From www.bloodjournal.org by guest on July 24, 2016. For personal use only.

Review Series

ADVANCES IN ACUTE MYELOID LEUKEMIA

An update of current treatments for adult acute myeloid leukemia

Hervé Dombret1,2 and Claude Gardin2,3
1
Department of Hematology, Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France; 2Leukemia Translational Laboratory,
EA3518, Institut Universitaire d’Hématologie, Université Paris Diderot, Paris, France; and 3Department of Hematology, Hôpital Avicenne, AP-HP,
Bobigny, France

Recent advances in acute myeloid leukemia
(AML) biology and its genetic landscape
should ultimately lead to more subset-
specific AML therapies, ideally tailored to
each patient’s disease. Although a growing
number of distinct AML subsets have been
increasingly characterized, patient man-
agement has remained disappointingly uni-
form. If one excludes acute promyelocytic
leukemia, current AML management still
relies largely on intensive chemotherapy
and allogeneic hematopoietic stem cell
transplantation (HSCT), at least in younger
patients who can tolerate such intensive
treatments. Nevertheless, progress has
been made, notably in terms of standard
drug dose intensification and safer alloge-
neic HSCT procedures, allowing a larger
proportion of patients to achieve durable
remission. In addition, improved identifica-
tion of patients at relatively low risk of re-
lapse should limit their undue exposure to
the risks of HSCT in first remission. The role
of new effective agents, such as purine
analogs or gemtuzumab ozogamicin, is still
under investigation, whereas promising
new targeted agents are under clinical de-
velopment. In contrast, minimal advances
have been made for patients unable to
tolerate intensive treatment, mostly rep-
resenting older patients. The availability
of hypomethylating agents likely repre-
sents an encouraging first step for this
latter population, and it is hoped will allow
for more efficient combinations with novel
agents. (Blood. 2016;127(1):53-61)

Introduction
Long-term cure of patients with acute promyelocytic leukemia (APL)
using retinoic acid and arsenic trioxide (ATO) therapy represents the
only dramatic therapeutic advance over the last 2 decades in acute
myeloid leukemia (AML).1 Although increasingly refined knowledge
of AML biology has led to the development of new targeted agents such
as the mutated FLT3 or IDH inhibitors, current advances in non-APL
patients lack innovation, relying instead on modifications to doses and
schedules of standard cytotoxic drugs or progress in hematopoietic stem
cell transplantation (HSCT) techniques. In younger patients, complete
remission (CR) rates of $80% may be reached, with 5-year overall
survival (OS) ;40%. In older patients, the use of hypomethylating agents
has improved median and short-term OS but has not translated into
improved cure rates, which remain disappointingly very low. Guidelines
for AML management are widely available. This review aims to provide
a balanced perspective of available data supporting AML treatment used
in routine practice today. We have focused on data from randomized
clinical trials using approved drugs. Early results with new inves-
tigational drugs will be discussed in depth in another article of this
Review Series.
Front-line induction therapy
Induction therapy with cytarabine and an anthracycline remains a
standard of care in AML. The standard combination is the 713, with a
7-day continuous infusion of cytarabine at the dosage of 100 or 200 mg/m2
per day on days 1 to 7 and daunorubicin at 60 mg/m2 per day on days 1
to 3. Recent randomized studies have investigated higher doses of
anthracyclines or cytarabine or the addition of a third agent during
induction. However, it is very difficult to compare these studies, because
they differ significantly in several key parameters, notably the number of
induction courses, doses in the control arm, and subsequent therapies
offered to responders or to patients with persistent marrow blasts after the
first induction course. Differences in study results may thus be caused by
differences in the design of either experimental or control arms.
Anthracyclines
Recently reported randomized studies exploring daunorubicin or
idarubicin doses during induction courses are summarized in Table 1.2-8
Four studies have evaluated higher daunorubicin doses.2,4-6 The
Eastern Cooperative Oncology Group (ECOG) trial included patients
aged #60 years,2 whereas the European trial from a Dutch, Belgian,
German, and Swiss consortium included patients aged $60 years.4
Both studies compared a daily dose of 45 mg/m2 vs a doubled dose of
90 mg/m2 for 3 days as part of 713 induction therapy. The higher
daunorubicin dose was associated with higher CR rates, without
delaying hematologic recovery or affecting the feasibility of planned
postremission therapies. In the younger population ECOG trial, OS was
significantly prolonged in the 90 mg/m2 arm.2 The OS benefit was
observed in all cytogenetic groups and in patients with internal tandem
duplication (ITD) of the FLT3 gene, as well as in those with NPM1 and
DNMT3A gene mutations.3 In the older population trial, the OS benefit
was restricted to patients between the age of 60 and 65 years and to the
few patients with core-binding factor (CBF) AML.4
These results demonstrate that the 45 mg/m2 daunorubicin daily
dose is suboptimal up until the age of 65 years. They do not, however,
establish that the 90 mg/m2 daily dose should be preferred over the
60 mg/m2 daily dose endorsed by the international 2010 guidelines.9

Submitted August 1, 2015; accepted October 3, 2015. Prepublished online as © 2016 by The American Society of Hematology
Blood First Edition paper, December 10, 2015; DOI 10.1182/blood-2015-08-
604520.

BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1 53

 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.

54 DOMBRET and GARDIN BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1

Table 1. Randomized studies of anthracycline dose and type for AML induction therapy
Study Age (y) Patients (N) Experimental arm Control arm Key conclusions

ECOG2,3 17-60 657 D, 90 mg/m2 d1-3 D, 45 mg/m2 d1-3 Higher response rate
A, 100 mg/m2 CIV d1-7 A, 100 mg/m2 CIV d1-7 Similar toxicity
cycle 1* cycle 1* Longer OS
HOVON-SAKK-AMLSG4 .60 813 D, 90 mg/m2 d1-3 D, 45 mg/m2 d1-3 Higher response rate
A, 200 mg/m2 CIV d1-7 A, 200 mg/m2 CIV d1-7 Similar toxicity
cycle 1 cycle 1 Similar OS†
Korean Group5 15-60 383 D, 90 mg/m2 d1-3 D, 45 mg/m2 d1-3 Higher response rate
A, 200 mg/m2 CIV d1-7 A, 200 mg/m2 CIV d1-7 Similar toxicity
cycle 1‡ cycle 1‡ Longer EFS and OS
NCRI AML176 16-72 1206 D, 90 mg/m2 d1/3/5 D, 60 mg/m2 d1/3/5 Similar response rate
A, 100 mg/m2/12 h d1-10 A, 100 mg/m2/12 h d1-10 Higher early death rate with 90 mg/m2
cycle 1§ cycle 1§ Similar EFS and OS
ALFA-98017 50-70 468 I, 12 mg/m2 d1-3 or d1-4 D, 80 mg/m2 d1-3 Higher response rate in one course
A, 200 mg/m2 CIV d1-7 A, 200 mg/m2 CIV d1-7 Similar early death rates
cycle 1 cycle 1 Similar EFS and OS
JALSG AML2018 15-64 1057 D, 50 mg/m2 d1-5 I, 12 mg/m2 d1-3 Similar response rate
A, 100 mg/m2 CIV d1-7 A, 100 mg/m2 CIV d1-7 Higher early death rate with control arm
cycle 1|| cycle 1|| Similar RFS and OS

A, cytarabine; CIV, continuous IV infusion; D, daunorubicin; EFS, event-free survival; I, idarubicin; OS, overall survival.
*A second 713 DA cycle with 45 mg/m2 per day daunorubicin was given to patients with residual marrow blasts on d12/14 of cycle 1.
†A significant EFS and OS benefit was observed in the subgroup of patients aged 60 to 65 years.
‡A second 512 DA cycle with 45 mg/m2 per day daunorubicin was given to patients with persistent leukemia after cycle 1.
§In this study, all patients but poor-risk received a second DA course with 50 mg/m2 per day daunorubicin.
||A second cycle, identical to the first one, was given to patients with persistent leukemia after cycle 1.

