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Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 384-389
The Risk of Residual Molecular and Cytogenetic Disease in Patients
With Philadelphia-Chromosome Positive First Chronic Phase Chronic
Myelogenous Leukemia Is Reduced After Transplantation of Allogeneic
Peripheral Blood Stem Cells Compared With Bone Marrow
By
Ahmet H. Elmaagacli,
Dietrich W. Beelen,
Bertram Opalka,
Siegfried Seeber, and
Ulrich W. Schaefer
From the Departments of Bone Marrow Transplantation and Internal
Medicine (Tumor Research), University Hospital of Essen, Essen,
Germany.
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ABSTRACT |
The detection of residual molecular and cytogenetic disease was
prospectively compared in patients with Philadelphia-chromosome (Ph1) positive first chronic phase chronic myelogenous
leukemia (CML) who underwent allogeneic transplantation of
unmanipulated peripheral blood stem cells (PBSCT) (n = 29) or bone
marrow (BM) (n = 62) using genotypically HLA-identical sibling donors
or partially HLA-matched extended family donors. A molecular relapse
(MR), as defined by two consecutive positive polymerase chain reaction (PCR) assays for the detection of M-bcr-abl transcripts in a 4-week interval, was found in two of 29 (7%) patients after PBSCT compared with 20 of 62 (32%) patients after bone marrow transplantation (BMT).
This corresponds to a 4-year molecular relapse estimate (± standard
error) of 7% ± 5% after PBSCT and of 44% ± 8% after BMT
(P < .009). With identical follow-up periods of survivors in
both patient subsets between 6 and 55 months (median, 28 months), 14 of
the 20 patients with MR after BMT progressed to an
isolated cytogenetic (n = 10) or a hematologic (n = 4) disease
recurrence, resulting in a 4-year cytogenetic relapse estimate of 47% ± 11%, while none of the patients after PBSCT has so far relapsed
(P < .006). Multivariate analysis including all potential
influencial factors of posttransplant disease recurrence identified the
source of stem cells (P < .02) as the only independent
predictor of molecular relapse. In conclusion, this prospective
comparison of molecular and cytogenetic residual disease demonstrates
that peripheral blood stem cell transplants have a more pronounced
activity against residual CML cells than bone marrow transplants.
Prospective randomized trials comparing PBSCT and BMT in patients with
first chronic phase Ph1-positive CML are strictly required
to further substantiate differences in the antileukemic activity of the
two stem cell sources.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
BECAUSE IT IS APPARENT that recombinant
human granulocyte colony-stimulating factor (rhG-CSF) can safely and
efficiently be administered to healthy individuals for the mobilization
of sufficient numbers of hematopoietic progenitor cells, allogeneic peripheral blood stem cell transplantation (PBSCT) becomes a rapidly developing alternative method to allogeneic bone marrow transplantation (BMT) as a broadly applied treatment modality of hematological diseases. For transplant recipients, accelerated hematologic and immune
reconstitution constitute potential advantages of peripheral blood stem
cell transplants over marrow grafts.1-4 These potential benefits, however, still need to be balanced against the potentially increased hazards of acute and chronic graft-versus-host disease (GVHD), which may result from the one log10 higher donor
T-cell numbers in transplants of peripheral blood stem cells (PBSCs) compared with marrow grafts.3
In 15% to 25% of patients with Philadelphia-chromosome
(Ph1) positive first chronic phase chronic myelogenous
leukemia (CML) who underwent unmanipulated allogeneic marrow
transplantation from genotypically HLA-identical sibling donors,
leukemic relapse remains the primary cause of treatment
failure.5,6 Relapse is considered to evolve from residual
malignant cells that survive the pretransplant conditioning regimen and
escape immune surveillance by allogeneic effector cells.
Residual CML cells can be detected through amplification of the unique
M-bcr-abl fusion messenger (m) RNA transcript as the molecular
correlate of transcriptional active Ph1-positive cells by
the polymerase chain reaction (PCR). The detection of bcr-abl-mRNA in
transplant patients is associated with an increased risk of CML
relapse, if repeated PCR assays show positive results later than 100 days posttransplant.7 Additionally, it has been reported
that the detection of bcr-abl transcripts between 6 and 12 months
posttransplant correlates with an increased relapse rate.8
Sustained PCR-negativity in the posttransplant course, in turn, is
generally accepted to be associated with an excellent prognosis with
regard to cytogenetic or hematologic disease recurrence.7-9
In the present prospective single-center study, we assessed minimal
residual disease as detected by regularly performed analyses of
reverse-transcription (RT)-PCR amplification of M-bcr-abl mRNA, as well
as cytogenetic evaluations in patients with first chronic phase
Ph1-positive CML after PBSCT (n = 29) and compared these
results with those obtained in patients who underwent allogeneic BMT (n = 62) during the same observation period.
