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Leukemia (2012) 26, 1743 -- 1751
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HOW TO MANAGEy
How to manage acute promyelocytic leukemia
J-Q Mi, J-M Li, Z-X Shen, S-J Chen and Z Chen
Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL is changing,
from the worst among AML as it used to be, to currently the best. The application of all-trans-retinoic acid (ATRA) to the
induction therapy of APL decreases the mortality of newly diagnosed patients, thereby significantly improving the response
rate. Therefore, ATRA combined with anthracycline-based chemotherapy has been widely accepted and used as a classic
treatment. It has been demonstrated that high doses of cytarabine have a good effect on the prevention of relapse for
high-risk patients. However, as the indications of arsenic trioxide (ATO) for APL are being extended from the original relapse
treatment to the first-line treatment of de novo APL, we find that the regimen of ATRA, combined with ATO, seems to be a
new treatment option because of their targeting mechanisms, milder toxicities and improvements of long-term outcomes; this
combination may become a potentially curable treatment modality for APL. We discuss the therapeutic strategies for APL,
particularly the novel approaches to newly diagnosed patients and the handling of side effects of treatment and relapse
treatment, so as to ensure each newly diagnosed patient of APL the most timely and best treatment.
Leukemia (2012) 26, 1743 -- 1751; doi:10.1038/leu.2012.57
Keywords: acute promyelocytic leukemia (APL); all-trans-retinoic acid (ATRA); arsenic trioxide (ATO)
INTRODUCTION
Acute promyelocytic leukemia (APL) is a distinct subtype of acute
myeloid leukemia (AML) characterized by its abnormal promyelocytes infiltrating bone marrow and other hematopoietic organs
and its t(15;17) translocation leading to PML -- RARa fusion gene.
There have been tremendous innovations in therapeutic strategies
and substantial improvement in the outcome of patients since the
application of all-trans-retinoic acid (ATRA).1 The leukemia cells
undergo terminal differentiation under the remission induction of
ATRA, in contrast to cytolysis with conventional chemotherapy,
which ameliorate the coagulopathy, thereby reducing the
requirement of blood products and the difficulty of initial
treatment. This effect has been particularly evident in developing
countries, due to the limitations of medical resources. At present,
ATRA combined with chemotherapy became the classic treatment
of APL owing to the significantly improved long-term survival rate.
The further amelioration of chemotherapy in the past two
decades, for example, the application of high-dose cytosine
arabinoside to high-risk patients2,3 and the recognition of the
importance of maintenance therapy,4 has led to further improvement of APL survival.5 However, it has always been our dream to
lower the relapse rate and to reduce side effects through even
more effective therapy targeting APL cells. The use of arsenic
trioxide (ATO) in the last two decades, from salvage therapy for
relapsed cases to the first-line therapy,6 gradually revealed its
superiority in the treatment of APL, proven by a sizable proportion
of patients cured by just a single agent as the compound directly
targets PML -- RARa. Moreover, a great majority of patients
achieved a 5-year disease-free survival when treated with the
combination of ATO and ATRA. Therefore, the association of ATO
and ATRA5 is gradually being accepted by all. We have confidence
in the hope that it will become a new standard treatment for APL,
although the results of randomised comparisons are still being
awaited.
In this review, we introduce the therapeutic strategies of APL,
including the treatment of newly diagnosed and relapsed
patients, as well as the ways to deal with the side effects.
In addition, we show a novel paradigm of translational medicine
here. The experimental and clinical researches have promoted and
inspired each other, which has led to a revolution in the treatment
of leukemia.
LEUKEMOGENESIS OF APL AND MECHANISMS UNDERLYING
EFFECT OF ATRA/ATO
More than 98% of APL patients harbor t(15;17) in leukemia cells,7
which results in the fusion of RARa on chromosome 17 to PML on
chromosome 15.8 The consequence is the generation of the
PML -- RARa fusion gene encoding a chimeric protein. APL has a
nearly constant incidence with age, suggesting that it arises from
a single rate-limiting genetic event and PML -- RARa is the constant
genomic abnormality in APL cells.9 Transgenic mice with
PML -- RARa develop a typical APL phenotype.10,11 These findings
in addition to other evidence have established PML -- RARa as the
key driver of APL leukemogenesis.
PML -- RARa protein is an abnormal transcriptional factor,
retaining N-terminal RBCC (RING, B Boxes and coiled coil) domains
of PML and most portions of RARa.12 PML -- RARa expression is
believed to exert a dominant-negative dual-function on each of its
parental proteins, which are demonstrated to be involved in
various cellular processes such as myeloid differentiation, apoptosis and DNA replication and repair.13 Several crucial PML -- RARa
features contribute to APL pathogenesis, such as the absolute
binding with RXRa,14 -- 16 interaction with the chromatin remodeling complexes17 -- 19 and functional disruption of other key
myeloid transcription factors (that is, PU.1).20 In addition, other
genetic alterations are present such as mutations in NRAS,
KRAS, FLT3 -- internal tandem duplication (FLT3 -- ITD) and point
State Key Laboratory for Medical Genomics and Department of Hematology, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai, China. Correspondence: Dr J-Q Mi or Dr Z Chen, State Key Laboratory for Medical Genomics and Department of Hematology, Shanghai Institute of
Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin Er Road, Shanghai 200025, China.
