Acute Myelogenous Leukemia After Treatment for Malignant Germ Cell Tumors in
Children
Dominik T. Schneider, Elisabeth Hilgenfeld, Dirk Schwabe, Wolfgang Behnisch, Andreas
Zoubek, Rüdiger Wessalowski, Ulrich Göbel
From the Department of Pediatric Hematology and Oncology, Heinrich-Heine-University
Düsseldorf, Medical Center, Düsseldorf; Department of Pediatrics, Charité, HumboldUniversity, Berlin; Department of Pediatrics, Johann Wolfgang Goethe University,
Frankfurt/Main; Department of Pediatrics, University of Ulm, Ulm, Germany; and Department
of Pediatrics, St Anna Spital, Vienna, Austria 2003.
PURPOSE: To identify the long-term sequelae of therapy for malignant germ cell tumors
(GCTs).
PATIENTS AND METHODS: Between 1980 and 1998, 1,132 patients were prospectively
enrolled onto the German nontesticular GCT studies. A total of 442 patients received
chemotherapy using combinations of the drugs cisplatin, ifosfamide, etoposide, vinblastine, and
bleomycin, and 174 patients were treated with a combination of chemotherapy and radiotherapy.
Median follow-up duration was 38 months (range, 6 to 199 months).
RESULTS: Six patients developed therapy-related acute myelogenous leukemia (t-AML). There
was no t-AML among patients treated with surgery (n = 392) or radiotherapy only (n = 124). The
Kaplan-Meier estimates of the cumulative incidence (at 10 years) of t-AML were 1.0% for
patients treated with chemotherapy (three of 442) and 4.2% for patients treated with combined
chemotherapy and radiotherapy (three of 174). Notably, four of these six patients had been
treated according to a standard protocol with modest cumulative chemotherapy doses. Five
patients had received less than 2 g/m2 epipodophyllotoxins, and four patients had received less
than 20 g/m2 ifosfamide. Four patients presented with AML, two with myelodysplasia in
transformation to AML. In five patients, cytogenetic aberrations were found, four of which were
considered characteristic for t-AML. Four patients died despite antileukemic therapy. One patient
is alive but suffered a relapse of his GCT, and one patient is alive and well. No secondary solid
neoplasm was observed.
CONCLUSION: In patients with AML after treatment for GCT, several pathogenetic
mechanisms must be considered. AML might evolve from a malignant transformation of GCT
components without any influence of the chemotherapy. On the other hand, the use of alkylators
and topoisomerase II inhibitors is associated with an increased risk of t-AML. Future studies will
show if the reduction of treatment intensity in the current protocol reduces the risk of secondary
leukemia in these patients.
ACUTE MYELOGENOUS leukemia (AML) and myelodysplastic syndromes are serious
complications after chemotherapy and radiotherapy in patients with malignant tumors. In
children with malignant tumors, the risk of therapy-related AML (t-AML) has been estimated to
be as high as 6.2%1 depending on the primary malignancy, the intensity of therapy, and
application protocol. The greatest risk was observed among patients with advanced tumors who
were treated with high cumulative chemotherapy doses or a combination of chemotherapy and
radiotherapy.1-7
This is the first report on the incidence of secondary leukemia in a large prospective study of
germ cell tumors (GCT) in children and adolescents. In most cases, these tumors show a good
response to cytotoxic treatment and have a favorable prognosis. Our patients were treated with a
standard chemotherapy regimen that contained both alkylating agents and topoisomerase II
inhibitors. The increased risk of leukemia observed by us is particularly relevant with respect to
the high cure rates in these tumors.
Between 1980 and 1998, 1,132 patients were prospectively enrolled onto the German studies on
nontesticular GCTs (Maligne Keimaelltumoren [MAKEI] 83/86, 89, and 96).8,9 Informed
consent for treatment and data evaluation was obtained after diagnosis. Tumor biopsy specimens
were reviewed by a reference pathologist. Patients were stratified according to primary tumor
site, tumor-node-metastasis classification, tumor histology, postoperative resection status, and
measurements of the tumor markers alpha-fetoprotein and beta-human chorionic gonadotropin.
Patients were treated with chemotherapy using three-agent combinations of cisplatin, etoposide,
ifosfamide, bleomycin, and vinblastine in standard doses (Table 1). In MAKEI 83/86 and 89,
patients received up to eight chemotherapy cycles as first-line treatment. In extracranial GCT,
radiotherapy was administered only occasionally. Granulocyte colony-stimulating factor therapy
was not administered routinely.
