Hematology and Leukemia
ISSN 2052-434X
Review
Open Access
Treatment related myeloid malignancies in childhood
Henk van den Berg
Correspondence:
[email protected]
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Department of Pediatric Oncology, Emma Children Hospital Academic Medical Centre, University of Amsterdam, The Netherlands.
Abstract
Incidence of treatment related AML/MDS (t-AML/MDS) in children is extremely low. Consequently assessment of data from
adults and to some extent extrapolation from adults is needed. Epipodophyllotoxin induced t-AML/MDS is more common, which
is likely to be related to the shorter latency period, FAB-M4, FAB-M5, APL, balanced karyotypes, 11q23 and 21q22 anomalies,
inv(16) and t(15;17) are noted more oten. Duration and short interval between administrations of epipodophyllotoxins results
in higher incidence of t-AML/MDS. Genetic (karyotypic) make up inluence duration of remission, although the relation with
overall-survival is less clear. Choice of therapy should be based on co-morbidity and the likelihood to undergo intensive therapy.
he majority of children with t-AML/MDS should have a transplantation. A minority of children with t-AML with inv(16), t(8;21)
and t(15;19) should be considered for chemotherapy according to de-novo protocols. Monitoring of early response criteria for
detection of primary resistance is advised.
Keywords: Leukemia, aml, children, secondary, alkylating agents, epipodophyllotoxins, etoposide
Introduction
Myeloid malignancies represent a number of clonal hematopoietic disorders with extensive production of non-differentiating
myeloid precursors cells. Due to infiltration in the bone marrow
limiting production of normal cells, anemia, thrombocytopenia
and neutropenia are often the first signs of the disease. Myeloid
malignancies are mostly denominated as leukemias and
myelodysplasia (MDS) and are delineated by the percentage
and characteristics of the malignant cells and are classified
in the same WHO category. Most patients with myeloid malignancies have no preceding disease. For those patients with
a preceding disease, which is related to the development of
a myeloid malignancy, a separate entity exists and is defined
as “Acute myeloid leukemia and myelodysplastic syndromes,
therapy related”. A subclassification was based on major related
inducing factors; i.e.,1. Alkylating agent/radiation–related type,
2. Topoisomerase II inhibitor–related type; 3. Others [1]. This
remaining subclassification; i.e., “others”, includes cases related
to e.g., fludarabine, chlorambucil and radiotherapy/radioactive
isotopes [2-6]. An additional cause of t-AML is immune suppression; e.g., due to azathioprine [7]. Since most patients had
combinations of inducing agents this WHO subclassification
is currently not seen as relevant [8]. Generally both therapyrelated AML of secondary-AML terms are used.
Review
Incidence
Incidence of acute myeloid leukemia in children is low. Based
on SEER data an incidence rate of 0.7 cases of AML per 100,000
children in the age group <20 years is noted. No epidemiological
data exist on the incidence of t-AML/MDS. St. Jude’s Hospital
reports on 36 (1%) out of 3,696 children over a 12 year period
[9]. Literature data indicate that around 6 to 13% of AML
cases, irrespective of age, can be designated as t-AML/MDS
[10,11]. In a study on 642 children who had suffered from
ALL and who developed a secondary malignancy t-AML/MDS
was seen in 255 children; i.e., AML in 186, MDS in 69 children
[12]. After a prolonged follow-up after being cured of their
primary malignancy, an increment in incidence in secondary
malignancies is noted, with a total ratio of observed versus
expected cases of 6603 for MDS and 226 for AML [13]. In a followup study on 14359 5-year survivors of childhood cancer 1402
patients developed 2703 neoplasms, among them 24 t-AML
and 11 undefined non-ALL leukemia, resulting in a standardized
increased risk (SIR) of 9.3 for all treatment related malignancies
and specific for t-AML/MDS a SIR of 6.0 [14]. In a long follow-up
study on 1378 patients surviving pediatric cancer, the standardized mortality rates (SMR) from secondary cancers tend to
decrease from 38.1 to 6.19, after follow-up from the first decade
to >25 years follow-up after initial diagnosis, respectively. A
similar reduction was seen calculating the absolute excess
risk (AER; decrease from 1.75 to 1.05 per 1,000 patient years).
Only 16% were t-AML/MDS. Explanatory for the lowering of
AER and SMR is the increase due to other cancers at older age
in the normal population. A factor influencing the observed
decrease in incidence rate in more recently treated children is
© 2014 Henk Van Den Berg; licensee Herbert Publications Ltd. his is an Open Access article distributed under the terms of Creative Commons Attribution License
(http://creativecommons.org/licenses/by/3.0). his permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Henk Van Den Berg, Hematology and Leukemia 2014,
http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf
the striving to reduce the alkylator dose as well as the trend to
irradiate less often, reducing irradiation dosages and limiting
irradiation fields [15-17].
