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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1814-1819
Detection of Abnormal Pretransplant Clones in Progenitor Cells of
Patients Who Developed Myelodysplasia After Autologous Transplantation
By
Elisabetta Abruzzese,
James E. Radford,
Jeffrey S. Miller,
James
J. Vredenburgh,
P. Nagesh Rao,
Mark J. Pettenati,
Julia M. Cruz,
James J. Perry,
Sergio Amadori, and
David D. Hurd
From the Section on Hematology and Oncology, the Department of
Medicine, and the Section on Medical Genetics, the Department of
Pediatrics, Wake Forest University School of Medicine, Winston-Salem,
NC; the Blood and Marrow Transplant Program, the Division of
Hematology, Oncology and Transplantation, University of Minnesota
Cancer Center, Minneapolis, MN; the Adult Bone Marrow and Stem Cell
Transplant Program, the Division of Hematology-Oncology, the Department
of Medicine, Duke University, Durham, NC; and Universita' degli Studi
di Roma Tor Vergata, Rome, Italy.
 |
ABSTRACT |
Secondary myelodysplastic syndromes (MDS) have been reported after
autologous transplantation. It is not known whether the MDS results
from the pretransplant conventional-dose chemotherapy or from the
high-dose chemotherapy (HDC) used for the transplant procedure. We
performed a multicenter, retrospective analysis of morphologically
normal pretransplant marrow or stem cell specimens from 12 patients who
subsequently developed myelodysplasia after HDC. To determine if the
abnormal clone was present before HDC, we used fluorescence in situ
hybridization (FISH) to detect the cytogenetic markers observed at the
onset of posttransplant MDS. Cryopreserved, pretransplant bone marrow,
peripheral blood stem cell specimens, obtained at the time of harvest,
or archival smears were used. Standard cytogenetic analysis had been
performed pretransplant in four patients, showing a normal karyotype.
In 9 of 12 cases, the same cytogenetic abnormality observed at the time
of MDS diagnosis was detected by FISH in the pre-HDC specimens. Our
findings support the hypothesis that, in many cases of posttransplant
MDS, the stem cell damage results from prior conventional-dose
chemotherapy and may be unrelated to HDC or the transplantation process itself.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
MYELODYSPLASTIC syndromes (MDS) are a
heterogeneous group of hematologic disorders characterized by
peripheral cytopenias associated with ineffective hematopoiesis in the
bone marrow.1 The illnesses can be primary (de novo) or
develop secondarily in patients previously treated for malignant and
nonmalignant disorders with cytotoxic agents, particularly alkylating
agents2,3 and/or radiotherapy.4,5 In the last
10 years, high-dose chemotherapy (HDC) followed by autologous bone
marrow transplantation (ABMT) or peripheral blood stem cell
transplantation (PBSCT) has been used with increasing frequency for the
treatment of both hematologic malignancies and solid
tumors.6,7 Secondary MDS are well-known complications of
antineoplastic therapy8,9 and recently have been described
with an increasing incidence after autologous
transplantation.10,11 It is not clear, however, whether the
stem cell damage leading to MDS is already present in pretransplant
hematopoietic progenitors, and probably caused by pretransplant
conventional-dose chemotherapy or if it arises during or after the HDC
used for the transplant procedure.12,13
To address this question, we studied pretransplant marrow or stem-cell
specimens from 12 patients who had received HDC with autologous marrow
or stem cell transplantation for the treatment of a lymphoma or solid
tumor and have subsequently developed posttransplant MDS.
Posttransplant bone marrow specimens obtained from all patients at the
time of MDS diagnosis exhibited 1 or more MDS-related cytogenetic abnormalities. These posttransplant cytogenetic abnormalities were used
as markers to determine retrospectively, by using fluorescence in situ
hybridization (FISH), whether the abnormal MDS clone was present in
pretransplant marrow or peripheral blood stem cell specimens.
| |
MATERIALS AND METHODS |
Patient eligibility.
Patients were identified retrospectively from the Bone Marrow
Transplantation Databases of the three institutions participating in
the study. Patients eligible for study met the following criteria:
| (1) |
They had undergone HDC with bone marrow and/or stem cell rescue for the
treatment of Hodgkin's or non-Hodgkin's lymphoma (NHL) or solid
malignancy. Patients transplanted for leukemia or myeloid disorders
were excluded from the study.
|
| (2) |
Morphologic examination of bone marrow aspirates and core biopsies
performed before transplant had not shown any dysplastic changes or
evidence of the primary malignancy.
|
| (3) |
They had developed posttransplant MDS, diagnosed according to
French-American-British (FAB) criteria.14
|
| (4) |
Bone marrow specimens obtained at the time of diagnosis of
posttransplant MDS exhibited 1 or more MDS-related15
cytogenetic abnormalities for which a FISH probe was available.
|
| (5) |
Pretransplant bone marrow or stem cell specimens were available for
analysis, in the form of cryopreserved cells or archival marrow smears.
|
Cytogenetic analysis.