With the excellent remission rates, therapy was reduced step by step to four cycles in high-risk
patients in the MAKEI 96 protocol. In this recent protocol, low-risk patients were treated
according to a watch-and-wait strategy, and intermediate-risk patients received two to three
cycles of chemotherapy.
AML was classified according to the French-American-British classification.10 Patients were
treated according to the AML–Berlin-Frankfurt-Münster 93 protocol.11 In accordance with this
protocol, cytogenetic analysis of the bone marrow punctuates was performed at local genetic
institutes and in reference laboratories.
Statistical analysis was performed by the use of an individualized database (provided by the
Institute of Medical Statistics and Documentation, University of Mainz, Germany) and the
commercially available SAS program (release 6.12; SAS Institute, Inc, Cary, NC). The
cumulative incidence of t-AML in correlation to the time interval between the diagnosis of GCT
and the development of t-AML was estimated according to the method of Kaplan and Meier.
Patients were censored at the time of their last reported follow-up examination.
GCT Diagnosis and Treatment
Of the 1,132 patients evaluated in the MAKEI studies, 392 were treated according to a watchand-wait strategy for their completely resected tumors. A total of 124 patients received
radiotherapy only. No patient in these cohorts developed leukemia over a median follow-up
period of 38 months (range, 6 to 199 months). A total of 442 patients received chemotherapy;
174 were treated with combined chemotherapy and radiotherapy. Among these two cohorts, six
patients developed t-AML during the follow-up period. The clinical characteristics of these
patients at the time of GCT presentation are listed in Table 2. All six patients suffered from
malignant GCT and received first-line chemotherapy according to the MAKEI 89 or 96 protocol.
Four of these patients were treated according to the standard protocol, receiving two to four
cycles of standard chemotherapy (Table 1). The cumulative chemotherapy doses are shown in
Table 3. Patient no. 2 suffered from a metastasizing and locally recurring yolk sac tumor and
received extraordinarily high cumulative chemotherapy doses. In addition, this patient received
nine chemotherapy cycles combined with locoregional hyperthermia and achieved remission
from GCT.
Figure 1 shows the cumulative risk of t-AML in our patients according to treatment modality
(Kaplan-Meier estimate). Patients who have received combined chemotherapy and radiotherapy
are most at risk of developing t-AML (Kaplan-Meier estimates at 10 years: 4.2% ± 1.82% for
patients who received chemotherapy and radiotherapy v 1.0% ± 0.37% for those who received
chemotherapy and 0% for those who received radiotherapy or watch-and-wait therapy;
generalized Wilcoxon test, P = .04). Moreover, the observed risk of AML was by far higher than
the incidence observed in a normal population (0.7 of 100,000 per year).12 The time from
manifestation of GCT to AML varied between 61 and 180 weeks. No patient developed a
secondary solid tumor.
Fig 1. Kaplan-Meier estimation of the cumulative risks of
acute leukemia in correlation to the previous treatment (N
= 1,132).
Figures 2 and 3 show the Kaplan-Meier estimates of the risk of t-AML in correlation to the
cumulative doses of etoposide and ifosfamide, respectively. Although the risk of t-AML was
higher in the small cohort of patients treated with high cumulative chemotherapy doses
(etoposide, P = .01; ifosfamide, P < .001; generalized Wilcoxon test), we did not observe a linear
dose-response relationship of the leukemogenic effect of chemotherapy. Moreover, there was no
unequivocal additive (or hyperadditive) effect when combinations of etoposide and ifosfamide
were applied (Table 5).
Fig 2. Kaplan-Meier estimation of the risk of acute
leukemia in correlation to the cumulative etoposide doses
(n = 1,115; 17 patients were excluded because of
incomplete data on the chemotherapy).
Fig 3. Kaplan-Meier estimation of the risk of acute
leukemia in correlation to the cumulative ifosfamide doses
(n = 1,115; 17 patients were excluded because of
incomplete data on the chemotherapy).
Table 5. Risk of AML in Correlation to the Cumulative Doses of Etoposide
View this
and Ifosfamide*
table:
View this table: Table 4. Clinical Profiles at Presentation of Leukemia
AML
Bone marrow failure symptoms such as thrombocytopenia and pancytopenia were the initial
symptoms of leukemia in all patients. Bone marrow examination showed AML in four patients
(Table 4). In patient no. 2, who presented with a 2-month history of pancytopenia, leukemia
could not be further classified because of the poor quality of the bone marrow aspirate due to
myelofibrosis. The diagnosis in this patient was based on the increased peripheral-blood
myeloblast count and fluorescence-activated cell sorter analysis.
