Clinical Therapeutics/Volume 31, Theme Issue, 2009
Current and Emerging Therapies for Acute Myeloid Leukemia
Tadeusz Robak, MD, PhD; and Agnieszka Wierzbowska, MD, PhD
Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland
ABSTRACT
Background: Acute myeloid leukemia (AML) is a
clonal disease characterized by the proliferation and
accumulation of myeloid progenitor cells in the bone
marrow, which ultimately leads to hematopoietic fail-
ure. The incidence of AML increases with age, and
older patients typically have worse treatment outcomes
than do younger patients.
Objective: This review is focused on current and
emerging treatment strategies for nonpromyelocytic
AML in patients aged <60 years.
Methods: A literature review was conducted of the
PubMed database for articles published in English.
Publications from 1990 through March 2009 were
scrutinized, and the search was updated on August 26,
2009. The search terms used were: acute myeloid leu-
kemia in conjunction with treatment, chemotherapy,
stem cell transplantation, and immunotherapy. Clinical
trials including adults with AML aged ≥19 years were
selected for analysis. Conference proceedings from
the previous 5 years of The American Society of Hema-
tology, The European Hematology Association, and
The American Society for Blood and Marrow Trans-
plantation were searched manually. Additional relevant
publications were obtained by reviewing the references
from the chosen articles.
Results: Cytarabine (AraC) is the cornerstone of
induction therapy and consolidation therapy for AML.
A standard form of induction therapy consists of AraC
(100–200 mg/m2), administered by a continuous infu-
sion for 7 days, combined with an anthracycline,
administered intravenously for 3 days. Consolidation
therapy comprises treatment with additional courses
of intensive chemotherapy after the patient has achieved
a complete remission (CR), usually with higher doses
of the same drugs as were used during the induction
period. High-dose AraC (2–3 g/m2) is now a standard
consolidation therapy for patients aged <60 years.
Despite substantial progress in the treatment of newly
diagnosed AML, 20% to 40% of patients do not
achieve remission with the standard induction chemo-
therapy, and 50% to 70% of first CR patients are
2009
expected to relapse within 3 years. The optimum
strategy at the time of relapse, or for patients with the
resistant disease, remains uncertain. Allogeneic stem
cell transplantation has been established as the most
effective form of antileukemic therapy in patients with
AML in first or subsequent remission. New drugs are
being evaluated in clinical studies, including immuno-
toxins, monoclonal antibodies, nucleoside analogues,
hypomethylating agents, farnesyltransferase inhibi-
tors, alkylating agents, FMS-like tyrosine kinase 3 in-
hibitors, and multidrug-resistant modulators. How-
ever, determining the success of these treatment strategies
ultimately requires well-designed clinical trials, based on
stratification of the patient risk, knowledge of the indi-
vidual disease, and the drug’s performance status.
Conclusions: Combinations of AraC and anthracy-
clines are still the mainstay of induction therapy, and
use of high-dose AraC is now a standard consolida-
tion therapy in AML patients aged <60 years. Although
several new agents have shown promise in treating
AML, it is unlikely that these agents will be curative
when administered as monotherapy; it is more likely
that they will be used in combination with other new
agents or with conventional therapy. (Clin Ther. 2009;
31[Theme Issue]:2349–2370) © 2009 Excerpta
Medica Inc.
Key words: acute myeloid leukemia, nonpromyelo-
cytic, cytarabine, induction therapy.
INTRODUCTION
Acute myeloid leukemia (AML) is a clonal disease
characterized by the proliferation and accumulation
of myeloid progenitor cells in bone marrow, which
ultimately leads to hematopoietic failure. Diagnosis of
AML is based on cellular morphology and immuno-
logic, cytogenetic, and molecular features.1 The inci-
Accepted for publication September 24, 2009.
doi:10.1016/j.clinthera.2009.11.017
0149-2918/$ - see front matter
© 2009 Excerpta Medica Inc. All rights reserved.
2349
 Clinical Therapeutics
dence of AML increases with age, with a median diag-
nosis between 65 and 75 years of age.2 Although
AML is the most common type of leukemia in adults,
it continues to have the lowest survival rate of all the
leukemias.3 AML accounts for ~25% of all leukemias
in adults in the Western world but comprises only
15% to 20% of cases in patients aged ≤15 years.4 In
the United States, 44,270 new cases of leukemia were
reported in 2008, of which 13,290 were AML cases.5
In 2007, nearly 9000 patients died of this disease. A
number of prognostic factors have been identified in
AML, including age, performance status, organ dys-
function, white blood cell count at presentation,
karyotype, and molecular abnormalities.6,7
AML is a heterogeneous disease in which a variety
of cytogenetic and molecular alterations have been
identified.1 Specific chromosomal abnormalities have
been established as particularly strong prognostic
markers for survival.1,7 Cytogenetic abnormalities
can be detected in ~50% to 60% of newly diagnosed
AML patients.
AML treatment includes at least one course of inten-
sive induction chemotherapy, followed by an additional
course of intensive consolidation therapy and then main-
tenance therapy. Moreover, autologous and allogeneic
stem cell transplantation (autoSCT and alloSCT, respec-
tively) procedures can be performed in selected pa-
tients. In addition, many new agents for the treatment of
AML have been developed recently and are currently
entering clinical trials.8,9 This review is focused on cur-
rent and emerging treatment strategies for nonpromyelo-
cytic AML in patients aged <60 years.
METHODS
A literature review was conducted of the PubMed
database for articles published in English. Publica-
tions from 1990 through March 2009 were scruti-
nized, and the search was updated on August 26,
2009. The search terms used were: acute myeloid leu-
kemia in conjunction with treatment, chemotherapy,
stem cell transplantation, and immunotherapy. Clini-
cal trials including adults with AML aged ≥19 years
were selected for analysis. Conference proceedings
from the previous 5 years of The American Society of
Hematology, The European Hematology Association,
and The American Society for Blood and Marrow Trans-
plantation were searched manually. Additional rele-
vant publications were obtained by reviewing the ref-
erences from the chosen articles. Review articles have
2350
been cited only if the primary source could not be
found or if valuable information about several clinical
trials was listed. Although the focus of this review was
on younger patients, studies involving older patients
are also presented, as usual practice in AML is that
new drugs are investigated in older patients first, as
this group usually has a particularly poor prognosis.
INDUCTION THERAPY
The treatment of patients with AML includes at least
one course of intensive myelosuppressive induction
chemotherapy.7,10 A widely accepted form of induction
therapy includes standard-dose cytarabine (SDAraC)
100 to 200 mg/m2, administered by a continuous infu-
sion for 7 days, combined with daunorubicin 45 to
60 mg/m2/d, administered intravenously for 3 days
(the 3+7 induction regimen).8,11 This therapy has been
reported to induce a complete remission (CR) in 65%
to 75% of patients aged 18 to 60 years.1,11–13 This
approach results in a long-term disease-free survival
of ~30%, with a treatment-related mortality (ie, the
percentage of patients who died during induction) of
5% to 10%.1,11–13
Efforts to improve the CR rate have included use of
alternative anthracyclines or anthracenodiones, incor-
poration of high-dose AraC (HDAraC), or addition of
other agents such as etoposide, fludarabine, or cladri-
bine.13–21 Some trials have reported that substitution of
idarubicin for daunorubicin in a 3+7 induction regimen
resulted in a higher CR rate (80% vs 58% [P = 0.005],
71% vs 58% [P = 0.032], and 70% vs 59% [P = 0.08],
respectively).13–15 Additionally, one trial found a signifi-
cant difference in overall survival (OS), which favored
the idarubicin arm (P = 0.025).13 In a meta-analysis of
5 trials comparing idarubicin and daunorubicin,
members of the AML Collaborative Group reported
that idarubicin performed more strongly than dauno-
rubicin in 3+7 induction therapy in terms of longer
disease-free survival (P = 0.07), 15% relapse rate re-
duction (P = 0.008), and 14% risk reduction for death
(P = 0.03).21 However, these trials used nonequivalent
doses of daunorubicin and idarubicin, in favor of the
latter.
The addition of etoposide to daunorubicin and
AraC did not improve the remission rate but increased
remission duration in a study of 264 previously un-
treated AML patients aged 15 to 70 years.17 Patients
were randomized to receive either AraC 100 mg/m2/d
continuous IV infusion on days 1 through 7 and
Volume 31 Theme Issue