The recent UK NCRI AML17 trial addressed this question in an up-
front comparison of the 60 and 90 mg/m2 doses in the first course.6 All
favorable- and intermediate-risk patients went on to receive a second
course with a 50 mg/m2 dose. In an interim analysis, a significant in-
crease in day 60 mortality was observed in the 90 mg/m2 arm, leading to
premature trial termination. No OS benefit was observed in this
analysis, although evidence of a survival benefit in subgroups may
require longer follow-up.
The Acute Leukemia French Association (ALFA) 9801 study com-
paring daunorubicin vs idarubicin, failed to demonstrate superiority of
80 mg/m2 daunorubicin over a standard 12 mg/m2 idarubicin dose.7
A similar outcome was reported in the Japan Acute Leukemia Study
Group (JALSG) AML201 study, which compared 2 courses of 50 mg/m2
daunorubicin for 5 days with 12 mg/m2 idarubicin for 3 days.8
Antileukemic activity of 60 and 90 mg/m2 daunorubicin or 12 mg/m2
idarubicin daily doses thus appears to be similar, as are the toxicity
profiles, at least in cases when a second anthracycline-containing
cycle is not given systematically to responders.
for 5 days during the first course and 2000 mg/m2 every 12 hours on
days 1, 2, 4, and 6 during the second course.12 Similar rates of CR,
event-free survival (EFS), and OS were observed in the 2 arms, with
more toxicity associated with the HiDAC arm.
In the second study, conducted by the EORTC and GIMEMA Leu-
kemia Groups, patients were randomized to receive either standard doses
at 100 mg/m2 per day cytarabine for 10 days or HiDAC at 3000 mg/m2
every 12 hours on days 1, 3, 5, and 7 during the first course.13 A higher
CR rate was observed in the HiDAC arm, with a trend for a longer OS
that reached statistical significance in the subset of patients aged
#45 years. Finally, in the randomized German Intergroup study that
included a double induction as a “common” arm or an IDAC or
HiDAC sequence during induction in at least 3 study arms, no
difference in OS was observed.14 It thus remains unclear whether
increasing the cytarabine dose during induction may benefit patients
planned to receive IDAC or HiDAC during postremission therapy.
“Dose-dense” regimens

Another approach to increasing induction intensity relies on systematic

Cytarabine administration of a second sequence of chemotherapy starting earlier
than normal after the completion of the first sequence (generally be-
Randomized studies exploring cytarabine dose and schedule during
tween day 7 and day 14). This timed-sequential concept was initially
induction are summarized in Table 2. Historical studies from the
developed by the Johns Hopkins group in Baltimore,15 then prospec-
Southwest Oncology Group (SWOG) and the Australian Leukemia
tively evaluated by the ALFA group without incorporating HiDAC.16
Study Group (ALSG) failed to demonstrate clinically relevant gains in
After investigating double induction containing 1 or 2 HiDAC se-
efficacy with higher cytarabine doses with alternative administration
quences (TAD-HAM or HAM-HAM),17 the German AML Coop-
regimens, whereas both reported increased toxicity.10,11 Two recent
erative Group recently conducted a phase 2 trial investigating a
studies further addressed this question, one in the context of idarubicin
sequential S-HAM.18 However, none of these studies provide
or amsacrine and the other using lower etoposide doses and alternative
evidence that a dose-dense regimen is superior to the standard 713
administration schedules.
regimen, especially when high doses of daunorubicin are used.
In the study conducted by the Dutch-Belgian Cooperative Trial
Group for Hemato-Oncology (HOVON) and the Swiss Group for Addition of a third drug
Clinical Cancer Research (SAKK), patients were randomized between
an IDAC arm, comprising 200 mg/m2 per day cytarabine during the first Gemtuzumab ozogamicin (GO). Randomized studies exploring
course and 1000 mg/m2 every 12 hours for 6 days during the second the addition of GO to intensive chemotherapy (ICT) are summarized
course, or a high-dose (HiDAC) arm with 1000 mg/m2 every 12 hours in Table 3.19-26 Six studies evaluating the addition of 3 or 6 mg/m2
 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.

BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1 TREATMENT OF ADULT AML 55

Table 2. Randomized studies of cytarabine dose for AML induction therapy

Study Age (y) Patients (N) Experimental arm Control arm Conclusions
SWOG10 15-64 723 A, 2000 mg/m2/12 h d1-6* A, 200 mg/m2 CIV d1-7 Similar response rate
D, 45 mg/m2 d7-9 D, 45 mg/m2 d5-7 Higher early death rate
cycle 1† cycle 1† Longer RFS in patients aged ,50 y
Similar OS
ALSG11 15-60 301 A, 3000 mg/m2/12 h d1/3/5/7 A, 100 mg/m2 CIV d1-7 Higher response rate in one course
D, 50 mg/m2 d5-7 D, 50 mg/m2 d5-7 Non significantly higher early death rate
E, 75 mg/m2 d1-7 E, 75 mg/m2 d1-7 Longer RFS
cycle 1‡ cycle 1‡ Similar OS
HOVON-SAKK12 18-60 860 A, 1000 mg/m2/12 h d1-5 I, 12 mg/m2 A, 200 mg/m2 CIV d1-7 I, 12 mg/m2 Similar response rate
d5-7 cycle 1 d5-7 cycle 1
A, 2000 mg/m2/12 h d1/2/4/6 Am, A, 1000 mg/m2/12 h d1-6 Am, Similar EFS and OS
120 mg/m2 d3/5/7 cycle 2§ 120 mg/m2 d3/5/7 cycle 2§
EORTC-GIMEMA 15-60 1942 A, 3000 mg/m2/12 h d1/3/5/7 A, 100 mg/m2 CIV d1-10 Higher response rate
AML1213 D, 50 mg/m2 d1/3/5 D, 50 mg/m2 d1/3/5 Similar early death rate
E, 50 mg/m2 d1-5 E, 50 mg/m2 d1-5 Longer RFS and OS in patients aged #45 y
cycle 1|| cycle 1||

A, cytarabine; Am, amsacrine; CIV, continuous IV infusion; D, daunorubicin; E, etoposide; I, idarubicin; RFS, relapse-free survival; OS, overall survival.
*During the first 2 years of the study, cytarabine was given at 3000 mg/m2 per bolus to patients aged ,50 years, then reduced to 2000 mg/m2 per bolus because of
excessive neurologic toxicity.
†In both arms a second cycle, identical to the first one, was given to patients with persistent leukemia after cycle 1; all CR patients from the control arm were then
randomized to either standard-dose cytarabine or HiDAC during consolidation, whereas all CR patients from the experimental arm received HiDAC during consolidation.
‡A second, then a third, cycle, identical to the first one, was given to patients with persistent leukemia after cycle 1 or 1-2, respectively.
§After cycle 2, CR patients received either allogeneic or autologous HSCT or a third chemotherapy cycle for consolidation.
||In both arms, a second cycle, identical to the first one, was given to patients with persistent leukemia after cycle 1, then all CR patients received one IDAC-containing
consolidation course followed by allogeneic or autologous HSCT.