Clonal cytogenetic abnormalities could be detected in the bone marrow of five patients.
Aberrations of chromosome 7 were observed in three patients. One patient showed the
translocation t(8;16), and two patients showed complex karyotype aberrations. Moreover, patient
no. 4 showed a translocation t(4;11)(q21;q23) that involved the region of the mll gene. In patient
no. 2, the work-up of the initial bone marrow specimen was not successful, but a second
specimen obtained during a phase of partial remission showed a mosaic with a monosomy X in
some of the metaphases studied. This patient showed no clinical signs of Turner's syndrome.
Prognosis
Prognosis was poor; two patients died from therapy-related complications, and one patient died
from refractory leukemia. Two patients achieved a remission from their leukemia, but both
suffered a recurrence of the primary tumor. Patient no. 4 developed a local relapse as a primitive
neuroectodermal tumor, which was considered as a malignant transformation of some immature
neural component of the primary GCT, and died from tumor progression. Patient no. 1 suffered
from a local recurrence that resembled a Sertoli-Leydig cell tumor and was treated with surgery
and radiotherapy. At the time of this report, she was in remission from both leukemia and ovarian
tumor.
Leukemia Associated With GCT
GCTs arise from pluripotent cells capable of extra-embryonic and embryonic differentiation.
Therefore, a malignant transformation of GCT components to carcinomatous or sarcomatous
tumors has been observed in significant numbers.13 In adult patients, there have been occasional
reports of leukemia developing simultaneously with GCT.13-17 This finding was most prevalent in
mediastinal yolk sac tumors,16 in which a significantly increased frequency of megakaryocytic
leukemia was observed. In some patients, hematopoietic foci could be demonstrated on
histopathologic examination, and it was concluded that leukemia might arise from these
hematopoietic spots.18 This hypothesis was strongly supported by cytogenetic examinations that
demonstrated identical clonal aberrations (eg, the GCT-associated isochromosome 12p) in both
GCT and leukemia.15,16
Recent studies demonstrated different cytogenetic and molecular-genetic aberrations in pediatric
and adult patients with GCT that suggest profound differences in tumor biology.19,20 In general,
the testicular GCTs in the adult, among which seminoma represents the most frequent histologic
subtype, are characterized by aberrations of chromosome 12 in virtually all tumors
(isochromosome 12p, tandem-amplification 12p, deletion 12q),21 whereas in pediatric patients
with GCT, these findings are uncommon.19,20 On the other hand, the yolk sac tumor
differentiation is the predominant histology in children, and these tumors often show deletions at
the short arm of chromosome 1 (1p36).19,20
Four of six patients with t-AML were diagnosed at an age younger than 10 years. The oldest
patient (patient no. 6) presented at age 16 years with an ovarian tumor. In view of the data that
ovarian tumors in adolescence may frequently show characteristic changes at chromosome 12,
this tumor may have had a biology similar to that of adult ovarian tumors.22 Patient no. 6
presented with a synchronous sacrococcygeal and mediastinal nonseminomatous GCT. Because
sacrococcygeal tumors are extremely uncommon in adults, we concluded that this tumor
resembles a pediatric rather than an adult GCT. In conclusion, in view of the biologic differences
between pediatric and adult GCT, the observations of GCT-related leukemia cannot be
transferred to pediatric patients without scrutiny.
Pathogenesis of Therapy-Related Leukemia
In therapy-related leukemia, several pathogenetic mechanisms have been discussed:
1. Ionizing radiation (eg, in atomic bomb survivors,23 fetuses exposed to diagnostic radiation,24
and patients after radiotherapy4,25) induces DNA damages and mutations that consecutively
promote the development of t-AML.
