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Next Article 
Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3273-3279
REVIEW ARTICLE
Therapy-related acute myeloid leukemia and myelodysplasia after
high-dose chemotherapy and autologous stem cell transplantation
Jens Pedersen-Bjergaard,
Mette Klarskov Andersen, and
Debes H. Christiansen
From the Section for Hematology/Oncology, Cytogenetic Laboratory;
Department of Clinical Genetics, Juliane Marie Center, Rigshospitalet,
Copenhagen, Denmark.
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Abstract |
Therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia
(t-AML) after high-dose chemotherapy (HD-CT) and autologous stem cell
transplantation (ASCT) for malignant diseases have become an important
problem. The actuarial risk has varied, but has often been high if
compared to the risk after conventional therapy. Prior chemotherapy
with large cumulative doses of alkylating agents is the most important
risk factor. In addition, patient age and previous radiotherapy,
particularly the use of total body irradiation (TBI) in the preparative
regimen for ASCT, have been identified as risk factors. In 3 studies,
patients transplanted with CD34+ cells from peripheral
blood after chemotherapy priming showed a higher risk of t-MDS or t-AML
than patients transplanted with cells isolated from the bone marrow
without priming. To what extent this higher risk relates to the prior
therapy with a different contamination with preleukemic, hematopoietic
precursors of the CD34+ cells obtained by the 2 methods,
or is a direct result of chemotherapy priming, or of an increasing
awareness of these complications, remains to be determined. The latent
period from ASCT to t-MDS and t-AML has often been short, 12 months or
less in 27% of the patients. Bone marrow pathology of early cases of
t-MDS after ASCT has often been neither diagnostic nor prognostic, but
most patients presented chromosome aberrations, primarily deletions or
loss of the long arms of chromosomes 5 and 7. The prognosis was in
general poor, although 17% with indolent t-MDS survived more than 18 months from diagnosis, and most of these presented a normal karyotype
or a single chromosome aberration.
(Blood. 2000;95:3273-3279)
© 2000 by The American Society of Hematology.
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Introduction |
During the last decade the issue of therapy-related
myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) following
high-dose chemotherapy (HD-CT) and autologous stem cell transplantation (ASCT) for malignant diseases has become increasingly important, as
discussed in previous reviews.1,2 The number of patients with hematologic malignancies and chemosensitive solid tumors undergoing this new type of treatment has expanded dramatically, and
because HD-CT and ASCT are followed by a limited morbidity and low
mortality, much attention has been paid to the long-term outcome,
including secondary malignancies. t-MDS and t-AML are the predominant
types of secondary malignancies observed after HD-CT and ASCT. The
actuarial risk of leukemic complications has varied considerably, but
has often been very high compared to the results in studies of patients
treated for the same diseases by conventional chemotherapy and
radiotherapy. Several risk factors, the clinical and cytologic
characteristics, the chromosome abnormalities, therapy, and survival of
this interesting subgroup of patients with t-MDS and t-AML have been
discussed in many studies. An important question has been the extent to
which the high risk of leukemic complications relates to prior therapy
with reinfusion of preleukemic hematopoietic precursor cells at ASCT,
the extent to which the high risk could result directly from the HD-CT
and ASCT procedures per se, or finally in a few cases could result from
chemotherapy administered after ASCT for late relapse of the primary tumor.
Risk and risk factors
Following a few early reports briefly discussing single
cases of t-MDS and t-AML,3-7 at least 16 studies,8-23 3 of which were a follow-up of previous
reports,9,11,14 have evaluated the actuarial risk of t-MDS
and t-AML following HD-CT and ASCT (Table
1). In these studies the cumulative risk of
t-MDS and t-AML has varied widely from 1.1% at 20 months16
and up to 24.3% 43 months after ASCT.17 Much of this
difference possibly relates to the wide confidence intervals, because
the calculations have often been based on only a few cases of
leukemia. However, major variations in risk factors from study to study
may also explain the surprising differences observed in these
well-conducted and well-controlled studies.