GO during induction have been performed.19-24 The first of them,
SWOG S0106, was negative and closed prematurely because of a
higher early mortality rate despite a reduced 45 mg/m2 per day
daunorubicin dose in the GO arm, leading to GO withdrawal by the
Food and Drug Administration in the United States.19 Conversely, 4
studies reported significant improvements when GO was combined
with induction or induction-and-consolidation chemotherapy.20-23 This
finding was confirmed in a recent meta-analysis.27 Nonetheless, the
addition of GO was associated with more frequent severe liver toxicity
and persistent thrombocytopenia. The benefit/risk ratio appeared to be at
least as good with 3 mg/m2 per dosing,24 a dose that can be administered
to older patients,21 and ultimately be repeated as successfully developed
by the ALFA group.22 In contrast, increased toxicity and an absence of
clinical benefit were observed in the EORTC/GIMEMA study, in which
single-agent GO administration preceded induction chemotherapy.25
Finally, the 2 studies that evaluated GO maintenance therapy were
negative.19,26 Clinical response to GO is likely to be influenced by
CD33 expression level, clonal hierarchy of the leukemic population,
and drug efflux intensity, all factors related to AML genetics. It has been
widely demonstrated that GO benefits patients of favorable and
intermediate risk, including those with FLT3-ITD, although not those
with an adverse karyotype.27 Together, these data suggest that the
license status of GO might need to be reviewed, at least for some patient
subsets. Early outcomes with the SGN-CD33A immunoconjugate
in AML are discussed elsewhere in this Review Series.
Purine analogs. Randomized studies exploring the addition of
purine analogs to ICT are summarized in Table 4.28-32 In the Polish
Acute Leukemia Group (PALG) study, the addition of cladribine was
associated with prolonged OS,28 although it should be noted that
outcomes in the control arm appeared to be suboptimal. Interestingly,
addition of cladribine appears to have particularly benefited high-risk
patients, notably those aged $50 years or those with unfavorable
cytogenetics. Clofarabine also demonstrated significant antileukemic
activity, both as a single agent and in combination with cytarabine in
various patient populations.33,34 However, it failed to show significant
benefit when combined with daunorubicin in the British AML16 trial in
newly diagnosed patients.29 Front-line results from 2 other trials are
imminent, including the combination of clofarabine with 713,35 and
clofarabine compared with 713 in an ECOG trial. The British AML15
trial in a younger population demonstrated that the fludarabine,
cytarabine, granulocyte colony-stimulating factor (G-CSF), and
idarubicin regimen (FLAG-Ida) yielded more frequent remissions with
one course and also reduced the risk of relapse.30
Sorafenib. Sorafenib is a multikinase inhibitor with in vitro
activity in FLT3-ITD AML. In an AML trial from the German Study
Alliance Leukemia, combination of sorafenib with standard induction
and IDAC consolidation was evaluated in older patients. Treatment in
the sorafenib arm did not result in significant improvement in EFS or
OS.36 This was also true for subgroup analyses, including the subgroup
positive for FLT3-ITD. Results of induction therapy were worse in the
sorafenib arm, with higher early mortality and a lower CR rate. The
same group has reported preliminary results of a similar trial conducted
in younger patients in which sorafenib was added to 713 induction and
HiDAC consolidations.37 No difference in the CR rate was observed,
whereas EFS and relapse-free survival (RFS) were significantly im-
proved in the sorafenib arm. In the subgroup of FLT3-ITD–positive
patients, no difference in EFS was observed; however, there was a trend
for prolonged RFS and OS favoring sorafenib.
Postremission therapy
HiDAC consolidation
For younger patients not undergoing HSCT, administration of several
HiDAC consolidation courses using cytarabine twice daily at a 3 g/m2
dose on days 1, 3, and 5 has been a widely used option since 1994.38
Even if the optimal cytarabine dose, schedule of administration, and
number of cycles need yet to be defined,39,40 the use of bolus admin-
istration of HiDAC or IDAC during consolidation should be recom-
mended. Interestingly, HiDAC and IDAC regimens are well suited to
evaluate the effects of added targeted or nontargeted drugs during
 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.

56 DOMBRET and GARDIN BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1

Table 3. Randomized trials of gemtuzumab ozogamicin (GO) associated with intensive chemotherapy
Treatment phase
Study (age range [y]) Patients (N) GO dose and schedule Conclusions
SWOG S010619 Induction (18-60) 637 GO, 6 mg/m2 Similar response rate
d4 cycle 1* Higher early death rate
Similar RFS
Similar OS
NCRI AML1520 Induction (18-60) 1113 GO, 3 mg/m2 Similar response rate
d1 cycle 1 Similar RFS and OS
d1 cycle 3† Longer OS in favorable AML
NCRI AML1621 Induction (.60) 1115 GO, 3 mg/m2 Similar response rate
d1 cycle 1 Longer RFS, OS from CR, and OS
ALFA-070122 Induction 278 GO, 3 mg/m2 Similar response rate
Consolidation d1/4/7 cycle 1 Longer EFS, RFS, and OS
(50-70) d1 conso 1
d1 conso 2
GOELAMS 200623 Induction (18-60) 254 GO, 6 mg/m2 Similar response rate
d4 cycle 1 Similar EFS and OS
d4 conso 1 Longer EFS in non–allo-HSCT patients
NCRI AML1724 Induction (0-81) 788 GO, 3 vs 6 mg/m2 Similar responses rate
d1 cycle 1 Lower early death rate with 3 mg/m2
Similar RFS and OS
EORTC-GIMEMA Prior to induction (61-75) 472 GO, 6 mg/m2 Similar response rate
AML-1725 d1/15 before cycle 1 Higher early death rate
Similar RFS
Similar EFS and OS
HOVON-SAKK-AMLSG26 Maintenance (.60) 232 GO, 6 mg/m2 Similar relapse incidence
3 monthly cycles Similar RFS and OS
SWOG S010619 Maintenance (18-60) 174 GO, 5 mg/m2 Similar RFS
3 monthly cycles

EFS, event-free survival; OS, overall survival; RFS, relapse-free survival.