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MATERIALS AND METHODS |
Patients.
All patients (n = 91) undergoing BMT (n = 62) or PBSCT (n = 29) in the
first chronic phase of CML with genotypically HLA-identical sibling
donors or partially HLA-identical extended family donors at the
University Hospital of Essen between October 1994 and June 1998 were
consecutively included in the present study. Approval for all aspects
of this study had been obtained by the Institutional Review Board on
Medical Ethics at the Essen University Hospital. Patients were
preferentially transplanted with PBSCs if at least one of the following
inclusion criteria was fulfilled: (1)
HLA-A,B,DR 1,DQ1,DP1 disparities between recipient and family donor with a maximum of one
class I and II antigen disparities in graft-versus-host (GVH)
direction; (2) prolonged pretransplant interferon- therapy; (3) a
history of documented serious infectious complications within 4 months
pretransplant; and (4) organ functional impairment of the donor
precluding anesthesia or marrow harvest.4
All patients who were discharged after transplantation were enrolled in
our long-term follow-up program. Outpatient visits were performed in at
least monthly intervals during the first 6 months and at 3-month
intervals during the the first 2 years posttransplant. After 2 years,
patients were usually seen at yearly intervals.
Conditioning regimen.
The conditioning regimen consisted of intravenous cyclophosphamide (60 mg/kg of body weight per day x 2) in combination with fractioned total body irradiation (TBI) delivered by a
60cobalt source in four daily fractions of 2.5 Gy (n = 85) or oral busulfan (BU) (1 mg/kg of body weight every 6 hours
over 4 days) in combination with intravenous cyclophosphamide (60 mg/kg
of body weight per day x 2) (n = 6).
All transplants were performed without ex vivo removal of donor
lymphocytes from the graft. Irradiated (30 Gy) and leukocyte-depleted blood products were exclusively used for blood component substitution throughout the posttransplant course. Prophylaxis of acute GVHD consisted of intravenous methotrexate (15 mg/m2, day 1; 10 mg/m2, days 3, 6, and 11) in combination with continuous
intravenous cyclosporine in all patients.10 Patient
demographic characteristics are summarized in
Table 1.
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Table 1.
Demographic and Treatment Characteristics of Patients
Undergoing Transplantation of Allogeneic PBSCT or BM
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Donors.
Sixteen blood stem cell donors (55%) and 51 bone marrow donors (82%)
were genotypically HLA-identical with their respective recipients,
while 13 blood stem cell donors (45%) and 11 bone marrow donors (18%)
had a single class I- or II-antigen mismatch with regard to acute GVHD.
Peripheral blood stem cells were mobilized by daily subcutaneous
injections of 10 to 16 µg rhG-CSF/kg of donor body weight over 5 to 6 consecutive days. Details of stem cell aphereses performed in this
study have been published previously.4
Isolation of mRNA and M-bcr-abl detection.
RNA was prepared from peripheral blood cells, bone marrow buffy coat
cells, and K562 cells (positive control). RNA was extracted by the acid
guanidium/phenol/chloroform method.11 The RNA was reverse
transcribed into complementary DNA (cDNA) with Moloney murine leukemia
virus (Mo-MuLV) reverse transcriptase (GIBCO-BRL, Gaithersburg, MD) using random hexamers (Boehringer, Mannheim, Germany). A nested PCR technique was used as previously
described.12 Briefly, the cDNA was divided into two tubes,
each containing a final volume of 25 µL with 1 × PCR buffer
consisting of 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 8.3),
1.5 mmol/L MgCL2, 0,001% gelatin (Perkin Elmer-Cetus,
Weiterstadt, Germany), 0.2 mmol/L each of deoxynucleoside triphosphates (dNTP), 2.5 U Taq polymerase
(Perkin Elmer-Cetus), and 12 pmol/L of each of the primers. To one half of the cDNA, a glyceraldehyde-3-phosphate dehydrogenase
(GAPDH) mRNA or -actin mRNA specific primer set was added. This
results in a positive 200 bp or 420 bp band from all human RNA, thereby controlling for the quality of mRNA and successful PCR amplification, especially in the absence of any detectable bcr-abl transcript amplification.13 To the other half, bcr-1 and abl-1 primers were added and amplification with a total of 35 cycles was performed with 45 seconds at 94°C, 45 seconds at 60°C, and 90 seconds at 72°C.12 The second round of PCR was performed using
internal primers bcr-2 and abl-2 with 1 µL of the first round PCR mix
as a template for an additional 35 cycles.12 PCR products
were visualized by electrophoresis in ethidium bromide stained agarose gels under ultraviolet (UV) light and photographed.
