Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights
Journal of Hematology & Oncology
RNevoiewvel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights
Xiongpeng Zhu 0 1
Yuehua Ma 1
Delong Liu 1
0 Department of Hematology, First Hospital of Quanzhou Affiliated to Fujian Medical University , Quanzhou, 362000 , China
1 Division of Hematology and Oncology, New York Medical College , Valhalla, NY 10595 , USA
Prognostic markers, such as NPM1, Flt3-ITD, and cytogenetic abnormalities have made it possible to formulate aggressive treatment plans for unfavorable acute myeloid leukemia (AML). However, the long-term survival of AML with unfavorable factors remains unsatisfactory. The latest data indicate that the standard dose of daunorubicin (DNR) at 45 mg/m2 is inferior to high dose 90 mg/m2 for induction therapy. The rates of complete remission and overall survival are significantly better in the high dose induction regimen. New regimens exploring the new liposomal encapsulation of Ara-C and DNR as well as addition of gemtuzumab ozogamicin monoclonal antibody have been studied. New agents, including the nucleoside analogues (clofarabine, sapacitabine, elacytarabine), FLT3 inhibitor (sorafenib), farnesyl-transferase inhibitor (tipifarnib), histone deacetylase inhibitor (vorinostat), lenalidomide, as well as DNA methyltransferase inhibitors (decitabine, azacitidine), were recently reported for AML treatment in the 2009 ASH annual meeting. This review also summarizes the updates of the clinical trials on novel agents including voreloxin, AS1413, behenoylara-C, ARRY520, ribavirin, AZD1152, AZD6244, and terameprocol (EM-1421) from the 2009 ASH annual meeting.
Acute myeloid leukemia (AML) is the most common type
of acute leukemia in adults. Over the past twenty years,
the studies on the pathogenesis and prognosis of AML
have made revolutionary progress. However, only
onethird of adult AML can be cured even to this date. The
treatment of refractory, relapsed and elderly AML
remains a major challenge. In recent years, new regimens
and novel agents are being studied in an effort to improve
complete remission (CR) rate and overall survival. This
study will review the latest advances in AML treatment
and summarize the highlights from the 2009 ASH Annual
New regimens for induction therapy of newly
High dose daunorubicin improves survival
The standard induction regimen for newly diagnosed
AML consists of daunorubicin (DNR) 45 mg/m2
intravenously for 3 days and cytarabine (AraC) 100 mg/m2 by
continuous infusion for 7 days . With this regimen 60%
to 80% of young adults and 40% to 60% of older adults can
achieve a CR.
Several major studies, particularly Cancer and
Leukemia Group B (CALGB) 9621 [2,3] and the French ALFA
9000 studies , have shown that higher doses of DNR
(80 or 90 mg/m2) can be administered safely. Recently,
there are two major prospective studies compared DNR
90 mg/m2 with 45 mg/m2 in the induction regimen.
Eastern Cooperative Oncology Group (ECOG) studied 657
AML patients between the age of 17 to 60 . The study
showed significantly higher CR rate for patients receiving
90 mg/m2 (70% versus 57%). More importantly, overall
survival (OS) was significantly prolonged (23.7 vs 15.7
months). The Dutch-Belgium Hemato-Oncology
Cooperative Group (HOVON)/Swiss Group for Clinical
Cancer Research (SAKK) compared DNR 90 mg/m2 versus 45
mg/m2 in 813 patients older than 60 years . The results
showed that CR rate was 64% and 54% respectively, while
CR rate after only one course of treatment was 52% and
35% respectively. The OS rate was not significantly
different for the whole group. However, for the patients
between the age of 60 to 65, the OS rate was significantly
better in the high dose group (38% vs 23%). The rates of
serious adverse events were similar in the two treatment
groups in both studies.
Based on historic trials and the most recent prospective
studies, Rowe points out that 45 mg/m2 of DNR should
no longer be the standard-dose for induction therapy .
Instead, for induction therapy of all age groups, DNR
dose should be between 60 mg/m2 to 90 mg/m2 for 3 days,
but the exact optimal dosage remains to be established.
New formulations of old agents
Liposomal encapsulation of drugs can reduce the toxicity
and decrease drug doses with controlled-release effect.