daunorubicin 50 mg/m2/d IV on days 1 through 3 (AD
regimen), or the same drugs intensified with etoposide
75 mg/m2/d IV on days 1 through 7 (ADE regimen) as
induction therapy. CR rates did not differ significantly
in either arm (56% vs 59%, respectively). However,
ADE significantly improved remission duration in
patients aged <55 years (P = 0.01). Moreover, induc-
tion and consolidation therapies with etoposide in-
creased OS in this group of patients, with a median of
9 months for the AD regimen and 17 months for the
ADE regimen (P = 0.03).
A randomized, multicenter trial by the Lederle Co-
operative Group involved 200 previously untreated
AML patients (median age, 60 years).16 Mitoxantrone
in combination with AraC was more effective than the
standard 3+7 induction regimen in terms of CR rates
after a single induction course (89% vs 53%, respec-
tively), the median time to CR and CR duration, and
the median length of survival.
The addition of purine nucleoside analogues (PNA)
to anthracycline and AraC induction therapy may
benefit some patients with AML.18–20,22 A Phase III
trial by Russo et al18 evaluated the efficacy and toxici-
ty of the FLAI regimen (fludarabine + AraC + idarubi-
cin) compared with the ICE regimen (idarubicin +
AraC + etoposide) in newly diagnosed AML patients
aged <60 years. After a single induction course, the
CR rate was 74% in the FLAI arm and 51% in the
ICE arm (P = 0.01); death during the induction period
was 2% and 9%, respectively. Moreover, hematologic
and nonhematologic toxicities were significantly low-
er in the FLAI group (P = 0.002 and P < 0.001, respec-
tively). The role of cladribine in addition to 3+7 in-
duction therapy in AML was also investigated in a
large multicenter, randomized study.18,19 A total of
400 untreated AML patients (mean age, 45 years; age
range, 16–60 years) were randomized to receive either
DAC-7 (daunorubicin + AraC + cladribine) or DA-7
(without cladribine). The overall response (OR) and
CR rates were similar in the DAC-7 and DA-7 arms.
However, after a single course of DAC-7 induction,
the CR rate was 64% and was significantly higher
than in the DA-7 arm (47%) (P < 0.001). Moreover,
there was a nonsignificant trend towards higher
3-year leukemia-free survival for patients aged >40
years receiving DAC-7 compared with DA-7 (44% vs
28%; P = 0.05). The subsequent randomized, 3-arm
study performed by the Polish Adult Leukemia Group
proved that adding cladribine to the standard DA-7
2009
T. Robak and A. Wierzbowska
induction regimen improved the CR rate and OS in
adults with AML aged ≤60 years, with no additional
toxicity.19 However, this beneficial effect was not ob-
served in patients taking daunorubicin combined with
fludarabine.
The effectiveness of an induction regimen comprising
HDAraC (2–3 g/m2) and SDAraC (100–200 mg/m2) has
been compared in several randomized trials.23–27 In a
study by the Southwest Oncology Group,24 the CR
rate was 55% for patients aged 15 to 49 years re-
ceiving HDAraC and 58% for those receiving SDAraC
(Table I). In patients aged 50 to 64 years, the CR rate
was 45% and 53% in the HDAraC and SDAraC
groups, respectively. With a median follow-up time of
51 months, survival was not significantly different.
The estimated survival rate at 4 years was 32% for
HDAraC and 22% for SDAraC in patients aged 15 to
49 years and 13% and 11%, respectively, in patients
aged 50 to 64 years.
An analysis of 3 large randomized trials has con-
firmed that there is no evidence that HDAraC leads to
an increase in CR rate.26 However, it has been re-
ported that HDAraC, used as a part of induction
therapy, has led to a longer remission duration and a
better 4-year OS in patients aged <60 years.
Double induction represents another method of
intensifying induction treatment in AML using the sys-
tematic administration of a second induction course,
irrespective of the bone marrow status after the first
course. A randomized study by the German AML
Cooperative Group found that SDAraC (100 mg/m2
on days 1–8) with daunorubicin (60 mg/m2 on
days 3–5) and 6-thioguanine (100 mg/m2 every 12 hours
on days 3–9) (TAD regimen) followed by HDAraC (3 g/m2
every 12 hours on days 1–3) with mitoxantrone
(10 mg/m2 on days 3–5) (HAM regimen) was associ-
ated with a nonsignificant trend towards a higher CR
incidence compared with 2 courses of TAD (71% vs
65%, respectively; P = 0.072).25 However, in another
German study, a more intensive induction regimen us-
ing 2 courses of HAM did not result in any improve-
ment in outcome (eg, response, OS, relapse-free survival,
early death rates).27
A randomized study by the Acute Leukemia French
Association compared the 3+7 induction regimen
(daunorubicin 80 mg/m2 on days 1–3 + SDAraC) with
double induction (3+7 induction regimen followed by
mitoxantrone with intermediate-dose AraC [IDAraC])
and time-sequential therapy (3+7 induction regimen
2351
 Clinical Therapeutics

Table I. The results of selected randomized trials comparing high-dose cytarabine (AraC) versus standard-
dose AraC induction regimens in acute myeloid leukemia.

AraC Dose, Age, No. of CR, DFS, 4-Year OS,

Study mg/m2/d y Patients % mo %
ALSG23
High dose 6000 × 4 days 15–60 149 71 22* 34
Standard dose 100 × 7 days 15–60 152 74 12* 25
SWOG24
High dose 4000 × 6 days 15–49 85 55 12† 32†
Standard dose 200 × 7 days 15–49 293 58 10 22
High dose 4000 × 6 days 50–64 87 45 8 13
Standard dose 200 × 7 days 50–64 200 53 8 11
AMLCG25
High dose 4000 × 6 days 16–60 365 71 23‡ 36§
Standard dose 200 × 7 days 16–60 360 65 18 32

CR = complete remission; DFS = disease-free survival; OS = overall survival; ALSG = Australian Leukemia Study Group;
SWOG = Southwest Oncology Group; AMLCG = German AML Cooperative Group.
*P = 0.007.
†P = 0.021.
‡P = 0.012.
§P = 0.009.

followed by an early course of mitoxantrone +
IDAraC) in newly diagnosed patients with AML aged
<65 years.28 No difference in CR rate, early death
incidence, or relapse-free survival was observed be-
tween the 3 randomization arms.
Presently, there is no conclusive evidence to recom-
mend one 3+7 induction regimen over another. How-
ever, the results of these studies clearly support the
claim that further intensification of the induction regi-
men is not associated with an increased CR rate.
CONSOLIDATION THERAPY
Consolidation therapy comprises treatment with addi-
tional courses of intensive chemotherapy after the patient
has achieved CR, usually with higher doses of the same
drugs as were used during the induction period.10,29 The
goal of consolidation therapy is to prevent relapse and
achieve a cure in patients who are in CR after induction
treatment. The median disease-free survival for patients
who received only the induction therapy is 4 to 8 months.30
However, 35% to 50% of adults aged <60 years who
receive consolidation treatment survive 2 to 3 years.30,31
HDAraC is now a standard consolidation therapy
in patients aged <60 years.32–35 In the Cancer and
Leukemia Group B trial,33 1088 patients were treated
with the standard 3+7 induction regimen of daunoru-
bicin and AraC followed by postremission therapy
with 1 of 3 doses of AraC: 100 mg/m2/d for 3 days,
400 mg/m2 for 5 days, or 3000 mg/m2 every 12 hours
on days 1, 3, and 5. For patients aged <60 years, the
4-year disease-free survival was 44% in the HDAraC
group, compared with 29% and 24% in the intermediate-
dose and low-dose groups, respectively (P = 0.002).
Serious neurotoxicity was reported only in the HDAraC
group (12%). Subsequent studies found that 3 or 4 con-
secutive consolidation courses with HDAraC (cu-
mulative dose, 54–72 g/m2) were more effective than one
course (18 g/m2) among patients with core-binding
factor leukemia (t[8;21] or inv[16]) in terms of both
disease-free survival (P = 0.03) and OS (P = 0.04).34,35
However, data from a meta-analysis indicate that
results found with 2 cycles in combination with an
anthracycline or mitoxantrone were not different
from those using 3 or 4 cycles.36 In a randomized
study by the Finnish Leukemia Group,37 there was no
significant difference in survival between patients who
had been randomized to receive 2 courses or 6 courses
of the consolidation therapy.