E-mail: [email protected] (J-QM) or [email protected] (ZC)
Received 24 August 2011; revised 20 February 2012; accepted 21 February 2012; accepted article preview online 16 March 2012; advance online publication, 30 March 2012
APL and its treatment
J-Q Mi et al
1744
mutations of FLT3 -- tyrosine kinase domain (FLT3 -- TKD) as well as
Jak1,21 -- 23 which favor APL progression in patients.
The critical role of PML -- RARa in APL leukemogenesis has also
suggested itself as a potential target for APL treatment. Indeed,
PML -- RARa represents the direct pharmaceutical target of two
effective agents for APL, ATRA and ATO (Figure 1a). Arsenic binds
to the RBCC domain of PML moiety,24,25 whereas ATRA targets the
RARa moiety of PML -- RARa. Both the agents can induce the
degradation of PML -- RARa,26 -- 29 which probably accounts for
their curable effects.
Leukemia-initiating cells (LICs) are a rare subpopulation in the
bulk of leukemia, which are pluripotent, self-renewing and
mitotically quiescent, and responsible for the development,
progression and maintenance of leukemia.30 The non-cycling
status and inherent or acquired drug-resistant feature of LICs
make them insensitive to conventional chemotherapy, that could
explain the later relapse of leukemia. Although nearly all the APL
patients could obtain complete remission using ATRA or ATO as a
single agent, most single ATRA-treated cases would relapse,
contrarily to the situation of ATO, which could cure a sizable
portion (around 65%) of the patients,31 -- 33 suggesting that ATO
targets the LICs in APL (Figure 1b). More recently, the targeted
clearance of LICs by arsenic treatment has been reported in
mouse models.34,35 Besides PML -- RARa, a number of proteins
have been described to have an important role in the
maintenance of LICs phenotype, many of which, indeed, have
been shown to be targeted by arsenic, including PML,35 Gli2(ref. 36)
and NFkB.37 However, ATRA has been reported to exert a dual
effect on LICs: induction of differentiation in the more mature
blast population and induction of proliferation and/or self-renewal
of the LICs.38 Studies have shown that ex vivo treatment with ATRA
decreases APL LICs frequency.34 However, secondary transplant
recipients still develop APL,34 suggesting that ATRA cannot
completely eradicate LICs. In vitro analysis of Sca1 þ /lin -- murine
hematopoietic stem cells transduced with PML -- RARa has further
shown that ATRA does not abrogate their stem cell capacity and
further induces proliferation of LICs.38
INITIAL APPROACH FOR SUSPECTED APL
In addition to common symptoms of leukemia, such as fever,
infection and anemia, APL is also characterized by a severe lifethreatening coagulopathy resulting from disseminated intravascular coagulation and/or fibrinolysis. Therefore, there are some
difficulties in the treatment of this disease. It is found that
leukocyte and platelet counts are important parameters to predict
the prognosis of patients. According to Sanz score, patients can be
divided into three groups: low risk of relapse (white blood
cell (WBC) count o10 109/l, platelet count440 109/l),
O
O
As
H3C CH3
CH3
intermediate risk (WBC count o10 109/l, platelet count
p40 109/l) and high risk (WBC count X10 109/l).39 Although
it is reported from time to time that CD56 expression in patients
with APL may be an independent factor predicting poor
prognosis, further confirmation is needed.40,41
We agree with the views of Sanz et al.42 that three simultaneous
actions should be done when a diagnosis of APL is suspected: the
start of ATRA therapy before confirmation of the diagnosis;
institution of supportive measures; and rapid confirmation of
genetic diagnosis. As Tallman et al.5 mentioned, bleeding is the
most dangerous complication and represents a major cause of
early death (ED) for the newly diagnosed APL patients. When APL
is highly suspected with clinical symptoms such as peripheral
blood smear and bone marrow morphology, it’s not necessary to
wait for the confirmation by cytogenetic or molecular studies.
Immediate application of ATRA would be a wise choice, so that the
biological signs of APL coagulopathy could be improved rapidly,
decreasing the risk of severe bleeding. For the high-risk patients
with hyperleukocytosis (for example, WBC410 109/l), once the
diagnosis is confirmed, chemotherapy should be initiated as soon
as possible (immediately or be delayed for up to 1 day) to prevent
serious APL differentiation syndrome (DS).
Supportive measures are particularly important in the first few
days after the beginning of APL treatment, especially for those
counteracting the coagulopathy. Although severe bleedings can
be significantly controlled with the use of ATRA, we still encounter
a small number of patients being on the verge of death when they
come to seek treatment, with chief complaints being serious
bleedings.43 It must be emphasized that every positive effort
should be made, both in detection and in treatment. The
determination of blood count, fibrinogen level, prothrombin time
and partial thromboplastin time should be performed at least
twice a day. Appropriate measures should be taken, such as
transfusions of fibrinogen, fresh frozen plasma and platelet
concentrates, to maintain the platelet count at 30 109/l or more
and fibrinogen level at 1.5 g/l or more. In the circumstances of
coagulopathy, the use of heparin has been basically abandoned,
except in major deep vein thrombosis, which is very rare. It should
be noted that lumbar puncture is not allowed until the
coagulopathy is fully resolved in order to prevent iatrogenic
bleeding, even for high-risk patients (such as patients with
hyperleukocytosis). In addition, the newly diagnosed APL patients
often present pancytopenia, and some of them develop
agranulocytosis leading to serious infection. For this reason, it is
essential to begin the anti-infectious therapy in a timely and
appropriate manner.