PCR controls.
Elaborate measures were taken to minimize contamination by following
the recommendations of Kwok and Higuchi.14 All PCR products
were kept in separate laboratory rooms from patients samples, RNA, and
PCR reagents. Negative control cells and blank controls were included
in all RNA extraction procedures as controls to assess quality and
cross-contamination between each samples. Cells from the K562 cell line
were included as positive controls. Oligonucleotide primers were
synthesized on an Applied Biosystems 380 B DNA synthesizer (Foster
City, CA). All PCR amplifications were performed with a Perkin-Elmer
model 9600 thermocycler.
Sensitivity of the PCR.
The PCR assay for the detection of BCR/ABL transcript is reported to
have a sensitivity of 0.0001%.12
Definition of positive and negative PCR assays.
The PCR assays were performed without knowledge of the patient's
cytogenetic results or hematologic remission status or type of
transplantation. A positive PCR test required a correct size of the
bcr-abl PCR product, as well as a negative "blank" and a positive
K562 amplification. A negative assay required the absence of a bcr-abl
PCR product, as well as no amplification of the "blank", but a
positive K562- and -actin- or GAPDH-PCR amplification. If a positive
or negative control did not amplify as expected, the entire panel of
patient samples performed in one amplification "batch" was
discarded and patient samples were reevaluated. No attempts were made
to quantify the PCR products in this study. For the diagnosis of
molecular relapse or persistence, only those positive bcr-abl-PCR
results, which were confirmed in a consecutive PCR assay from a patient
sample taken within a 4-week interval were considered positive. A total
of 811 evaluable peripheral blood (n = 519) or marrow samples (n = 292)
were prospectively included in the present study. Blood samples were
evaluated monthly within the first 6 months posttransplant and in
3-months intervals during the first 2 posttransplant years thereafter.
After 2 years, those patients without evidence of molecular or
cytogenetic disease were evaluated once per year. Marrow samples were
evaluated by bcr-abl-PCR according to the schedule of cytogenetic
analyses or in case of repeatedly positive blood samples.
Cytogenetic analysis.
Cytogenetic evaluations for the detection of the Ph1-chromosome were
performed by standard metaphase karyotyping technique as previously
described.15 Karyotypes of bone marrow samples were
performed routinely every 3 months during the first posttransplant year
and in 6-month intervals thereafter. In case of a positive bcr-abl-PCR
assay in peripheral blood or bone marrow samples, an additional
cytogenetic bone marrow evaluation was performed within a 4-week
interval. A minimum of 20 metaphases was analyzed in all bone marrow
samples. All 91 patients included in the present study had a completely
Ph1-positive karyotype in pretransplant cytogenetic bone
marrow evaluations.
Definition of relapse.
Hematologic relapse was diagnosed on the basis of standard hematologic
criteria. An isolated cytogenetic relapse was assumed if
Ph1-positive metaphases were detected in repeated
cytogenetic analyses without evidence of hematologic disease.
Clinical evaluation and statistical analysis.
The diagnosis of acute and chronic GVHD was based on the characteristic
clinical appearance of the symptoms of organ involvement. In case of
doubt, the clinical diagnosis had to be confirmed by histologic
examinations of the suspected organ whenever possible. Grading of acute
or chronic GVHD followed the commonly accepted criteria.16,17 For the estimates of molecular or
cytogenetic posttransplant disease, the event times of those patients
who never achieved a bcr-abl- or Ph1-negative status or
converted to a bcr-abl- or Ph1-positive status were
calculated as the time intervals between transplant and the first date
at which a positive bcr-abl- or Ph1-assay was detected.