2352 Volume 31 Theme Issue


The current data on consolidation chemotherapy
for AML patients in first CR suggest that multiple
courses of HDAraC remain the mainstay of a curative
therapy for core-binding factor leukemia. The aug-
mentation of the cytogenetic risk stratification by
molecular prognostic markers may help define addi-
tional subgroups of AML patients who will benefit
from the intensified chemotherapy.
MAINTENANCE THERAPY
Maintenance therapy, which is considered less myelo-
suppressive than the induction and consolidation forms
of treatment, is used in patients who have previously
obtained CR.10 It is a strategy to further reduce the
number of residual leukemic cells and prevent a
relapse.38–41 However, its role in the routine manage-
ment of AML patients is controversial and depends
mainly on the intensity of the induction and consoli-
dation therapies.39,42 A randomized study by Sauter et
al38 found that the use of maintenance chemotherapy
every 8 weeks for 2 years after 1 course of consolida-
tion therapy had no advantage in terms of OS compared
with observation only. However, the German AML
Cooperative Group reported that monthly mainte-
nance therapy based on AraC (100 mg/m2 SC every
12 hours on days 1–5), with daunorubicin (45 mg/m2
IV on days 3 and 4), thioguanine (100 mg/m2 orally
on days 1–5), or cyclophosphamide (1 g/m2 IV on day 3)
given alternatively as a second agent, was associated
with 31.4% of patients being relapse free at 5 years ver-
sus 24.7% patients in the sequential HAM arm being
relapse free (P < 0.02). Relapse-free survival after
maintenance therapy was better in patients with poor
risk by unfavorable karyotype, age ≥60 years, lactate
dehydrogenase level >700 U/L, or day 16 bone mar-
row blasts >40% (P = 0.006).40 It should be empha-
sized that in these German studies, patients without
maintenance therapy received only 1 course of
HDAraC-containing consolidation therapy, which may
explain these results. According to the current guidelines
of the British Committee for Standards in Haematology,
there is no evidence that maintenance therapy benefits
AML patients who have undergone intensive consolida-
tion therapy.31
TREATMENT OF RELAPSED AND
REFRACTORY DISEASE
Despite the substantial progress in the treatment of
newly diagnosed AML, 20% to 40% of patients still
2009
T. Robak and A. Wierzbowska
do not achieve remission with standard induction
chemotherapy, and 50% to 70% of first CR patients
are expected to relapse over 3 years.42,43 The progno-
sis for patients with AML refractory to first-line treat-
ment or in first or subsequent relapse is generally
poor. The duration of first remission in relapsed pa-
tients is the most important prognostic factor correlat-
ing with the probability of second CR and survival.44
Patients with primary refractory and early relapsed
disease with a CR duration <6 months have a signifi-
cantly poorer response to therapy and OS than do pa-
tients who relapsed after a first CR lasting ≥6 months
(CR rate 10%–30% vs 40%–60%, respectively).45–48
The optimum strategy at the time of relapse or for
patients with resistant disease remains uncertain. Use
of alloSCT may be curative for a minority of patients
who achieve a second CR and who have an available
donor.42,49 For the majority of patients, additional che-
motherapy is given in the hope of achieving remission.
Most salvage therapies use high (2–3 g/m2) or inter-
mediate (1–1.5 g/m2) doses of AraC in combination
with other agents to overcome resistance in leukemia
cells.43,50,51
The results of randomized trials in patients with
relapsed or refractory AML are summarized in Ta-
ble II.45,52–62 There is no single regimen or approach
that is considered the standard of care in relapsed and
refractory AML. The factors most predictive of re-
sponse in relapsed patients are the duration of previ-
ous remission and the number of previous salvage
courses.63 Salvage therapy is associated with CR rates
of 40% to 60% in patients with a first CR lasting
≥1 year. However, in patients with the first CR lasting
<1 year, the rate of second CR is only 10% to 15%.10,63
In the past 10 years, several prospective Phase II clini-
cal trials have been conducted to evaluate new combi-
nations of standard chemotherapies or novel agents in
patients with relapsed or refractory disease.7,64
Table III summarizes studies using combinations of
PNAs with AraC in the treatment of adult patients
with relapsed or refractory AML.48,65–74 Several inves-
tigations have revealed that PNAs, especially cladri-
bine and fludarabine, are active agents in relapsed or
refractory AML.64 PNAs in combination with AraC
increase the accumulation of AraC triphosphate,
which is responsible for the cytotoxic effect in leuke-
mic blasts.64 The combination of fludarabine or cla-
dribine with AraC has been extensively explored in
relapsed and refractory AML.51,65–74 The combination
2353
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Clinical Therapeutics
Table II. The results of randomized trials in patients with relapsed or refractory acute myeloid leukemia.

No. of Age, Second CR Median Second Early Median

Study Treatment Patients y Rate, % CR Duration, mo Death, % OS, mo

Kern et al45 HDAraC + Mit vs IDAC + Mit 186 50 vs 50 52 vs 45 5.3 vs 3.3 32 vs 17 5 vs NG

Martiat et al52 HDAraC + Amsa vs HDAraC + Mit 52 NG 53 vs 60 11 vs 12 15 vs 8 8 vs 11
Larson et al53 HDAraC vs HDAraC + Amsa 36 52 14 vs 53* NG 25 vs 25 2 vs 6
Vogler et al54 HDAraC vs HDAraC + Eto 131 119 patients 40 vs 45 12 vs 25 NG 5 vs 5
aged <70 years
Ohno et al55 MAE vs MAE + G-CSF 58 47 vs 43 42 vs 54 14 vs 12 8 vs 0 NG
Karanes et al56 HDAraC vs HDAraC + Mit 162 14–76 32 vs 44 9 vs 5 10 vs 16 8 vs 6
Thomas et al57 EMA vs EMA + GM-CSF 72 46 vs 47 81 vs 89 4 vs 5 8 vs 5 8.5 vs 10
Liu Yin et al58 ADE with or without CSA vs 235 48 (4–75) 57 vs 38 NG 16 vs 24 NG
seq ADE with or without CSA (<60 y)*
48 vs 25
(≥60 y)
List et al59 HDAraC + daunorubicin vs HDAraC +
daunorubicin + CSA 226 NG 33 vs 39 NG 15 vs 18 NG
Greenberg et al60 MEC vs MEC + PSC-833 129 70% of patients 25 vs 17 9.3 vs 10 10 vs 16 5.4 vs 4.6
aged ≥50 years
Feldman et al61 MEC vs MEC + lintuzumab 191 55.4 vs 48.8 23 vs 29 NG NG 8.1 vs 5.7
Giles et al62 HDAraC vs HDAraC + laromustine 178 59 (22–84) 19 vs 35† 332 vs 275 2 vs 11‡ 177 vs 128
Volume 31 Theme Issue

CR = complete remission; OS = overall survival; HDAraC = high-dose cytarabine; Mit = mitoxantrone; IDAC = intermediate-dose AraC; NG = not given; Amsa =
amsacrine; Eto = etoposide; MAE = Mit + AraC + Eto; G-CSF = granulocyte-colony stimulating factor; EMA = Eto + Mito + AraC; GM-CSF = granulocyte,
macrophage–colony stimulating factor; ADE = AraC + daunorubicin + Eto; CSA = cyclosporine; seq ADE = sequential ADE; MEC = Mit + Eto + AraC.
* P < 0.01.
† P = 0.005.
‡ P = 0.016.
 T. Robak and A. Wierzbowska

Table III. Combinations of purine nucleoside analogues with cytarabine (AraC) in the treatment of adult pa-
tients with relapsed or refractory acute myeloid leukemia.