CPX-351 is a liposomal formulation that encapsulates
cytarabine and daunorubicin at a 5:1 molar ratio. A
recently completed phase 1 study recommended that
90minute infusions of 101 u/m2 be given on days 1, 3, and 5
(1 u = 1 mg Ara-C + 0.44 mg DNR) . The results
showed that liposomal encapsulation of this
chemotherapy doublet changed the safety profile by reducing
nonhematologic toxicities including hair loss, gastrointestinal
toxicities and hepatic toxicity, while retaining
hematopoietic cytotoxicity. A phase IIb randomized study was
initiated to compare CPX-351 with conventional DA regimen
(Ara-C + DNR) in AML patients aged 60-75. CPX-351
exhibits an acceptable safety profile for use in older,
newly diagnosed AML patients.
Targeted therapy regimens
In recent years, encouraging results have been achieved
by using monoclonal antibodies for targeted therapy of
the solid and hematologic malignancies. CD33 antigen is
expressed in more than 90% of AML cells, while
expression in normal tissue is very weak. Gemtuzumab
ozogamycin (GO) is chemoimmunotherapy agent consisting of
a monoclonal antibody against CD33 conjugated to
calichemycin. GO triggers apoptosis when hydrolyzed in the
leukemic blasts. GO has been approved by the U.S. FDA
for the treatment of the elderly (> 60 years) with AML in
first relapse . Standard induction regimen with or
with out GO were compared in a randomized study
which enrolled 1115 younger adults with AML. The
results showed a similar CR rate in both arms, but a
significantly improved DFS among patients receiving
GO-51% versus 40% at 3 years (P = .008).
GO + chemotherapy is also used in AML with special
chromosome abnormalities. GO + FLAG has been used
to treat 34 cases of newly diagnosed AML younger than
60 with core binding factor (CBF) abnormality [Inv(16) =
10; t(8;21) = 24]. The induction regimen consisted of the
following agents: Fludarabine 30 mg/m2/d, d1-5, Ara-C 2
g/m2/d, d1-5, GO 3 mg/m2/d1, and G-CSF 3 mg/kg/d.
The GO-FLAG regimen in CBF+ AML yielded impressive
clinical and molecular response in 29 of the 34
A phase II study of My-FLAI aiming to assess toxicity
and efficacy was done in patients with newly diagnosed
AML aged more than 60 years. Fifty-one patients were
enrolled with a median age of 68 years. Twenty-five
patients had a secondary AML and 31% had a complex
karyotype. Fludarabine (25 mg/m2), cytarabine (1 g/m2),
and idarubicin (5 mg/m2) were administered for three
consecutive days. GO (5 mg) was infused at day four.
Twenty-seven patients achieved a CR and 4 obtained a
partial response for an overall response rate (ORR) of
61%. The results showed that the four drug regimen
MyFLAI was well tolerated in an elderly AML population,
but its efficacy did not appear to be superior to that of
standard "3+7" regimen.
New regimens for refractory/relapsed AML
High-dose cytarabine (HiDAC) is commonly used for
induction of relapsed or refractory AML. At the 2009
ASH meeting, Sarah et al reported a novel,
timedsequential regimen that takes advantage of synergy when
mitoxantrone is given after cytarabine . It was a
retrospective analysis of patients with relapsed or refractory
high-risk AML. Those patients received
HiDAC/mitoxantrone regimen, with cytarabine at 3 gm/m2 over four
hours on days 1 and 5 plus mitoxantrone at 30 mg/m2
over one hour immediately following the HiDAC on days
1 and 5. HiDAC/mitoxantrone induction was well
tolerated and demonstrated an overall response rate of 55%
with induction death rate of 9%.
To further enhance the CR rate in refractory/relapsed
AML, the Japanese Adult Leukemia Study Group
(JALSG) reported a phase II study of FLAGM
(Fludarabine + High-Dose Ara-C + G-CSF + mitoxantrone) in 41
patients with relapsed or refractory AML. The patients
were treated with fludarabine 15 mg/m2 twice daily
(d14), Ara-C 2 g/m2 (d1-4), G-CSF 300 g/m2 (d1-4), and
mitoxantrone 10 mg/m2 (d3-5). FLAGM yielded a 70%
response rate in either relapsed or refractory AML
patients. Although randomized studies are still needed,
FLAGM appears to be a good option for the treatment of
either relapsed or refractory AML patients .