Conversely, those patients who attained a sustained bcr-abl- or
Ph1-negative posttransplant status were right-censored at
the last time point at which they were at risk for molecular or
cytogenetic disease recurrence. Thus, patients surviving without
molecular or cytogenetic disease were censored at the time point of the last molecular or cytogenetic evaluation or at the time of death. Cumulative estimates (± standard errors) were calculated by the product-limit method.18 Differences between time-to-event
distribution functions were compared by the log-rank test. Comparisons
between continuous covariates were performed by the two-tailed Wilcoxon rank-score test across strata. Differences between frequencies were
compared by the two-tailed Fisher's exact test (2 × 2 contingency tables) or the Mantel-Haentzel test (2 × 4 contingency table). Stepwise proportional hazards
general linear model (PHGLM) analysis was used to evaluate interactions
of different covariates on the analytical endpoints of molecular
relapse.19 Covariates in PHGLM analyses were the stratified
pretransplant disease duration ( 12 months v > 12 months),
the stratified pretransplant treatment duration with hydroxycarbamide,
busulfan, or interferon- ( 12 months v > 12 months),
patient and donor age ( median value v > median value),
type of donor (genotypically HLA-identical sibling donor v
partially HLA-matched extended family donor), patient and donor gender
combinations, transplanted nucleated and CD34+ cell dose/kg
of recipient body weight ( median value v > median value),
acute GVHD (grades 0 to I v grades II to IV) and chronic GVHD
(absent v present), and the type of stem cell source (BMT v PBSCT). Acute and chronic GVHD were analyzed as
time-dependent covariates in PHGLM analyses. Conditional risk ratios
(RR) and their 95% confidence intervals (95% CI) were derived from
PHGLM analyses after adjustment for significant covariates in the
models.20
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RESULTS |
Bcr-abl-PCR results.
Twenty-eight of 62 patients (45%) after BMT and six of 29 patients
(21%) after PBSCT were positive in at least one bcr-abl-PCR assay
(P < .04). According to the applied definition of MR, a repeatedly positive bcr-abl-PCR assay within a 4-week interval was
detectable in 20 patients (32%) after BMT compared with 2 patients
(7%) after PBSCT (P < .009). The median time interval between transplant and the detection of MR was 181 days (range, 38 to
627 days) after BMT. In the two patients who developed MR after PBSCT,
this was detected at 91 and 98 days posttransplant, respectively. The
4-year estimate (± standard error) of MR was 44% ± 8% after
BMT and 7% ± 5% after PBSCT (P < .009)
(Fig 1).
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| Fig 1.
Four-year cumulative estimates of molecular relapse (left
panel) and cytogenetic relapse (right panel) after transplantation of
allogeneic bone marrow (BMT) or peripheral blood stem cells (PBSCT) in
patients with first chronic phase CML. Molecular relapse was defined as
two consecutive M-bcr-abl-positive PCR assays within a 4-week interval.
Cytogenetic relapse was defined as reappearance of Philadelphia
(Ph1) chromosome-positive marrow metaphases after
transplant. Tick marks indicate patients who survive in continuous
molecular (left panel) or cytogenetic (right panel) remission of CML.
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In recipients of sibling donor transplants, the estimate of MR was not
significantly different from those of extended family donor transplants
(37% ± 7% v 19% ± 9%) in this study. In patients with sibling donors, this estimate appeared higher after BMT (45% ± 9%) compared with PBSCT (14% ± 9%), but this difference
was not significant. Patients with extended family donors, however, had
a significantly higher estimate of MR after BMT (44% ± 17%) than
after PBSCT (0%) (P < .02).
Because acute or chronic GVHD may interfere with disease recurrence, we
further examined the association between the development of acute or
chronic GVHD and the detection of MR. No significant difference between
the estimate of MR in patients with grades 0 to I acute GVHD (38% ± 7%) and in those with grades II to IV acute GVHD (15% ± 9%) was detectable. In addition, the estimate of MR between patients
with (28% ± 6%) or without chronic GVHD (47% ± 15%) was not
significant. The influence of acute or chronic GVHD on MR in patients
after BMT or PBSCT is summarized in Table 2.