Age, y
No. of Salvage Overall OS and Early
Study Patients Regimen Median Range CR Rate, % Time Death, %
Wierzbowska et al48 118 CLAG-M 45 20–66 58 14% at 4 years 8
Steinmetz et al65 36 FLAG-IDA 49 19–75 52 0% at 1 year 14
52 30–75 15% at 1 year
Jackson et al66 83 FLAG 48 18–69 – 9% at 2 years 18
47 21–74 81 50% at 2 years
de la Rubia et al67 32 FLAG-IDA 59 18–79 53 40% at 1 year 9
Clavio et al68 59 FLAG/FLANG 64 33–76 59 NA 10
Carella et al69 41 FLAG 52 16–72 56 20% at 2 years 7
Wrzesień-Kuśet al70 58 CLAG 45 18–67 50 42% at 1 year 17
Pastore et al71 46 FLAG-IDA 41 15–60 52 NA 6.6
Hänel et al72 29 Mit-FLAG 59 18–75 59 34% at 1 year 14
Huhmann et al73 22 FLAG 46 24–63 50 58 at 1 year, 5
24 at 2 years
Camera et al74 61 FLAD 43 26–81 52 5.8 months 12
(median)

CR = complete remission; OS = overall survival; CLAG-M = CLAG + mitoxantrone (Mit); FLAG = fludarabine + AraC +
granulocyte-colony stimulating factor (G-CSF); IDA = idarubicin; FLANG = FLAG + Mit; NA = not available; CLAG =
cladribine + AraC + G-CSF; FLAD = fludambine + AraC + daunorubicin.

of fludarabine with AraC, with or without granulo-
cyte-colony stimulating factor (G-CSF) and/or an
anthracycline, induced a second CR in 30% to 80%
of patients with relapsed or refractory disease. Simi-
lar results were obtained when cladribine was used
instead of fludarabine.48,70 A multicenter study by
The Medical Research Council compared ADE (AraC
+ daunorubicin + etoposide) with FLA (fludarabine
+ HDAraC), with patients further randomized to re-
ceive all-trans retinoic acid and G-CSF.51 In this
study, 250 patients with relapsed, resistant/refractory,
or adverse genetic AML were randomly assigned to
receive either ADE or FLA. The CR rate was 61%,
with a 4-year disease-free survival of 29%. There
were no significant differences in the CR rate, deaths
during CR, relapse rate, or disease-free survival be-
tween the ADE and FLA groups. However, survival
at 4 years was better in the ADE arm (27%) than in
the FLA arm (16%) (P = 0.05).
NOVEL AND EMERGING DRUGS FOR
ACUTE MYELOID LEUKEMIA
The current data on postremission therapy in AML
suggest that further dose intensification of presently
available cytotoxic drugs is unlikely to improve the
clinical outcome.25,28,37 Optimizing the AML therapy
will incorporate new cytotoxic treatments and new
targeted therapies into the standard approach. Target-
ing essential cell functions creates drugs with narrow
therapeutic indices. These new agents are unlikely to
be curative when administered as monotherapy. Thus,
new compounds with an antileukemic activity, which
have previously been evaluated in small Phase I and II
studies, should be tested in combination with other new
agents or with already approved conventional drugs.
Emerging agents potentially useful in the treatment of
patients with AML include immunotoxins, monoclonal
antibodies, nucleoside analogues, hypomethylating
agents, farnesyltransferase inhibitors, alkylating agents,

2009 2355
 Clinical Therapeutics

FMS-like tyrosine kinase 3 (FLT3) inhibitors, and
multidrug-resistant modulators (Table IV).75–80
Immunotoxins and Monoclonal Antibodies
The only antibody approved by the US Food and
Drug Administration (FDA) for AML therapy is gem-
tuzumab ozogamicin* (GO).77 GO consists of a hu-
manized anti–CD33 antibody (hP 67.6) linked to N-
acetyl-calicheamicin 1,2-dimethyl hydrazine chloride,
a potent cytotoxic antibiotic. CD33 antigen is present
*Trademark: Mylotarg ® (Wyeth Pharmaceuticals, Madison,
New Jersey]).
on the surface of AML cells in 80% to 90% of pa-
tients with AML. After binding with CD33, the
toxin is internalized, causing double-strand DNA
breaks, which lead to cell death.77 In a Phase I dose-
escalation study, the drug was evaluated in 40 patients
with relapsed or refractory AML.79 Infusion-related
toxicity, including fever and chills, occurred in 32
of 40 patients (80%) within 2 to 4 hours from the
start of treatment. The maximum tolerated dose (MTD)
was established as 9 mg/m2 and dosing intervals as
14 days. Three patients achieved CR and 6 patients
had clearance of bone marrow blast cells with incom-
plete platelet recovery. In the Phase II studies, GO as

Table IV. Novel agents potentially useful for acute myeloid leukemia.75–80

Drug Class Agents Mechanism of Action

Immunotoxins Gemtuzumab ozogamicin (Mylotarg® [Wyeth CD33 binding, toxin

Pharmaceuticals, Madison, New Jersey]) internalization, and double-
strand DNA breaks
Monoclonal Lintuzumab (HuM195 [Seattle Genetics Inc., Bothell, CD33 binding, complement-
antibodies Washington]) dependent cytotoxicity, and
antibody-directed cellular
cytotoxicity
Newer nucleoside Clofarabine (Evoltra® [Genzyme Corporation, Cambridge, Inhibition of ribonucleotide
analogues Massachusetts]); troxacitabine (Troxatyl® [SGX reductase and DNA
Pharmaceuticals, San Diego, California]); sapacitabine polymerase; induction of
(CYC682, CS-682 [Cyclacel Ltd., Dundee, United Kingdom]) apoptosis
Hypomethylating Azacitidine (Vidaza® [Celgene Corporation, Summit, Inhibition of DNA
agents New Jersey]); Decitabine (Dacogen® [Eisai Inc., Woodcliff methylation
Lake, New Jersey])
Farnesyltransferase Tipifarnib (Zarnestra™ [Johnson & Johnson Pharmaceutical Inhibition of farnesyl-
inhibitors Research & Development, L.L.C., Raritan, New Jersey]); transferase, inhibition of
lonafarnib (Sarasar® [Schering-Plough Corporation, angiogenesis, and induction
Kenilworth, New Jersey]) of cellular adhesion
Alkylating agents Laromustine (Onrigin ® [Vion Pharmaceuticals, Inc., New DNA alkylation and DNA
Haven, Connecticut]) cross-linking
Tyrosine kinase Lestaurtinib (CEP701 [Cephalon, Inc., Frazer, Pennsylvania]); Inhibition of FLT 3
inhibitors (FLT 3 tandutinib (MLN518 [Millennium Pharmaceuticals, phosphorylation,
inhibitors) Cambridge, Massachusetts]); PKC412 (Novartis induction of apoptosis
Oncology, East Hanover, New Jersey)
Multidrug-resistant Valspodar (PSC-833 [Novartis Pharmaceuticals, East Binding to P-glycoprotein
modulators Hanover, New Jersey]); zosuquidar (LY335979 [Kanisa and inactivation of its
Pharmaceuticals, Inc./Lilly, San Diego, California]) efflux function
FLT 3 = FMS-like tyrosine kinase 3.