In several previous studies of t-MDS and t-AML following conventional
chemotherapy, the risk has been shown to increase with patient age and
with the exposure to alkylating agents.24-29 More precisely, in patients with Hodgkin disease the risk has been shown to
increase by the square of age and is almost directly proportional to
the cumulative dose of alkylating agents.30 In patients
treated with HD-CT and ASCT, the risk of t-MDS and t-AML seems also to
increase with age and with the burden of alkylating agents administered
before the transplantation procedure (Table 1). In the study from
Nebraska12 and in the follow-up study from
Minnesota9 of patients transplanted for Hodgkin disease and
non-Hodgkin lymphomas, ages over 40 and 35 years, respectively, were
risk factors (Table 1). In the EBMT cooperative study20 of
the same type of patient, age at transplantation was an independent and
significant risk factor. In the French cooperative study of patients
transplanted for Hodgkin disease,18 age over 40 years was a
significant risk factor for the development of all types of
secondary malignancy.
Increased duration of previous chemotherapy and treatment with
alkylating agents were significant risk factors in 1 study from the
Dana Farber Institute of patients with non-Hodgkin
lymphomas13 (Table 1), and in a later study from the same
institution,15 the number of prior relapses, also
reflecting the burden of previous chemotherapy, was a significant risk
factor. In the EBMT cooperative study,20 the interval from
diagnosis of lymphoma to ASCT, likewise reflecting the burden of
previous therapy, was a significant risk factor. In the British
cooperative study of patients transplanted for Hodgkin
disease,19 the quantity of previous therapy and chemotherapy with MOPP and with lomustine were all significant and
independent risk factors for t-MDS and t-AML. In the study from
Arkansas21 of patients transplanted for multiple myeloma, all patients who developed t-MDS belonged to a subgroup of 117 patients
initially treated with more than 1 cycle of conventional chemotherapy
including an alkylating agent, whereas 71 patients who underwent ASCT
after only 1 cycle of chemotherapy did not develop leukemic
complications (P = .02). In a study from
Newcastle16 of patients transplanted for Hodgkin
disease and non-Hodgkin lymphomas, in most cases early in the course
of their disease, the cumulative risk of t-MDS and t-AML was only
1.1% at 20 months, whereas in our simultaneously published study from
Copenhagen17 of multitreated patients of the same type, a
very high risk of 24.3% at 43 months was observed. However, this high
risk was at the same level as in our previous studies of patients
multitreated for the same diseases with conventional
chemotherapy.30 These observations all indicate a marked
dose-response effect of prior chemotherapy with alkylating agents
on the risk of t-MDS and t-AML following ASCT.
The risk of t-MDS and t-AML was low in the 2 studies of ASCT for solid
tumors22,23 (Table 1). In both studies patients were
apparently less pretreated than patients in the lymphoma studies,
and patients with germ cell tumors were in general young. In addition, in the study of germ cell tumors, 2 cases of t-MDS were excluded from the risk estimate because the authors
considered them as unrelated to therapy.23 Thus, different
factors may have contributed to the low risk of t-MDS and t-AML
observed in the 2 studies of HD-CT and ASCT for breast cancer and germ
cell tumors.
In previous studies of patients treated traditionally with
chemotherapy, including alkylating agents, for lymphomas and solid tumors, the leukemogenic potential of additional high-voltage radiotherapy has been controversial, because no increase in risk was
observed in several studies.25,26,28-30 The risk of t-MDS or t-AML after radiotherapy alone, observed in 1 study, was
approximately 10-fold lower than the risk following treatment with
alkylating agents.27 In 2 independent studies from the Dana
Farber Institute,13,15 the first a study of patients
treated with ASCT for non-Hodgkin lymphomas, the second of patients
treated with ASCT for Hodgkin disease and non-Hodgkin lymphomas,
previous radiotherapy, in particular irradiation toward the pelvic
region, was a significant risk factor for development of t-MDS and
t-AML (Table 1). Perhaps even more important, in the study from
Nebraska12 total body irradiation (TBI), used in the
preparative regimen for ASCT, reached almost significance as a risk
factor. A comparison of the 2 studies from the Dana Farber Institute
supports that TBI could be a risk factor. In patients transplanted for
non-Hodgkin lymphoma, the use of TBI in the preparative regimen for
ASCT resulted in a very high actuarial risk of 18% at 6 years and
19.8% at 10 years,13,14 whereas in the parallel study from
the same institution of patients transplanted for Hodgkin disease and
non-Hodgkin lymphomas conditioned solely by chemotherapy,15
the risk was only 4.2% at 5 years. Finally, in the recently published
EBMT cooperative study,20 radiotherapy used in the
conditioning regimen for ASCT was a significant and independent risk
factor. Low-dose whole-body or hemibody irradiation was used many years
ago as therapy for indolent lymphoid malignancies but was abandoned
because it resulted in many cases of AML,31 and an
actuarial risk of 17% after 15 years was observed.32 As a
result of this experience, TBI in the preparative regimen for ASCT is
now in many centers used more selectively in patients with malignancies
that are highly sensitive to radiotherapy.