Standard G-banding cytogenetic technique was performed on direct
preparations and short-term unstimulated cultures of fresh or thawed
heparinized bone marrow. Karyotypes were designated according to the
International System for Human Cytogenetic Nomenclature.16
Molecular cytogenetic (FISH) analysis.
In 8 cases, cryopreserved, pretransplant marrow or stem cell specimens
were available for analysis. These were thawed and prepared
(uncultured) for interphase FISH analysis after standard molecular
cytogenetic techniques, including a 20-minute incubation at 37°C in
hypotonic solution (0.075 mol/L KCl) and fixing in methanol/acetic acid
3:1. One or more slides were prepared per patient and per cytogenetic
abnormality. Cells were then denatured for 3 minutes at 73°C in 70%
formamide/2× SSC and dehydrated in an ethanol series. In 4 cases,
analysis was performed on archived pretransplant bone marrow smears.
After hematologic analysis, coverslips from Wright-Giemsa-stained bone
marrow smears were flipped up by immersing the slides in liquid
nitrogen. Slides were dipped in xylene at room temperature for 30 minutes to clear the mounting medium as previously
described.17
Hybridization was performed with standard FISH protocols. To reduce
cell loss during the procedure, bone marrow slides were processed by
using the HYBrite System (VYSIS, Downers Grove, IL) following the
manufacturer's directions. The FISH probes used were chosen depending
on the cytogenetic abnormalities found in posttransplant marrows and
obtained from VYSIS. The probes used for this study included LSI EGR-1
(5q31) and centromeric probes CEP 7, CEP 8, CEP11, and CEP 21 (Spectrum
Orange direct labeled). DAPI counterstain was used for detection.
Cytogenetically normal samples were used as controls for each probe,
following the same hybridization procedure. Two hundred cells per slide
were examined by 2 independent observers for each patient, and the
results reported as a mean of these determinations. A conservative
threshold of 10% abnormal cells was established; any specimens below
10% were considered to be negative for presence of the
clonal abnormality.
| |
RESULTS |
Patient characteristics.
Twelve patients met the criteria for study. The median age at the time
of transplant was 38 years (range, 25 to 65 years), with 5 males and 7 females. Four patients were referred to transplant for breast cancer
(BC), 4 for NHL, 3 for Hodgkin's disease (HD), and 1 patient for
melanoma. The majority of patients had received multiple cycles of
chemotherapy and radiotherapy before HDC. Only 1 patient was
transplanted at diagnosis, without prior chemotherapy or radiotherapy.
HDC regimens varied and 3 patients received total body irradiation
(TBI) together with HDC. The time from diagnosis to HDC ranged from 1 month to 96 (median, 33) months.
Posttransplant, 3 patients were diagnosed as having refractory anemia
(RA), 1 RA with ringed sideroblasts, 6 RA with excess of blasts (RAEB),
and 2 RA with excess of blasts in transformation (RAEB-t). The time
between HDC and MDS diagnosis ranged from 10 to 60 (median, 38) months.
The clinical characteristics and a summary of the pertinent patient
data are presented in Table 1.
Cytogenetic analyses.
All the patients developed clonal karyotypic abnormalities
posttransplant (Table 2). Many were
complex, but all included aberrations associated with MDS, most
commonly extra copies of chromosome 8 or deletions of all or parts of
chromosomes 5 or 7. In 4 cases, standard cytogenetic analyses had been
performed before transplantation and were normal.
FISH analyses.
FISH analyses were performed on aliquots of cryopreserved,
pretransplant bone marrow or peripheral blood stem cells obtained at
the time of harvest (9 cases) or on archival smears of pretransplant bone marrow (4 cases), with the patient-specific probes listed in Table
2 (Figs 1 and
2).
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| Fig 1.
Pretransplant bone marrow smear cells from patient no. 3 screened for del(5)(q31). Nucleated cells (2 of 6) show a single signal
instead of the two normal signals indicating deletion 5q31 (arrows).
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| Fig 2.
A (left) neutrophil and an (right) erytroblast from
pretransplant bone marrow smear of patient no. 6 showing trisomy 8.
|
|
In 9 of these 12 patients, the same cytogenetic abnormality(ies)
identified by conventional cytogenetic analysis at the time of
posttransplant MDS diagnosis was detected by FISH in pretransplant marrow or stem-cell specimens. The percentage of abnormal cells in the
pretransplant specimens ranged from 11% to 46% (Fig 3, see page
1817). Two of these patients had 2 cytogenetic markers analyzed independently by FISH. In the case of
patient no. 1, 46% and 35% of pretransplant exhibited monosomy 11 and
monosomy 7, respectively (Fig 4). In the
case of patient no. 12, 27% of pretransplant cells exhibited monosomy
5, although only 7% cells demonstrated monosomy 7. Three of
these 9 patients had a normal karyotype in all metaphases
examined pretransplant with standard cytogenetic analysis.