2356 Volume 31 Theme Issue


monotherapy led to a 25% to 30% OR rate in unselected
patients newly diagnosed with AML.75 The drug is highly
myelosuppressive and causes prolonged thrombocyto-
penia. Infections, veno-occlusive disease, and abnormal
results on liver function tests have been reported.80
The value of the combination of GO and standard
chemotherapy in AML is currently being evaluated in
randomized trials.81 Preliminary results of the Medi-
cal Research Council AML 15 Trial indicate that ad-
dition of GO improved outcomes in patients with in-
termediate and favorable cytogenetics.82 A combination
of GO (9 mg/m2) with IDAraC (1 g/m2) and mitoxan-
trone (12 mg/m2) was evaluated in 62 patients with
relapsed and refractory AML. Thirty-one patients
(50%) achieved a CR and 8 patients (13%) had a CR
with delayed platelet recovery. A significantly higher
OR rate was observed in relapsed (73%) than in re-
fractory patients (39%; P = 0.007), and overall disease-
free survival was 41% and 33% (P = 0.03), respec-
tively. Candoni et al83 evaluated GO in combination
with IDAraC, idarubicin, and fludarabine in first-line
chemotherapy in patients aged <65 years. CR was
obtained in 26 of 29 treated patients (90%), and the
probability of 1-year OS was 90%.
The combination of low doses of GO with hydroxy-
urea and azacitidine was assessed in previously un-
treated elderly patients.84 Treatment was initialized
with hydroxyurea 1500 mg/m2 twice daily to decrease
white blood cell counts to <10,000/m2, followed by
azacitidine 75 mg/m2 subcutaneously for 7 days and
GO 3 mg/m2 on day 8. Consolidation therapy was
administered to those patients who achieved a CR.
Fourteen of 18 patients (78%) achieved a CR, and the
median disease-free survival was 8 months.
The results of these studies suggest that combina-
tions of GO with chemotherapy are promising and
support the need for further investigations using well-
designed randomized trials.
Lintuzumab* is a humanized monoclonal antibody
consisting of a human immunoglobulin G1 frame-
work that contains human constant regions and
complementarity-determining regions.61 Lintuzumb
induces cell death by complement-dependent cytotox-
icity and antibody-directed cellular cytotoxicity.85
Phase I studies found that lintuzumab induced a clini-
cal response in 5 of 23 patients with AML, including
one CR.86,87 In a Phase II trial, lintuzumab was inves-
*HuM195 (Seattle Genetics Inc., Bothell, Washington).
2009
T. Robak and A. Wierzbowska
tigated at a dosage of 12 or 36 mg/m2 on days 1 to 4
and days 15 to 18 in patients with relapsed or refrac-
tory AML.88 Two CRs and one partial remission
were achieved among 49 assessable patients. In
9 other patients, a decrease in blast counts was ob-
served. More recently, lintuzumab in combination
with mitoxantrone, etoposide, and IDAraC was
evaluated in a Phase III, randomized, multicenter
trial.61 A total of 191 patients with relapsed and
primary resistant AML were randomly assigned to
receive mitoxantrone 8 mg/m2, etoposide 80 mg/m2,
and AraC 1 g/m2 daily for 6 days (MEC regimen) in
combination with lintuzumab 12 mg/m2, or MEC
alone. The CR rate was 28% in the group receiving
MEC alone and 36% in patients treated with MEC
and lintuzumab (P = NS). The median OS was 156
days and was similar in both arms. The results of
these studies suggest that the addition of this mono-
clonal antibody to induction chemotherapy is well
tolerated but has no additional benefit compared
with chemotherapy alone.
Newer Nucleoside Analogues
Three newer nucleoside analogues—clofarabine,
troxacitabine, and sapacitabine—have recently been
studied in patients with AML.89,90 Clofarabine† is a
second-generation PNA synthesized to combine the
most favorable pharmacokinetic properties of flu-
darabine and cladribine.89 This drug acts by inhibiting
ribonucleotide reductase and DNA polymerase, as
well as by inducing apoptosis.91 In a Phase II study,
clofarabine monotherapy was used in 31 patients with
relapsed or refractory disease.92 The overall CR rate
was 42%; however, for patients with a first remission
lasting >12 months, the CR rate was 87%. A single-
center, Phase II trial was conducted with clofarabine
as first-line treatment in 28 patients aged >70 years
with AML who were not suitable for conventional
chemotherapy.93 Clofarabine was administered daily
at a dosage of 30 mg/m2 IV for 5 days every 4 weeks.
Seventeen patients achieved CR, and grade 3/4 hepa-
totoxicity was observed in 11 patients. In a multi-
center, Phase II study of 26 elderly patients with newly
diagnosed AML who were ineligible for standard che-
motherapy, the OR rate was 44%, including a 21%
CR rate.94
†Trademark:Evoltra® (Genzyme Corporation, Cambridge,
Massachusetts).
2357
 Clinical Therapeutics
The results of the preclinical study and other en-
couraging data from the single-agent experience led to
trials of clofarabine in combination with AraC.95,96
Faderl et al95 reported the results of a Phase II study
in patients aged ≥50 years with previously untreated
AML. For 5 days, clofarabine was given as a 1-hour IV
infusion at a dose of 40 mg/m2 followed 4 hours later
by AraC as a 2-hour infusion at a dose of 1 g/m2. The
OR rate was 60%, including a 52% CR rate. Subse-
quently, in a randomized study, clofarabine alone was
compared with clofarabine and low-dose AraC in
70 patients with AML aged ≥60 years.96 Sixteen pa-
tients received clofarabine 30 mg/m2 intravenously for
5 days and 54 patients received clofarabine with
20 mg/m2 AraC given SC for 14 days. The OR and CR
rates were significantly higher in patients treated with
the combination regimen than in those receiving clo-
farabine alone (67% vs 31% [P = 0.012] and 63% vs
31% [P < 0.003], respectively). Toxicity was compa-
rable in both groups.
Troxacitabine* is an l-enantiomer nucleoside ana-
logue that differs from AraC in structure, mechanism
of action, and resistance.97 The results of Phase I and
I/II studies in AML revealed that prolonged infusion
of this drug was more active than bolus adminis-
tration.98–100 A Phase I study of troxacitabine given
as a 30-minute IV infusion daily for 5 days found that
its MTD is 8 mg/m2/d.98 In this study in 30 patients
with acute leukemia, the CR rate was 10%. In a larger
Phase I/II study of continuous troxacitabine infusion,
an MTD of 12 mg/m2/d for 5 days was established.100
Dose-limiting toxicities were mucositis and hand–foot
syndrome. Seven patients (15%) achieved CR or CR
with incomplete platelet recovery. Troxacitabine was
also evaluated in combination with AraC and/or ida-
rubicin in untreated AML patients aged ≥50 years
with adverse karyotypes.101 However, neither troxacita-
bine combination was better than treatment with ida-
rubicin and AraC.
Sapacitabine† is a 2-deoxycytidine analogue that
has displayed antiproliferative activity in a variety of
cell lines, including those shown to be resistant to
several anticancer drugs.102 The antiproliferative ef-
fects of sapacitabine in terms of IC50 values were
better than those observed with AraC. Combination
*Trademark: Troxatyl® (SGX Pharmaceuticals, San Diego,
California).
† CYC682, CS-682 (Cyclacel Ltd., Dundee, United Kingdom).
2358
studies reported synergistic effects with oxaliplatin,
gemcitabine, docetaxel, and doxorubicin in human
colon cancer cells.102 Sapacitabine is still in single-
agent phases of development, and its activity in AML
is not yet known.90
Hypomethylating Agents
DNA methylation is the addition of a methyl group
to specific stretches of DNA sequences often located
in or near promoter regions.103 DNA methylation
occurs when a methyl group is attached to a cytosine
by 1 of the 3 known active DNA methyltransferases
(DNMTs). DNA methylation causes loss of gene func-
tion induced by epigenetic gene silencing. Such changes
may be reversible using methylation inhibitors. Aber-
rant DNA methylation has been described in several
malignancies, including AML.104,105
Two DNMT inhibitors, azacitidine‡ and decitabine§,
are pyrimidine analogues of cytidine that can be incor-
porated into RNA and/or DNA. Both agents were used
at higher doses in salvage therapy of relapsed/
refractory AML in the 1980s, but the treatment-related
toxicity, especially bone marrow suppression, was
considerable.105,106 A retrospective analysis of 171 pa-
tients with AML who were treated with higher doses of
azacitidine found 18% had a CR, with an OR of
27%.106 Remission was achieved in a mean of 46 days
(median, 112 days). More recently, lower doses of
azacitidine (75 mg/m2 SC on days 1–7) and decitabine
(20 mg/m2 IV on days 1–5) were studied in myelodys-
plastic syndrome (MDS) and AML, and were approved
by the FDA for the treatment of MDS.106,107 However,
lower doses of azacitidine and decitabine are also active
in AML and are being studied, especially in secondary
AML and AML in elderly patients.108,109
Sudan et al108 retrospectively analyzed 20 patients
(median age, 66 years; age range, 40–80 years) with
AML who had bone marrow blast counts between
21% and 36% and who were treated with azacitidine
75 mg/m2/d administered SC for 7 days every 4 weeks.
Nine of the patients were originally reported as hav-
ing MDS refractory anemia with excess blasts in
transformation subtype. The OR was 60%, and the
CR rate was 20%. The median survival of responders
was 15 months. The most common toxic events were
‡Trademark: Vidaza® (Celgene Corporation, Summit, New
Jersey).
§Trademark: Dacogen® (Eisai Inc., Woodcliff Lake, New Jersey).
Volume 31 Theme Issue