Among other risk factors under discussion for development of t-MDS and
t-AML was prior splenectomy. In the French cooperative study18 of patients with Hodgkin disease, splenectomy was a risk factor with borderline significance. However, in the British cooperative study19 of the same type of patient,
splenectomy was not a significant and independent risk factor. In the
follow-up study from the Dana Farber
Institute14 a lower number of CD34+ cells
reinfused at ASCT was a risk factor. In the study of patients with
multiple myeloma from Arkansas21 a high risk of
12% at 4 years was observed in the subgroup of 117 patients
transplanted late in the course of their disease and 73% of these had
received tandem transplantation. A specific effect on the risk of
leukemia of repeated transplantations was confirmed by the EBMT
cooperative study,20 in which the number of transplants
received by each patient was a significant risk factor.
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Risk evaluation |
In previous studies of patients with malignant diseases treated
conventionally with chemotherapy, often combined with radiotherapy, major variations in the risk estimates of t-MDS and t-AML have been
observed. In patients treated with HD-CT and ASCT, similar variations
are observed, likewise with an often much higher risk of t-MDS and
t-AML in many smaller single-institute
studies8-11,13,14,17,21 in which cytogenetic data are
provided for each patient, as compared to a lower risk in many of the
larger cooperative studies.18-20,23 These obviously benefit
from more statistical power, and in the smaller studies a selection for
publication of series presenting a very high risk, and the delimitation
of the cohorts, could both contribute to a relatively high risk.
However, a difference in case ascertainment should also be considered.
The systematic use of bone marrow cytogenetics as an important
diagnostic tool in most single-institute studies, especially in
patients with refractory cytopenia but without an excess of blasts in
the blood or the bone marrow, and a more careful clinical follow-up,
even of patients with relapse of their primary tumor after ASCT, could
also contribute to the difference in risks observed between the 2 types
of study. Only rather few undiagnosed cases of t-MDS may lead to a
marked underestimate of the actuarial risk of t-MDS and t-AML.
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Source of stem cells |
Some years ago, hematopoietic stem cell support for ASCT was always
obtained as direct aspirates from the iliac crest without chemotherapy
priming. Subsequently, because of a number of potential advantages, the
harvesting procedures were changed, and CD34-enriched cells were
obtained from peripheral blood after chemotherapy priming and
administration of hematopoetic growth factors. The effects of this
change on the outcome of the primary malignancy and on the risk of
t-MDS and t-AML after ASCT have never been studied prospectively. A
retrospective, matched-pair comparison of patients transplanted for
Hodgkin disease treated with stem cells from the 2 sources has, as
expected, demonstrated an equivalent survival outcome.33
However, 3 independent retrospective studies have so far
suggested,18 or even significantly
demonstrated,8,9,11 a higher risk of t-MDS and t-AML
following ASCT with CD34-enriched cells isolated from peripheral blood
after chemotherapy priming and growth factors, as compared to ASCT
using CD34+ cells from the bone marrow without
pretreatment. There could be at least 3 reasons for this important
difference. First, hematopoietic precursor cells critically damaged by
chemotherapy priming, harvested before DNA repair is completed,
reinfused and thereby forced to a marked proliferation and
self-renewal, could explain the excess of t-MDS and t-AML with the use
of cells isolated from peripheral blood. Second, CD34-enriched cells
from peripheral blood could, for some reason, be more contaminated with
preleukemic, clonogenic cells originating from the prior treatment,
than cells isolated from the bone marrow. Third, an increased awareness
of the risk of t-MDS and t-AML after the switch from harvesting cells
from bone marrow to harvesting cells from peripheral blood, is also a consideration.