Currently there are several common methods to establish the
diagnosis, among which the fastest and the best is the reverse
transcriptase PCR for the PML -- RARa fusion transcript. It requires a
CH3 O
OH
As
ATO
Binding
PML RBCC
ATRA
ATO
CH3
O
ATRA
Binding
APL cells
RARα
Partial
differentiation
Apoptosis
LIC
clearance
Ternimal
differentiation
Figure 1. Molecular mechanisms of ATO and ATRA for APL. (a) Synergistically targeted therapy of ATO and ATRA in APL. Arsenic binds to PML
moiety of PML -- RARa while ATRA binds through its RARa moiety, both of which initiate the degradation of PML -- RARa in a proteasomedependent way. (b) ATO facilitates the clearance of LIC of APL.
Leukemia (2012) 1743 -- 1751
& 2012 Macmillan Publishers Limited
APL and its treatment
J-Q Mi et al
small sample, is easy to perform, even in case of low WBCs, and its
positive result directly indicates that the ATRA treatment should
be effective.44 At the same time, we conduct karyotyping
routinely. Although this procedure costs more time and energy,
it remains a classic diagnostic tool. Especially, in patients lacking
the typical PML -- RARa fusion gene, other rare molecular subtypes
could be identified by karyotyping, and subsequent reverse
transcriptase PCR analysis, such as PLZF -- RARa resulted from
t(11;17) (q23; q21),45 NuMA -- RARa from t(11;17) (q13; q21)46 and
NPM1 -- RARa from t(5;17) (q35; q21).47 Florescence in situ
hybridization analysis has a role in the diagnosis with its unique
sensitivity and specificity, although it has limitations in probes.
Florescence in situ hybridization remains currently the quickest
method in some countries to confirm the diagnosis. Anti-PML
monoclonal antibody testing is a relatively effective screening
method with many advantages, such as specificity, quickness and
easy performance, but it is not yet widely used clinically.48
INDUCTION THERAPY
ATRA plus chemotherapy
Given that the efficacy of chemotherapy alone on APL was
far from perfect, although some reports were surprisingly good,
the search for a more effective therapy had been a long-time
desire. A group from the Shanghai Institute of Hematology
(SIH) revealed in the 1980s that ATRA could induce the cell
differentiation of leukemic promyelocytes and could thus greatly
improve the response rate of de novo APL. The complete
remission (CR) rates are usually 87 to 94% using a classical dosage
of 45 mg/m2/day for 4 to 6 weeks.49 However, within 6 months of
remission, 8 out of the 24 patients in the first reported series
relapsed while even higher relapse rates were reported elsewhere,
indicating that ATRA monotherapy still led to a relatively high
recurrence rate.1,50,51 Several working groups worldwide confirmed that ATRA, followed by chemotherapy, was superior to
chemotherapy alone.52,53 Consequently, European APL group
compared the efficacy of two regimens, which were ATRA plus
chemotherapy and sequential ATRA followed by chemotherapy,
respectively. It was found that the former regimen gave out a
lower recurrence rate than the latter, with 2-year event-free
survival (EFS) rates of 84 and 77%.54 ATRA plus chemotherapy
(anthracyclines alone or with cytarabine (Ara-C)) has since been
considered as the classic approach, in which the use of
anthracyclines is mainly involved with daunorubicin and Idarubicin. Their effects were believed to be basically the same,5 except
for a slight advantage of Idarubicin reported by a small number of
literature, especially for the younger patients.55 Currently, we do
not find significant effects of Ara-C for the low-risk patients (WBC
count p10 109/l). In a joint analysis of results from a LPA 99
trial Programa para el Estudio de la Terapeutica en Hemopatia
Maligna (PETHEMA group), where patients received no Ara-C in
addition to ATRA, a high cumulative dose of idarubicin, and
mitoxantrone and an APL 2000 trial (French -- Belgian -- Swiss APL
group), where patients received Ara-C in addition to ATRA and a
lower cumulative dose of daunorubicin, 3-year survival was similar
in patients with a WBC count less than 10 109/l; although, 3-year
cumulative incidence of relapse was significantly lower in the LPA
99 trial: 4.2 versus 14.3% (P ¼ 0.03).4 However, for high-risk (WBC
count410 109/l) patients, large doses of Ara-C could act
better.2,4,56
Although ATRA plus chemotherapy gained great effects, there
are still problems such as relapse, severe side effects of
chemotherapy and so on. The 5-year relapse-free survival and
overall survival (OS) from SIH were only around 34.0 and 52%.57
That’s why we were trying to find other alternative clinical
approaches. The aim was to further improve the cure rate. In this
context, the appearance of ATO gives us new hope.
