) of the
juxtamembrane domain or point mutations in the tyrosine kinase
domain (TKD) of FLT3, with the ITD being most closely
associated with an adverse prognosis. These activating mutations
lead to constitutive signaling that may promote growth and
survival of AML blasts. A high allelic burden of mutant FLT3 in
an AML sample may suggest dependence on FLT3 signaling and
a greater sensitivity to FLT3-inhibitor signaling . Several
small-molecule FLT3-ITD inhibitors have been developed and
demonstrated benefit as single agents and in combination with
sorafenib. Sorafenib is a multikinase inhibitor that potently
inhibits FLT3-ITD and yields significant single-agent activity
FLT3-ITD-mutated AML . Combination studies with higher
and lower intensity chemotherapy have also demonstrated
improvement in outcomes for patients with FLT3-ITD-mutated
AML. In a phase I/II study of sorafenib (median age 53 years)
combined with idarubicin and HiDAC, the overall CR rate was
75% . In patients with FLT3-ITD mutation, the CR rate was
93%, with a 1-year OS of 74%. The SORAML trial randomized
276 patients (aged 18–60 years) to daunorubicin and cytarabine
(7 + 3) with or without sorafenib . The CR rates between
the two arms were similar. However, there was a significant
prolongation of 1-year EFS in the sorafenib arm (64% versus 50%,
P = 0.023). This result was in all patients, with a trend for more
significant improvement in patients with FLT3-ITD mutations
. A second randomized study in older patients (61–80 years)
evaluated the same approach in 201 patients . In contrast to
the younger patient study, there was a trend toward lower CR rate
(48% versus 60%, P = 0.12), higher early death (17% versus 7%,
P = 0.052), and no improvement in EFS or OS with sorafenib .
These results suggest an important role for sorafenib combined
with intensive chemotherapy in AML, particularly patients with
FLT3-ITD mutations. However, this combination may be too
toxic for older patients. A lower intensity approach using sorafenib
in combination with 5-azacytidine (5-AZA) has generated
promising results . Thirty-seven assessable patients (median
age 64 years) with R/R FLT3-mutated AML received sorafenib
(400 mg b.i.d.) combined with 5-AZA (75 mg/m2 i.v. on D1–5).
The ORR was 46% (16% CR; 27% CRi; 3% PR), with 3% 4- and
8week mortality . Combination sorafenib studies are ongoing to
better define the efficacy and toxicity of this FLT3 inhibitor and
determine its place in AML treatment.
midostaurin. Midostaurin is an orally bioavailable multikinase
inhibitor with nanomolar inhibitory activity against FLT3-ITD.
After observing single-agent activity in FLT3-mutated patients
, midostaurin was studied in combination with chemotherapy.
A phase Ib trial of midostaurin combined with 7 + 3 in newly
diagnosed AML demonstrated safety and efficacy at a dose of
50 mg daily . The combination produced a higher CR rate
in FLT3-mutated patients (92% versus 74%). This led to a
randomized, placebo-controlled phase III trial of 7 + 3 with or
without midostaurin in patients with newly diagnosed
FLT3mutated AML whose results were recently released . Among
717 patients, with a median age of 48 years, there was no significant
difference in toxicity or CR rate between the two arms. However,
the study demonstrated a significant improvement in EFS and OS
favoring the combination with midostaurin . This benefit
persisted after censoring for transplant and remained across
FLT3 subgroups. The clear survival benefit with midostaurin in
this subset of AML could translate into a new standard of care
for a molecular defined patient population. Lower intensity
combinations with midostaurin are also being studied [60, 61].
quizartinib. Quizartinib is a highly potent small-molecule TKI
designed specifically as FLT3 inhibitor . In a phase I
doseescalation study in patients with R/R AML, the MTD was
determined to be 200 mg/day and the DLT was grade 3 QTc
prolongation . Among patients with FLT-ITD mutations,
the ORR was 53%, compared with 14% in FLT3-ITD-negative
patients. Due to the higher incidence of QTc prolongation
associated with higher doses and preserved FLT3-inhibitory
activity at lower doses, subsequent phase II trials studied lower
dose levels. A phase II trial of quizartinib in patients with R/R
AML used doses of 90 mg/day in females and 135 mg/day in
males. In patients ≥60 years of age, the composite CR rate was
54% in FLT3-ITD-positive patients and 32% in FLT3-negative
patients . These were associated with remission durations of
12.7 and 22 weeks, respectively . Among younger patients, the
composite CR rates were 44% and 34% in the FLT3-ITD-positive
and -negative groups, respectively . These were associated with
remission durations of 11.3 and 25.6 weeks, respectively .