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| Fig 3.
Percentage of cytogenetically abnormal cells in
pretransplant specimens per marker studied. Two patients had 2 abnormalities analyzed by molecular cytogenetics. One patient presented
with both abnormalities in pretransplant marrow, and the other patient
had only 1 of the 2 abnormalities detected in a sufficient number of
cells to be considered present pretransplant.
|
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| Fig 4.
Cells from patient no. 1 harvest. Arrows indicate (A)
monosomy 11 cells and (B) monosomy 7 cells.
|
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In the remaining 3 patients, the cytogenetic abnormalities identified
at the time of posttransplant MDS diagnosis were not detected in
pretransplant specimens in a sufficient number of cells to be
considered positive. One of these, patient no. 7, had not received
previous therapy for his primary malignancy; pretransplant cytogenetic
studies were also normal in this case. Patient no. 5 had a complex
karyotype; the marker studied with FISH (+8) was present in only 3 of
24 posttransplant metaphases by standard cytogenetic analysis. Patient
no. 10 had initial cytogenetic analysis done at the time of
posttransplant MDS diagnosis showing: 46,XX, del(3)(p25p21)
[2]/46,XX, t(3;18)(q21q23) [2]/46,XX [16]. It was not possible to
analyze these abnormalities by using interphase FISH. A second bone
marrow sample was sent for cytogenetic analysis 9 months later
showing: 46,XX, del(3)(p25p21),  5, add(6)(p21.3), add(7)(p15),
del (9)(p13p24), 15, +mar [20]. FISH analysis of the
pretransplant specimen was then performed by screening the cells for
monosomy 5, which was identified in 5% of pretransplant cells.
| |
DISCUSSION |
Many previous studies have attempted to identify the mechanisms related
to the onset of secondary leukemias (SL) and MDS after conventional-dose chemotherapy.18,19 Factors considered
important in determining the onset of SL/MDS have been the intensity
and timing of conventional-dose chemotherapy and the dose and the extent of radiation therapy. The most commonly reported cytogenetic abnormalities associated with therapy-related SL/MDS have been abnormalities of chromosomes 5, 7, and 11.20-22
Recent studies have examined the incidence of SL/MDS after HDC with
marrow and/or stem cell rescue for hematologic and nonhematologic diseases.23-30 One large study reported an overall
incidence for lymphoma patients of 5%, with an actuarial risk of
developing SL/MDS of 2.6% at 5 years,27 in other studies,
the cumulative risk has been as high as 15%.10 In his
editorial, Stone12 commented that the interval between the
conventional-dose therapy and the onset of MDS after HDC corresponded
closely to the typically alkylating agent-related SL/MDS that develops
in nontransplant settings. This, together with the extent of
pretransplant conventional-dose chemotherapy received by the affected
patients, led him to hypothesize that the pretransplant
conventional-dose therapy was likely to be causative. However, no
scientific data were available to confirm this hypothesis.
Chao et al28 described 7 patients considered for autologous
transplantation for HD. Three had histologically normal bone marrows
and underwent HDC. All 3 developed MDS at 9, 12, and 12 months
posttransplant, respectively. In 2 of the 3 patients, retrospective analysis failed to showed cytogenetic abnormalities in the frozen marrow samples from the time of marrow harvest. In the other 4 patients, cytogenetic abnormalities were detected and the HDC was
deferred. From these data, Chao et al28 suggested that
SL/MDS may be related to pretransplant conventional-dose therapy and that standard cytogenetic analysis may not be sensitive enough to
detect the abnormal clone.
Govindarajan et al29 compared 2 groups of myeloma patients.
Group 1 had received limited alkylating-agent-based therapy before
peripheral stem-cell mobilization. Group 2 had significantly more
prolonged exposure to chemotherapy before mobilization. None of the
patients in group 1 (71 patients; 39 months median follow-up) developed
MDS as compared with 7 in group 2 (117 patients; 29 months median
follow-up). The investigators suggested that the more extensive
pretransplant treatment may have contributed to the posttransplant MDS.