Thomas et al conducted a retrospective analysis of
response (CR and CRi) and survival for patients with first
relapsed AML treated with either IHDAraC or IHDAraC
+ GO regimen . Univariate analysis showed that
IHDAraC +GO induction, as compared with IHDAraC,
was associated with a better response rate (68% vs 48%, p
= 0.08), a lower relapse rate (31% vs 66%, p = 0.02), a
better overall survival (median 35 months vs 19 months, p =
0.02) and a better event free survival (median not reached
vs 10 months, p = 0.02).
Nucleoside analogues transform into active metabolites
(triphosphate nucleoside analogues) in the cells and
inhibit DNA synthesis. Clofarabine is a new nucleoside
analogue, a potent inhibitor of both ribonucleotide
reductase and DNA polymerase. At the 2009 ASH
meeting, a few studies on clofarabine were reported, either
clofarabine alone or in combination with low-dose
AraC, or high-dose Ara-C with the monoclonal antibody GO
in the treatment of elderly AML or relapsed AML
. Two novel nucleoside analogues, sapacitabine and
elacytarabine, were also reported for the therapy of the
elderly with refractory or relapsed AML [22,23] (Table 1).
In a preliminary study, twenty patients with relapsed/
refractory AML were enrolled to receive a regimen
including intermediate dose Ara-C, clofarabine and GO
. The preliminary results was 10 of 20 (50%) patients
achieved a complete remission, 1/20 a partial response, 7/
20 had resistant disease, 2/20 died of complications
during the aplastic phase. Further studies are warranted
In a single-arm, multi-center, phase II, open-label trial,
112 patients of previously untreated AML, 60 years old,
and with at least one unfavorable prognostic factor were
enrolled to receive single agent clofarabine . In
patients 70 y (n = 69), ORR was 39%, CR 33%; In
patients with unfavorable cytogenetics(n = 62), ORR was
42%, CR 32%. Patients with 2 unfavorable prognostic
factors (n = 45) had ORR of 51%. Patients with 3 unfavorable
factors (n = 40) had ORR 38%. Patients 70 with
intermediate or unfavorable karyotype (n = 25) had ORR 48%
HD Cytarabine, Relapsed and
22,5 mg/m2 i.v qd, d1-5
GO 6 mg/m2 d6
and CR 40%; in patients 70 with unfavorable karyotype
(n = 9) ORR and CR were 56%. Patients 70 with both
AHD and unfavorable karyotype (n = 18), ORR was 33%
and CR 22%. In patients 70 with AHD and intermediate
karyotype (n = 8), ORR and CR were 63% (Table 1). It
therefore appears that single agent clofarabine has
reasonable activity in newly diagnosed elderly AML patients.
There was another report of a phase II trial which
enrolled 38 patients with relapsed or refractory AML.
The patients received a regimen with G-CSF priming,
clofarabine and high dose Ara-C (GCLAC) . The CR
was 45% and the CR +CRp rate was 64%. These rates were
50% CR and 65% CR+CRp among 1st salvage patients
(95% CI 41-85%), respectively, and 70% CR + CRp
excluding patients who relapsed after allogeneic SCT (Table 1).
It is important to point out that the relatively higher CR
rate could be in part due to the higher dose of AraC.
Clofarabine was tested in a phase I, dose escalation
study in fourteen patients with relapsed and refractory
AML, who received clofarabine in combination with
fractionated GO in 2 cohorts. The MTD of clofarabine in
combination with fractionated GO is 20 mg/m2/day for 5
days  (Table 1).
Forty patients with AML were enrolled in a phase II
study to receive clofarabine plus low-dose Ara-C
induction followed by consolidation with clofarabine plus
lowdose Ara-C alternating with decitabine. Of the 34
patients evaluable for response, 20 (59%) achieved CR
and 2 (6%) CRp for an overall response rate (ORR) of 65%.
The therapy achieves high response rate with a
manageable toxicity profile and low induction mortality in elderly
patients with previously untreated AML (Table 1).