Recently, the preliminary results of a randomized trial studying
even lower doses of quizartinib were reported . Seventy-six
patients with R/R FLT3-ITD-positive AML were randomized to
receive either 30 or 60 mg of quizartinib per day. The composite
CR rate was 50% in both arms, and the median OS was 146 versus
197 days, respectively . Notably, the rate of grade 2 QTc
prolongation was 11% versus 17%, respectively, and the rate of
grade 3 QTc prolongation was only 3% in both arms. There was
no grade 4 QTc prolongation . The development of this drug
demonstrates the importance of targeting a biologically effective
dose, rather than the clinical MTD, when studying a targeted
agent, to minimize toxicity. Combination studies investigating
quizartinib in relapsed and frontline FLT3-ITD-positive AML are
ongoing [66, 67] (NCT01892371).
Activating point mutations in the FLT3 TKD also lead to
constitutive downstream signaling in AML and are associated
with resistance to FLT3 inhibitors. Newer FLT3 inhibitors are
currently in development that may help circumvent this and
other mechanisms of resistance. Crenolanib is a potent small
molecular inhibitor that has activity against both the FLT3-ITD
and the FLT3-D835 TKD mutation. Preliminary results of
crenolanib monotherapy in 19 patients with FLT3-mutated
AML demonstrate an ORR of 50% . The dual FLT3/AXL
inhibitor ASP2215 and the FLT3/CDK4/6 inhibitor FLX925 are
also being studied in R/R AML [69, 70]. Recent data also suggest
an important role for FLT3 inhibitors as post-SCT maintenance
in patients with FLT3-mutated AML [71–73]. As we gain more
insight into the efficacy and toxicity of these newer agents, their
role in the treatment of R/R AML will become clearer.
Monoclonal antibodies have improved outcomes in patients
with lymphoid hematologic malignancies and may also have an
important role in the treatment of AML. Clinical experience
with the anti-CD33 monoclonal antibody-drug conjugate GO
underscores the importance of this approach in AML. Although
withdrawn from the US market, recent studies of GO [74–76] in
combination with chemotherapy have demonstrated
improvements in relapse-free and OS in select subgroups of patients,
validating CD33 as an important target .
SGN-33A is a humanized anti-CD33 monoclonal antibody
conjugated to a potent DNA-crosslinking toxin . Rather than the
calecheamicin toxin in GO which is a substrate of drug-efflux
enzymes, SGN-33A carries a pyrrolobenzodiazepine dimer .
Preclinical evaluation demonstrated more potent antileukemia
activity than GO in cell lines, primary patient samples, and
xenograft models . SGN-33A is currently undergoing clinical
investigation as a single agent and combination in several clinical
settings (NCT02326584). Preliminary data from the phase I
doseescalation trial of SGN-33A were recently reported . Among
38 assessable patients with relapsed AML treated with escalating
doses of SGN-33A (5–60 μm/kg i.v. every 3 weeks), 16 (42%) had
clearance of marrow blasts, with acceptable tolerability .
Studies with this new compound are ongoing and more data are
expected soon. Careful development of this compound at the
optimal dose schedule and in defined subgroups that had benefit
with GO may lead to an important candidate for regulatory
approval in AML.
Another approach to targeting the CD33 antigen on AML blasts
involves recruiting the host immune system to recognize
and eradicate the leukemia blasts by cell-mediated cytotoxicity.
A new antibody construct, the bispecific antibody, has two motifs
of specificity—one that recognizes a tumor-specific antigen, and
the second one, CD3, which is present on T cells. This bispecific
T-cell engaging antibody or ‘BiTE’ can recruit CD3+ effector
T cells to the target cancer cell and trigger immune cytotoxicity.