To evaluate interactions between different potential influencial
factors of MR, multivariate analysis including acute and chronic GVHD
as time-dependent covariates was applied
(Table 3). This analysis confirmed that the
relative risk (RR) of MR was significantly higher after BMT compared
with PBSCT (RR, 5.7; [95% CI, 1.3 to 24.3]) (P < .02).
After adjustment for the influence of the stem cell source, no other
factor had a significant influence on the occurence of MR.
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Table 3.
Proportional Hazards General Linear Model of Potential
Influencial Factors of Molecular Relapse of CML After Allogeneic
BMT or PBSCT
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Cytogenetic results.
Cytogenetic relapse developed in 14 of 62 patients after BMT (23%),
but in none of the patients after PBSCT (Fig 1). The median number of
Ph1-positive metaphases was 10 (range, 1 to 20) of 20 marrow metaphases at time of the diagnosis of cytogenetic relapse. With
a median interval of 86 days (range, 15 to 997), diagnosis of
cytogenetic relapse followed the detection of MR in 13 of the 14 cytogenetically relapsing patients after BMT. A repeated positive
bcr-abl-PCR analysis had a specificity of 84%, a sensitivity of 90%,
and a negative predictive value of 99% with respect to the development of cytogenetic relapse in this study. No significant association of
cytogenetic relapse with either acute or chronic GVHD or the type of
donor was detectable by univariate analysis (data not shown).
Clinical results.
With a median follow-up of 28 months (range, 6 to 55), 41 of 61 patients after BMT (66%) and 19 of 29 patients after PBSCT (66%) are
currently alive (not significant). This translates into 4-year survival estimates of 64% ± 6% after BMT and 61% ± 11% after PBSCT, respectively (n.s.). The estimate of survival in continuous cytogenetic and hematologic remission at 4 years
posttransplant is 36% ± 9% after BMT and 61% ± 11% after
PBSCT (n.s.). Of the 14 patients who developed a cytogenetic or a
hematologic relapse after BMT, 10 patients are currently alive. Eight
of these patients achieved a molecular remission after withdrawal of
cyclosporine, treatment with interferon- or donor buffy-coat
transfusions, while two patients survive in hematologic relapse. The
remaining four patients died of chronic GVHD (n = 2), blastic phase
CML, or influenza A virus interstitial pneumonia after donor buffy-coat transfusion as the leading cause of death.
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DISCUSSION |
This is the first prospective study, which compared the detection of
residual disease by means of sequentially performed bcr-abl-PCR assays
and cytogenetic analyses in patients with first chronic phase CML after
allogeneic transplantation of unmanipulated bone marrow or PBSCs.
As the most important finding, the present study demonstrates that
chronic phase CML patients have a significantly lower risk of residual
molecular disease after PBSCT than patients after BMT. This finding was
based on at least two consecutive positive bcr-abl-PCR assays within a
4-week time interval, because this approach has been shown to be more
predictive with regard to posttransplant CML relapse than isolated
findings of bcr-abl transcripts.7 The clinical significance
of this approach is best illustrated by the high specificity and
sensitivity between the detection of MR by bcr-abl-PCR and the
development of cytogenetic relapse in this study: as expected from the
molecular analyses of residual disease, patients after BMT had a
significantly increased risk of cytogenetic disease recurrence compared
with patients after PBSCT. Because multivariate analysis including all
potential influencial factors of disease recurrence confirmed that the
source of the transplant was the only independent predictor of MR, it
appears justified to conclude that allogeneic transplantation of PBSCs in first chronic phase CML patients is associated with a lower risk of
posttransplant disease recurrence than allogeneic BMT.
The rate of cytogenetic and hematologic relapses in patients who
underwent BMT in this study (23%) is in the expected range of 15% to
25%, which has been described in most larger series of chronic phase
CML patients after unmanipulated sibling donor BMT. The median time
intervals from allogeneic BMT to cytogenetic or hematologic relapse
have been reported to be 9 and 12 months, respectively.21
The median follow-up of surviving patients in both of our patient
subsets is now 28 months, and it is therefore apparent that the time
frame in which the majority of cytogenetic or hematologic relapses
typically manifest after BMT has been covered by the present analysis.
It remains to be seen, however, whether the lower risk of MR after
PBSCT is a consequence of a more effective elimination of residual CML
cells or will be counterbalanced by delayed relapse events.