Abbreviations: GO: gemtuzumab ozogamycin; HD: high dose; LD, low dose; CRp: CR without platelet recovery; MTD: maximal tolerated dose;
25 mg/m2/d 1-5d
20 mg/m2/d or 30 mg/m2/d d1-5 Phase I
20 mg/m2 i.v qd, d1-5
Elderly Relapsed 200 or 300 mg po bid 7d, 400 mg Phase II
and refractory AML po bid 3d/w 2w
2,000 mg/m2 CIV d1-5q3w
FLT3 inhibitors (Fms-like tyrosine kinase 3 inhibitors)
The Flt3-internal tandem duplication (ITD) can be found
in approximately 30% of all AML patients and confers a
poor risk status characterized by an increased relapse rate
and poor overall survival . Moreover,
Flt3-ITD-positive AML patients relapsing after allogeneic stem cell
transplantation (SCT) have very limited therapeutic
options. Sorafenib is a multikinase inhibitor that is
approved for the treatment of metastatic renal cell and
hepatocellular carcinoma. A questionnaire was
developed and sent to 28 centers in Germany in order to
obtain more insight into the clinical efficacy and
tolerability of sorafenib monotherapy in Flt3-ITD positive
AML. Of the 18 patients treated with sorafenib, five were
primary refractory to induction chemotherapy and 13
were in first (n = 11) or second (n = 2) relapse. Patients
received between 200 mg and 800 mg sorafenib p.o. daily.
The median treatment duration was 98 days (range,
16425 days). All patients achieved a hematological response
(HR) characterized by complete (n = 16) or near complete
peripheral blast clearance (n = 2). After a median
treatment duration of 180 days (range, 82-270 days), 7 of 18
(39%) patients developed clinical resistance. Therefore,
sorafenib monotherapy has significant clinical activity in
Flt3-ITD positive relapsed and refractory AML .
In addition, combination therapy with sorafenib was
shown to be effective in reducing mutant clones in
patients with FLT3 mutations but was not able to
completely eradicate them. These data suggest that sorafenib
can achieve temporary disease control, but should be
integrated into induction and consolidation regimens to
achieve maximal outcome [26-28] (Table 2).
Another retrospective study analyzed sorafenib
treatment in 128 patients . Among these patients,
twentythree patients (18 FLT3-WT, 5 FLT3 mutated) received
FLT3 inhibitors as part of their induction and 9 of them
achieved either CR (n = 6) or CRp (n = 3). These results
suggest that therapy with FLT3 inhibitors has the
potential to improve the outcome of patients with FLT3
mutations (Table 2). Prospective study is needed to confirm
In another clinical study, sorafenib was evaluated in 8
AML patients with FLT3+ either prior to or after
allogeneic stem cell transplantation (allo-SCT) . Two of
four patients who received sorafenib for refractory/
relapsed AML after allo-SCT achieved complete
remission (CR), the other two pts had hematological response.
The rest four patients were treated prior to allo-SCT. Two
of the four relapsed patients showed response to
sorafenib treatment, thereby permitting allo-SCT. One of
these two patients achieved HR, the other had regression
of multiple isolated cutaneous manifestations. Sorafenib
treatment was well tolerated (Table 2).
In a phase II study, eighteen patients with newly
diagnosed AML and mutated FLT3 were enrolled to receive
sorafenib, idarubicin, and Ara-C . 94% of the patients
achieved a morphological CR/CRp and 6% achieved PR.
This regimen was found to be effective in reducing the
mutant clones (Table 2).
In summary, sorafenib appears to provide a useful
option for treatment of relapsed/refractory AML
patients. However, large prospective study is needed to
confirm the results from the small observational studies.
Farnesyl-transferase inhibitor (FTI)
In recent years, studies have shown that Ras gene
mutation plays an important role in leukemogenesis . By
inhibiting farnesyl protein transferase, FTI prohibits the
Ras protein farnesylation, schizolysis and carboxyl
methylation, thus disrupting the critical Ras signaling pathway.