& 2012 Macmillan Publishers Limited
Introduction of ATO and ATRA/ATO combination therapy
Chinese groups were able to report on the first controlled study
with pure ATO to deal with both relapsed and newly diagnosed
APL patients.6,29,58 Of note, the response rate was as high as 85%
among cases relapsed after previous ATRA and chemotherapy
treatment. In line with these successful therapeutic practices,
several working groups administered a single agent of ATO as
first-line therapy, which turned out to be a good attempt and the
effect was much better as compared with ATRA alone,59 -- 62
suggesting that ATO could target the leukemia stem cells in an
APL setting.
Several lines of evidence prompted us to consider a possible
new strategy in APL by combining ATRA and ATO for newly
diagnosed patients. First, there is no obvious cross-resistance
between ATRA and ATO.29,58 Second, combination of the two
agents allows a significantly prolonged survival or even disease
eradication in APL animals.63,64 Third, the two compounds target
PML -- RARa and modulate key networks involved in apoptosis/
differentiation via distinct but related pathways.24,65,66 Mechanistically, the combined use of ATO with ATRA has brought about a
conceptual revolution of synergistic targeting of leukemia and
thus impacts the conventional chemotherapy-based treatment.
Nevertheless, the possible additional side effects due to the
combined use of the two agents likewise raised some concerns.
We therefore carefully examined this aspect while conducting
animal experiments and while analyzing the transcriptome and
proteome analysis data. No obvious enhancement of side effects
or further activation of stress pathways was detected. On the basis
of these facts, we decided to initiate the new clinical trial of
combination therapy in 2000. Indeed, we found61 that the ATRA/
ATO combination for remission (with maintenance) therapy of APL
brought much better results than either of the two drugs used
alone in terms of the quality of CR and the status of the diseasefree survival. According to data from the SIH, Kaplan -- Meier
estimates that the 5-year EFS and OS in a group of 85 newly
diagnosed APL patients were 89.2% and 91.7%, respectively,
demonstrating the high efficacy of ATRA/ATO treatment for newly
diagnosed APL.67 Recent literature supports our data in that the
CR rate and EFS were relatively higher in the working groups using
ATO/ATRA combination 68,69 compared with the groups using ATO
alone.59,60,62 GIMEMA group carried out a randomized phase III
study to compare ATO þ ATRA versus standard ATRA þ anthracycline-based chemotherapy (AIDA regimen) for newly diagnosed
non high-risk APL. We are eagerly anticipating their results.
Mathews et al.70 suggested that mutant FLT3 was not an adverse
indicator of poor prognosis for APL with ATO-based therapy,
which was supported by our group.67
At present, our induction therapy program is as follows61,67
(Figure 2): 25 mg/m2 ATRA orally per day, and 0.16 mg/kg As2O3
i.v. per day until documentation of CR. The reason for us to reduce
the initial dose of 45 mg/m2 ATRA, which was once our own
recommendation, to 25 mg/m2 is to avoid ATRA toxicity; we
showed that this relatively low-dose ATRA achieved the same
therapeutic effects as the conventional dosage,28 although the
standard dose of 45 mg/m2 is still used in many other medical
centers worldwide. When the patient’s WBC is more than
10 109/l, we use hydroxyurea 20 -- 40 mg/kg daily at first, which
can be effective in some patients, then 3 days after, switch to IA
regimen if the WBC count keeps rising.
Our novel strategy in APL therapy has thus broken away from
the conventional chemotherapy-based approaches to remission
induction of leukemia, and it has translated the targeted killing
effect of ATO on APL cells proven in experimental studies into
clinical practice efficiently. In addition, our program has also
demonstrated its economic advantages, especially as compared
with high-dose chemotherapy. Currently in China, the daily cost of
ATO (provided by Yida Pharmaceutical Company of the Harbin
Medical University, Harbin, China) is 30 US dollars, whereas the
Leukemia (2012) 1743 -- 1751
1745
APL and its treatment
J-Q Mi et al
1746
Figure 2. Shanghai APL trial. DA, DNR+Ara-C; DNR, Daunorubicin;
HA, HH+Ara-C; HH, Homoharringtonine; HU, Hydroxyurea; 6-MP,
6-Mercaptopurine; MTX, Methotrexate.
ATRA (provided by Shanghai Rui Jin Hospital pharmacies,
Shanghai, China) costs no more than 20 US dollars for each
course (4 -- 6 weeks) of treatment.
Introduction of other arsenic compounds for APL therapy
It was reported by Lu et al.71 that, instead of the first-line i.v. ATO
treatment, oral tetra-arsenic tetra-sulfide (As4S4) also yielded good
responses in APL patients. The randomized and controlled clinic
trial, led by Peking University Institute of Hematology and SIH,
investigating ATO or As4S4 combined with ATRA for the newly
diagnosed APL, is being conducted in many hospitals in China.
This clinical trial is scheduled to include 250 patients randomized
to ATRA þ ATO or ATRA þ As4S4 group. Currently, the
enrollment is nearing completion. The preliminary results
suggested As4S4 yielded a similar CR and 2-year EFS rate as the
ATO did. However, the side effects seemed fewer and the patients
needed much less hospitalization time (Huang XJ et al., personal
communication). We expect good results, for the oral As4S4
(provided by Tian Kang Pharmaceutical Company, Anhui, China) is
more conveniently used, and also cheaper.