Diagnosis
Clinical symptoms and physical findings of t-AML/MDS are to
some extent similar to de-novo AML/MDS. Signs of leukemia
are more often linked to hyperleukocytosis and cytopenias of
normal cells, whereas MDS results in most cases in cytopenias;
leading to tiredness, infections and bruises. The primary
diagnosis is based on morphology and histochemical staining.
Subtyping is done similar to de-novo AML/MDS and based
on the FAB-classification. Epiphyllotoxins and anthracyclines/
mitoxantrone related secondary myeloid malignancies are
mainly FAB-M4 (among them M4eo~inv (16)), M5 and acute
promyelocytic leukemia (APL–FAB- M3~t(15;17)) presenting
as acute onset disease. Alkylating agent related t-AML/MDS
more often present as FAB-M6 and -M7 subtypes. Secondary
myeloid malignancies related to alkylating agents have (in
contrast to epipodophyllotoxins related mali-gnancies) a more
protracted course presenting initially in many cases as MDS
[15]. It was shown that the dominant clone in t-AML as seen
after preceding t-MDS is derived by further evolution from
the MDS clone [18]. In adults there is a relation on incidence
with type of alkylating agent and occurrence of t-AML/MDS.
It is claimed that melphalan induced more often secondary
AML as compared to cyclophosphamide. Dose relationships
were noted for cyclophosphamide [19-21].
Similar to de-novo AML in M4 and M5 subtypes a high frequency of rearrangements of 11q23 anomalies, t(8;21), inv(16)
and t(8;16) are noted [22]. Compared to de-novo AML, the
incidence of polyclonality is higher in t-AML/MDS. Secondary
APL forms a peculiar exception; it has been found to be similar
to de-novo APL in respect to morphology, immunology and
cytogenetics [23].
doi: 10.7243/2052-434X-2-3
topoisomerase induced myeloid leukaemia [26]. This might
in part be related to the age limits restricting the standard
follow-up period by paediatricians and is in contrast to
findings in adults. The number of patients included in the
cited document was also low (n=24) and low-risk t-AML/
MDS related to epipodophyllotoxin cases are absent in the
report. In adults epipodophyllotoxins related AML tends to
present between 1-4.5 years, and a preceding MDS phase is
often lacking, whereas alkyting agents induced-AML often
occurs after 1-20 years [10,21,27]. As a result reports on only
children may have missed a part of alkylator induced t-AML/
MDS and/or the epipodophyllotoxin related low-risk patients.
Cytogenetics
Distribution of karyotype aberrations is different from de-novo
AML since more 11q23 and complex karyotypes are noted
[10]. T-AML patients more often have a balanced karyotype as
compared to patients with t-MDS [27]. Also in relation to the
preceding therapy differences are noted. Alkylating agents are
linked more frequently with cytogenetic anomalies involving
chromosomes 5 and 7. The latter anomalies were noted in 76%
cases in a series of 306 patients, which is substantially higher
as compared to de-novo AML [28,29]. Affymetrix mapping
confirmed the occurrence of single nucleoside polymorphism
(SNP) in a subset of patients with loss of chromosomes 5 and/
or 7, which was associated in that study with prior treatment
with alkylating agents [30]. In topoisomerase II inhibitor related
secondary AML more balanced translocations are noted; more
often involving 11q23 and 21q22. Translocations related with
epipodophyllotoxins involving 21q22, inv(16) and t(15;17) have
received more often anthracyclines as well [25,31-39]. These
findings were also confirmed for children in a study on 20
patients [40]. However, 11q23 and 21q23 abnormalities have
been identified in non-anthracycline treated patients as well [9].
Further DNA analysis revealed in epipodophyllotoxin related
t-AML/MDS MLL-rearrangements, EML1-1, CBFβ-MYH11and
Adults
PML-RARα. Whereas in alkylating agent specific genetic
In adults often an initial phase compatible with MDS evolving aberrations are less specific [15]. It is hypothesized that the
in to AML is common. In children this is not as usual. In adults differences between alkylator induced and epipodophyllotoxin
the percentage of patients presenting with a t-MDS (in contrast induced t-AML/MDS in respect both to latency to develop a
to t-AML) is substantially higher as compared to adults [24]. t-AML and chromosomal findings are related to differences
Higher rates of uncommon AML subtypes such as FAB-M6 in oncogene alterations. In alkylating agent induced t-AML/
and M7, i.e., erythroblastic and megakaryoblastic AML, are MDS multiple tumor suppressor or oncogenes are needed
noted in t-AML in contrast to de-novo AML. In adults a peak to induce a malignancy, resulting in imbalanced karyotypes.
incidence is noted 4-6 years after cytotoxic therapy given Epipodophyllotoxins result in balanced karyotypes related
for the first malignancy. Occurrence after a latency period to an activation of an oncogene in a dominant fashion [21].
as short as 12 months but even ranging to 15-20 years are Several pathways more or less specific for either alkylator- or
not uncommon.
epipodophyllotoxins have been constructed; it is beyond this
review to discuss these hypotheses [41].