infections (observed in 8 patients). In another study,
azacitidine was combined with phenylbutyrate in 29 pa-
tients with AML.110 All patients received azacitidine
25 to 75 mg/m2/d SC for 5, 10, or 14 days followed by
a continuous 7-day intravenous infusion of phenylbu-
tyrate. Overall, 11 of 29 evaluable patients responded,
including 14% with CR. Response duration ranged
from 8 to >19 months.
Decitabine has also been studied in patients with
AML.109,111,112 In a Phase II study, the drug was used
in low doses of 20 mg/m2 over 1 hour for 5 consecu-
tive days every 4 weeks in untreated patients with
AML aged >60 years.109 CR was obtained in 7 of
27 patients (26%). Garcia-Manero et al112 reported
results from a study of decitabine in combination with
the histone deacetylase inhibitor valproic acid in 54 un-
treated patients with AML (median age, 60 years; age
range, 5–80 years). Decitabine was administered at a
dosage of 15 mg/m2 IV for 10 days concomitantly
with escalating doses of valproic acid orally, also for
10 days. Twelve patients (22%) displayed an objective
response: 10 patients (19%) with CR and 2 (4%) with
incomplete platelet recovery. The OS in responders
was 15.3 months (range, 20.2–46 months). This thera-
py was associated with DNA hypomethylation, induc-
tion of histone acetylation, and gene reactivation.
Blum et al111 reported the results of a similar Phase I
study in 25 patients (median age, 70 years), 12 previ-
ously untreated and 13 with relapsed AML. Estrogen re-
ceptor promoter demethylation, global DNA hypomethy-
lation, depletion of DNMT, and histone hyperacetylation
were observed. Response was achieved in 11 of 21 assess-
able patients (52%), including 4 with morphologic and
cytogenetic CRs. However, because the addition of val-
proic acid led to encephalopathy in some patients, no
clinical benefit was observed compared with decitabine
alone at a dosage of 20 mg/m2/d for 10 days.
Farnesyltransferase Inhibitors
Farnesyltransferase is an enzyme involved in cell
signaling, proliferation, and differentiation. It cata-
lyzes the transfer of the farnesyl moiety to the cysteine
terminal residue of a substrate protein in the Ras pro-
tein.113 Farnesylation is an important posttransla-
tional modification of Ras. Farnesylated protein prod-
ucts of the Ras gene family are frequently activated in
MDS and AML. Farnesyltransferase inhibitors selec-
tively target intracellular enzyme; they also affect an-
giogenesis, cellular adhesion, mitosis, and cellular
2009
T. Robak and A. Wierzbowska
survival.113 Two farnesyltransferase inhibitors, tipi-
farnib* and lonafarnib†, are currently under develop-
ment for the treatment of AML.114–117
Tipifarnib is an orally available, nonpeptidomi-
metic methylquinolone that has shown in vitro and in
vivo activity against AML.115–117 Lancet at al117 inves-
tigated tipifarnib as a single agent in 158 previously
untreated patients with poor-risk AML. The median
age was 74 years, and a majority of patients had ante-
cedent MDS. Tipifarnib was given orally at a dosage
of 600 mg twice daily for 21 days, followed by a rest
period of up to 42 days to allow for recovery of pe-
ripheral blood counts. The CR rate was 14% and the
OR rate was 13%, with a median duration of response
of 7.3 months. Unfortunately, tipifarnib showed no
benefit over best supportive care, including hydroxy-
urea, in a large randomized Phase III study, which in-
cluded 457 patients aged ≥70 years with newly diag-
nosed AML.118 However, some patients with poor-risk
AML, including patients with secondary AML and ad-
verse cytogenetics, may benefit from tipifarnib mainte-
nance therapy.119 In addition, tipifarnib may be more
active when combined with other antileukemic agents.
Karp et al120 recently reported the results of a Phase
I trial of tipifarnib and etoposide. A total of 84 patients
aged >70 years received 222 cycles of tipifarnib at a
dosage of 300 to 600 mg twice daily for 14 or 21 days
and oral etoposide at a dosage of 100 to 200 mg daily
on days 1 through 3 and days 8 through 10. CR was
achieved in 50% of two 14-day tipifarnib cohorts re-
ceiving either tipifarnib 600 mg with etoposide 100 mg
or tipifarnib 400 mg with etoposide 200 mg. The re-
sults of this study are encouraging in that they highlight
the therapeutic progress in a population of poor-risk,
older AML patients who are very difficult to treat.
Lonafarnib is another orally bioavailable, farnesyl-
transferase inhibitor.121,122 In a Phase I study, this
agent was administered at a dosage of 200 mg twice
daily for 3 courses of 4 weeks to 16 patients with
MDS and secondary AML.121 The median age was
70 years (age range, 53–77 years). Partial remission
was observed in 1 of 5 AML patients. This study indi-
cates that lonafarnib had limited activity in older pa-
tients with secondary AML.
*Trademark: Zarnestra™ (Johnson & Johnson Pharmaceutical
Research & Development, L.L.C., Raritan, New Jersey).
† Trademark: Sarasar ® (Schering-Plough Corporation,
Kenilworth, New Jersey).
2359
 Clinical Therapeutics
Laromustine
Laromustine* is an alkylating agent that belongs to
the group of sulfonyl hydrazine prodrugs. This drug
spontaneously generates nucleophilic species that ef-
ficiently lead to DNA alkylation, resulting in DNA
cross-linking and cell death.123 In in vitro studies, la-
romustine showed significant antileukemic activity
against myeloid leukemia blast cells both as a single
agent and in combination with AraC or daunorubi-
cin.124 This agent was also active in patients with re-
lapsed or refractory AML.125–128 In a Phase I study,
28 patients with AML and 5 patients with MDS
received 52 courses of treatment.125 Dose escalation
was terminated at 708 mg/m2 given as a single intra-
venous infusion. In a subsequent Phase II study,
104 previously untreated patients (median age, 72 years;
age range, 60–84 years) were treated with laromustine
at a dosage of 600 mg/m2 intravenously, given as a
single dose.127 Patients were eligible to receive a sec-
ond course if they had a response of less than CR or
CR with incomplete platelet recovery after the first
cycle. The OR rate was 32%, with 29 patients (28%)
achieving a CR. Median OS was 94 days, with a
1-year survival of 14%. Nineteen patients (18%)
died within 30 days of receiving laromustine therapy,
and 84% of the deaths occurred in patients with
pancytopenia.
A randomized, double-blind, placebo-controlled
study of HDAraC with or without laromustine was
subsequently conducted in patients with relapsed or
refractory disease.62 A total of 164 patients were en-
rolled (median age, 59 years; age range, 22–83 years).
Patients received 1.5 g/m2/d of AraC in a continuous
infusion for 3 days, with a subgroup of these patients
also receiving laromustine 600 mg/m2 on day 2. The
CR rate was significantly higher for the laromustine
group (35%) than for those receiving AraC alone
(19%) (P = 0.005). However, early mortality was
higher in patients treated with laromustine (11% vs
2%; P = 0.016). There were also no differences in
progression-free survival or OS rates in either group
because of the excessive number of early deaths asso-
ciated with combination therapy. Further studies
should concentrate on optimization of the laromus-
tine doses in this patient population.
*Trademark: Onrigin® (Vion Pharmaceuticals, Inc., New
Haven, Connecticut).
2360
Tyrosine Kinase Inhibitors
FLT3 is a transmembrane enzyme that promotes
proliferation after activation by ligand binding.76
FLT3 plays an important role in the survival and pro-
liferation of AML blasts. Several studies have shown
that FLT3 mutations are among the most prevalent
genetic abnormalities in AML and have been report-
ed in 30% to 35% of patients with AML.45,129–131
The most common FLT3–internal tandem duplication
(FLT3-ITD) is observed in 25% to 30% of AML pa-
tients. FLT3 mutations are associated with an adverse
prognosis.130–132
In recent years, a number of FLT3 inhibitors have
been developed and tested in Phase I/II trials. Lestaurti-
nib† is an orally available, FLT3-selective indolocarba-
zole alkaloid compound synthetically derived from
compounds of microbial origin. In vitro studies noted
preferential killing of AML cells with FLT3-ITD.133 In a
Phase I/II trial, lestaurtinib was evaluated in 14 patients
with relapsed, refractory, or poor-risk AML harboring
FLT3 mutations.134 The patients were given lestaurtinib
at an initial dosage of 60 mg orally twice daily. Five pa-
tients had limited responses, including reduction in pe-
ripheral blast count and transfusion frequency, with
minimal treatment-related toxicity. Knapper et al135
conducted a Phase II trial of lestaurtinib used as a single
agent in previously untreated, elderly AML patients.
Twenty-nine patients unfit for intensive chemotherapy
(median age, 73 years; age range, 67–82 years) entered
the study. Initially, the drug was administered at a dos-
age of 60 mg twice daily, with subsequent dose escala-
tion to 80 mg twice daily for 8 weeks. Transient reduc-
tion in bone marrow blasts and peripheral blood or
reduction in blood transfusion was observed in 60% of
patients with mutated FLT3 and in 23% of patients
with wild-type FLT3 mutations. However, the median
time to progression was 25 days.
Tandutinib‡ is another quinazoline-based FLT3 in-
hibitor with known activity in AML.136 In a Phase I
trial, tandutinib was given orally in doses ranging
from 50 to 700 mg twice daily.137 Forty AML and
high-risk MDS patients (median age, 70.5 years) were
included. The dose-limiting toxicity of the drug was re-
versible and included generalized muscular weak-
ness and fatigue, which occurred at doses >525 mg.
†CEP701(Cephalon, Inc., Frazer, Pennsylvania).
‡MLN518 (Millenium Pharmaceuticals, Cambridge,
Massachusetts).
Volume 31 Theme Issue

