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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 1910-1917
Cytogenetic Abnormalities in Primary Myelodysplastic Syndrome Are
Highly Predictive of Outcome After Allogeneic Bone Marrow
Transplantation
By
Thomas J. Nevill,
Henry C. Fung,
John D. Shepherd,
Douglas E. Horsman,
Stephen H. Nantel,
Hans-G. Klingemann,
Donna L. Forrest,
Cynthia L. Toze,
Heather J. Sutherland,
Donna E. Hogge,
Sheldon C. Naiman,
Alan Le,
Daphne A. Brockington, and
Michael J. Barnett
From The Leukemia and Bone Marrow Transplantation Program of British
Columbia, the Divisions of Hematology and Laboratory Medicine, British
Columbia Cancer Agency, Vancouver Hospital and Health Sciences Centre,
and the University of British Columbia, Vancouver, British Columbia,
Canada.
 |
ABSTRACT |
Allogeneic bone marrow transplantation (BMT) is the only curative
therapy available for patients with myelodysplastic syndrome (MDS). In
an attempt to identify prognostic factors influencing outcome, we
collected data retrospectively on 60 consecutive adult patients who had
undergone BMT at our center for primary MDS or acute myelogenous
leukemia evolving from preexisting primary MDS (sAML). Patients were
divided into subgroups according to cytogenetic abnormalities based on
a recently described International MDS Workshop categorization system.
The 7-year actuarial event-free survival (EFS), relapse rate, and
nonrelapse mortality (NRM) for all patients were 29% (95% confidence
interval [CI], 16% to 43%), 42% (CI, 24% to 67%), and 50% (CI,
37% to 64%), respectively. The EFS for the good-, intermediate-, and
poor-risk cytogenetic subgroups were 51% (CI, 30% to 69%), 40% (CI,
16% to 63%), and 6% (CI, 0% to 24%), respectively (P
= .003). The corresponding actuarial relapse rates were 19% (CI,
6% to 49%), 12% (CI, 2% to 61%), and 82% (CI, 48% to 99%),
respectively (P = .002) with no difference in NRM between the
subgroups. Univariate analysis showed cytogenetic category,
French-American-British (FAB) subtype, and graft-versus-host disease
(GVHD) prophylaxis used to be predictive of relapse and
EFS. In multivariate analysis, only the cytogenetic category was
predictive of EFS, with the relative risk of treatment failure for the
good-, intermediate-, and poor-risk cytogenetic subgroups being 1.0, 1.5, and 3.5, respectively (P = .004). For adults with
primary MDS and sAML, even after BMT, poor-risk cytogenetics are
predictive of an unfavorable outcome; novel treatment strategies will
be required to improve results with allogeneic BMT in this patient
population.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
MYELODYSPLASTIC syndrome (MDS) is a
clonal hematopoietic disorder characterized by bone marrow dysplasia,
cytopenias, and frequent evolution to acute myelogenous leukemia
(sAML). However, there is significant heterogeneity in the clinical
presentation, laboratory findings, and prognosis. In patients treated
with standard or supportive therapies, median survival duration has
been correlated with age, the number/severity of cytopenias,
French-American-British (FAB) morphological classification, and the
percentage of marrow blast cells.1-4 More recently, bone
marrow karyotype has gained acceptance as a key predictor of clinical
outcome in MDS.5-10 An International MDS Risk Analysis
Workshop found that patients with untreated primary MDS could be
divided into cytogenetic subgroups with good, intermediate, and poor
prognoses that could then be incorporated into an International
Prognostic Scoring System (IPSS).11
Treatment options in MDS are limited,12-15 with the only
proven curative therapy being allogeneic bone marrow transplantation (BMT). With this approach, 30% to 50% of patients can experience long-term event-free survival (EFS); however, both relapse of disease
and nonrelapse mortality (NRM) are significant.16-20
Although a number of pre-BMT variables, including younger
age,16-19 shorter disease duration,17 absence
of marrow fibrosis,18 and a low marrow blast
percentage,19,21 have been suggested to be predictive of
EFS in MDS, there have been conflicting reports on the influence of
marrow cytogenetics.16,19,21-23 In an attempt to determine prognostic factors predictive of relapse, NRM, and EFS after allogeneic BMT, we incorporated the IPSS cytogenetic categories into a review of
the 10-year MDS experience at the Vancouver Hospital and Health Sciences Centre (VHHSC).
| |
MATERIALS AND METHODS |
Patient characteristics.