Children
It is stated that in children the occurrence of t-AML is negligible 6-years after treatment cessation of the primary disease
[25]. Also the latency period to development of t-AML/
MDS was found to be the same for alkylator-induced as for
Risk factors
Secondary myeloid malignancies are in the majority of cases
related to cytotoxic chemotherapy and organic compounds
such as benzene [42]. Earliest reports date from Hodgkin pat-
2
Henk Van Den Berg, Hematology and Leukemia 2014,
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ients receiving mechlorethamine, vincristine, procarbazine and
prednisone (MOPP) courses. In patients treated before the age
of 16 years, the relative risk of leukemia was about 80 times
higher than the control population (relative risk of 321.3). After
replacing mechlorethamine by cyclophosphamide a lower SIR
of 122 was found. After introducing doxorubicin, bleomycin,
vinblastine and dacarbazine (ABVD) another reduction was
noted [15,43-46]. Cytostatic drugs most commonly linked
with secondary malignancies are topoisomerase II inhibitors
(epipodophyllotoxins, anthracyclines and anthracenediones)
and alkylating agents. Topoismerase inhibitors interfere with
the enzymes involved in uncoiling the DNA in order to form
single strands. This results in deletions, insertions, inversions
and translocations [8]. Additional risk factors related to the
use of medication are duration of exposure and cumulative
dosage [47]. Cyclophosphamide has been mentioned earlier.
In respect to cumulative and duration of administration of
epipodophyllotoxins several reports mention the link of a
higher cumulative dosage and a higher risk [48,49]. Others
do not confirm such a finding, but link the risk to the dosing
schedule. They noted that higher cumulative dosages did
not result in increased incidence rates, but prolonged
administration had a more pronounced effect [50]. Being
the most prominent factor of secondary malignancies noted
in children; pediatric data are available on the increase
related to the dosing interval. Prolonged administration of
epipodophyllotoxin twice weekly or weekly was independently
associated with the development of secondary AML. The
overall cumulative risk of AML at six years was 3.8 percent;
but in subgroups treated twice weekly or weekly, the risks
were 12.3 percent and 12.4 percent [51]. Alkylating agents
act by transferring alkylgroups to oxygen or nitrogen atoms
of DNA bases. Alkylating agents with two active sites are
additionally capable of cross linking DNA strands. Effects
of alkylating agents on SIR are less clearly reported. In most
cases they are used in combination with other chemotherapy.
As a result the exact effect on induction of t-AML/MDS is less
elucidated. It is claimed that anthracenediones (mitoxantrone
e.g.,) induce more frequently secondary t-AML as compared
to anthracyclines. However, data are mainly based on adults
[52-55]. The effects of other agents may be clarified in the
future. For instance campthotecans are potential candidates
since the mode of action, i.e., blocking topoisomerase I, is
quite similar to topoisomerase II inhibitors. It is probable
that due to the low number of patients treated with these
compounds (in most cases in combination with other drugs)
the leukemia inducing effect is still unnoticed [56].
High levels of irradiation and radioactive isotopes are reported to induce secondary myeloid malignancies [6,9,57].
Ionizing irradiation induces the formation of reactive oxygen
species through radiolysis of water molecules, which oxidize
or deaminate DNA bases and induces DNA strand breakage.
Proton irradiation leads to DNA strand breaks as well. It was
described that radiotherapy as such is not related to t-AML/
doi: 10.7243/2052-434X-2-3
MDS. However in combination with chemotherapy there was
a clear relation [33,58]. The findings reported by others do not
support the finding that radiotherapy given as single treatment
modality is not related to induction of t-AML/MDS [27].
Synergy in respect to the induction of second malignancies
in relation to other cytostatic drugs and host factors are well
known as based on findings in Fanconi anemia, neurofibromatosis type 1 and gluthatione transferase polymorphisms
[59-61]. An increase of risk of epipodophyllotoxin induced
t-AML/MDS was related to the combination with other anticancer drugs. For asparaginase and alkylating agents, cisplatin
and antimetabolites this has been reported as well. In respect
to the effects of asparaginase a decrease of protein levels and
as consequence a decrease in recombinogenesis activity is
relevant in epipodophyllotoxin treatment. Which is explanatory
for the increase of t-AML/MDS occurrence if asparaginase is
given immediately before epipodophyllotoxin administration
[9,15,25,33,37,48,62,63].