This approach, using the CD19/CD3 BiTE blinatumumab, has
shown significant clinical activity in B-cell ALL and is now
approved in the salvage setting . A similar approach is now
being investigated in AML. AMG-330 is a CD33/CD3 BiTE that
demonstrated significant antileukemia activity in preclinical
experiments . In ex vivo primary patient samples, AMG-330
led to T-cell recruitment and expansion, followed by significant
antibody-mediated cytotoxicity, lysing autologous blasts in the
majority of samples . Clinical trials of AMG-330 are
underway and may represent an important new tool in the therapy of
The current standard of care for the treatment of adults with AML
remains suboptimal. Scientific advances are helping better
understand the biological differences among different patients’
leukemias and identifying potential targets for novel therapies. It will
therefore become mandatory to routinely molecularly characterize
cases of newly diagnosed AML to identify these targets before
therapy. As we gain more experience with these novel agents on
clinical trials and compare them to existing therapies, we hope to
raise the bar of efficacy and improve longer term outcomes.
Carefully designed studies in selected subsets of patients as well as
increased clinical trial enrollment will help advance the field.
This research is supported in part by the National Institutes of
Health through MD Anderson’s Cancer Center Support Grant
TMK has served on an advisory board for Sunesis and as a
consultant for Novartis. FR has served on an advisory board for
Astex, Amgen, Pfizer, Seattle Genetics, Sunesis, Incyte, and
Boehringer Ingelheim and has received research support from
Amgen, Seattle Genetics, Array, Merck, Sunesis, Incyte, and
BMS. JC has served as a consultant for Novartis, Astellas and
has received research support from Ariad, Ambit, Astellas,
Arog, Celator, and Novartis. HK has received research support
from Novartis, BMS, Pfizer, Amgen, Cyclacel, and Astex.
| Kadia et al.
Breakthrough therapies in B-cell non-Hodgkin
1Department of Haematology, Sir Charles Gairdner Hospital and Pathwest Laboratory Medicine WA, Nedlands; 2University of Western Australia, Crawley, Australia;
3Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, USA
The last 5 years have seen significant advances in our understanding of the molecular pathogenesis of B-cell lymphomas.
This has led to the emergence of a large number of new therapeutic agents exploiting precise aspects of the tumor cell’s
signaling pathways, surface antigens or microenvironment. The purpose of this comprehensive review is to provide a
detailed analysis of the breakthrough agents in the field, with a focus on recent clinical data. We describe agents targeting
the B-cell receptor pathway, Bcl-2 inhibitors, emerging epigenetic therapies, new monoclonal antibodies and antibody
drug conjugates, selective inhibitors of nuclear export, agents targeting the programmed cell death axis and chimeric
antigen receptor T cells.
Key words: lymphomas, treatment, novel agents, ibrutinib, idelalisib, venetoclax
1. Kadia T , Kantarjian H , Garcia-Manero G et al. Prognostic significance of the Medical Research Council cytogenetic classification compared with the European LeukaemiaNet risk classification system in acute myeloid leukaemia . Br J Haematol 2015 ; 170 ( 4 ): 590 - 593 .
2. Bross PF , Beitz J , Chen G et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia . Clin Cancer Res 2001 ; 7 ( 6 ): 1490 - 1496 .
3. Ravandi F , Estey EH , Appelbaum FR et al. Gemtuzumab ozogamicin: time to resurrect? J Clin Oncol 2012 ; 30 ( 32 ): 3921 - 3923 .
4. Dohner H , Estey EH , Amadori S et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet . Blood 2010 ; 115 ( 3 ): 453 - 474 .
5. Dohner H , Weisdorf DJ , Bloomfield CD . Acute myeloid leukemia . N Engl J Med 2015 ; 373 ( 12 ): 1136 - 1152 .
6. Przepiorka D , Deisseroth A , Farrell AT . Acute myeloid leukemia response measures other than complete remission . J Clin Oncol 2015 ; 33 ( 31 ): 3675 - 3676 .