CONSOLIDATION THERAPY
Although consensus has not yet been reached on the details of
specific consolidation therapy, it has been widely accepted that at
least 2 -- 3 times of anthracycline-based chemotherapy should be
given to the low-risk and intermediate-risk patients.5,49 However,
there is no conclusion whether or not the administration of ATRA
is really an advantage for the consolidation therapy, although
some investigators reported that the relapse rate of APL was
reduced in their results as compared with the historical
control.72,73
In 2006, the European APL Group reported2 a randomized
study of 340 patients. For the high-risk patients (WBC410 109/l),
it was shown that adding Ara-C to anthracyclines was superior to
high-dose anthracyclines used as single agents, especially in
reducing relapse rate. In 2009, the same working group3
compared the results of APL93 trial and APL2000 trial and
confirmed that high-dose Ara-C could significantly lower the
cumulative incidence of relapse and ameliorate survival in highrisk patients, which was supported by both German AML
Cooperative Group74 and PETHEMA Group.75 However, one should
pay attention to the severe bone marrow suppression resulting
Leukemia (2012) 1743 -- 1751
from high-dose Ara-C, which could thereby increase the risk of
serious infections.
Our recommendation is (Figure 2) three courses of consolidation therapy: Each course includes three consecutive regimens,
that is, DA regimen (daunorubicin, 45 mg/m2 per day for 3 days;
Ara-C, 100 mg/m2 per day for 7 days), Ara-C ‘pulse’ regimen (Ara-C,
1.5 -- 2.5g/m2 per day for 3 days) and HA regimen (homoharringtonine, 2 -- 3 mg/m2 per day for 3 days; Ara-C, 100 mg/m2 per day
for 7 days). In the countries where homoharringtonine is
unavailable, we recommend application of MA regimen (Mitoxantrone 6 -- 10 mg/m2 per day for 3 days, Ara-C 100 mg/m2 per day
for 7 days). This program can be said to be a supplement to the
remission induction program mentioned above, for few chemotherapy is given in our remission induction regimen. However,
in consideration of the toxicities of high-dose Ara-C, we just select
the middle dosage.
In contrast, the remission induction regimen of the North
American work group only consists of ATRA and conventional
chemotherapy, which explains why this group aptly adds ATO in
the consolidation therapy. According to the recent data of this
important trial (Leukemia Intergroup Study C9710), the addition of
ATO is an important improvement to the treatment strategy since
the 3-year EFS reached 80%,76 which is consistent with our point
of view that the treatment of APL should target both PML and
RARa to fulfill a maximum efficacy. In this study, both of the two
randomized groups were given the same induction therapy (ATRA,
Ara-C and daunorubicin). For the consolidation regimen, the
trial group received two 25-day courses of ATO consolidation
immediately after induction, while the control group received two
courses of consolidation therapy with ATRA plus daunorubicin. A
very significant advantage in 3-year EFS and DFS (80% and 90%,
respectively) was shown in the ATO group compared with the
control group, although the results of the control group were
slightly unsatisfactory. The administration of ATO allows us to
generate further thinking: For the consolidation, can ATO replace
all or part of the conventional chemotherapy? And, when is the
best time to use ATO? Future research will tell us the answers to
these questions of great interest.
No matter which consolidation therapy used, patients must
reach a molecular remission (MR) (PCR negativity of PML -- RARa in
the marrow) before commencement of maintenance therapy. If
not yet met, the prognosis of the patient will be poor, and salvage
therapy should be considered. If MR is obtained after salvage,
autologous hematopoietic stem-cell transplantation (HSCT) is
suggested, but if the fusion gene transcripts are persistently
positive, allogeneic HSCT should be recommended.
MAINTENANCE THERAPY
The importance of ATRA plus chemotherapy maintenance was
addressed by both the North American Intergroup Study I0129
and the European APL Group.53,54 Ten years later, the European
APL Group re-analyzed this issue. It was shown that the 10-year
relapse rate was the lowest (13.4%) in the ATRA plus chemotherapy maintenance group, as compared with that of chemotherapy
alone, ATRA alone as maintenance and no maintenance groups,
which were 23.4%, 33% and 43.2%, respectively. The differences of
relapse rates were more significant in the patients with initial WBC
count higher than 5 109/l, which was 20.6% with combined
(ATRA plus chemotherapy) maintenance and 68.4% with no
maintenance. However, the Japan Adult Leukemia Study Group
(JALSG) found little difference with or without maintenance. One
explanation to this situation could be that the JALSG trial only
compared no maintenance versus six courses of intensified
maintenance chemotherapy rather than ATRA maintenance.77
Although ATRA plus chemotherapy was originally considered to
be the best solution of maintenance therapy, with our in-depth
in vitro study on the mechanisms of ATRA and ATO, a better
& 2012 Macmillan Publishers Limited
APL and its treatment
J-Q Mi et al
understanding has been obtained on the importance of the
combined use of various drugs with different therapeutic targets.