Co-medication has been debated to play a role in induction
of secondary malignancies. Especially the use of growth
factors (G-CSF) and dexrazoxane have been under focus. In
adults data on G-CSF are contradictory. An increased risk
was found in breast cancer patients diagnosed at a younger
age as compared with older patients [52,64,65]. In children
with Ewing sarcoma no relation was noted, whereas in ALL
patients a relation was suggested [66,67]. In a study by Relling
et al., on 412 children treated for ALL receiving etoposide and
anthracyclines, 99 had received G-CSF, 284 cyclophosphamide,
58 of these 284 also received cranial irradiation. There were 20
children who developed t-AML/MDS after median interval of
2.3 years (range, 1.0-6.0 years; 16 AML, 3 MDS, and 1 chronic
myeloid leukemia). The 6-year cumulative incidence of t-AML
was 12.3% (5.3%) Excluding children receiving irradiation, the
incidence rate was higher in those receiving G-CSF (P=0.019)
[67]. Although G-CSF is mentioned to be linked with the
development of secondary malignancy, especially AML, this
is at least in adults minimal with an absolute risk increase
of 0.43%. In contrast its use resulted in reduction of death
(3.4%) probably due to the possibly to give more intensive
treatment schedule [68]. Dexrazoxane is used as agent giving
cardioprotection to prevent side effects of anthracyclines.
The induction of secondary malignancies is claimed by some.
Others question such a side effect. As a result the product is
only marketed for adults. The debate in children in respect
to risk-benefit has not been finalized yet [69-71]. For both
G-CSF and dexrazoxane the setting of this drug administered
in relation to other carcinogenetic medication is probably of
major importance in inducing t-AML/MDS.
Immune-suppression is related with secondary malignancies.
Lymphomas are quite common, but AML is relatively scarce.
In heart-lung recipients and kidney recipients relative risks
of 5.5 and 2.1 for t-AML were reported. Non-DNA as well as
DNA damaging immune-suppressants (e.g., azathioprine) are
noted to be related with t-AML [7]. In hematopoietic stem
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Henk Van Den Berg, Hematology and Leukemia 2014,
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cell transplantation patients a higher incidence as compared
to patients treated without transplantation was reported in
several manuscripts. However, administered cytostatic drugs
and total body irradiation administered to these patients may
be even more important in comparison with the resulting
immune deficient state and the extensive cellular proliferation
in these procedures [27,72-75]. In a study on 1487 paediatric
autologous hematopoietic cell transplantation 35 secondary
malignancies were noted; among them 6 cases with t-AML
and 7 with t-MDS. For all secondary malignancies these children had a 24 times higher risk for developing a secondary
malignancy, for AML and MDS the observed versus expected
ratios were 266 and 6603 respectively. Analysis for specific
risk factors did not reveal any significances [13].
Some inborn metabolic host factors are also linked with an
increased susceptibility for t-AML/MDS. Low thiopurine-methyltransferase activity and polymorphism of a CYP3A4 enzyme
results in as DNA-damaging metabolite of epipodophyllotoxins
[38,76,77]. Also glutathione-S-transferase, NAD(P)H: quinine
oxireductase and polymorphisms of DNA repair genes are
linked with an increased occurrence of t-AML/MDS [28,36,78-87].
Extensive reviews on genetic susceptibility and biological
pathogenesis were published [21,56,66,82].
Some (often inheritable) anomalies attribute to the development of AML/MDS and AML/MDS without the need for
prior therapy. In principle the term secondary AML/MDS
is more applicable instead of treatment related AML/MDS.
Based on similarities in disease characteristics some reports
on t-AML/MDS deal with these anomalies, as well. Examples
of genetic predisposition are Down syndrome, Fanconi
anemia, Li-Fraumeni syndrome, Leopard syndrome, Noonan
syndrome and Costello syndrome. Several of them are related
to RAS-MAPK pathways [8,88-94]. The higher incidence of
malignancies in relatives of patients with t-AML then in
relatives of patients with de-novo AML and the occurrence of
new malignancies in cancer patients treated with only surgery
can be put forward for existence of yet unidentified factors
[91]. As such it is assumed that at least some patients have
an inheritable susceptibility to develop t-AML [7].
Patients with specific primary malignancies run an additional
risk for t-AML/MDS; e.g., pediatric Hodgkin’s lymphoma,
osteosarcoma and APL after breast carcinoma [49,95]. The
percentage of patients suffering from a specific secondary
malignancy is not only related to former therapy; the primary
disease itself is related to the distribution of type of malignancy
as well. For instance t-AML is rare in chemotherapy treated
patients with retinoblastoma treated who are prone to develop
second malignancies. It is hypothesized that this is related to
the fact that the underlying mutation of the Rb1 gene does
not play a role in hematopoietic stem cells [96].
Prognosis
Since AML is more frequent in adults and t-AML/MDS only
occurs after a preceding oncogenic exposure t-AML/MDS has
doi: 10.7243/2052-434X-2-3
a very low incidence in children. As a consequence many data
have to be extrapolated from adults. In adults the prognosis
of secondary AML is dismal in comparison with de-novo AML.