*Daunorubicin dose was reduced from 60 mg/m2 per day in the control arm to 45 mg/m2 per day in the GO arm.
†Additional randomization for GO during cycle 3, irrespective of cycle 1 GO treatment.

consolidation. For instance, a prolonged RFS was observed in the ran-
domized ALFA-0702/CLARA study in intermediate- and unfavorable-
risk patients with clofarabine/IDAC compared with HiDAC consolidation
cycles.31
Allogeneic HSCT
One of the most important treatment decisions in AML is to estimate the
benefit/risk associated with allogeneic HSCT in first remission for a
given patient. Transplantation offers the best means of preventing AML
recurrence, but remains associated with higher treatment-related mor-
bidity and mortality (TRM), especially in older patients. In patients with
favorable-risk AML, the relapse risk may be low enough and the
salvage rate high enough to postpone HSCT to second remission. This
strategy has been validated in several donor vs no-donor studies.41,42 In
these studies, favorable patients (ie, those with CBF-AML) from the no-
donor group did as well as those from the donor group, whereas all other
patients appeared to benefit from undergoing allograft. One should

Table 4. Randomized trials of purine analogs associated to intensive chemotherapy

Treatment phase Patients
Study Analog (age range [y]) (N) Treatment modalities Conclusions

PALG28 Cladribine or fludarabine Induction (16-60) 652 DAC vs DAF vs DA DAC: Higher response rate, similar RFS, longer OS*
cycle 1 DAF: Similar response rate, similar RFS and OS†
NCRI AML1629 Clofarabine Induction (.60) 806 DA vs DClo Similar response rate‡
cycle 1-2 Similar RFS and OS
NCRI AML1530 Fludarabine Induction (0-73) 3106 DA vs ADE vs FLAG-Ida ADE: similar response rate, RFS and OS
cycle 1-2 FLAG-Ida: Similar response rate§, higher rate of death
in CR, longer RFS, similar OS
ALFA-070231 Clofarabine Postremission (18-60) 221 CLARA vs HiDAC Longer RFS in non allo-HSCT patients
consolidation cycle 1-3 Similar OS
CLASSIC I32 Clofarabine First salvage (.55) 320 CLARA vs IDAC Higher response rate
up to 3 cycles Higher early death rate
Longer EFS
Similar OS