Thus, for the maintenance treatment, we have been optimizing
the idea of ATO/ATRA combined with chemotherapy. On the basis
of a previous report,61 our maintenance therapy currently consists
of five cycles of sequential use of ATRA, ATO and low-dose
chemotherapy (Figure 2): ATRA, 25 mg/m2 per day for 30 days;
As2O3, 0.16 mg/kg per day for 30 days; 6-mercaptopurine, 100 mg/
day for 30 days or 15 -- 40 mg of methotrexate once a week for 4
weeks. Notably, the 5-year relapse-free survival and OS of our
patients who achieved CR were 94.8% and 97.4%, respectively.67
Although it was usually a common practice to avoid CNS
prophylaxis for patients without hyperleukocytosis, among whom
the risk of CNS relapse is extremely low,42 we still recommend 4 -- 6
times of CNS prophylaxis, methotrexate (10 -- 15 mg), dexamethasone (5 mg) (or Prednisolone 40 mg) and Ara-C (40 -- 50 mg),
during maintenance therapy, in considering that the first site of
relapse was exclusively the CNS in all of the total four relapses out
of our recent series of 80 patients achieving complete remission,
and most of the relapsed patients exhibited no hyperleukocytosis
initially.67 Nevertheless, for the patients with high WBC counts, the
CNS prophylaxis should be carried out for at least 6 -- 8 times.
APL DS
DS is a common life-threatening complication in the ATRA or ATO
treatment, with a frequency being around 25% both in US and in
Europe.53,78 The common clinical symptoms were dyspnea with
interstitial pulmonary infiltrates, peripheral edema, unexplained
fever, weight gain, hypotension and acute renal failure.79 When
these happen, early use of chemotherapy and high dose of
dexamethasone can decrease the mortality down to 1% or
lower.42
It has been described that prophylactic treatment of APL DS by
prednisolone can reduce the incidence of DS significantly,80 but it
is risky to use the steroids routinely as prophylaxis. We echo Dr
Tallman’s view: ‘caution should be exercised, because the
administration of corticosteroids to neutropenic patients may
predispose them to infection, such as sepsis, or fungal infection’.5
Therefore, only in the treatment of patients with hyperleukocytosis (at least WBC430 109/l) at diagnosis, sometimes accompanied by coagulopathy, should dexamethasone be given
preventively at a dose of 10 mg twice daily. Moreover, when
dealing with DS, corticosteroids can also participate in hemostasis.
Troubled by the serious DS, since the late 1990s, at SIH, ATRA
has been used at an oral dose of 25 mg/m2 per day as a routine
treatment for APL patients, after a study showing that lower doses
of ATRA had the same therapeutic effect as the conventional
dosage but with fewer side effects, including DS.28,61 In the past
two decades, the frequency of DS in our patients has been very
low,67 with the exception of a few patients presenting hyperleukocytosis at the diagnosis of the disease.
SIDE EFFECTS OF ATO
ATO proves to be quite safe. When compared with anthracyclines,
bone marrow myelosuppression due to ATO appears to be minor.
The common adverse effects are mainly grade I -- II hepatotoxicity,
gastrointestinal reactions, neurotoxicity and very rarely, grade III -IV hepatotoxicity, which are usually reversible.59,60 Thus, in clinical
practice, we recommend administration of some therapeutic
agents (for example, Diammonium Glycyrrizinate, a drug based on
the Traditional Chinese Medicine; Polyene Phosphatidylcholine) to
prevent liver damage.
Another important potential adverse event related to ATO is
manifested by prolongation of the QT interval on the ECG, which
may lead to torsade de pointes, a life-threatening ventricular arrhythmia. Proper management of patients given ATO
& 2012 Macmillan Publishers Limited
emphasizes ECG monitoring and maintenance of electrolyte
within normal ranges, for example, the serum potassium above
4.0 mEq/l and serum magnesium above 1.8 mg/dl. In patients
whose absolute QT interval value is longer than 500 ms, ATO
should be withheld or discontinued if necessary.81 -- 83
The total dose of ATO is 1600 -- 1800 mg in our entire treatment
regimen. We believe that this dosage is safe, as no patient
discontinued the treatment because of the toxicity of ATO. At the
same time, arsenic concentrations in the urine of patients who
had ceased maintenance treatment for 2 years were below the
safety limits recommended by government agencies in several
countries or regions, whereas arsenic levels in plasma, nails and
hair were only slightly higher than those found in healthy
controls.67
MANAGEMENT OF RELAPSE
The determination of minimal residual disease is especially
important to the patients in remission. The first sign of recurrence
is usually indicated by the PCR detection of PML -- RARa transcripts
in bone marrow. The vast majority of patients relapse in the first 3
years after the end of treatment;84 however, there are also
individuals who only relapse in the extramedullary sites (such as
the CNS).