However, remission rates reported range in a single report up
to 82%. But in an analysis of 13 different studies an overall CR
rate was calculated to be 27%. Survival at 5 years was reported
to be less than 10%. The recent study reported by Godley et al.,
states an overall survival at 1 year of 51%. Overall survival at
1 year was 74% for patients who had achieved a CR, but only
20% for patients who had achieved only a partial remission
after induction. After allogeneic stem cell transplantation
median survival was 673 days, compared to 399 days for those
who had an autologous transplant and 93 days in case no
transplantation was done. Overall survival at 1 year was 72%,
75%, and 17% for patients respectively [27,97-101].
The number of children suffering from t-AML/MDS reported
in literature is very low [12,102-105]. Tabori et al., reported
on 21children with t-AML and 2 with t-MDS. Both event free
survival and overall survival were 14%. Leahey et al., report
on 11 children. Only 3 survived, resulting in a 3-years survival
of 24%. Causes of death were recurrence of primary disease
and new malignancies [103]. Sandler reported on 16 children,
9 out of 13 children who achieved complete remission were
transplanted. Two transplanted children survived over 2 years,
whereas one not transplanted patient survived at least 8
months [104]. One of the larger studies reports on 62 children.
Compared to de-novo AML they had a poorer induction rate
(50% vs 72%), overall survival (26% vs 47% at 3 years, and
event-free survival (21% vs 39% at 3 years) [15]. Children with
t-AML/MDS who received intensive-timing induction had
better outcomes than those who received standard-timing
induction (overall survival 32% vs 0%) [26]. In a study on 642
children who had suffered from ALL and later developed a
secondary malignancy t-AML/MDS 5-year survival estimates
for AML were 11.2% for 125 patients diagnosed before 2000
and 34.1% for 61 patients diagnosed after 2000 (P<0.001);
5-year survival estimates for MDS were 17.1% for 36 patients
and 48.2% for 33 patients, respectively. Allogeneic stem-cell
transplantation failed to improve outcome of secondary
myeloid malignancies after adjusting for waiting time to
transplantation [12].
Prognostic factors
Adults
Dismal prognosis is related to age, and co-morbid conditions
and restrictions in treatment due to preceding treatments
[106-109]. In many cases t-AML/MDS is a fatal condition. Additionally factors are organ and vascular supply injury. Bone
marrow function may be severely hampered due to cytostatic
use and extensive irradiation [108,110].
In respect to the preceding treatment alkylator related t- AML
has a dismal prognosis, due to the more frequent harboring
of anomalies of chromosomes 5 and 7. Remission rates of 24
and 26% were noted in t-AML versus 52 and 42% in de-novo
4
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doi: 10.7243/2052-434X-2-3
AML. Long-term survival rates approximate 10% [108,111,112].
On the other hand patients with t-AML due to epipodophyllotoxins are reported to have a better prognosis. In epipodophyllotoxins related cases remission rates are as high as 81%, but
ultimate outcome is still low; i.e., 8% at 2-years [104]. In t-AML
the expression rate of MDR1 is high. But in contrast to adults
expression of the multidrug resistance gene MDR1 in children
is expected to be (at least in de-novo AML) non-relevant [113].
Relevance in pediatric t-AML/MDS is undetermined.
matching for these anomalies of secondary versus de-novo
patients. It was concluded that karyotypes were influencing
survival duration, however ultimate prognosis irrespective of
cytogenetic findings was very poor [10]. Similar findings for
adults were reported from Chicago, 29 patients with t-AML
with favorable cytogenetics had a median survival time of 27
months; those with intermediate cytogenetics had a survival
time of 12 months which contrasted with 16 months for denovo AML. This was however not significant (p=0.19). For t-AML
and de-novo AML patients with unfavorable cytogenetics
Genetics
survival was 6 and 7 months, respectively [29,118]. In another
Prognosis in adults is related to the karyotype observed. Several report on adult patients from Germany a shorter survival time
classifications delineating prognostic groups exist (Table 1) was noted in t-AML versus de-novo AML. In a later update of
[114-116]. A relative old report mentions that patients with their study it was shown that karyotype is a factor in respect
t(8;21) (n=26), inv (16) (n=16) and t(15;17) (n=6) have similar to duration of survival, but also in the favorable group 5-years
outcomes as compared to de-novo AML [117]. Schoch et al., overall survival is below 25% and a plateau is not reached
defined, based on data of 93 patients that unfavorable anomalies [10,119]. Smith et al., reported similar data, however not all
were 3q21q26, 5q-/-5, 7q-/-7, 11q23, 12p 17p, >2 abnormalities, patients had received intensive remission induction chemointermediate anomalies (normal karyotype and other abnorma- therapy. Even patients responding to therapy and patients
lities) and favorable (i.e., t(15;17), t(8;21) and inv (16)) karyotypes. with favorable karyotypes died either from t-AML or from
Unfavorable karyotypes are more frequently noted in t-AML; their primary malignancy. The incidence of unfavorable karyoi.e., favorable , intermediate and unfavorable karyotypes 26%, types was over two-third, the worst prognosis was noted in
28% and 46% respectively. Rates in de-novo patients are 22, patients with anomalies of chromosome 5 and 7 [27]. In a
57 and 20% (p<0.001). Matching de-novo with therapy related Korean report on outcome in 48 patients multivariate analysis
cases only in patients with secondary AML with t(8;21), inv (16) showed that only APL and presence of non-complex karyotypes
and t(15;17) a shorter overall survival was noted; higher relapse were related with a more profitable outcome [120]. For APL
rate but similar CR rate were noted. Among these karyotypes no differences as compared to de-novo AML were reported
t(8;21) was found to have the poorest prognosis. Unfavorable [121]. Which once again suggests, similar to the findings in
and intermediate karyotypes had a similar outcome after morphological and immunological cell characteristics, that
Table 1. Risk groupings according to cytogenetics in literature.