Abbreviations: CR: complete remission; CRp: CR without platelet recovery; CHR: complete hematological response
A phase II study assessed the efficacy and toxicity of
tipifarnib-bortezomib combination in 80 AML patients
>18 years, unfit for conventional therapy, or >60 years, in
relapse (Table 3). Nine patients (11%) achieved CR, 1
patient had PR, and in 2 cases an hematological
improvement (HI) was documented for an overall response rate
(ORR) of 19%. Tipifarnib ( bortezomib) may represent
an important option in a subset of high risk/frail AML
Feldman et al compared efficacy of tipifarnib +/- oral
etoposide with traditional
cytarabine/anthracyclinebased induction regimen in older patients with AML.
The results suggest that better CR did not translate into
better survival outcomes (median OS 6.2 vs 7.7 months; p
= 0.82 by log-rank test) .
Histone deacetylase inhibitors
Vorinostat is a new anti-cancer agent inhibiting histone
deacetylase and has been shown to have some efficacy in
treatment of AML [32-34]. Vorinostat in combination
with idarubicin and ara-C has synergistic antileukemia
activity in a sequence dependent fashion [35,36]. A phase
II study of vorinostat in combination with idarubicin and
cytarabine as front line therapy for AML or MDS patients
was reported (Table 4). This study enrolled 52 pts at the
time of the report, and 45, all with AML, are evaluable for
response (median age 53 yeas (range 19-65). The CR after
one course of therapy was achieved in 35 pts and 1 pt
achieved a CRp with incomplete platelet recovery for an
overall response rate of 80%. Seven (15%) pts did not
respond to therapy. Therefore, the combination of
vorinostat, idarubicin and cytarabine is safe and active in
AML. CR or CRi was achieved by 18% pts with MDS,
8% with relapsed/refractory AML, and 36% with
untreated AML; and HI was reported in 9% pts with
MDS, 4% with relapsed/refractory AML, and 8% with
There was also a preliminary report of a Phase I,
openlabel, multicenter, dose-escalating study, designed to
determine the maximum-tolerated dose (MTD)
vorinostat combined either concurrently or sequentially with
decitabine in patients (pts) with AML/MDS. 72 patients
were enrolled. CR or CRi (CR with incomplete count
recovery) was achieved by 18% pts with MDS, 8% with
relapsed/refractory AML, and 36% with untreated AML.
Thus, the combination of vorinostat with decitabine,
either concurrently or sequentially, is possible without
significant toxicity, and shows activity in MDS and
DNA Methyltransferase inhibitors
Decitabine inhibits DNA methyltransferase, leading to
DNA hypomethylation and cell differentiation or
apoptosis. A combination of decitabine and GO was found to be
effective with low side effects in previously untreated or
refractory/relapsed AML patients, especially in elderly
patients. In this phase II study, 33 previously
untreated patients with AML/high-Risk MDS were
enrolled to received GO with decitabine. 24% of the
patients had CR/CRp. Five (15%) patients had clearance
of marrow blasts and 1 patient had hematological
improvement (hemoglobin). The toxicities were minimal
and the regimen can be safely delivered to older patients
(Table 5). In a retrospective study, 79 patients with
relapsed or refractory AML received decitabine/GO
combination. 34% patients responded: 16% CR; 5% CRp;
13% PR-. It is noteworthy that the response rates
from these two studies are similar to that of the single
agent GO, and therefore could be mainly due to the
activity of GO (Table 5)
The French ATU program performed a retrospective
analysis of 184 patients with refractory or relapsed AML
who received azacytidine . 11% of the patients
responded (7%CR,3%CRi,1%PR). It appears that single
agent azacytidine has only limited activity in AML
patients relapsed or refractory to intensive frontline
therapy (Table 5).
Combination of azacitidine with bortezomib or
lowdose GO was also studied in relapsed or refractory AML
patients [41-43] (Table 5).
In a retrospective analysis, 56 patients with poor-risk
AML/MDS received treatment with azacitadine and
lowdose GO. 27% of the patients achieved a CR/CRi. An
additional seven patients cleared their peripheral blood
blasts or had hematologic improvement but did not have
remission  (Table 5).
In a phase I study, 23 patients with relapsed or
refractory AML were enrolled to receive bortezomib and
5azacytidine. The response rate was 26% (6/23) (3-CR,
2CRi, and 1-PR). The combination of 5-azacytidine and
bortezomib was well tolerated and appeared to be active
in this cohort of relapsed or refractory AML patients 
In a phase I dose-finding trial, twenty eight patients
with AML/MDS were enrolled to receive vorinostat plus
azacitidine (AZA) in 8 cohorts . Surprisingly, 53% of
the patients achieved CR. In particular, 10 of 12 high-risk
MDS/AML patients (83%) went into CR. This
combination was found to be well tolerated in repetitive cycles.