7. Evanchik MJ , Allen D , Yoburn JC , Silverman JA , Hoch U. Metabolism of (+)-1 , 4 - dihydro -7-(trans-3-methoxy-4-methylamino-1-pyrrolidinyl)-4-oxo-1-(2-thiaz olyl)-1 , 8 - naphthyridine -3-carboxylic acid (voreloxin; formerly SNS-595), a novel replicationdependent DNA-damaging agent . Drug Metab Dispos 2009 ; 37 ( 3 ): 594 - 601 .
8. Hawtin RE , Stockett DE , Byl JA et al. Voreloxin is an anticancer quinolone derivative that intercalates DNA and poisons topoisomerase II . PLoS One 2010 ; 5 ( 4 ): e10186 .
9. Mjos KD , Cawthray JF , Jamieson G , Fox JA , Orvig C. Iron(III)-binding of the anticancer agents doxorubicin and vosaroxin . Dalton Trans 2015 ; 44 ( 5 ): 2348 - 2358 .
10. Walsby EJ , Coles SJ , Knapper S , Burnett AK . The topoisomerase II inhibitor voreloxin causes cell cycle arrest and apoptosis in myeloid leukemia cells and acts in synergy with cytarabine . Haematologica 2011 ; 96 ( 3 ): 393 - 399 .
11. Dennis M , Russell N , Hills RK et al. Vosaroxin and vosaroxin plus low-dose Ara-C (LDAC) vs low-dose Ara-C alone in older patients with acute myeloid leukemia . Blood 2015 ; 125 ( 19 ): 2923 - 2932 .
12. Lancet JE , Ravandi F , Ricklis RM et al. A phase Ib study of vosaroxin, an anticancer quinolone derivative, in patients with relapsed or refractory acute leukemia . Leukemia 2011 ; 25 ( 12 ): 1808 - 1814 .
13. Lancet JE , Roboz GJ , Cripe LD et al. A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia . Haematologica 2015 ; 100 ( 2 ): 231 - 237 .
14. Stuart RK , Cripe LD , Maris MB et al. REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia . Br J Haematol 2015 ; 168 ( 6 ): 796 - 805 .
15. Ravandi F , Ritchie EK , Sayar H et al. Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind , multinational, phase 3 study. Lancet Oncol 2015 ; 16 ( 9 ): 1025 - 1036 .
16. Willemze R , Suciu S , Meloni G et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial . J Clin Oncol 2014 ; 32 ( 3 ): 219 - 228 .
17. Lowenberg B , Pabst T , Vellenga E et al. Cytarabine dose for acute myeloid leukemia . N Engl J Med 2011 ; 364 ( 11 ): 1027 - 1036 .
18. Fernandez HF , Sun Z , Yao X et al. Anthracycline dose intensification in acute myeloid leukemia . N Engl J Med 2009 ; 361 ( 13 ): 1249 - 1259 .
19. Lowenberg B , Ossenkoppele GJ , van Putten W et al. High-dose daunorubicin in older patients with acute myeloid leukemia . N Engl J Med 2009 ; 361 ( 13 ): 1235 - 1248 .
20. Gardin C , Chevret S , Pautas C et al. Superior long-term outcome with idarubicin compared with high-dose daunorubicin in patients with acute myeloid leukemia age 50 years and older . J Clin Oncol 2013 ; 31 ( 3 ): 321 - 327 .
21. Mandelli F , Vignetti M , Suciu S et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol 2009 ; 27 ( 32 ): 5397 - 5403 .
22. Feldman EJ , Lancet JE , Kolitz JE et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia . J Clin Oncol 2011 ; 29 ( 8 ): 979 - 985 .
23. Cortes JE , Goldberg SL , Feldman EJ et al. Phase II, multicenter, randomized trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus intensive salvage therapy in adults with first relapse AML . Cancer 2015 ; 121 ( 2 ): 234 - 242 .
24. Lancet JE , Cortes JE , Hogge DE et al. Phase II, multicenter, randomized, open label trial of CPX-351 (cytarabine:daunorubicin) liposome injection versus cytarabine and daunorubicin in patients with untreated AML 60-75 years of age . Blood 2014 ; 123 : 3239 - 3246 .