Stölzel et al., 2011
Kröger et al., 2009
AML
Low
(Stölzel/Kröger)
Favorable
(Armand)
Intermediate
(Stölzel/Kröger)
Standard
(Armand)
High
(Stölzel/Kröger)
Adverse
(Armand)
Poor
(Litzow)
Litzow et al., 2011
MDS
AML
t(8;21) or inv(16)
normal and t(8;21), ns
inv 16 or t(15;17
ns
patients not
harboring high- or
low-risk
aberrations
one or two
abnormalities not
mentioned under
low or high risk
ns
ns
del(5q)/25,
27/del(7q), abn
3q, 9q, 11q, 20q,
21q, 17p, t(6;9),
t(9;22) and
complex
karyotypes (≥3
unrelated abn)
complex (ie, ≥3 Complex
anomalies) or
t(9;22)
chromosome 7 t(6;9)
abnormalities
-5/del(5q); -7/del (7q); 11q; t(6;9); -7;
monosomies of other
del(7q); del 5q or
chromosomes (with
complex ( ≥3)
exception for the loss of
chromosomes X or
Y); inv(3q); abn12p;
abn11q;+11; +13; +21;
+22; t(6;9); t(9;22);
t(3; 3); complex
aberrant karyotype
(≥ three independent
abnormalities)
Armand et al., 2007
MDS or AML
arising from MDS
t(8;21) alone
inv(16/t(16;16)/del(16q22)
with M4
t(15 ;17)
Normal
Del(9q)
t(8 ;21)+del(9q) or complex
Trisomy 8
Abnormal 5 or 7
Abnormal 11q23
All others
Normal
Abnormal 3q
Abnormal 5
Trisomy 8
All others
Abnormal 7
Complex
ns=not speciied
*=restricted to post-hematopoietic transplantation patients
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doi: 10.7243/2052-434X-2-3
t-APL is similar to the de-novo APL).
inclusive the therapy for the first malignancy may therefore
be important factors in the poor outcome of t-AML patients in
the early phase of treatment [10,119,122,125]. In a report from
FTL3
In respect to FLT3 internal tandem duplications (FLT3-ITD) it was Seattle outcome was noted after correction for risk factors in
shown that the percentage expressing cells was significantly HLA-identical or partially mismatched family hematopoietic
lower in t-AML, indicating that t-AML leukemogenesis in most transplantation. Relapse probability and relapse-free survival
cases follows mechanisms different from those seen in de- correlated significantly with disease stage and karyotypes.
novo AML. For de-novo AML FTL3-ITD was found to be a risk Relapse incidence was lower and relapse-free survival superior
factor, for t-AML such conclusion was not made [122]. Also (P=0.02) with unrelated donor transplants. Their data also
nucleophosmin-1 mutations were found to be less frequent in suggest that inferior outcome in patients with t-AML/MDS
t-AML as compared to de-novo AML and presence was found was related to the frequency of high-risk cytogenetics [126].
to be a risk factor in patients below the age of 60 years [116]. Similar findings were reported from the Dana Faber Cancer
Institute [114]. A Danish report on 157 adults with t-AML and
Transplantation
473 de-novo AML patients showed in univariate analysis a
In adults undergoing transplantation for t-AML/MDS 2-year better outcome for patients not reaching a complete remission.
survival rates of 30%, relapse rates of 42% and treatment Differences were not significant after correction for age, cytorelated mortality of 49% were reported in a French study genetic anomalies, performance status and WBC [127].