Biologically, CD34-enriched cells isolated from bone marrow without
priming, and cells obtained from peripheral blood after chemotherapy
priming, differ in several respects. Most importantly, they possess a
different capacity to restore bone marrow function after myeloablative
therapy. The more effective recovery of hematopoiesis, particularly of
thrombopoiesis, by using cells isolated from peripheral blood, possibly
relates to a higher content of clonogenic, normal hematopoietic
precursor cells. This source of cells could likewise preferentially contain clonogenic preleukemic cells.
The CD34-enriched cells from the 2 sources show other important
differences. As an example, in leukemia, cells isolated from peripheral
blood after HD-CT may contain fewer or no cytogenetically abnormal
cells, although such cells are still present in the bone marrow.34,35 Although this finding does not unambiguously
indicate reasons for a higher risk of t-MDS and t-AML after ASCT with
CD34-enriched cells from peripheral blood, it emphasizes the major
biologic differences between the cells obtained by the 2 methods.
The possibility that the higher risk of t-MDS and t-AML observed
following the shift of stem cell harvest from bone marrow to peripheral
blood could actually be due to an increasing awareness of the problem
has recently been supported by data from the EBMT cooperative
study.20 In this study, the risk of leukemic complications increased significantly in time from 1978, whereas no difference in the
risk was observed in relation to the procedure for stem cell harvest.
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Origin of the disease |
The cellular origin of t-MDS and t-AML following HD-CT and ASCT has
been subject to much debate. The significant impact of primary
chemotherapy with alkylating agents on the risk of t-MDS and t-AML
after transplantation, outlined in different ways in several
studies,13,15,17,19-21 with an actual risk similar to that
of patients treated intensively with traditional types of chemotherapy,30 points toward a disease origin in events
before transplantation, but perhaps triggered by a reinfusion of
preleukemic hematopoietic precursors. Such an origin is supported by
the very short latent period from HD-CT and ASCT to t-MDS or t-AML
observed in many patients (see below), and by a recent
study36 in which specific cytogenetic abnormalities
observed in t-MDS or t-AML after transplantation were shown to be
present already in the stem cell harvest in 9 of 12 patients.
Other findings, however, support the view that t-MDS and t-AML could be
a direct result of the transplant procedure. The facts that the use of
TBI in the preparative regimen for ASCT, and the use of CD34-enriched
cells from peripheral blood after chemotherapy priming, have both been
reported to increase the risk of t-MDS and t-AML, indicate that at
least some cases of t-MDS and t-AML could be directly initiated or
triggered by the transplantation procedure. A leukemogenic effect of
TBI could seem intriguing because its purpose is a complete bone marrow
ablation. However, in allogeneic bone marrow transplantation it has
been demonstrated that residual recipient stem cells may often survive
a preparative regimen of high-dose cyclophosphamide and
TBI, as mixed chimerism was observed in 51% of such
patients.37 Analogously, surviving hematopoietic precursors
could be the origin of t-MDS and t-AML after ASCT. Also, the
significantly increasing risk of t-MDS and t-AML with the number of
transplants observed in the EBMT-conducted study,20 and, in
cases of AML de novo, a shift in cytogenetic characteristics
from balanced translocations to deletions or loss of chromosome arms 5q
and 7q at relapse after conditioning with busulfan and
cyclophosphamide,38 could be taken into account as a
leukemogenic effect of the HD-CT and ASCT procedure itself.
The extent to which the origin of t-MDS and t-AML predominantly relates
to prior chemotherapy or to the ASCT procedure has recently been
addressed by the major British cooperative study19 of 4576 patients treated for Hodgkin disease. In this study, the general risk
of t-MDS and t-AML was closely related to prior therapy with alkylating
agents, and in a multivariate analysis, when taking the extent of this
therapy into account, HD-CT and ASCT treatment in a subgroup of 595 patients was not associated with a significantly increased risk of
leukemic complications (RR 1.83, CI 0.66-5.11). Thus, most cases of
t-MDS and t-AML following HD-CT and ASCT are probably initiated by
therapy prior to transplantation, whereas a minor part possibly is the
result of the transplantation procedure.