However, this Phase I trial was limited in its ability to
assess the antileukemic activity of tandutinib.
PKC412* was originally developed as a protein ki-
nase C inhibitor.138 However, it is also a potent inhibitor
of FLT3 phosphorylation and cell proliferation, and it
may induce leukemic cell apoptosis. PKC412 was evalu-
ated as a single agent in patients with relapsed/refractory
AML and in MDS patients with FLT3 mutations.139 The
drug was used at a dosage of 75 mg orally 3 times a
day. The peripheral blast count decreased by ≥50% in
14 patients, and bone marrow blast reduction by ≥50%
was observed in 6 of the 20 patients. Two patients de-
veloped fatal pulmonary events of unclear etiology.
PKC412 was also evaluated in combination with AraC
and daunorubicin in newly diagnosed AML patients
aged ≤60 years.140 All 6 patients with FLT3 mutations
and 8 of 13 patients (62%) with wild-type FLT3
achieved a CR. This combined regimen was generally
well tolerated, and no drug-related deaths occurred. The
preclinical observations and clinical studies suggest that
FLT3 inhibitors are promising agents in the treatment
of AML patients with FLT3 mutations, especially when
they are used in combination with chemotherapy.
Multidrug-Resistant Modulators
P-glycoprotein (P-gp) is a cellular membrane pro-
tein encoded by the MDR1 gene, which belongs to the
ABC superfamily and serves as an efflux pump to ex-
trude chemotherapeutic agents from the cell.6,131
Overexpression of P-gp is an important mechanism of
multidrug resistance in AML and has been incorpo-
rated into prognostic models for AML.141
Several multidrug-resistant modulators, including
cyclosporine and quinine in combination with chemo-
therapy, have been tested for the treatment of relapsed
AML.6 In one study, the addition of cyclosporine to
conventional induction treatment increased relapse-free
survival and OS.59 However, in 2 other studies, no sig-
nificant difference was found in CR rate or disease-free
survival and OS.142,143
The addition of valspodar† to induction therapy was
tested in 2 randomized trials.144,145 In one study, AraC,
daunorubicin, and etoposide were compared with an
identical regimen incorporating PSC-833.144 This study
was stopped prematurely because of increased early
treatment-related mortality and lack of significant dif-
*PKX412 (Novartis Oncology, East Hanover, New Jersey).
† PSC-833 (Novartis Pharmaceuticals, East Hanover, New Jersey).
2009
T. Robak and A. Wierzbowska
ferences in terms of disease-free survival, OS, and OR
rates in the interim analysis. Similarly, in a second trial
comparing 2 cycles of induction therapy (AraC +
daunorubicin), one given with valspodar and one with-
out, there were no significant between-group differenc-
es.145 In the updated analysis, there was even a nonsig-
nificant trend for inferior response in the valspodar
arm due to a higher death rate during induction.146
A more potent third generation of P-gp modulator—
zosuquidar‡—has been under clinical investigation.147
Zosuquidar is a difluorocyclopropyl dibenzosuberane
that binds allosterically to P-gp and inactivates its efflux
function. In a Phase I study, zosuquidar was given as a
72-hour intravenous infusion together with induction
therapy using AraC and daunorubicin.147 The recom-
mended dose of this agent for Phase II study was estab-
lished as a 72-hour continuous infusion at 700 mg/d.
Although the drug was generally well tolerated, its clini-
cal activity should be further defined in well-designed
clinical trials.
HEMATOPOIETIC STEM CELL
TRANSPLANTATION
Use of alloSCT has been established as the most effec-
tive form of antileukemic therapy in patients with
AML in first or subsequent remission.148,149 This
treatment modality combines high-dose chemothera-
py, with or without radiotherapy, with alloreactive
immunotherapeutic effects against leukemia, also known
as graft-versus-leukemia activity. Several studies have
shown a reduction in relapse rate and an increased
disease-free survival benefit in AML patients undergo-
ing transplantation in first CR, as well as in patients
with more advanced disease (second CR or primary
refractory disease), compared with patients treated
with chemotherapy alone.148–151 However, the benefi-
cial effect of alloSCT on OS is in part attenuated by
the high nonrelapse mortality related to toxicity of
high-dose conditioning, as well as the disparity of
host–recipient histocompatibility.30,49,152–154 There-
fore, alloSCT should be offered to those AML patients
with a relatively high risk of relapse and a relatively
low risk of nonrelapse mortality.
One of the most noteworthy areas of interest in the
current clinical use of alloSCT includes the clarifica-
tion of prognostic factors, which has led to improved
‡LY335979 (Kanisa Pharmaceuticals, Inc./Lilly, San Diego,
California).
2361
 Clinical Therapeutics
risk determination. Currently, AML patients are
stratified into 3 risk categories based on cytogenetics:
favorable, intermediate, and unfavorable.
AlloSCT in Acute Myeloid Leukemia Patients in
First Complete Remission
There is evidence that sibling alloSCT improves
disease-free survival and OS in patients with AML in
first CR.49,148,154,155 The findings from 5 major studies
revealed a ~50% reduction in relapse rate in each cyto-
genetic risk group.49,148,152,154,155 Moreover, in a meta-
analysis, a statistically significant OS benefit of 12%
(hazard ratio, 0.84 [95% CI, 0.74–0.95]; P = 0.01) was
reported for all patients but those with good-risk cyto-
genetics.148 In this group of patients, the relatively low
relapse probability (≤35%) was offset by a relatively
high nonrelapse mortality (≥20%). Therefore, myelo-
ablative alloSCT in first CR is not generally recom-
mended for AML patients with favorable cytogenetics.
However, molecular genetics are being used to define
new prognostic factors that often recategorize the new
AML subset into another prognostic group, particu-
larly within the intermediate and favorable sub-
groups.130 There is evidence that adults with favorable-
risk AML but with c-kit mutations appear to do as
poorly with standard chemotherapy as patients with
unfavorable cytogenetics.156 Thus, in these patients,
alloSCT might be considered in first CR. Similarly, the
mutational status of NPM1, FLT3, and CEBPA might
stratify AML patients with normal karyotypes into
groups with better and worse prognosis. The patients
with NPM1 or CEBPA mutations without FLT3-ITD,
which has also been associated with favorable progno-
sis, do not benefit from alloSCT in first CR.129
Based on recent studies, therefore, it appears rea-
sonable to offer alloSCT from a matched sibling do-
nor in first CR for younger AML patients with poor-
risk cytogenetics, intermediate-risk cytogenetics apart
from the NPM1+/FLT3-ITD and CEBPA+/FLT3-ITD
subgroups, and favorable-risk cytogenetics with c-kit
mutations.
AlloSCT in Acute Myeloid Leukemia Patients
With Relapsed and Primary Refractory Disease
AlloSCT is the best treatment option for AML pa-
tients with relapsed and refractory disease151,157; how-
ever, the outcome beyond first CR is inferior to that in
first CR. Retrospective data report 39% disease-free
survival and a 42% relapse rate and 32% nonrelapse
2362
mortality in AML patients undergoing transplanta-
tion in second CR.158 However, the outcome of
alloSCT recipients in terms of OS has been found to
be better than other patients treated with chemothera-
py alone or autotransplantation.157 In young patients
lacking a sibling donor match, the alloSCT from a
well-matched unrelated donor is associated with 35%
to 40% disease-free survival and is comparable to re-
sults of alloSCT from sibling donors.159–161 Because
the chance of surviving without a transplant is very
low, the use of an alternative source such as a well-
matched unrelated donor, cord blood, or haploidenti-
cal family donors represents the sole possibility of
survival.160 A similar approach may be followed in
primary refractory AML. There is evidence that ap-
proximately one third of patients with primary re-
fractory AML could achieve durable remission after
alloSCT.151 In study by Fung et al,151 the 3-year prob-
abilities of disease-free survival, OS, and relapse rate
for 68 patients with primary refractory AML were
31%, 30%, and 51%, respectively.
Reduced-Intensity alloSCT in
Acute Myeloid Leukemia
During the last decade, new, less-intensive condi-
tioning regimens have been explored for alloSCT in
older AML patients or in patients with significant
comorbidities who are considered incapable of toler-
ating traditional high-dose regimens. Several stud-
ies have confirmed that it is possible for older pa-
tients with AML to undergo transplantation and that
reduced-intensity alloSCT (RIC-alloSCT) is associated
with lower morbidity and mortality compared with
alloSCT with myeloablative conditioning.161–163 How-
ever, some trials have also found a concomitant in-
crease in relapse rates that attenuated the disease-free
survival benefit.161,162 Other research appears to sug-
gest a better outcome for older patients treated with
RIC-alloSCT compared with conventional chemo-
therapy.163 Larger studies are still required, however,
to better evaluate the long-term value of RIC-alloSCT
from sibling and unrelated donors in older patients
with AML.
AutoSCT in Acute Myeloid Leukemia
A number of randomized AML trials have investi-
gated the role of autoSCT compared with other treat-
ment modalities.164 Over the past 10 years, a reduc-
tion in treatment-related mortality has been observed;
Volume 31 Theme Issue