[123]. In a series of 46 patients undergoing transplantation
5-years disease-free survival was 24%, relapse and non-relapse Children
mortality was 31% and 44% respectively. In this cohort no As already mentioned the data in children are scarce. A major
statistical differences existed for patients treated with chemo- difference is the more frequent relation with epipodophyllotherapy before conditioning for stem cell transplantation ver- toxins in children as compared with adults. Remission rates
sus those who were not pretreated [124].
are as high as 81%, but ultimate outcome is still low, i.e., 18%
Patients after hematopoietic stem cell transplantation for at 2-years [104]. In a study on 20 children only 3 children were
their primary malignancy are at high risk since they have in alive after 1, 12 and 68 months; no correlation was found
the majority of cases a history with high dose irradiation and with chromosomal abnormalities [40]. Hale et al., reported
cytostatic use. In a report from the European Society for Blood on epipodophyllotoxin induced t-AML in 19 children. Ten
and Marrow Transplantation t-AML and t-MDS multivariate patients died from a relapse, and only 4 were alive 3 years
analysis revealed a better prognosis in case of an age <40 after allogeneic transplant [102]. In a report on 38 allogeneic
years, normal cytogenetics and a status of CR at the moment transplanted patients from St Judes Hospital 3-year overall and
of transplantation; overall survival rates were 62%, 33% and event free survival were both 15%, the non-relapse mortality
24% at 2 years, respectively. Cytogenetic anomalies were rel- was found to be 60% at 3-years. Severe (grade III–IV) acute
evant, but sub-analysis on specific anomalies seemed not to graft-versus-host disease and relapse rate were 24% and 19%,
be relevant in their prognostic scoring system (Table 2) [22]. respectively [128]. A report from the MD Anderson Hospital
In multivariable analyses on 2853 adults t-AML was an describes 22 patients from a group of 2589 children treated
adverse prognostic factor for death in complete remission for a malignancy 2-year survival rates of 20%, 40%, and 25%
but not relapse as compared to de-novo AML. In contrast to in children who underwent stem cell transplantation without
older patients the younger patients were more intensively induction, children transplanted in remission after induction
treated and did not show higher induction failures, but more therapy and receiving a stem cell transplantation as salvage
relapse in complete remission. As a result it is suggested therapy, differences were not significant. Risk factors identified
that co-morbidity, cumulative toxicity of cancer treatment, were poor/intermediate-risk cytogenetics (p=0.01), lower
hemoglobin level (P=0.0001), and t-MDS/AML (vs. de-novo)
(p=0.003) [129]. Barnard et al., describe 24 children with t-AML/
Table 2. European society for blood and marrow transplantation
MDS who were assigned randomly to standard- or intensiverisk scoring for t-AML/MDS (Kröger et al.,).
timing induction. A comparison was done with 62 de-novo
Risk factor
Number of points
MDS and 898 de-novo AML children. T-AML/MDS children
Age >40 years
+2
were older, had lower white blood cell counts and more often
Not in complete remission
+2
MDS (21% vs 7%) and trisomy. None of the patients had the
Abnormal cytogenetics
+1
classic t(8;21), t(15;17) and 16q22 anomalies. Patients were
Risk group
Overall Relapse free Non-relapse Relapse
randomized for time- and G-CSF- intensification of therapy.
survival survival
mortality
rate
Induction
rate comparing t-AML/MDS with de-novo AML
(2 year) (2 year)
(2 year)
(2 years)
was
lower
50% vs 72%, overall survival was 26% vs 47% at
Low (0-1 factors)
96%
58%
22%
20%
3
years),
and
event-free survival was 21% vs 39% at 3 years.
Moderate (2-3 factors)
33%
32%
37%
31%
T-AML/MDS
children
who received intensive-timing induction
High-risk (4-5 factors)
24%
20%
38%
42%
6
Henk Van Den Berg, Hematology and Leukemia 2014,
http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf
had a trend for a better outcomes than those who received
standard-timing induction, but this was not significant (overall
survival 32% vs 0%, P=0.54). The authors state that most
chil-dren with t-AML/MDS have disease resistant to current
therapies. Unfortunately they only did univariate analysis and
did not correct for specific risk factors [26].
doi: 10.7243/2052-434X-2-3
Table 4. German alliance leukemia study group (Stölzel et al.,).