A number of international clinical trials, such as the APL study of
German AML Cooperative Group (GMLCG) including HD ARAC-C,
the APL2000 trial of European APL Group and ours, have shown
that the CR rate of APL is more than 90%,1,4,74 the 10-year relapse
free survival was similar in GMLCG (75.5%) as that of European APL
Group (76.3%), but there are still about 25% of patients who suffer
from relapse.85 For the APL patients in relapse, the treatment
strategy is remission re-induction and remission consolidation.5,49
ATO is considered to be the first-line treatment of relapsed APL
without previous exposure to the compound, which could allow a
remission rate of re-induction to more than 80%.86 In a multicenter clinical study in the US, 40 relapsed APL patients were
given ATO as remission induction, and 34 (85%) of them achieved
CR. With subsequent ATO treatment or HSCT, the 18-month OS
and relapse-free survival were 66% and 56%, respectively.81
Alimoghaddam et al.87 have also conducted similar research in
which 31 patients who relapsed from ATRA plus chemotherapy
were reinduced to remission and consolidated by a single agent of
ATO. After a median time of 32 months of follow-up, it was found
that 10 (41.6%) patients relapsed in the 24 CR2 patients. The
2-year DFS and OS were 54.6% and 81.1%, respectively. This report
from Iran reminds us that, although the single agent of ATO is
quite effective on remission induction, the recurrence rate after
CR2 induced by ATO is not low. Thus, post-remission therapy is
essential for the prognosis of patients.
Once CR2 is achieved, the treatment strategy after induction
therapy remains controversial. The options include continued
administration of ATO, ATRA combined with chemotherapy and/or
ATO, and HSCT.49,88 Thirugnanam et al.89 treated 37 patients with
relapsed APL. Of these patients, 33 attained MR with ATO-based
induction therapy (including three types of regimens, that is, ATO
alone, ATO plus ATRA, ATO plus ATRA plus anthracycline). Among
them, 14 patients chose autologous stem cell transplantation as
subsequent treatment, and the remaining 19 were given a single
agent of ATO or ATO combined with ATRA. The 5-year EFS of these
two groups of patients were 83.33% and 34.45% (P ¼ 0.01),
respectively, as calculated with the Kaplan -- Meier method. In
the study of Ferrara et al.,90 of the six patients who underwent
autologous stem cell transplantation after achieving MR after
relapse, five survived and remained in MR for a long term, and
only one died of primary disease after recurrence. In 2007, the
European Group for Blood and Marrow Transplantation compared
the follow-up data of 625 patients treated by HSCT and found that
there was no significant difference in leukemia-free survival
Leukemia (2012) 1743 -- 1751
1747
APL and its treatment
J-Q Mi et al
1748
between the autologous group and the allogeneic group,91 with a
lower transplant-related mortality and a higher relapse incidence
in the autologous group. We therefore recommend that, for
patients with relapsed APL, once MR is achieved by ATO-based
therapy, the autologous stem cell transplantation should be
conducted, whereas for those who can not achieve MR, allogeneic
stem cell transplantation could be the choice.
As an anti-CD33 monoclonal antibody, gemtuzumab ozogamicin (GO) was approved by the US FDA in 2000 for the single-agent
treatment of elder patients with relapsed APL. The recommended
dose was 9 mg/m2 i.v. (given on days 1 and 15). As the CD33
antigen is often expressed on the surface of APL cells, the
administration of GO could increase the MR rate. Lo-Coco et al.92
gave GO to 16 molecularly relapsed patients, 14 patients
responded, with a median MR time of 15 months for 7 of them,
with the other 7 patients relapsing soon after. Among the relapsed
patients, two continued GO treatment and both achieved MR
again. It was demonstrated that a single agent of GO exerts
significant effects on the APL patients with molecular relapse. As
to the combination therapy, Aribi had conducted relevant
research88 in which the re-remission rate was 100% with
combination treatment of ATO, ATRA and GO. However, because
of the limited sample size (n ¼ 8), these data need to be further
investigated.
CNS RELAPSE
As the prognosis of APL patients is getting much better, the issue
of CNS relapse is becoming increasingly important and we believe
an overall treatment strategy of APL seems unreasonable without
intrathecal prophylaxis. At present, the relapse rate is more than
1% in a 5-year follow-up, especially in patients with initial WBC
greater than 10 109/l, in which the recurrence rate could exceed
5%.49,93 Once a CNS relapse is recognized, we recommend
intrathecal therapy with methotrexate (10 -- 15 mg), dexamethasone (5 mg) (or Prednisolone 40 mg) and Ara-C (40 -- 50 mg) 2 -- 3
times per week until complete clearance of blasts in the
cerebrospinal fluid. At the same time, systemic medication,
including ATO and ATRA, should be started. However, simultaneous chemotherapy is not recommended because of its
myeloablative effect resulting in a rapid decline in platelets count,
which may lead to the unavailability of lumbar puncture.
Subsequently, at least 6 -- 8 intrathecal therapiess are to be
performed as consolidation. Owing to unfortunately repeated
lumbar punctures, each of them should be carried out cautiously.
The chemotherapy drugs should be injected after confirmation of
the successfulness of the procedure, thereby reducing the
iatrogenic possibilities of paralysis resulted from multiple intrathecal therapies. For consolidation chemotherapy, regimens
with high CNS penetration (for example, high-dose Ara-C)
could be given, and allogeneic or autologous transplants
including appropriate craniospinal irradiation should be under
consideration.
FUTURE PERSPECTIVES
It has been 27 years since 1985, when the world’s first patient
received ATRA in Shanghai. APL has experienced the conversion
from the most lethal to the most curable acute leukemia. The ways
of treatment have also turned from the original single chemotherapy to comprehensive treatment, which consists of not only
chemotherapy, but particularly targeting therapy of ATRA and
ATO and salvage therapy of autologous or allogeneic HSCT,
as well.