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Latent period from ASCT to t-MDS or t-AML |
The latent period from HD-CT and ASCT to development of t-MDS and
t-AML has been specified for at total of 100 patients (Table 2). Four cases were observed within 4 months, an additional 6 cases were observed within 8 months, and as
many as 26 of 102 cases of t-MDS and t-AML were observed up to only 12 months after ASCT. Because previous studies have shown that a latent
period of 12 months or less is rather rare in patients treated with
conventional chemotherapy including alkylating agents,24-27,30
these data likewise, as discussed, support an origin of the
disease as being mainly prior to ASCT. Five cases of t-MDS were
observed more than 5 years after ASCT. All 5 patients had previously
received chemotherapy with alkylating agents, all 5 had characteristic
defects of chromosome 5 or 7 or both, and there was no information on
chemotherapy for relapse of their primary malignancy after ASCT. These
cases emphasize that, although the general risk of t-MDS and t-AML
decreases markedly 5 to 7 years after cessation of
therapy,30 cases of late occurrence may occasionally be
observed.
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Table 2.
Latent period for the development of t-MDS or t-AML
after autologous stem cell transplantation review of the
literature
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Pathology and presentation of the disease |
In MDS and AML de novo, most cases can be diagnosed and subgrouped
morphologically according to the French-American-British (FAB)
classification.39,40 In MDS de novo, this classification is
an important and independent prognostic factor that can contribute substantially to a prognostic score.41 Whereas many cases
of overt t-AML and t-MDS with a high percentage of blasts can be classified according to the FAB criteria, cases of t-MDS with a low
percentage of blasts after ASCT often do not meet the FAB criteria for
classification.42-44 The bone marrow is often hypoplastic and fibrotic in such patients, and dysplastic changes are observed regularly, also in cases without evidence of t-MDS. For this reason neither the diagnosis nor a prediction of the outcome can be based on
bone marrow pathology in such patients, but must rely on the presence of refractory cytopenia as well as clonal
chromosome abnormalities in the bone marrow. The course of the
disease may differ even in cases with chromosome abnormalities,
and an aggressive type as well as a more indolent type of t-MDS
have been described.42
The disease presented as t-MDS in 132 patients and as overt t-AML in
only 36 patients in well-documented reports. This large excess of t-MDS
is characteristic for leukemic complications following alkylating
agents45-47 and can be taken into account for a generally high diagnostic accuracy in these studies.
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Cytogenetic characteristics |
Detailed cytogenetic characteristics have been published
for at least 75 patients with t-MDS or t-AML after HD-CT and
ASCT.5,7,8,10,12,13 16,17,21-23,36,38,44
Only 4 of these patients presented a normal karyotype, whereas 17 patients (23%) had a complex karyotype with more than 5 different
cytogenetic abnormalities (Table 3). As in
patients with t-MDS and t-AML in general,45-47 deletions or
loss of the long arms or loss of the whole chromosomes 5 or 7 were most
common, confirming that the majority of these cases are a result of
prior therapy with alkylating agents. Interestingly, 11 patients
presented balanced translocations to chromosome bands 11q23 or 21q22
and 2 patients a t(9;22). Twelve of these 13 patients had previously
received chemotherapy with DNA topoisomerase II inhibitors, confirming
the association between this type of chemotherapy and t-AML with
balanced chromosome aberrations.48-51 Likewise, in the
follow-up study from City of Hope,11 exposure to DNA topoisomerase II inhibitors before ASCT and priming with high-dose etoposide were significantly associated with the development
of t-MDS and t-AML with balanced translocations to chromosome bands 11q23 and 21q22.
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Table 3.