ADE, DA 1 etoposide; CLARA, clofarabine 1 IDAC; DA, daunorubicin 1 cytarabine; DAC, DA 1 cladribine; DAF, DA 1 fludarabine; DClo, daunorubicin 1 clofarabine;
FLAG-Ida, fludarabine 1 IDAC 1 G-CSF 1 idarubicin; HiDAC, high-dose cytarabine; HSCT, hematopoietic stem cell transplantation; IDAC, intermediate-dose cytarabine.
*Longer OS in patients .50 years of age, those with initial leukocyte count .50 3 109/L, and those with unfavorable cytogenetics.
†Longer OS in patients with unfavorable cytogenetics.
‡Lower CR in one course after DClo.
§Higher CR in one course after FLAG-Ida.
 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.
BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1
keep in mind that patients in these studies mostly underwent sibling
donor myeloablative conditioning (MAC) transplantation and as such,
the benefit associated with HSCT was only demonstrated for patients
,40 years of age. Based on another donor vs no-donor analysis,
patients with cytogenetically normal (CN) AML and a favorable geno-
type (defined as mutated CEBPA or NPM1 without FLT3-ITD) were
recently categorized in the favorable subgroup.43 Because the outcome
after allogeneic HSCT from fully matched unrelated donors appears
to be similar compared with allogeneic HSCT from matched related
donors, all younger patients with intermediate- and unfavorable-risk
AML are generally considered candidates for allogeneic HSCT from
sibling or fully-matched unrelated donors in cases of first CR.7
This HSCT benefit/risk assessment, based on the European
LeukemiaNet (ELN) genetic classification only,7 needs however to be
reconsidered in the near future. As discussed in another article of this
Review Series, the incidence of TRM has been substantially reduced
over the last few decades,44 particularly in older patients, by using
reduced-intensity conditioning (RIC). Alternative stem cell sources are
more widely used and are safer, as illustrated by post-transplant ad-
ministration of cyclophosphamide in haplo-identical HSCT.45,46 Of
particular interest are the recent results of studies evaluating RIC
transplantation in middle-aged patients.47-50 Using a time-dependent
Mantel-Byar comparison in patients .45 years of age, the MRC
AML15 trial showed that, compared with chemotherapy, RIC trans-
plantation was associated with longer survival.47 Two recent studies
have even suggested that RIC might be preferred to MAC transplan-
tation in this age range, given the lower TRM as well as better survival
in some risk subgroups.49,50
Reliance on genetic profiles as the main treatment-stratifying tool is
being increasingly challenged because of multiple recently described
genetic mutations and the potential impact of mutated allele frequencies.
Not all patients with ELN favorable-risk AML have a favorable out-
come; for instance, should we take into account the presence of ad-
ditional KIT or FLT3 poor-risk mutations in a patient with CBF-AML,
or of additional ASXL1, IDH1 or DNMT3A mutations in a patient with
NPM1-mutated CN-AML and no FLT3-ITD? Likewise, should HSCT
be considered the best postremission option in ELN intermediate-risk
patients with NPM1-mutated FLT3-ITD–positive CN-AML but a low
FLT3-ITD allelic ratio?51-54
Assessment of minimal residual disease (MRD) using molecular
markers or leukemia-associated aberrant immunophenotypes is therefore
proposed as a more straightforward, easy-to-use prognostic decision
tool, including deciding which patients should be advised to undergo
allogeneic HSCT.55,56 As in acute lymphoblastic leukemia, MRD has
been suggested as ultimately superseding other prognostic factors for
HSCT decision-making, including genetic factors,57 as is already the case
for CBF-AML.58 Nevertheless, whether allogeneic HSCT may be the
option of choice in poor early MRD responders remains an open issue.59
Targeted treatments for specific
AML subgroups
Core binding factor AML
A subgroup analysis of the MRC AML15 younger population
AML trial, along with a subsequent meta-analysis,20-24,27 strongly
suggests that the combination of GO with ICT is associated with a
significant OS benefit in CBF-AML, renewing interest in this drug,
which is currently unavailable outside the context of clinical studies, for
this AML subset.
TREATMENT OF ADULT AML 57
Frequent KIT mutations or overexpression of the KIT receptor were
described some time ago in CBF-AML. Recent studies have evaluated
the potential benefit of dasatinib, a potent KIT inhibitor, in these
patients. In a French study, patients with persistent MRD or molecular
relapse after intensive consolidations were eligible to receive 12 months
of maintenance with dasatinib if they were not a candidate for HSCT.60
No significant impact of dasatinib on time-to-relapse was seen. Two
phase 1-2 trials combined dasatinib with up-front ICT led to a currently
ongoing phase 3 trial.61,62
AML with FLT3 gene mutation
The FLT3-ITD mutation is one of the most frequent bad-prognosis
mutations observed in AML, at least in younger or relapsed patients,
and has led to the evaluation of multikinase or more specific kinase
inhibitors in this AML subset. Lestaurtinib associated with chemother-
apy failed to improve outcomes in relapsed/refractory (R/R) FLT3-ITD
AML patients or during front-line consolidation in the MRC AML15
trial.63,64 Positive results from a large international phase 3 trial in newly
diagnosed FLT3-ITD–positive patients in which midostaurin
was compared to placebo in association with 7+3 should be available
soon. As mentioned before, to date there is no clear evidence of
increased clinically significant activity when sorafenib is added to ICT
in FLT3-ITD–positive patients. A phase 2 study of sorafenib combined
with ICT in older patients, restricted to those diagnosed with FLT3-
mutated AML, is expected to shed light on this issue (Clinical-
Trials.gov #NCT01253070). Conversely, sorafenib delivered after
HSCT seems to be particularly effective in FLT3-ITD–positive
patients.65 Selection of FLT3-resistant mutants has been a general
phenomenon observed in most early trials with first- or second-
generation inhibitors.66 An overview of novel promising FLT3
inhibitors is presented elsewhere in this Review Series.
AML with NPM1 gene mutation
Approximately 30% of CN-AML patients have an NPM1 mutation
and, in contrast to the frequently associated FLT3-ITD, the NPM1
mutation seems to be an early event in most of these cases. Several trials
have reported the effects of adding all-trans retinoic acid (ATRA) to
chemotherapy in non-APL AML, with conflicting results. In the large
MRC trial, no significant effect of the addition of ATRA was
observed.67 Alternatively, 2 studies from the German AML Study
Group reported a benefit of the addition of ATRA restricted to NPM1-
mutated AML patients.68,69 An explanation for these contradictory
results is yet to be defined. More recently, preclinical studies of arsenic
trioxide (ATO) in NPM1-mutated AML from 2 groups strongly
suggested that ATO may have a beneficial effect in this subset.70,71
Because extensive clinical experience with ATO has been gained in the
therapy of APL, clinical studies are planned to confirm whether there is
a beneficial role of ATO in the treatment of NPM1-mutated patients.
AML with mutated IDH
Isocitrate dehydrogenase 1 and 2 gene mutations are present in 10% to
15% of AML patients. As detailed in another article of this Review
Series, early phase 1/2 results of specific inhibition of IDH2- and IDH1-
mutated enzymes are impressive. A phase 3 study will soon be initiated
in relapsing IDH2-mutated patients.
AML with adverse cytogenetic features
In this hard-to-treat AML population, improvement of early response
rate remains an important clinical end point, especially when HSCT can
be envisioned in a timely manner. However, results of trials with novel
 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.
58 DOMBRET and GARDIN
drugs are disappointing. In the PALG cladribine study,28 the subgroup
of patients with unfavorable cytogenetics appeared, nevertheless,
to have a greater benefit. Similarly, a combination of cladribine,
cytarabine, priming with G-CSF, and mitoxantrone (CLAG-M) was
reported to be of benefit compared with 713 in a large, retrospective,
single-center study that primarily included high-risk AML patients.72
Among other nontargeted agents, amonafide combined with cytarabine
failed to yield a benefit over 713 in a secondary AML study.73 Early
results of new drugs, including the CPX-351 liposomal combination,
are discussed elsewhere in this Review Series.
Treatment of older AML patients
Outcome in older patients with AML remains dismal, with lower CR
rates and very few long-term survivors compared with younger
patients. Treatment of older AML patients is thus an active field of
antileukemic drug investigation. Even when short-term benefits have