More recently, Laughlin et al25 reported the
cumulative incidence of posttransplant MDS in a series of BC patients
treated with HDC was low (only 5 cases in 864 patients). More
importantly, in all 4 cases studied, cytogenetic abnormalities were
present posttransplant, and all 4 were cytogenetically normal
pretransplant. The investigators concluded from these data that the HDC
in these patients was likely the etiology for the development of the
MDS. Similarly, Traweek et al30 noted that, among 275 patients undergoing autologous transplantation for HD or NHL, 10 with
morphologically normal bone marrow and normal cytogenetic analysis
immediately before transplantation subsequently developed clonal
karyotypic abnormalities posttransplant. The investigators noted that
the presence of normal chromosomes at the time of marrow harvest does not fully negate the risk of developing subsequent hematopoietic cell abnormalities.
However, an alternative interpretation, supported by our data, is that
conventional cytogenetic analysis may be unable to detect the abnormal
clone pretransplant as a result of a low sensitivity. The abnormal
clone may not yet have acquired a growth advantage in the
presymptomatic state and, therefore, may not grow well enough to be
detected with standard metaphase techniques.
The use of clonal analysis of X-linked polymorphism may be useful in
identifying an emerging clonal population in the bone marrow.31 This technique has been used to identify patients who are at risk of developing SL/MDS.32 Retrospective
studies have showed the presence of clonal hematopoiesis in
morphologically normal pretransplant marrow of some patients who
developed MDS posttransplant.33 However, the technique can
only be used in selected females and is not sensitive enough to detect
clones that represent less than 30% to 40% of cells in the marrow population.
We identified 12 patients who were transplanted for lymphomas or solid
tumors and had developed a secondary MDS post-HDC. All had an
MDS-related cytogenetic abnormality at the time of the MDS diagnosis.
Pretransplant marrows were examined by using molecular cytogenetics to
determine whether the same cytogenetic abnormality that was found
posttransplant was also present in presymptomatic, pretransplant
marrow, or stem cells. FISH was chosen because of its ability to study
interphase nuclei (thus, allowing analysis of both dividing and
nondividing cells) and because of the greater sensitivity conferred by
the ability to study a large number of cells. Pretransplant cells from
9 of 12 patients were found to contain the same MDS-related
abnormalities identified at the time of diagnosis of posttransplant
MDS. Of these patients, 3 had previously been studied with standard
cytogenetic analysis and found to have normal karyotypes. These data
support the hypothesis that the progenitor cell damage, which led to
posttransplant MDS in these cases, antedated the HDC given in
association with autologous transplantation.
In 3 of the 12 cases, the cytogenetic marker(s) found posttransplant
were not found in pretransplant specimens. Patient no. 7 had not
received any antineoplastic therapy for his melanoma before HDC and
developed RAEB 43 months after transplantation that rapidly evolved
into acute myeloid/myelogenous leukemia (FAB-M7). Pretransplant
cytogenetics were also normal in this case. In patient no. 5, the
cytogenetic abnormality analyzed (+8) was present only in a small
percentage of cells posttransplant (3 of 24) and represented a subclone
of the abnormal karyotype. As such, it may have been acquired late in
the evolution of the clone, and it is possible that the original clone
arose pretransplant but was not identified with the chromosome 8 probe.
Similarly, in patient no. 10, the abnormality studied (monosomy 5)
arose (by standard cytogenetic analysis) between the patient's first
and second posttransplant cytogenetic studies, again suggesting that it
may have been acquired late in clonal evolution.
We conclude from these data that in many patients, the posttransplant
MDS evolves from an abnormal clone that is present in the progenitor
cells before autologous transplantation. If this proves to be true,
this finding would have important implications for patients for whom
HDC might be considered appropriate. If the stem cell damage leading to
posttransplant MDS results from prior conventional-dose therapy,
strategies intended to reduce the incidence of posttransplant MDS
should focus on the conventional-dose therapy rather than on the HDC
itself. Such strategies might include attempts to limit the dose and/or
duration of therapy or the avoidance of alkylating agents during this
phase of treatment. Alternatively, if molecular cytogenetic analysis
can detect clonal abnormalities in pretransplant progenitor cells, then
the focus could be on the use of selection technologies that can
identify, isolate, and possibly permit expansion of unaffected
progenitors.34 Prospective identification of such
abnormalities before HDC would be limited by one's inability to
determine in advance the specific probe to use for a given patient.
However, the use of a panel of probes for the common MDS abnormalities
might be feasible, particularly in patients with substantial prior
therapy and, therefore, might permit the prospective identification of
patients at high risk for development of posttransplant MDS. Clinical
trials of such strategies are warranted to determine if these
approaches will reduce the incidence of MDS after autologous transplantation.
| |
FOOTNOTES |
Submitted November 19, 1998; accepted May 3, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to David D. Hurd, MD, c/o Comprehensive Cancer
Center, Wake Forest University School of Medicine, Medical Center
Blvd, Winston-Salem, NC 27157-1082; e-mail: dhurd{at}wfubmc.edu.
| |
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TOP
ABSTRACT
INTRODUCTION