however, the results with autoSCT have remained
constant. In large intergroup studies,164 the treatment-
related mortality range in autoSCT was 3% to 14%
compared with 3% to 7% in conventional chemo-
therapy. However, the relapse rate in the autoSCT
group (35%–48%) was lower than that in conven-
tionally treated patients (60%–68%).164 In some stud-
ies, a higher disease-free survival was evident in pa-
tients assigned to autoSCT compared with those
receiving conventional chemotherapy (48% vs 30%),
but no significant difference in OS was observed.165 In
most trials, the patients with poor-risk cytogenetics
benefited the least from autoSCT. AutoSCT produces
durable second remission in 25% to 30% of patients
with relapsed AML who have achieved second
CR.166
CONCLUSIONS
Considerable advances have been made over the past
20 years in the prognosis and treatment of patients
with AML. At present, risk-adapted therapy based on
chemotherapy response and cytogenetic abnormalities
are recommended for use. However, there has been
little development in OS. Combinations of anthracy-
clines and AraC are still the mainstay of induction
therapy, and use of HDAraC is now a standard con-
solidation therapy in AML patients aged <60 years.
For younger patients with poor-risk cytogenetics and
an available donor, alloSCT offers the best opportu-
nity for cure. For older patients and for younger pa-
tients with relapsed or primary refractory disease,
there is an obvious need to develop better strategies
with new, more specific and active drugs. Recently,
several new agents have been explored and have
shown promise in treating AML. However, it is un-
likely that these agents will be curative when admin-
istered as monotherapy; it is more likely that they
will be used in combination with other new agents or
with conventional therapy.
ACKNOWLEDGMENTS
This work was supported in part by a grant (no. 503-
1093-1) from the Medical University of Lodz and by
the Foundation for the Development of Diagnostics
and Therapy (Warsaw, Poland). The authors have in-
dicated that they have no other conflicts of interest
regarding the content of this article.
The authors would like to thank Ms. Anna Rychter
for editorial assistance.
2009
T. Robak and A. Wierzbowska
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Address correspondence to: Tadeusz Robak, MD, PhD, Department of
Hematology, Medical University of Lodz, Copernicus Memorial Hospital,
93-510 Lodz, Ul. Ciołkowskiego 2, Poland. E-mail: robaktad@csk.umed.
lodz.pl
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