been demonstrated, very few older patients survive beyond 2 years of
follow-up, raising the question of the appropriateness of OS as an
efficacy end point for drug development in this patient population. Age
itself does not, however, define a homogeneous patient population. In
older patients, prognosis is governed by patient-related and AML-
related factors that are only partly age-related. General health status
and the presence of organ dysfunctions or comorbidities affect ICT
tolerance. As observed in younger patients, cytogenetics can also affect
efficacy. One predominant bad-risk characteristic of older AML is the
increased frequency of prior myelodysplastic syndromes, although
clonal hematopoiesis characterized by the presence of myelodysplastic
syndromes–related gene mutations has also been associated with aging
in healthy individuals.74,75
The most important clinical decision remains to estimate the benefit/
risk associated with ICT in the individual older patient. As for the
decision to recommend HSCT in first CR, there is no unique decision-
guiding score. Older patients with favorable-risk AML according to
ELN classification are likely to benefit from a standard treatment.76,77 In
those unlikely to benefit from ICT, low-dose cytarabine (LDAC) has
been considered as a possible standard, based on the nonintensive
AML14 MRC trial results, despite the fact that patients with adverse
cytogenetics did not draw any benefit from LDAC therapy.78 In 2
large international trials, the hypomethylating agents decitabine and
azacitidine yielded better mid-term results, with longer median and
higher 1-year survival than those observed in LDAC arms, even if they
did not result in a higher proportion of long-term survivors.79,80 Of
interest, azacitidine appeared to offer particular benefit to patients with
adverse cytogenetics and/or those with myelodysplasia-related
changes.80
Current trials in older AML patients often address the effects of the
addition of a new agent to LDAC, azacitidine, or decitabine. To date,
negative results with tipifarnib, ATO, GO, and vosaroxin in combi-
nation with LDAC have been reported by the British group.81-84 Single-
agent sapacitabine or clofarabine also failed to improve outcomes over
LDAC.85,86 Addition of quizartinib, ganetespib, tosedostat, or selinexor
to LDAC is currently under investigation. Interesting phase 2 results
have been observed when combining the polo-like kinase inhibitor
volasertib with LDAC,87 or vosaroxin with decitabine in a single-center
evaluation.88 Too frequently, the evaluation of the efficacy of the com-
binations is hindered by their poor tolerance in older patients deemed
unfit for standard ICT, raising the issue of their evaluation in fitter
patients, potentially against ICT.
BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1
Treatment of relapsed/refractory AML
Treatment of relapsed AML remains poorly defined. Simple clinical
and disease parameters such as age, duration of first remission,
cytogenetics, and prior HSCT remain the most useful parameters
to evaluate treatment effects at relapse.89 In most AML subsets
(other than APL) the main clinical objective of salvage therapy is
to “bridge” patients to HSCT, either with targeted therapies such as
FLT3 inhibitors or with ICT, at least in patients fit enough to
tolerate it. A very large cohort of relapsed AML patients subjected
to salvage therapy after being treated frontline in successive MRC
AML trials has recently been described.90 Analysis of the long-
term outcomes clearly established that allogeneic transplan-
tation when a second response was obtained, strongly benefited
intermediate- and high-risk AML subsets based on initial disease
characteristics.
Optimal salvage drug combinations, drug doses, and administration
schedules remain open issues. In particular, the benefits of the addition
of an anthracycline, or any other drug, to cytarabine, and what
cytarabine dose should be recommended are unclear at best. Recently,
2 large company-sponsored studies evaluated the combination of
clofarabine or vosaroxin to IDAC, with OS as the end point in R/R
AML patients. In the CLASSIC I trial, addition of clofarabine increased
the response rate in patients .55 years of age, albeit at the expense of
increased toxicity and early mortality, but failed to improve OS despite
a higher number of patients bridged to HSCT.32 In the preliminary
results of the largest trial ever performed in R/R patients, the VALOR
trial, combination of vosaroxin to IDAC similarly increased the re-
sponse rate across all ages in both relapsed and refractory patients.
Nonetheless, despite the absence of a significant increase in early
mortality and a large proportion of younger patients bridged to HSCT,
this did not translate into general improvement in OS. A significant,
although modest, survival improvement was only observed in older
patients $60 years of age.91
Conclusion
Despite some advances in the treatment of adult AML patients, many
issues remain to be addressed, as reflected by current recommenda-
tions.7,92 Given the poor long-term outcome for most adult AML
patients, although many novel promising drugs or therapeutic ap-
proaches are currently under development for this population, their
inclusion into prospective clinical trials should be strongly encouraged.
In addition, standardization of trial procedures and control arms would
greatly assist comparison of trial results and strengthen future treatment
recommendations.
Authorship
Contribution: H.D. and C.G. wrote this review article jointly.
Conflict-of-interest disclosure: H.D. is on the Advisory Board of
Celgene, Pfizer, Sunesis, and Agios Pharmaceuticals. C.G. is on the
Advisory Board of Celgene.
Correspondence: Hervé Dombret, Hopital Saint-Louis, Assis-
tance Publique - Hopitaux de Paris (AP-HP), Paris, France; e-mail:
herve.dombret@aphp.fr.
 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.
BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1
References
1. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic
acid and arsenic trioxide for acute promyelocytic
leukemia. N Engl J Med. 2013;369(2):111-121.
2. Fernandez HF, Sun Z, Yao X, et al. Anthracycline
dose intensification in acute myeloid leukemia.
N Engl J Med. 2009;361(13):1249-1259.
3. Luskin MR, Lee J-W, Fernandez HF, et al. High
dose daunorubicin improves survival in AML up
to age 60, across all cytogenetic risk groups
including patients with unfavorable cytogenetic
risk and FLT3-ITD mutant AML: updated analysis
from Eastern Cooperative Oncology Trial E1900
[abstract]. Blood. 2014;124(21). Abstract 373.
4. Löwenberg 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.
5. Lee JH, Joo YD, Kim H, et al. A randomized
trial comparing standard versus high-dose
daunorubicin induction in patients with acute
myeloid leukemia. Blood. 2011;118(14):
3832-3841.
6. Burnett AK, Russell NH, Hills RK, et al.
A randomized comparison of daunorubicin
90 mg/m2 vs 60 mg/m2 in AML induction:
results from the UK NCRI AML17 trial in 1206
patients. Blood. 2015;125(25):3878-3885.
7. Pautas C, Merabet F, Thomas X, et al.
Randomized study of intensified anthracycline
doses for induction and recombinant interleukin-2
for maintenance in patients with acute myeloid
leukemia aged 50 to 70 years: Results of the
ALFA-9801 Study. J Clin Oncol. 2010;28(5):
808-814.
8. Ohtake S, Miyawaki S, Fujita H, et al.
Randomized trial of induction therapy comparing
standard-dose idarubicin with high-dose
daunorubicin in adult patients with previously
untreated acute myeloid leukemia: the JALSG
AML201 Study. Blood. 2011;117(8):2358-2365.
9. Döhner 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.
10. Weick JL, Kopecky KJ, Appelbaum FR, et al.
A randomized investigation of high-dose versus
standard-dose cytosine arabinoside with
daunorubicin in patients with previously untreated
acute myeloid leukemia: a Southwest Oncology
Group study. Blood. 1996;88(8):2841-2851.
11. Bishop JF, Matthews JP, Young GA, et al.
Randomized study of high-dose cytarabine in
induction in acute myeloid leukemia. Blood. 1996;
87(5):1710-1717.
12. Löwenberg B, Pabst T, Vellenga E, et al.
Cytarabine dose for acute myeloid leukemia.
N Engl J Med. 2011;364(11):1027-1036.
13. 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.
14. Büchner T, Schlenk RF, Schaich M, et al. Acute
myeloid leukemia (AML): different treatment
strategies versus a common standard arm:
combined prospective analysis by the German
AML Intergroup. J Clin Oncol. 2012;30(29):
3604-3610.
15. Karp JE, Donehower RC, Enterline JP, Dole GB,
Fox MG, Burke PJ. In vivo cell growth and
pharmacologic determinants of clinical response
in acute myelogeneous leukemia. Blood. 1989;
73(1):24-30.
16. Castaigne S, Chevret S, Archimbaud E, et al.
Randomized comparison of double induction and