The biological basis for the observed differences in the rates of
molecular and cytogenetic relapse after allogeneic BMT and PBSCT in
first chronic phase CML patients is currently not clear. Two major
differences between grafts of marrow cells and PBSCs may contribute to
a higher antileukemic potential of allogeneic PBSCT: first, as in the
present study, PBSC grafts contain higher numbers of hematopoietic
progenitor cells compared with marrow grafts, and this may result in a
more rapid and more stable donor cell engraftment.22 This
hypothesis is supported by our previous preliminary observation that
complete donor chimerism is attained earlier and minimal residual
disease persists less frequently after PBSCT compared with
BMT.23 In recipients of marrow cells from unrelated donors
for treatment of high-risk acute leukemia, marrow cell doses above the
median were independently associated with a better leukemia-free
survival, if the transplant was performed in remission.24
Both observations are consistent with a stem cell competition effect,
by which a rapidly expanding normal progenitor cell compartment can
inhibit or displace residual clonogenic leukemic cells after
transplant. Second, unmanipulated PBSC grafts contain one
log10 higher numbers of donor T and accessory
cells.3,22,25,26 Because donor T cells are the most
important effector cells of graft-versus-leukemia reactions in humans,
transfusion of substantially higher donor T-cell numbers along with
PBSCs may be associated with a more pronounced antileukemic effect
against residual leukemic cells. In considering the improved numerical
and functional T-cell reconstitution after allogeneic PBSCT compared
with BMT and the particularly high antileukemic activity of donor
buffy-coat transfusions demonstrated in patients with posttransplant
CML relapse, it is tempting to speculate that the substantially lower
risk of residual disease observed in the present study is at least
partially mediated by donor T cells with antileukemic activity against
residual CML cells.3,27 An improved graft-versus-leukemia
effect associated with allogeneic PBSCT has been convincingly
demonstrated in a murine leukemia model.28
Neither acute nor chronic GVHD had a significant influence on residual
molecular or cytogenetic disease in the present study. This may be
taken as indirect evidence that the higher antileukemic activity
associated with allogeneic PBSCT does not simply rely on a
graft-versus-host reaction, which acts against residual recipient hematopoietic tissue. The hypothetical mechanism of stem cell competition thus represents a new concept for a graft-versus-leukemia reaction, which is separate from GVHD and may be
especially operative after allogeneic PBSCT.
In conclusion, the present study provides laboratory and clinical
evidence that peripheral blood stem cell transplants have a more
pronounced activity against residual CML cells than bone marrow
transplants. Prospective randomized trials comparing PBSCT and BMT in
patients with first chronic phase Ph1-positive CML are
strictly required to further substantiate differences in the
antileukemic activity of the two stem cell sources.
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ACKNOWLEDGMENT |
The authors thank Jitka Stockova, Melanie Kroll, and Susanne Hiebel for
their excellent technical performance of the PCR analyses and are
indebted to Annette Parr and Anneliese Patzelt at the cytogenetic
laboratory of the Department of Internal Medicine (Tumor Research),
University Hospital of Essen, for the continuous support in cytogenetic evaluations.
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FOOTNOTES |
Submitted September 11, 1998; accepted March 10, 1999.
Supported by a grant from `Aktion Kampf dem Krebs' of the German
Cancer Society and a grant from `Deutsche Krebshilfe' (Project-No. 70-1669-EL I).
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 Dietrich W. Beelen, MD, Department of Bone
Marrow Transplantation, University Hospital of Essen, Hufelandstr. 55, 45122 Essen, Germany; e-mail: dietrich.beelen{at}uni-essen.de.
| |
REFERENCES |
1.
Bensinger WI, Clift R, Martin P, Appelbaum FR, Demirer T, Gooley T, Lilleby K, Rowley S, Sanders J, Storb R, Buckner CD:
Allogeneic peripheral blood stem cell transplantation in patients with advanced hematologic malignancies: A retrospective comparison with marrow transplantation.
Blood
88:2794, 1996[Abstract/Free Full Text]
2.
Russel JA, Brown C, Bowen T, Luider J, Ruether JD, Steward D, Chaudhry A, Booth K, Jorgenson K, Coppes MJ, Turner AR, Larratt L, Desai S, Poon M-C, Klassen J:
Allogeneic blood stem cell transplants for hematological malignancy: Preliminary comparison of out comes with bone marrow transplantation.