Risk factor
Number of points
Age >60 years
1
High risk karyotype
1
NPM1 wild-type in bone marrow
1
9
Platelet count <50x10 /l in peripheral blood
herapy
Risk group
1
Overall
survival
(2 year)
Event free
Patients with t-AML have generally a poor tolerance for
survival
(2 year)
standard chemotherapy. Generally it is stated that patients
Favorable (0-1 factors)
58%
40%
with t-AML who have a good performance status should
intermediate (2 factors)
be treated similar as patients with de-novo AML. For those
28%
21%
patients who have favorable cytogenetic abnormalities,
High-risk (3-4 factors)
9%
7%
such as t(15;17), inv(16), and t(8;21); intensive chemotherapy
is advocated. Hematopoietic stem cell transplantation is
advised for unfavorable karyotypes. Supportive care alone in childhood. For the cases expressing 11q and 22p anomalies
may be warranted for those with poor performance status this statement is in line with data from adults. However, for
[21,29,98,99]. Recently the European Group for Bone Marrow those with APL and inv(16) such an advise cannot be given
Transplantation and the Center for International Bone Marrow since no or very low numbers of APL and inv(16) cases were
Transplantation Research devised scores to predict outcome among the patients with t-AML/MDS and the advice is not in
including age, cytogenetics, disease status at transplantation line with recommendations in adults. In children the general
and donor characteristics (Tables 2 and 3) [22,115]. The German rule not to transplant patients with APL can be adopted, as it
Alliance Leukemia Study Group devised a similar scoring, but is based on the finding that cell characteristics and outcome
incorporated NPM1 as additional factor and platelet count in this subgroup is similar to de-novo APL [21,95,130]. For
(Table 4) [116]. EFS and OS were, however, quite different non-APL patients with low-risk t-AML/MDS pediatric patients
applying these scores. Based on these scoring the treatment treatment advises could align with advices in adults. As such
advises per subgroup can be formulated as mentioned above. the presented algorithm can be applied in choosing treatment
However, whether these scorings are useful in children is (Figure 1). Those with unfavorable karyotypes should be
doubtful considering the better tolerance of chemotherapy transplanted; preferably (if feasible) after bringing them in
and less co-morbidity in children as compared to adults and remission. Those with favorable karyotypes (e.g., t(15:17), t(8;21)
the inclusion of age as risk factor in these scorings It is has and inv (16)) could be treated according protocols similar to
been stated that most children with t-AML/MDS have disease de-novo AML protocols. Current new protocols use minimal
resistant to current therapies and all should be classified as residual disease (MRD) as surrogate marker for resistant
high-risk patients. This might not be fully appropriate as disease and adapt treatment accordingly. As a result some
the advised is based on univariate analysis only and did not children with t-AML/MDS with good risk characteristics will
correct for specific risk factors [26]. Since epipodophyllotoxin be transplanted in the end. For some transplantation can be
induced t-AML/MDS is the most common form of t-AML/MDS withheld. Only a few patients will be sorted in the supportive
care category, since physical condition in children is usually
better as compared to adults.
Table 3. Center for International Bone Marrow Transplantation
Research risk scoring for t-AML/MDS (Litzow et al.,).
Risk factor
Age
Poor risk
cytogenetics
Disease state
Donor type
Risk group
No risk factors
1 factor
2 factors
3 factors
4 factors
Each valid 1 point
>35 year
AML: del(5q)/25, 27/del(7q), abn 3q, 9q, 11q, 20q,
21q, 17p, t(6;9), t(9;22) and complex karyotypes
(≥3 unrelated abn)
MDS: complex (ie, ≥3 anomalies) or chromosome
7 abnormalities
Not in remission at moment of grating
Non-sibling related donor and mismatched donor
Overall survival (5 year)
50%
26%
21%
10%
5%
Conclusion
The incidence of treatment related AML/MDS (t-AML/MDS) in
children is extremely low. Consequently assessment of data
from adults and to some extent extrapolation from adults
is needed. Epipodophyllotoxin induced t-AML/MDS is more
common in children, which is likely to be related to the shorter
latency period to develop this condition. I FAB-M4, FAB-M5,
APL, balanced karyotypes, 11q23 and 21q22 anomalies, inv
(16) and t(15;17) are noted more often. Duration and short
interval between administrations of epipodophyllotoxins in
children results in a higher incidence of t-AML/MDS. Genetic
(karyotypic) make up is influencing duration of remission,
although the relation with overall-survival is less clear.
Choice of therapy should be based on co-morbidity and the
7
Henk Van Den Berg, Hematology and Leukemia 2014,
http://www.hoajonline.com/journals/pdf/2052-434X-2-3.pdf
doi: 10.7243/2052-434X-2-3
Diagnosis of t-AML/MDS
Good performance
Poor performance
T-APL
favorable karyotype
i.e. Inv(16) and t(8;21)
Unfavorable karyotype
Chemotherapy+
ATRA
Treat as de novo AML
according to protocol with or without
stem cell transplantation
Allogeneic stem cel transplantation;
preferably in complete remission
Supportive care
Figure 1. Algorithm for choice of treatment in t-AML/MDS in children.
likelihood to undergo intensive therapy. The majority of
children with t-AML/MDS should have hematopoietic stem
cell transplantation. A minority of children with t-AML with
inv(16), t(8;21) and t(15;19) translocation should be considered
for chemotherapy according to de-novo AML protocols. Monitoring of early response criteria for detection of primary
resistance is advised.
Competing interests
The author declares that he has no competing interests.
Publication history
Editor: Mingjiang Xu, Indiana University School of Medicine, USA.
EIC: Evangelos Terpos, University of Athens School of Medicine, UK.
Received: 20-Mar-2014 Final Revised: 19-Apr-2014
Accepted: 25-Apr-2014 Published: 09-May-2014
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Citation:
van den Berg H. Treatment related myeloid
malignancies in childhood. Hematol Leuk. 2014;
2:3. http://dx.doi.org/10.7243/2052-434X-2-3
12