Although good prognosis has been demonstrated in APL as
compared with other leukemia, how to further improve the cure
rate is always a question worth thinking about. ED, the term
proposed 20 years ago when ATRA had not been widely used,94
Leukemia (2012) 1743 -- 1751
has recently attracted attention again from investigators.33,95,96
Park et al.97 reported 1400 cases of APL from 1992 to 2007, the overall
ED rate was 17.3%, and only a modest change in ED was observed
over time. Lehmann et al.98 reported 105 cases of APL patients
among whom the frequency of ED (within 30 days) actually
reached 29%, a rate significantly higher than those in non-APL
AML, especially evident in the elderly (460 years) population.
For those EDs, 41% died from hemorrhagic complications, most of
which were CNS bleeding. Therefore, early diagnosis, and proper
handling of hemorrhagic diathesis is proven to be especially
important.98 Thus, for the novo APL patients, the treatment should
be further optimized. Our aim is to deliver the most timely and
best treatment to each newly diagnosed APL patient, that is, to
mobilize our entire human and material resources if necessary,
including emergency room, intensive care unit, multi-disciplinary
team of physicians and nurses, to ensure the maximum saving of
lives at the onset of disease. More importantly, as Park et al.97
mentioned, there is a clear need to provide the knowledge
necessary to recognize APL as a medical emergency that requires
specific and simultaneous actions, including a prompt initiation of
ATRA, aggressive supportive care to counteract the coagulopathy
and transfer to experienced medical centers when the disease is
first suspected.
For those high-risk patients, we are further looking for better
treatment; will it be the median-dose or high-dose chemotherapy,
or ATO, or even a combination of both? The answer is to be given
in the future series of clinical trials. However, for those low-risk
patients, ATO þ ATRA combined with less chemotherapy may be a
more appropriate choice. In our 85 cases of APL patients,67 none
of them developed therapy-related myelodysplastic syndromeacute myelogenous leukemia or other malignancies. The possible
explanation may be the absence of VP-16 in our protocol, and also
may be the relatively lower intensity of chemotherapy. In the
reports of working groups with more intensive chemotherapy, for
example, in the GIMEMA group using VP-16, the incidence of MDS
or AML after APL treatment was 6.5%, whereas in the studies of
European APL group which omitted the application of VP16 that
incidence was 0.97%.99,100
The cheaper prices of ATRA and ATO (provided by the Chinese
pharmaceutical manufacturers) make them widely used in China.
In some other developing countries like India and Iran ATO is also
available, however, these two drugs are more expensive on
international markets, especially ATO. Thus, they are often more
accessible in the richer North America and Western countries, yet
lack affordability to the APL patients from many other countries.
For this reason, we regret that such a good treatment is difficult to
be widely spread because of economic reasons. To a certain
extent, there is an absence in the fairness of health care for those
patients in poor countries. Currently, the As4S4 developed
independently in China is similar to the ATO in terms of efficacy,
and its oral administration makes it more conveniently used. After
further clarifying its efficacy, in consideration of its relatively lower
price, we will encourage the Chinese companies to provide it to
the world when possible at a reasonably low cost, to make sure
that each patient receives treatment of an equally high quality.
However, arsenic is not a panacea, and there are still relapses
after ATO. Recently, a Japanese working group demonstrated from
a study of two cases of relapsed patients that the mechanism for
ATO-resistance may be missense mutations in PML -- RARa coding
sequence, resulting in amino-acid substitutions of A216V and
L218P in the PML B2 motif of the RBCC domain.101 On the other
hand, we recently found DNMT3A mutations in a relapsed
patient.102 These results have prompted us to further identify
the mechanisms of drug resistance in future work, so that the
subset of patients who may develop resistance could be screened
out earlier in the treatment, and specific therapeutic strategies can
be given from the very beginning, to finally alter the prognosis of
these patients.
& 2012 Macmillan Publishers Limited
APL and its treatment
J-Q Mi et al
1749
It should be particularly emphasized that where ATO or
conventional ATRA is ineffective, either given alone or combined,
other different therapeutic strategies, such as liposomal ATRA, can
be tried under permitting conditions. Douer et al.103 reported that
liposomal ATRA was effective in inducing CR in newly diagnosed
and relapsed patients, and it can induce MRs without chemotherapy in some patients, especially in the low-risk cases. However,
this drug is currently unavailable commercially, and we are
looking forward to more and better results.104
How to improve the quality of life of patients without affecting
treatment efficacy? It is also an issue we are often thinking about.
Oral ATRA, oral arsenics and even oral chemotherapy drugs have
given rise to our expectations. We believe that the successful
model of APL can also shed light on the therapy of other acute
leukemias, and even solid tumors, thereby improving the efficacy
of our anti-tumor therapy in various fields.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
This work was supported in part by the Chinese National Key Basic Research Project
(973: 2010CB529203). We would like to thank to Drs Kan-Kan Wang and Xiao-Wei
Zhang for their expert contributions to the study on the leukemogenesis of APL.
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