Bone Marrow Transplant
17:703, 1996[Medline]
[Order article via Infotrieve]
3.
Ottinger HD, Beelen DW, Scheulen B, Schaefer UW, Grosse-Wilde H:
Improved immune reconstitution after allotransplantation of peripheral blood stem cells instead of bone marrow.
Blood
88:2775, 1996[Abstract/Free Full Text]
4.
Beelen DW, Ottinger HD, Elmaagacli AH, Scheulen B, Basu O, Kremens B, Havers W, Grosse-Wilde H, Schaefer UW:
Transplantation of filgrastim-mobilized peripheral blood stem cells from HLA-identical sibling or alternative family donors in patients with hematologic malignancies: A prospective comparison on clinical outcome, immune reconstitution, and hematopoietic chimerism.
Blood
90:4725, 1997[Abstract/Free Full Text]
5.
Thomas ED, Clift RA, Fefer A, Appelbaum FR, Beatty P, Bensinger WI, Buckner CD, Cheever MA, Deeg HJ, Doney K, Flournoy N, Greenberg P, Hansen JA, Martin P, McGuffin R, Ramberg R, Sanders JE, Singer J, Stewart P, Storb R, Sullivan K, Weiden PL, Witherspoon R:
Marrow transplantation for the treatment of chronic myelogenous leukemia.
Ann Intern Med
104:155, 1986
6.
Goldman JM, Gale RP, Horowitz MM, Biggs JC, Chamblin RE, Gluckman E, Hoffmann RG, Jacobsen SJ, Marmont AM, McGlave PB, Messner HA, Rimm AA, Rozman C, Speck B, Tura S, Weiner RS, Bortin MM:
Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: Increased risk of relapse associated with T-cell depletion.
Ann Intern Med
108:806, 1988
7.
Roth MS, Antin JH, Ash R, Terry VH, Gotlieb M, Silver SM, Ginsburg D:
Prognostic significance of Philadelphia chromosome-positive cells detected by the polymerase chain reaction after allogeneic bone marrow transplant for chronic myelogenous leukemia.
Blood
79:276, 1992[Abstract/Free Full Text]
8.
Radich JP, Gehly G, Gooley T, Bryant E, Clift RA, Collins S, Edmands S, Kirk J, Lee A, Kessler P, Schoch G, Buckner CD, Sullivan KM, Appelbaum FR, Thomas ED:
Polymerase chain reaction detection of the BCR/ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: Results and implications in 346 patients.
Blood
85:2632, 1995[Abstract/Free Full Text]
9.
Diekmann L, Beelen DW, Quabeck K, Becher R, Schulte Holthausen H, Botzler R, Schaefer UW, Opalka B:
Presence or re-appearance of BCR-ABL-positive cells years after allogeneic bone marrow transplantation for chronic-phase chronic myelogenous leukemia in patients in hematological remission.
Acta Haematol
92:169, 1994[Medline]
[Order article via Infotrieve]
10.
Beelen DW, Quabeck K, Kaiser B, Wiefelspütz J, Scheulen ME, Graeven U, Grosse-Wilde H, Sayer HG, Schaefer UW:
Six weeks of continuous intravenous cyclosporine and short course methotrexate as propyhlaxis for acute graft-versus-host disease after allogeneic bone marrow transplantation.
Transplantation
50:421, 1990[Medline]
[Order article via Infotrieve]
11.
Chomczynski P, Sacchi N:
Single step method of RNA isolation by acid guanidium thiocyanate phenol chloroform extraction.
Anal Biochem
162:156, 1987[Medline]
[Order article via Infotrieve]
12.
Roth MS, Antin JH, Bingham EL, Ginsburg D:
Detection of Philadelphia chromosome-positive cells by the polymerase chain reaction following bone marrow transplant for chronic myelogenous leukemia.
Blood
74:882, 1989[Abstract/Free Full Text]
13.
Dveksler GS, Basile AA, Dieffenbach CW:
Analysis of Gene Expression: Use of Oligonucleotide Primers for Glyceraldehyde-3-Phosphate Dehydrogenase.PCR Methods and Applications (vol 1). Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, 1992, p 283.
14.