2. Rearrangements involving the mll breakpoint on chromosome 11q23 have frequently been
found in patients with leukemia after treatment with topoisomerase II inhibitor.26,27 The
topoisomerase II enzyme has the unique capability of passing one DNA double-strand through
another, thereby allowing chromosomal condensation. Topoisomerase II inhibitors stabilize the
covalent topoisomerase II–DNA complex, thus increasing the risk of DNA cleavage and
chromosomal rearrangement.28 t(9;11)(p21;q23) is most commonly found.28,29 Usually, the time
lag from cytotoxic treatment to t-AML is short, and most cases display a monocytic
morphology.2
3. Alkylating agents such as the nitrogen mustard derivatives induce DNA damage by DNA
alkylation, nucleic-base transition, and consecutive base-pairing errors. The most common
cytogenetic findings are losses of chromosomes 5 or 7 or deletions at 7q.30 The time interval
between treatment and development of t-AML is longer for patients who receive alkylating
agents than for those who receive epipodophyllotoxin treatment, and the response to antileukemic
treatment is poor.29
Therapy-Related AML After Treatment for GCT
There have been various reports that documented the risk of t-AML in adult GCT patients.5-7,31-34
One review summarized a study of 1,868 patients who received standard chemotherapy with
topoisomerase II inhibitor doses less than 2,000 mg/m2. Only 11 of 1,868 patients developed tAML,35 and the risk has been estimated to be significantly less than 1%. Other studies reported
that the use of radiotherapy and topoisomerase II inhibitors and the combination of
chemotherapy and radiotherapy were the most significant risk factors for the development of tAML.6,31-34 For patients treated with high doses of epipodophyllotoxin (> 2 g/m2), the cumulative
incidence has been reported to be 1.3%.32 Our data on the cumulative incidence of t-AML after
chemotherapy for pediatric GCT treated with chemotherapy only is still comparable to that
reported by other investigators,5-7,31-33,35 although most report a slightly lower incidence. The
different estimations of the cumulative incidence of t-AML may be partly attributed to the
different statistical methods used for the estimation of the risk of t-AML. We analyzed the
cumulative risk of t-AML with the Kaplan-Meier estimation. This method may probably
overestimate the proportion of patients who finally develop t-AML because late events have a
strong influence on the outcome. On the other hand, patients who died from GCT or other
causes, or patients lost to follow-up, are censored. Thus, only the survivors who are at risk of
developing t-AML were analyzed. Moreover, the latency between GCT and t-AML was
considered in the analysis. For example, only three (1.72%) of 174 patients treated with a
combination of chemotherapy and radiotherapy developed t-AML. Nevertheless, after censoring
the nonsurvivors (n = 46) and the patients with a shorter follow-up duration, the cumulative
incidence at 10 years' follow-up was 4.2% according to the Kaplan-Meier method. In conclusion,
we regard the Kaplan-Meier method as a powerful way to define the specific and time-correlated
risk of t-AML. It addresses the specific question of the risk of serious therapy-related
complication after surviving GCT.
Our data again demonstrate that the combination of chemotherapy and radiotherapy bears the
highest risk of t-AML (Fig 1).35 In modern protocols, a multimodal approach that includes
radiotherapy and chemotherapy is applied to patients with secreting intracranial GCT.36,37 With
regard to the estimated maximum cumulative incidence of 4% we observed, the risk of
developing t-AML should be considered as one of the possible sequelae of therapy. Nevertheless,
these tumors bear an inferior prognosis compared with intracranial germinoma and GCT at other
sites.36,37 Therefore, reduction of chemotherapy or radiotherapy is obsolete in these patients
because it will probably put the patients at a higher risk of recurrence of GCT.
Intensive radiotherapy bears the risk of treatment-related solid tumors, which predominantly
arise from organs in the irradiation field (eg, gastrointestinal tumors, renal and bladder carcinoma
and sarcoma).31,35,38,39 On the other hand, the development of solid neoplasms did not seem to be
associated with chemotherapy alone.35,38,39 Of the 1,132 patients we studied, we did not observe
any with solid secondary neoplasms. This might be because of the low frequency of radiotherapy
in our cohort with extracranial GCT.
Therapy-Related Leukemia Versus GCT-Associated Leukemia
Our data show no linear correlation between the cumulative doses of ifosfamide and etoposide or
the combination of both. On the other hand, we did not observe t-AML in the patients who
received no systemic chemotherapy (or no etoposide). This observation led us to the conclusion
that treatment with chemotherapy and topoisomerase II inhibitor is causative in at least a
proportion of patients. To test this hypothesis, cytogenetic analysis of the t-AML provides
additional information because typical cytogenetic findings may indicate a different biology of
the t-AML.
Patient no. 2, who suffered from a metastasizing and recurrent malignant GCT, received
extraordinarily high cumulative doses of both alkylating agents and topoisomerase II inhibitors,
partly combined with hyperthermia and radiotherapy.40 In view of the treatment intensity, it is
evident that in this patient, the development of leukemia is secondary to cytotoxic treatment. In
addition, this patient showed a typical clinical picture of a sustained pancytopenia before
progression to AML occurred. The same arguments account for patient no. 6, who was
intensively treated with a combination of chemotherapy and radiotherapy and who presented with
sustained pancytopenia and showed a complex karyotype on cytogenetic analysis.