25. Hanaoka K , Suzuki M , Kobayashi T et al. Antitumor activity and novel DNA-selfstrand-breaking mechanism of CNDAC (1-(2-C-cyano-2-deoxy-beta-D-arabinopentofuranosyl) cytosine) and its N4-palmitoyl derivative ( CS-682). Int J Cancer 1999 ; 82 ( 2 ): 226 - 236 .
26. Kantarjian H , Garcia-Manero G , O'Brien S et al. Phase I clinical and pharmacokinetic study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome . J Clin Oncol 2010 ; 28 ( 2 ): 285 - 291 .
27. Matsuda A , Nakajima Y , Azuma A , Tanaka M , Sasaki T. Nucleosides and nucleotides. 100 . 20-C-cyano-20-deoxy-1-beta-D-arabinofuranosyl-cytosine (CNDAC): design of a potential mechanism-based DNA-strand-breaking antineoplastic nucleoside . J Med Chem 1991 ; 34 ( 9 ): 2917 - 2919 .
28. Kantarjian H , Faderl S , Garcia-Manero G et al. Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study . Lancet Oncol 2012 ; 13 ( 11 ): 1096 - 1104 .
29. Burnett AK , Russell N , Hills RK et al. A randomised comparison of the novel nucleoside analogue sapacitabine with low-dose cytarabine in older patients with acute myeloid leukaemia . Leukemia . 2015 ; 29 ( 6 ): 1312 - 1319 .
30. Ravandi F , Kadia TM , Borthakur G et al. Pooled analysis of elderly patients with newly diagnosed AML treated with sapacitabine and decitabine administered in alternating cycles . Blood (ASH Annual Meeting Abstracts ) 2012 ; 120 ( 21 ): 2630 .
31. Quintas-Cardama A , Ravandi F , Liu-Dumlao T et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia . Blood 2012 ; 120 ( 24 ): 4840 - 4845 .
32. Dombret H , Seymour JF , Butrym A et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts . Blood 2015 ; 126 ( 3 ): 291 - 299 .
33. Kadia TM , Thomas XG , Dmoszynska A et al. Decitabine improves outcomes in older patients with acute myeloid leukemia and higher blast counts . Am J Hematol 2015 ; 90 ( 7 ): E139 - E141 .
34. Chuang JC , Warner SL , Vollmer D et al. S110 , a 5 - Aza-20-deoxycytidinecontaining dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth . Mol Cancer Ther 2010 ; 9 ( 5 ): 1443 - 1450 .
35. Srivastava P , Paluch BE , Matsuzaki J et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts . Leuk Res 2014 ; 38 ( 11 ): 1332 - 1341 .
36. Yoo CB , Jeong S , Egger G et al. Delivery of 5-aza-20-deoxycytidine to cells using oligodeoxynucleotides . Cancer Res 2007 ; 67 ( 13 ): 6400 - 6408 .
37. Issa JP , Roboz G , Rizzieri D 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 ( 9 ): 1099 - 1110 .
38. Griffiths EA , Kantarjian HM , Roboz GJ et al. First results of a phase 2 study using a 10-day subcutaneous (SC) regimen of the novel hypomethylating agent (HMA) SGI-110 for the treatment of relapsed/refractory acute myeloid leukemia (r/r AML) . J Clin Oncol (ASCO Meeting Abstracts ) 2014 ; 32 (15 suppl): 7030 .
39. Ikezoe T , Yang J , Nishioka C et al. A novel treatment strategy targeting polo-like kinase 1 in hematological malignancies . Leukemia 2009 ; 23 ( 9 ): 1564 - 1576 .
40. Gjertsen BT , Schoffski P. Discovery and development of the Polo-like kinase inhibitor volasertib in cancer therapy . Leukemia 2015 ; 29 : 11 - 19 .
41. Bug G , Schlenk RF , Muller-Tidow C et al. Phase I/ II study of BI 6727 (volasertib), an intravenous Polo-like kinase-1 (Plk1) inhibitor, in patients with acute myeloid leukemia (AML): results of the dose finding for BI 6727 in combination with lowdose cytarabine . Blood (ASH Annual Meeting Abstracts ) 2010 ; 116 ( 21 ): 3316 .