Kwok S, Higuchi R:
Avoiding false positives with PCR.
Nature
339:237, 1989[Medline]
[Order article via Infotrieve]
15.
Becher R, Beelen DW, Mahmoud HK, Schaefer UW:
Cytogenetics and bone marrow transplantation, in
Becher R,
Sandberg AA
(eds):
Chromosomes in Hematology. Heidelberg, Germany, Springer, 1986, p 58.
16.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neimann PE, Clift RA, Lerner KG, Thomas ED:
Clinical manifestations of graft-versus-host-disease in human recipients of marrow from HLA-matched sibling donors.
Transplantation
18:295, 1974[Medline]
[Order article via Infotrieve]
17.
Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, Neimann PE, Lerner K, Glucksberg H, Buckner CD:
Bone marrow transplantation.
N Engl J Med
292:895, 1975[Medline]
[Order article via Infotrieve]
18.
Kaplan EL, Meier P:
Non-parametric estimation from incomplete observations.
J Am Stat Assoc
53:457, 1958
19.
Cox DR:
Regression models and life-tables.
J R Stat Soc
34:187, 1972
20.
Cox DR:
Partial likelihood.
Biometrika
62:269, 1975[Abstract/Free Full Text]
21.
Arcese W, Goldman JM, D'Arcangelo E, Schattenberg A, Nardi A, Apperley JF, Frassoni F, Aversa F, Prentice HG, Ljungman P, Ferrant A, Marosi C, Sayer H, Niederwieser D, Arnold R, Bandini G, Carreras E, Parker A, Frappaz D, Mandelli F, Gratwohl A:
Outcome for patients who relapse after allogeneic bone marrow transplantation for chronic myeloid leukemia.
Blood
82:3211, 1993[Abstract/Free Full Text]
22.
Körbling M, Huh YO, Durett A, Mirza N, Miller P, Engel H, Anderlini P, van Besien K, Andreeff M, Przepiorka D, Deisseroth AB, Champlin RE:
Allogeneic blood stem cell transplantation: Peripheralization and yield of donor-derived primitive hematopoietic progenitor cells (CD34+ Thy-1dim) and lymphoid subsets, and possible predictors of engraftment and graft-versus-host disease.
Blood
86:2842, 1995[Abstract/Free Full Text]
23.
Elmaagacli AH, Beelen DW, Becks HW, Mobascher A, Stockova J, Trzensky S, Opalka B, Schaefer UW:
Molecular studies of chimerism and minimal residual disease after allogeneic peripheral blood progenitor cell or bone marrow transplantation.
Bone Marrow Transplant
18:397, 1996[Medline]
[Order article via Infotrieve]
24.
Sierra J, Storer B, Hansen JA, Bjerke JW, Martin PJ, Petersdorf EW, Appelbaum FR, Bryant E, Chauncey TR, Sale G, Sanders JE, Storb R, Sullivan KM, Anasetti C:
Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: The effect of leukemic burden, donor HLA-matching, and marrow cell dose.
Blood
89:4226, 1997[Abstract/Free Full Text]
25.
Weaver CH, Longin K, Buckner CD, Bensinger W:
Lymphocyte content in peripheral blood mononuclear cells collected after the administration of recombinant human granulocyte colony-stimulating factor.
Bone Marrow Transplant
13:411, 1994[Medline]
[Order article via Infotrieve]
26.
Dreger P, Haferlach T, Eckstein V, Jacobs S, Suttorp M, Löffler H, Müller-Ruchholtz W, Schmitz N:
G-CSF-mobilized peripheral blood progenitor cells for allogeneic trans plantation: Safety, kinetics of mobilisation, and composition of the graft.
Br J Haematol
87:609, 1994[Medline]
[Order article via Infotrieve]
27.
Kolb H, Mittermüller J, Clemm C, Holler E, Lederose G, Brehm G, Heim M, Wilmanns W:
Donor leucocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients.
Blood
76:2462, 1990[Abstract/Free Full Text]
28.
Glass B, Uharek L, Zeis M, Dreger P, Löffler H, Steinmann J, Schmitz N:
Allogeneic peripheral blood progenitor cell transplantation in murine model: Evidence for an improved graft-versus-leukemia effect.
Blood
90:1694, 1997[Abstract/Free Full Text]
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ABSTRACT
INTRODUCTION