Cytogenetic characteristics of t-MDS and t-AML after
autologous stem cell transplantationreview of the literature
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The presence of a cytogenetically abnormal clone in the bone marrow
after HD-CT and ASCT is considered by most investigators as diagnostic
for a leukemic complication, also in cases without an excess of blasts
or other cytologic abnormalities characteristic of t-MDS or t-AML. A
few cases of this type with uncharacteristic cytogenetic abnormalities
have been shown to relate to bone marrow involvement of the primary
tumor, detected due to the presence of cytogenetically unrelated
clones.52 In other cases, cytogenetically abnormal clones,
with uncharacteristic chromosome aberrations, have been observed in
some patients without other evidence of MDS.10,11,13,42,53
The origin and the significance of these findings have been discussed.
In some cases the abnormalities have persisted for prolonged periods of
time; in other cases refractory cytopenia and t-MDS have gradually
developed. In our experience of t-MDS and t-AML54 as well
as in other series, a few patients turn out to be long-term survivors.
These are often patients with t-MDS and a single cytogenetic
abnormality, mainly monosomy 7, and they may survive for many years
before the disease, in all cases, shows progression.
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Survival, therapy, and prediction |
The survival of patients with t-MDS and t-AML after HD-CT and
ASCT was in general poor, as demonstrated in Table
4. Median survival was 6 months
and thereby identical to the survival of patients with t-MDS and
t-AML in general.45,54 However, 11 patients were still
alive more than 18 months after diagnosis, without further treatment.
Five of these 11 long-term survivors, whose disease was discussed
in more detail, presented defects of chromosome number 7, in
3 cases as the only cytogenetic abnormality present. Another 3 patients presented a normal karyotype.
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Table 4.
Survival of patients from the diagnosis of t-MDS and
t-AML after autologous stem cell transplantationreview of the
literature
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Because of the generally poor response to conventional, intensive,
antileukemic chemotherapy of patients with t-AML in general and after
ASCT, allogeneic bone marrow transplantation has been attempted. In one
study of patients with t-AML in general, the actuarial disease-free
survival was 24% at 3 years.55 In this study, however,
only 5 of 18 patients presented characteristic abnormalities of
chromosomes 5 and 7, and only 2 a complex karyotype. In a study from
Seattle,56 the 5-year disease-free survival of patients
transplanted for t-AML in general was only 7.8% with no difference
between untreated patients and patients brought into remission with
intensive antileukemic chemotherapy before transplantation. Finally, in
the study from the Dana Farber Institute all 13 patients who underwent
allogeneic bone marrow transplantation for t-AML after ASCT have
died.14 For this reason intensive antileukemic chemotherapy
with subsequent harvest of karyotypically normal progenitor cells
followed by HD-CT and ASCT has been attempted, and so far demonstrated
a clinical effect in a few cases.35 To what extent this
type of therapy or other regimens will be a future option, remains to
be determined.
As demonstrated in an important joint study from Stanford and City of
Hope, cytogenetic screening of the bone marrow before harvesting cells
for ASCT is of major importance, particularly in heavily pretreated
patients, to avoid transplantation in patients with an already
established t-MDS.57
Because of the poor prognosis, attempts have been made to predict the
development of t-MDS and t-AML following ASCT. This has so far been
possible to some extent in women by studying clonality, as
revealed by the X-chromosome inactivation pattern of the human androgen
receptor gene.58,59 To what extent this type of analysis will find a place in clinical practice remains to be determined.
| |
Conclusions |
Although t-MDS and t-AML after HD-CT and ASCT do not seem to differ
from t-MDS and t-AML after conventional chemotherapy and radiotherapy
as far as clinical characteristics, phenotype, and chromosome
abnormalities are concerned, the leukemic complications following ASCT
present specific problems. Because of the high risk observed in many
studies and the dramatically increasing number of patients undergoing
this type of therapy, efforts to decrease the risk of t-MDS and t-AML
should have a high priority together with a search for more effective
types of therapy in patients who have acquired a leukemic complication.
Among the possibilities of decreasing the risk of t-MDS and t-AML in
patients suffering from a primary tumor with poor prognostic indices is transplantation early in first complete remission. This may improve the
outcome with regard to the primary tumor as well as reduce the risk of
t-MDS and t-AML. Such measures are already undertaken in many centers,
primarily in patients with malignant lymphomas. Likewise, a restrictive
use of TBI in the preparative regimens for ASCT must be considered if
the risk of leukemic complications should be shown to outweigh the
potential benefit of radiotherapy.