timed-sequential induction to a « 317 » induction
in adults with AML: long-term analysis of the
Acute Leukemia French Association (ALFA) 9000
study. Blood. 2004;104(8):2467-2474.
17. Büchner T, Berdel WE, Schooch C, et al. Double
induction containing either two courses or one
course of high-dose cytarabine plus mitoxantrone
and post-remission therapy by either autologous
stem-cell transplantation or by prolonged
maintenance for acute myeloid leukemia. J Clin
Oncol. 2006;24(16):2480-2489.
18. Braess J, Spiekermann K, Staib P, et al. Dose-
dense induction with sequential high-dose
cytarabine and mitoxantrone (S-HAM) and
pelfilgrastim results in a high efficacy and a short
duration of critical neutropenia in de novo acute
myeloid leukemia: a pilot study of the AMLCG.
Blood. 2009;113(17):3903-3910.
19. Petersdorf SH, Kopecky KJ, Slovak M, et al.
A Phase 3 study of gemtuzumab ozogamicin
during induction and postconsolidation therapy
in younger patients with acute myeloid leukemia.
Blood. 2013;121(24):4854-4860.
20. Burnett AK, Hills RK, Milligan D, et al.
Identification of patients with acute myeloid
leukemia who benefit from the addition of
gemtuzumab ozogamicin: results of the MRC
AML15 trial. J Clin Oncol. 2011;29(4):369-377.
21. 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.
22. Castaigne S, Pautas C, Terré 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.
23. Delaunay J, Recher C, Pigneux A, et al. Addition
of gemtuzumab ozogamicin to chemotherapy
improves event-free survival but not overall
survival of AML patients with intermediate
cytogenetics not eligible for allogeneic
transplantation: results of the GOELAMS AML
2006 IR study [abstract]. Blood. 2011;118(21).
Abstract 79.
24. Burnett AK, Russell N, Hills RK, et al. A
comparison of single-dose gemtuzumab
ozogamicin 3 mg/m2 and 6 mg/m2 combined with
induction chemotherapy in younger patients
with AML: data from the UK NCRI AML17 trial
[abstract]. Blood. 2014;124(21). Abstract 2308.
25. Amadori S, Suciu S, Stasi R, et al. Sequential
combination of gemtuzumab ozogamicin and
standard chemotherapy in older patients with
newly diagnosed acute myeloid leukemia: results
of a randomized phase III trial by the EORTC and
GIMEMA consortium (AML-17). J Clin Oncol.
2013;31(35):4424-4430.
26. Löwenberg B, Beck J, Graux C, et al.
Gemtuzumab ozogamicin as post-remission
treatment in AML at 60 years of age or more:
results of a multicenter phase 3 study. Blood.
2010;115(13):2586-2591.
27. Hills RK, Castaigne S, Appelbaum FR, et al.
Addition of gemtuzumab ozogamicin to induction
chemotherapy in adult patients with acute myeloid
leukaemia: a meta-analysis of individual patient
data from randomised controlled trials. Lancet
Oncol. 2014;15(9):986-996.
28. Holowiecki J, Grosicki S, Giebel S, et al.
Cladribine, but not fludarabine, added to
daunorubicin and cytarabine during induction
prolongs survival of patients with acute myeloid
leukemia: a multicenter, randomized phase III
study. J Clin Oncol. 2012;30(20):2441-2448.
TREATMENT OF ADULT AML 59
29. Russell N, Burnett A, Kjeldsen L, et al.
A comparison of daunorubicin/ara-c versus
daunorubicin/clofarabine as induction treatment in
older patients with AML and high-risk MDS: Long
term results of the UK NCRI AML16 trial in 806
patients [abstract]. Haematologica. 2015;100(s1).
Abstract 514.
30. Burnett AK, Russell NH, Hills RK, et al.
Optimization of chemotherapy for younger
patients with acute myeloid leukemia: results of
the medical research council AML15 trial. J Clin
Oncol. 2013;31(27):3360-3368.
31. Thomas X, de Botton S, Chevret S, et al.
Clofarabine-based consolidation improves
relapse-free survival of younger adults with
non-favorable acute myeloid leukemia (AML) in
first remission: results of the randomized
ALFA-0702/CLARA study [abstract]. Blood.
2015;126(23). Abstract 218.
32. Faderl S, Wetzler M, Rizzieri D, et al. Clofarabine
plus cytarabine compared with cytarabine alone
in older patients with relapsed or refractory acute
myelogenous leukemia: results from the
CLASSIC I Trial. J Clin Oncol. 2012;30(20):
2492-2499.
33. Faderl S, Verstovsek S, Cortes J, et al.
Clofarabine and cytarabine combination as
induction therapy for acute myeloid leukemia
(AML) in patients 50 years of age or older. Blood.
2006;108(1):45-51.
34. Kantarjian HM, Erba HP, Claxton D, et al. Phase II
study of clofarabine monotherapy in previously
untreated older adults with acute myeloid
leukemia and unfavorable prognostic factors.
J Clin Oncol. 2010;28(4):549-555.
35. Willemze R, Suciu S, Muus P, et al. Clofarabine in
combination with a standard remission induction
regimen (cytosine arabinoside and idarubicin) in
patients with previously untreated intermediate
and bad-risk acute myelogenous leukemia (AML)
or high-risk myelodysplastic syndrome (HR-MDS):
phase I results of an ongoing phase I/II study of
the leukemia groups of EORTC and GIMEMA
(EORTC GIMEMA 06061/AML-14A trial). Ann
Hematol. 2014;93(6):965-975.
36. 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.
37. 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 [abstract]. Blood. 2014;
124(21). Abstract 6.
38. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive
postremission chemotherapy in adults with acute
myeloid leukemia. N Engl J Med. 1994;331(14):
896-903.
39. Löwenberg B. Sense and nonsense of high-dose
cytarabine for acute myeloid leukemia. Blood.
2013;121(1):26-28.
40. Schlenk RF. Post-remission therapy for acute
myeloid leukemia. Haematologica. 2014;99(11):
1663-1670.
41. Cornelissen JJ, van Putten WL, Verdonck LF,
et al. Results of a HOVON/SAKK donor versus
no-donor analysis of myeloablative HLA-identical
sibling stem cell transplantation in first remission
acute myeloid leukemia in young and middle-aged
adults: benefits for whom? Blood. 2007;109(9):
3658-3666.
42. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic
stem cell transplantation for acute myeloid
leukemia in first complete remission: systematic
 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.
60 DOMBRET and GARDIN
review and meta-analysis of prospective clinical
trials. JAMA. 2009;301(22):2349-2361.
43. Schlenk RF, Döhner K, Krauter J, et al. Mutations
and treatment outcome in cytogenetically normal
acute myeloid leukemia. N Engl J Med. 2008;
358(18):1909-1918.
44. Gooley TA, Chien JW, Pegam SA, et al. Reduced
mortality after allogeneic hematopoietic-cell
transplantation. N Engl J Med. 2010;363(22):
2091-2101.
45. Luznik L, O’Donnell PV, Fuchs EJ. Post-
transplantation cyclophosphamide for tolerance
induction in HLA-haploidentical bone marrow
transplantation. Semin Oncol. 2012;39(6):
683-693.
46. Ciurea SO, Zhang MJ, Bacigalupo AA, et al.
Haploidentical transplant with post-transplant
cyclophosphamide versus matched unrelated
donor transplant for acute myeloid leukemia.
Blood. 2015;126(8):1033-1040.
47. Russell NH, Kjeldsen L, Craddock C, et al.
A comparative assessment of the curative
potential of reduced intensity allografts in acute
myeloid leukaemia. Leukemia. 2015;29(7):
1478-1484.
48. Lioure B, Béné MC, Pigneux A, et al. Early
matched sibling hematopoietic cell transplantation
for adult AML in first remission using an age-
adapted strategy: long-term results of a
prospective GOELAMS study. Blood. 2012;
119(12):2943-2948.
49. Cornelissen JJ, Versluis J, Passweg JR, et al.
Comparative therapeutic value of post-remission
approaches in patients with acute myeloid
leukemia aged 40-60 years. Leukemia. 2015;
29(5):1041-1050.
50. Passweg JR, Labopin M, Cornelissen J, et al.
Conditioning intensity in middle-aged patients with
AML in first CR: no advantage for myeloablative
regimens irrespective of the risk group-an
observational analysis by the Acute Leukemia
Working Party of the EBMT. Bone Marrow
Transplant. 2015;50(8):1063-1068.
51. Brunet S, Martino R, Sierra J. Hematopoietic
transplantation for acute myeloid leukemia with
internal tandem duplication of FLT3 gene (FLT3/ITD).
Curr Opin Oncol. 2013;25(2):195-204.
52. Pratcorona M, Brunet S, Nomdedéu J, et al.
Favorable outcome of patients with acute myeloid
leukemia harboring a low-allelic burden FLT3-ITD
mutation and concomitant NPM1 mutation:
relevance to post-remission therapy. Blood. 2013;
121(14):2734-2738.
53. Linch DC, Hills RK, Burnett AK, Khwaja A, Gale
RE. Impact of FLT3(ITD) mutant allele level on
relapse risk in intermediate-risk acute myeloid
leukemia. Blood. 2014;124(2):273-276.
54. Schlenk RF, Kayser S, Bullinger L, et al.
Differential impact of allelic ratio and insertion
site in FLT3-ITD-positive AML with respect to
allogeneic transplantation. Blood. 2014;124(23):
3441-3449.
55. Grimwade D, Freeman SD. Defining minimal
residual disease in acute myeloid leukemia: which
platforms are ready for “prime time”? Blood. 2014;
124(23):3345-3355.
56. Kayser S, Walter RB, Stock W, Schlenk RF.