In patients no. 3 and 4, the cytogenetic findings provide strong evidence that leukemia may be
related to treatment with alkylating agents, because aberrations of chromosome 7 and 7q are
most commonly found in these circumstances.27,29,30 In addition, the cytogenetic analysis in
patient no. 4 showed a translocation, including the long arm of chromosome 11 at 11q23.
Translocations at this region have been reported to be strongly associated with former
epipodophyllotoxin treatment. Nevertheless, compared with data published by other
investigators,4 the cumulative doses given to our patients were low. Moreover, patient no. 3
received only one cycle of ifosfamide.
The translocation t(8;16) found in patient no. 1 has been observed in patients with both de novo
AML and chemotherapy- and irradiation-related AML with a myelomonocytic or monocytic
appearance.24,41 The underlying pathogenetic mechanism seems to be a fusion of a putative
acetyltransferase to the c-AMP response elements–binding protein, which is involved in
Rubinstein-Taybi syndrome.41,42 Interestingly, patients with this clinical condition are at an
increased risk of malignancies, and several patients with Rubinstein-Taybi syndrome and
malignant GCT have been described in the literature.42 This patient did not show clinical features
of Rubinstein-Taybi syndrome, but cytogenetic aberrations of these genes might account for the
clinical course of this patient.
Finally, patient no. 5 received only two courses of chemotherapy. Despite the small cumulative
doses of chemotherapy, this patient developed an AML within 61 weeks from diagnosis of GCT,
which is a short latency period compared with those observed in t-AML.25 For these reasons, the
development of an AML is surprising in this patient. No hematopoietic foci could be
demonstrated on the initial GCT specimen, but these might well be missed on microscopic
evaluation of this large tumor (tumor size, 14 x 12 x 8 cm). Because we did not see characteristic
chromosomal changes, there is no strong evidence that the AML might have evolved from a
small hematopoietic component within the GCT. Nevertheless, in view of the moderate
pretreatment, an evolution of the leukemic clone from the GCT may be considered.
In conclusion, in patients with secondary leukemia after treatment for GCT, different
pathophysiologic concepts must be discussed. In most patients, clinical history and cytogenetic
findings suggest that the leukemia is caused by cytotoxic treatment. Keeping in mind the
relatively low cumulative doses of cytotoxic treatment, other causes of AML may be considered
in some patients. For example, leukemia might arise from a leukemic clone within the GCT.
Another possible explanation may be a yet-undefined constitutional aberration in these patients,
leading to an increased risk for both GCT and leukemia or to a high susceptibility to potentially
mutation-inducing agents. However, the data reported by us do not provide strong evidence of a
primary association of AML and GCT because we did not observe leukemic events in the group
of patients treated with surgery only. Nevertheless, the early development of t-AML in one
patient treated with only two cycles of chemotherapy was unexpected.
With respect to the high cure rates in childhood GCT, treatment intensity has been reduced step
by step, with no increase of the rate of tumor recurrences. The reported low cumulative incidence
of t-AML in the patients treated with chemotherapy only does not argue for a further reduction of
chemotherapy, because this may jeopardize the excellent cure rates. Nevertheless, follow-up of
patients treated less intensively according to the current protocol will reveal to what extent the
reduction of cytotoxic therapy will result in a reduction of the risk of t-AML in these patients.
Even patients in whom AML evolves from the GCT might profit from this reduction of GCT
therapy, because they will start specific antileukemic treatment with less pretreatment-related
organ damage. This will hopefully reduce complications related to t-AML treatment and increase
the chances of cure from leukemia.
We thank all 150 institutions that participated in the MAKEI and International Society of
Pediatric Oncology CNS GCT studies for contributing data. We also thank Prof. Dr. D. Harms
(Institute of Pathology, Department of Children's Pathology, University of Kiel, Germany) for
review of the tumor biopsy specimens; Prof. Dr. O.A. Haas (cytogenetic laboratory, St. Anna
Spital, Vienna, Austria), Prof. Dr. F. Lampert (Oncogenetic Laboratory, Justus-Liebig-University
Giessen, Germany), and Prof. Dr. B. Royer-Pokora (Institute of Human Genetics, HeinrichHeine-University, Düsseldorf, Germany) for the cytogenetic studies; and Prof. Dr. U. Creutzig
(Department of Pediatrics, University of Münster, Germany) for t-AML treatment data and for
review of the manuscript. We also thank Dr. H. Boenig for reviewing the manuscript. Finally, we
thank S. Dippert for expert data management.
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