42. Dohner H , Lubbert M , Fiedler W et al. Randomized , phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy . Blood 2014 ; 124 ( 9 ): 1426 - 1433 .
43. Losman JA , Looper RE , Koivunen P et al. ( R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible . Science 2013 ; 339 ( 6127 ): 1621 - 1625 .
44. Ward PS , Patel J , Wise DR et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alphaketoglutarate to 2-hydroxyglutarate . Cancer Cell 2010 ; 17 ( 3 ): 225 - 234 .
45. Xu W , Yang H , Liu Y et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases . Cancer Cell 2011 ; 19 ( 1 ): 17 - 30 .
46. DiNardo CD , Stein EM , Altman J et al. AG-221, An oral, selective, first-in-class, potent inhibitor of the IDH2 mutant enzyme, induced durable responses in a phase I study of IDH2 mutation-positive advanced hematologic malignancies . Blood (EHA Annual Meeting Abstracts ) 2015 ; Abstr 100170.
47. De Botton S , Pollyea DA , Stein EM et al. Clinical safety and activity of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a phase 1 study of patients with advanced IDH1-mutant hematologic malignancies . Blood (EHA Annual Meeting Abstracts ) 2015 ; Abstr 100704.
48. Pan R , Hogdal LJ , Benito JM et al. Selective BCL-2 inhibition by ABT-199 causes ontarget cell death in acute myeloid leukemia . Cancer Discov 2014 ; 4 ( 3 ): 362 - 375 .
49. Konopleva M , Pollyea DA , Potluri J et al. A phase 2 study of ABT-199 (GDC-0199) in patients with acute myelogenous leukemia (AML) . Blood 2014 ; 124 ( 21 ): 118 .
50. Chan SM , Thomas D , Corces-Zimmerman MR et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia . Nat Med 2015 ; 21 ( 2 ): 178 - 184 .
51. Pratz KW , Sato T , Murphy KM et al. FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML . Blood 2010 ; 115 ( 7 ): 1425 - 1432 .
52. Zhang W , Konopleva M , Shi YX et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia . J Natl Cancer Inst 2008 ; 100 ( 3 ): 184 - 198 .
53. Ravandi F , Cortes JE , Jones D 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 ( 11 ): 1856 - 1862 .
54. Röllig C , Müller-Tidow C , Hüttmann A et al. Sorafenib versus placebo in addition to standard therapy in younger patients with newly diagnosed acute myeloid leukemia: results from 267 patients treated in the randomized placebo-controlled SAL-Soraml trial . Blood 2014 ; 124 ( 21 ): 6 .
55. Serve H , Krug U , Wagner R 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 ( 25 ): 3110 - 3118 .
56. Ravandi F , Alattar ML , Grunwald MR 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 ( 23 ): 4655 - 4662 .
57. Fischer T , Stone RM , Deangelo DJ et al. Phase IIB trial of oral Midostaurin (PKC412), the FMS-like tyrosine kinase 3 receptor (FLT3) and multi-targeted kinase inhibitor, in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome with either wild-type or mutated FLT3 . J Clin Oncol 2010 ; 28 ( 28 ): 4339 - 4345 .
58. Stone RM , Fischer T , Paquette R 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 ( 9 ): 2061 - 2068 .
59. Stone RM , Mandrekar S , Sanford BL et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients ( pts) age 18-60 with FLT3 mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]) . Blood 2015 ; 126 ( 23 ): 6 .
60. Cooper BW , Kindwall-Keller TL , Craig MD et al. A phase I study of midostaurin and azacitidine in relapsed and elderly AML patients . Clin Lymphoma Myeloma Leuk 2015 ; 15 ( 7 ): 428 - 432 e422.
61. Strati P , Kantarjian H , Ravandi F 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 ( 4 ): 276 - 281 .
62. Levis M. Quizartinib for the treatment of FLT3/ITD acute myeloid leukemia . Future Oncol 2014 ; 10 ( 9 ): 1571 - 1579 .
63. Cortes JE , Perl AE , Dombret H 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 (ASH Annual Meeting Abstracts ) 2012 ; 120 ( 21 ): 48 .