The optimal dose of AZA in this regimen appears to be
55 mg/m2. Phase II study is being done.
Voreloxin is a first-in-class anticancer quinolone
derivative that intercalates DNA, inhibits topoisomerase II, and
induces apoptosis. A preliminary report on a voreloxin
trial revealed clinical activity in previously untreated
elderly (age 60) AML patients who are unlikely to
benefit from standard chemotherapy. In this phase II dose
optimization study, 105 patients were treated, with 93
patients evaluable. The CR + CRp rate of the 3 dose
schedules was 41%, 29%, 38%, respectively. ORR across
the 3 schedules was 35%; (Table 6). The study is still
Amonafide L-malate (AS1413)
Amonafide L-malate (amonafide, AS1413) is a unique
DNA intercalator. In a phase II study, 88 patients with
secondary AML were enrolled to receive amonafide and
Ara-C. Overall CR + CRi rate was 42%. CR rates among
age <60 and 60, was 39.4% and 43.6%, respectively;
among tAML and prior MDS, 40% and 44.2%,
respectively; for patients with intermediate and unfavorable
cytogenetics, the CR rates were 61.1% and 23.8%,
respectively (Table 6). This study showed that amonafide in
combination with cytarabine produced a high complete
remission rate and durable responses in both older and
younger patients with secondary AML.
Behenoylara-C has three-phosphoryl in the fourth N of
Ara-C, making it more lipophilic than Ara-C. Its
concentration is maintained longer in the blood (especially
blood cells) and tissues. This agent is transformed into
Ara-C in the liver, spleen, kidney and leukemia cells,
which inhibits DNA synthesis. Taiichi et al studied 165
patients with untreated AML using the combination of
behenoylara-C and idarubicin. 86.7% of the patients had
CR. The patients with good or intermediate risk factors
had remarkable improvements. The study showed that
the treatment is effective and safe  (Table 6).
Lenalidomide is one of the three new drugs approved by
the U.S. FDA to treat MDS [48,49]. Treatment of
5q-lowrisk MDS with LEN can achieve high rate of cytogenetic
CR. In a recent phase II study of LEN in combination
with Ara-C and daunorubicin in high risk MDS/AML
with del 5q, 28% responded (Table 6). The results show
that LEN combined with chemotherapy in AML
treatment is feasible, without significant additional
The eukaryotic translation factor, eIF4E, is overexpressed
in AML, and is associated with poor prognosis. Ribavirin
is clinically used as an antiviral molecule, and its
structure is similar to the m(7)G cap of mRNA, thus inhibiting
eIF4E-induced export and translation of sensitive
transcripts. Assouline et al carried out the first clinical trial
targeting eIF4E with ribavirin in combination with AraC
in AML patients (Table 6). Clinical and molecular
efficacy has been evaluated in 13 patients. The treatment
was well tolerated by all patients. No hemolytic anemia
was seen. There was one complete remission, two partial
remissions, two blast responses and four patients with
stable disease. Unfortunately, all patients eventually
acquired resistance to therapy and eventually relapsed.
Hence, the novel therapies combined with ribavirin are
being sought to overcome resistance and prolong
The kinesin spindle protein (KSP) plays a major role for
the assembly of a normal bipolar spindle and is also
required for cell cycle progression through mitosis.
ARRY-520 is a potent, selective inhibitor of KSP.
Thirtythree patients with AML were enrolled to receive
different schedule of ARRY-520: 15 in the single-dose schedule
(dose levels 2.5, 3.75, 4.5 and 5.6 mg/m2) and 18 in the
divided dose schedule (dose levels 0.8, 1.2, 1.5 and 1.8
mg/m2/day). The maximal tolerated dose (MTD) was 4.5
mg/m2 for the single-dose schedule with the
dose-limiting toxicity (DLT) of grade 3 mucositis. The MTD was 1.5
mg/m2/day (cumulative dose per cycle of 4.5 mg/m2) for
the divided dose schedule, with DLTs being grade 3
mucositis, hand-foot syndrome and hyperbilirubinemia.