Minimal residual disease in acute myeloid
leukemia–current status and future perspectives.
Curr Hematol Malig Rep. 2015;10(2):132-144.
57. Chen X, Xie H, Wood BL, et al. Relation of clinical
response and minimal residual disease and their
prognostic impact on outcome in acute myeloid
leukemia. J Clin Oncol. 2015;33(11):1258-1264.
58. Jourdan E, Boissel N, Chevret S, et al.
Prospective evaluation of gene mutations and
minimal residual disease in patients with core
binding factor acute myeloid leukemia. Blood.
2013;121(12):2213-2223.
BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1
59. Walter RB, Buckley SA, Pagel JM, et al.
Significance of minimal residual disease before
myeloablative allogeneic hematopoietic cell
transplantation for AML in first and second
complete remission. Blood. 2013;122(10):
1813-1821.
60. Boissel N, Renneville A, Leguay T, et al.
Dasatinib in high-risk core binding factor
acute myeloid leukemia in first complete
remission: a French Acute Myeloid Leukemia
Intergroup trial. Haematologica. 2015;100(6):
780-785.
61. Paschka P, Schlenk RF, Weber D, et al. Dasatinib
(DAS) in combination with chemotherapy and as
maintenance in core-binding factor (CBF) acute
myeloid leukemia (AML): a phase Ib/IIa study of
the German-Austrian AML Study Group (AMLSG)
[abstract]. Haematologica. 2015;100(s1). Abstract
515.
62. Marcucci G, Geyer S, Zhao W, et al. Adding
KIT inhibitor dasatinib (DAS) to chemotherapy
overcomes the negative impact of KIT mutation/
over-expression in core binding factor (CBF)
acute myeloid leukemia (AML): results from
CALGB 10801 (Alliance) [abstract]. Blood. 2014;
124(21). Abstract 8.
63. Levis M, Ravandi F, Wang ES, et al. Results from
a randomized trial of salvage chemotherapy
followed by lestaurtinib for patients with FLT3
mutant AML in first relapse. Blood. 2011;117(12):
3294-3301.
64. Knapper S, Hills RK, Cavenagh JD, et al. A
randomised comparison of the sequential addition
of the FLT3 inhibitor lestaurtinib (CEP701) to
standard first line chemotherapy for FLT3-
mutated acute myeloid leukemia: The UK
experience [abstract]. Blood. 2014;124(21).
Abstract 3736.
65. Chen YB, Shuli L, Andrew LA, et al. Phase I
trial of maintenance sorafenib after allogeneic
hematopoietic stem cell transplantation for
patients with FLT3-ITD AML [abstract]. Blood.
2014;124(21). Abstract 671.
66. Daver N, Cortes J, Ravandi F, et al. Secondary
mutations as mediators of resistance to targeted
therapy in leukemia. Blood. 2015;125(21):
3236-3245.
67. Burnett AK, Hills RK, Green C, et al. The impact
on outcome of the addition of all-trans retinoic
acid to intensive chemotherapy in younger
patients with nonacute promyelocytic acute
myeloid leukemia: overall results and results in
genotypic subgroups defined by mutations in
NPM1, FLT3, and CEBPA. Blood. 2010;115(5):
948-956.
68. Schlenk RF, Döhner K, Kneba M, et al. Gene
mutations and response to treatment with all-trans
retinoic acid in elderly patients with acute myeloid
leukemia. Results from the AMLSG trial AML
HD98B. Haematologica. 2009;94(1):54-60.
69. Schlenk RF, Döhner K, Krauter J, et al. All-trans
retinoic acid improves outcome in younger
patients with nucleophosmin-1 mutated acute
myeloid leukemia. Results of the AMLSG 07-04
randomized treatment trial [abstract]. Blood.
2011;118(21). Abstract 80.
70. El Hajj H, Dassouki Z, Berthier C, et al. Retinoic
acid and arsenic trioxide trigger degradation of
mutated NPM1, resulting in apoptosis of AML
cells. Blood. 2015;125(22):3447-3454.
71. Martelli MP, Gionfriddo I, Mezzasoma F, et al.
Arsenic trioxide and all-trans retinoic acid target
NPM1 mutant oncoprotein levels and induce
apoptosis in NPM1-mutated AML cells. Blood.
2015;125(22):3455-3465.
72. Jaglal MV, Duong VH, Bello CM, et al. Cladribine,
cytarabine, filgrastim, and mitoxantrone
(CLAG-M) compared to standard induction in
acute myeloid leukemia from myelodysplastic
syndrome after azanucleoside failure. Leuk Res.
2014;38(4):443-446.
73. Stone RM, Mazzola E, Neuberg D, et al. Phase III
open-label randomized study of cytarabine in
combination with amonafide L-malate or
daunorubicin as induction therapy for patients with
secondary acute myeloid leukemia. J Clin Oncol.
2015;33(11):1252-1257.
74. Genovese G, Kähler AK, Handsaker RE, et al.
Clonal hematopoiesis and blood-cancer risk
inferred from blood DNA sequence. N Engl J Med.
2014;371(26):2477-2487.
75. Jaiswal S, Fontanillas P, Flannick J, et al. Age-
related clonal hematopoiesis associated with
adverse outcomes. N Engl J Med. 2014;371(26):
2488-2498.
76. Becker H, Marcucci G, Maharry K, et al.
Favorable prognostic impact of NPM1 mutations
in older patients with cytogenetically normal de
novo acute myeloid leukemia and associated
gene- and microRNA-expression signatures: a
Cancer and Leukemia Group B study. J Clin
Oncol. 2010;28(4):596-604.
77. 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.
78. Burnett AK, Milligan D, Prentice AG, et al.
A comparison of low-dose cytarabine and
hydoxyurea with or without all-trans retinoic acid
for acute myeloid leukemia and high-risk
myelodysplastic syndrome in patients not
considered fit for intensive treatment. Cancer.
2007;109(6):1114-1124.
79. Kantarjian HM, Thomas XG, Dmoszynska A,
et al. Multicenter, randomized, open-label,
phase III trial of decitabine versus patient
choice, with physician advice, of either
supportive care or low-dose cytarabine for
the treatment of older patients with newly
diagnosed acute myeloid leukemia. J Clin
Oncol. 2012;30(21):2670-2677.
80. 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.
81. Burnett AK, Russell NH, Culligan D, et al. The
addition of the farnesyl transferase inhibitor,
tipifarnib, to low dose cytarabine does not improve
outcome for older patients with AML. Br J
Haematol. 2012;158(4):519-522.
82. Burnett AK, Hills RK, Hunter A, et al. The addition
of arsenic trioxide to low-dose Ara-C in older
patients with AML does not improve outcome.
Leukemia. 2011;25(7):1122-1127.
83. Burnett AK, Hills RK, Hunter AE, et al. The
addition of gemtuzumab ozogamicin to low-
dose Ara-C improves remission rate but does
not significantly prolong survival in older
patients with acute myeloid leukaemia: results
from the LRF AML14 and NCRI AML16 pick-a-
winner comparison. Leukemia. 2013;27(1):
75-81.
84. 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.
85. 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.
86. Burnett AK, Russell NH, Hunter AE, et al.
Clofarabine doubles the response rate in older
patients with acute myeloid leukemia but does
 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.
BLOOD, 7 JANUARY 2016 x VOLUME 127, NUMBER 1
not improve survival. Blood. 2013;122(8):
1384-1394.
87. Döhner H, Lübbert 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.
88. Naval D, Kantarjian HM, Garcia-Manero G,
et al. Phase I/II study of vosaroxin and
decitabine in newly diagnosed older patients
(pts) with acute myeloid leukemia (AML)
and high risk myelodysplastic syndrome
(MDS) [abstract]. Blood. 2014;124(21).
Abstract 385.
89. Breems DA, Van Putten WL, Huijgens PC, et al.
Prognostic index for adult patients with acute
myeloid leukemia in first relapse. J Clin Oncol.
2005;23(9):1969-1978.
90. Burnett AK, Goldstone A, Hills RK, et al. Curability
of patients with acute myeloid leukemia who did
not undergo transplantation in first remission.
J Clin Oncol. 2013;31(10):1293-1301.
TREATMENT OF ADULT AML 61
91. Ravandi F, Ritchie E, Sayar H, et al. Improved
survival in patients with first relapsed or refractory
acute myeloid leukemia (AML) treated with
vosaroxin plus cytarabine versus placebo plus
cytarabine: results of a phase 3 double-blind
randomized controlled multinational study
(VALOR) [abstract]. Blood. 2014;124(21).
Abstract LBA 6.
92. O’Donnell MR, Abboud CN, Altman J, et al. Acute
myeloid leukemia. J Natl Compr Canc Netw.
2012;10(8):984-1021.
 From www.bloodjournal.org by guest on July 24, 2016. For personal use only.

2016 127: 53-61

doi:10.1182/blood-2015-08-604520 originally published
online December 10, 2015

An update of current treatments for adult acute myeloid leukemia

Hervé Dombret and Claude Gardin

Updated information and services can be found at:

http://www.bloodjournal.org/content/127/1/53.full.html
Articles on similar topics can be found in the following Blood collections
Clinical Trials and Observations (4361 articles)
Free Research Articles (3946 articles)
Myeloid Neoplasia (1519 articles)
Review Articles (645 articles)
Review Series (109 articles)

Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests

Information about ordering reprints may be found online at:

http://www.bloodjournal.org/site/misc/rights.xhtml#reprints

Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml

Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society
of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.