64. Levis MJ , Perl AE , Dombret H 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 secondline chemotherapy or hematopoietic stem cell transplantation . Blood (ASH Annual Meeting Abstracts ) 2012 ; 120 ( 21 ): 673 .
65. Cortes J , Tallman MS , Schiller G et al. Results of a phase 2 randomized, open-label, study of lower doses of quizartinib (AC220; ASP2689) in subjects with FLT3-ITD positive relapsed or refractory acute myeloid leukemia (AML) . Blood 2013 ; 122 ( 21 ): 494 .
66. Altman J , Foran JM , Pratz KW et al. Results of a phase 1 study of quizartinib (AC220, ASP2689) in combination with induction and consolidation chemotherapy in younger patients with newly diagnosed acute myeloid leukemia . Blood 2013 ; 122 ( 21 ): 623 .
67. Borthakur G , Kantarjian HM , O'Brien S 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 2014 ; 124 ( 21 ): 388 .
68. Collins R , Kantarjian HM , Levis MJ et al. Clinical activity of crenolanib in patients with D835 mutant FLT3-positive relapsed/refractory acute myeloid leukemia (AML) . J Clin Oncol (ASCO Meeting Abstracts ) 2014 ; 32 (15 suppl): 7027 .
69. Daver NG , Konopleva M , Kohrt HE et al. First-in-human study of FLX925, an orally administered FLT3/CDK4/CDK6 inhibitor, in subjects with relapsed or refractory acute myeloid leukemia (AML). First-in-human study of FLX925, an orally administered FLT3/CDK4/CDK6 inhibitor, in subjects with relapsed or refractory acute myeloid leukemia (AML) . J Clin Oncol (ASCO Meeting Abstracts ) 2015 ; 33 (15 suppl): TPS7098.
70. Levis MJ , Perl AE , Altman JK et al. Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) . J Clin Oncol (ASCO Meeting Abstracts ) 2015 ; 33 (15 suppl): 7003 .
71. Antar A , Kharfan-Dabaja MA , Mahfouz R , Bazarbachi A. Sorafenib maintenance appears safe and improves clinical outcomes in FLT3-ITD acute myeloid leukemia after allogeneic hematopoietic cell transplantation . Clin Lymphoma Myeloma Leuk 2015 ; 15 ( 5 ): 298 - 302 .
72. Chen YB , Li S , Lane AA et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia . Biol Blood Marrow Transplant 2014 ; 20 ( 12 ): 2042 - 2048 .
73. Schlenk R , Döhner K , Salih H et al. Midostaurin in combination with intensive induction and as single agent maintenance therapy after consolidation therapy with allogeneic hematopoietic stem cell transplantation or high-dose cytarabine (NCT01477606) . Blood 2015 ; 126 ( 23 ): 322 .
74. Burnett AK , Hills RK , Milligan D et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial . J Clin Oncol 2011 ; 29 ( 4 ): 369 - 377 .
75. Burnett AK , Russell NH , Hills RK et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia . J Clin Oncol 2012 ; 30 ( 32 ): 3924 - 3931 .
76. Castaigne S , Pautas C , Terre C et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study . Lancet 2012 ; 379 ( 9825 ): 1508 - 1516 .
77. Hills RK , Castaigne S , Appelbaum FR et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a metaanalysis of individual patient data from randomised controlled trials . Lancet Oncol 2014 ; 15 ( 9 ): 986 - 996 .
78. Kung Sutherland MS , Walter RB , Jeffrey SC et al. SGN-CD33A: a novel CD33- targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML . Blood 2013 ; 122 ( 8 ): 1455 - 1463 .
79. Stein EM , Stein A , Walter RB et al. Interim analysis of a phase 1 trial of SGNCD33A in patients with CD33-positive acute myeloid leukemia (AML) . Blood (ASH Annual Meeting Abstracts ) 2014 ; 124 ( 21 ): 623 .
80. Topp MS , Gokbuget N , Stein AS et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study . Lancet Oncol 2015 ; 16 ( 1 ): 57 - 66 .
81. Krupka C , Kufer P , Kischel R et al. CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330 . Blood 2014 ; 123 ( 3 ): 356 - 365 .