Because of its many advantages, harvesting of CD34+ cells
from peripheral blood after chemotherapy priming has become the
dominant standard procedure in obtaining stem cells for
transplantation. In consequence, it is now impossible prospectively to
solve the question as to what extent this procedure is particularly
leukemogenic. Instead, a modification of the priming procedure should
be considered. Most rational would be to substitute alkylating agents
and DNA topoisomerase II inhibitors in the preparative regimens for
ASCT by cytostatic drugs without leukemogenic potential, such as the antimetabolites. Also, the methods for an early detection of clonality before and after transplantation will possibly improve, and if clonality is observed, purging of the CD34+ cells harvested
for ASCT could be a possibility.
The generally poor results of intensive antileukemic chemotherapy in
patients with advanced t-MDS and t-AML after HD-CT and ASCT is
analogous to the experience in t-MDS and t-AML following conventional
chemotherapy.47-49 They relate primarily to an initial phase of t-MDS observed in most patients and to the cytogenetic characteristics with deletion or loss of the long arms of chromosomes 5 and 7 and a complex karyotype. In addition, in t-MDS and t-AML after
HD-CT and ASCT a reduced pool of hematopoietic stem cells may explain
the many treatment-related deaths due to persistent bone marrow
hypoplasia after intensive antileukemic therapy. Although allogeneic
bone marrow transplantation in some studies offers rather poor results,
it may at present represent the best choice of therapy in younger
patients with advanced t-MDS or t-AML following HD-CT and ASCT, but
also new therapeutic approaches should be considered, such as
autologous tandem transplantations.
Note added in proof. Since submission of this manuscript, 3 important studies have been published discussing t-MDS and t-AML after
HD-CT and ASCT.60-62
Micallef et al reported an actuarial risk of t-MDS and t-AML of 14.2%
and 36.5% at 5 and at 10 years after HD-CT and ASCT in 230 patients
transplanted for non-Hodgkin lymphomas.60 Prior therapy
with fludarabine and older age were significant risk factors. Twenty-two out of 24 patients with cytogenetic data available showed
monosomy of chromosome arms 5q or 7q. The study confirms the high risk
of t-MDS and t-AML observed in other single institute studies using
cytogenetics as a diagnostic tool.
Yakoub-Agha et al demonstrated a 2-year overall survival of
30% in 70 patients with t-MDS or t-AML after HD-CT and ASCT following allogeneic bone marrow transplantation.61 Age 37 years or
younger, female sex, negative CMV serology, and the use of an intensive conditioning regimen were predictive for a more favorable outcome, and
patients with abnormalities of chromosome 7 and a complex karyotype had
an inferior survival rate. The study confirms that allogeneic bone
marrow transplantation must be considered in younger patients with
t-MDS or t-AML after HD-CT and ASCT.
Krishnan et al reported a follow-up study of patients transplanted for
Hodgkin disease and non-Hodgkin lymphomas.62 The actuarial
risk of t-MDS and t-AML was 8.6% at 6 years. An increased risk was
observed in 61 out of 612 patients primed with VP-16 for stem cell
harvest (P = .002), which likewise was significantly associated with development of t-AML with 11q23/21q22 chromosome abnormalities (P = .006). The study for the first time
demonstrates that the type of priming may be of importance.
| |
Acknowledgments |
The authors are indebted to Professor Flemming Skovby, MD, to Mr Harry
Cowan, BSc, and to Hanne Nielsen for their help in preparing the manuscript.
| |
Footnotes |
Submitted August 2, 1999; accepted January 24, 2000.
Supported by grants from the Danish Cancer Association and H:S
Forskningspulje 1997.
Reprints: J. Pedersen-Bjergaard, Department of Clinical
Genetics, Section 4052, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen
Ø, Denmark.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
References |
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Myelodysplastic syndrome after autologous transplantation for lymphoma: the price of progress?
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Abstract
Introduction