ARRY-520 was well tolerated. Four of 33 patients (12%)
showed at least 50% reduction in bone marrow blasts
(Table 6). Therefore, ARRY-520 showed promising
clinical activity and was well tolerated in both schedules.
Aurora B kinase plays a major role in regulating mitosis
and is overexpressed in AML. AZD1152 is a highly
potent and selective inhibitor of aurora B kinase. It has
been shown to inhibit tumor growth in vivo. A phase I/II
study was conducted to assess the safety and efficacy of
Abbreviations: CR: complete remission; CRp: CR without platelet recovery; MTD: maximal tolerated dose;
AZD1152 in patients aged >18 years with advanced AML
(Table 6). The MTD of AZD1152 was defined as 1200 mg
in patients with relapsed AML, and an overall clinical
response rate (CR+CRi+PR) of 23% was observed .
AZD6244 is one of the orally bioavailable small molecule
inhibitors of MEK kinase [54,55]. AZD6244 was studied
in 47 relapsed or refractory AML in a phase II
multicenter clinical study . Among these patients, FLT3
ITD or TKD mutation was positive in 10, negative in 36,
mutational status was unknown in 1. Median number of
prior therapies for AML and/or MDS was 2 (range, 0-6).
The AZD6244 dose was 100 mg twice daily; 42 pts were
evaluable. Median number of cycles administered was 1
(range, 1-9). AZD6244 related serious adverse events
included fatigue, nausea and dehydration, occurring in
7%, 5% and 5%, respectively. Minor responses were seen,
no CR was reported. The study showed that the oral MEK
inhibitor AZD6244 is tolerable in AML. Further
investigation of AZD6244 in combination with drugs that target
other critical signaling/transcriptional pathways in AML
is being considered.
The inhibitor of apoptosis protein (IAP), survivin, is a key
regulator of cell cycles. In leukemic cells, survivin is
involved in leukemia cell survival and resistance to
chemotherapeutics and Flt-3 inhibitors. A clinical trial with
terameprocol (EM-1421), a novel survivin and cdc2
(CDK1) inhibitor, was done in patients with advanced
hematological malignancies (Table 6). In a phase I
dosefinding trial, 16 patients with advanced, relapsed or
refractory hematological malignancies were treated with
1000, 1500 or 2200 mg of intravenous terameprocol 3/
week (wk) for 2 of 3 wks. The MTD was found to be 1500
mg 3/week for 2 of 3 wks .
Conclusions and future directions
Prognostic markers, such as NPM1, Flt3-ITD, and
cytogenetic abnormalities have made it possible to
prospectively formulate aggressive treatment plans for
unfavorable AML. However, the long-term survival of
AML with unfavorable factors remains unsatisfactory.
Combination of azacytidine and vorinostat showed
surprisingly high response rate. Prolonged survival without
curing high risk MDS/AML patients with azacytidine
therapy suggests that disease modification instead of cure
of AML patients may be an alternative goal of treating
elderly patients not suitable for aggressive therapy. New
regimens and novel agents targeting specific pathways
reviewed in this report may bring AML treatment into a
No Pts Response
75 mg/m2/d IV, d1-7 retrospective
Abbreviations: GO: gemtuzumab ozogamycin; CR: complete remission; CRi: CR with incomplete count recovery; CRp: CR without platelet recovery;
MTD: maximal tolerated dose;
20 mg/m2 IV 5d
75 mg/m2/d IV, d1-7
CR/CRp: 42% 
CR/CRp: 21% 
Other agents Disease
Clinical trails No Pts Response
72 mg/m2 qw 3
Secondary AML 600 mg/m2/d IV d1-5
10 mg/d po d1-21
refractory AML 0.8-5.6 mg/m2 IV
1000-2200 mg iv, 3/w, 2-3w Phase I/II
MTD: 4.5 mg/m2 
Abbreviations: CR: complete remission; CRi: CR with incomplete count recovery; CRp: CR without platelet recovery; MTD: maximal tolerated dose;
The authors declare that they have no competing interests.
XZ and DL are involved in concept design. All authors participated in data
collection, drafting and critically revising the manuscript.
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