Between August 1986 and April 1996, 60 patients with a history of
primary nonfamilial MDS underwent allogeneic BMT
(Table 1); patients with a history of prior
chemoradiotherapy exposure (tMDS/AML) were excluded from the analysis.
Patients with MDS were considered for BMT if they were  50 to 55 years
old, had a suitable donor, and had at least one of the following: (1)
life- threatening neutropenia (<0.5 × 109/L) or
thrombocytopenia (<20 × 109/L); (2) marrow blast
count  5%; or (3) evidence of incipient organ damage due to
transfusional iron overload. All patients provided informed consent and
all research studies were approved by the University and Institutional
Review Boards. Bone marrow histopathology was centrally reviewed at
VHHSC with diagnoses based on standard FAB criteria.1
Twelve patients had MDS that had evolved, at a median of 7 months
(range, 2 to 324 months) from diagnosis, to frank acute
leukemia24 (sAML) before BMT. Additionally, 9 patients with
a hypocellular bone marrow and less than 5% blast cells were
classified as hypoplastic MDS, a recognized subcategory of refractory
anemia (RA), based on the presence of nonconstitutional cytogenetic
abnormalities25 (5 patients), significant marrow dysplasia
(5 patients), and/or blast cell colonies in marrow
culture26 (2 patients). As a general policy, conventional cytoreductive therapy was administered only when required for hematologic stabilization while tissue typing of potential marrow donors was being completed. Nineteen patients (2 RA with excess blasts
[RAEB], 9 RAEB in transformation [RAEBIT], and 8 sAML) received
conventional chemotherapy before BMT, with 9 patients (5 RAEBIT and 4 sAML) attaining a complete remission (CR); 4 of these patients remained
in CR1 until the time of BMT.
Cytogenetics.
Fifty-seven of 60 patients had successful marrow karyotyping before
BMT; in 3 patients, no analyzable metaphases were obtained. Cytogenetic
analyses were performed on direct and/or unstimulated cultured
marrow specimens at 4 reference laboratories and reviewed at VHHSC.
Patients were divided into prognostic subgroups according to
cytogenetics as defined by the IPSS.11 Good-risk patients were defined as those patients with a normal karyotype (22 patients), -Y alone (1 patient), del (5q) alone (2 patients), or del (20q) alone;
none of the patients studied had the latter finding. Poor-risk patients
had either anomalies of chromosome 7 with (3 patients) or without (4 patients) a second anomaly or complex cytogenetics (3 abnormalities,
10 patients). One-half of the complex karyotypes included anomalies of
chromosome 7. Patients with a marrow karyotype that did not meet the
criteria for good- or poor-risk were grouped as intermediate-risk
patients. The most frequent finding in these patients was +8 (5 patients). Other abnormalities observed included isolated trisomies for
chromosome 2, 4, 13, or 14 (1 patient each); single deletions of the
long arm of chromosome 6, 12, 15, or 16 (1 patient each); and inv 16 or
t(2;12) alone (1 patient each).
Conditioning regimen.
Details of the conditioning regimens are shown in
Table 2; all doses were based on the lesser
of ideal or actual body weight. A diagnostic lumbar puncture was
performed on commencement of conditioning in each patient with
instillation of intrathecal cytosine arabinoside (Ara-C) at 30 mg/m2. In general, cyclophosphamide (Cy) with fractionated
total body irradiation (TBI) was used before unrelated-donor (UD) BMT
and a busulfan (Bu)-based regimen, primarily BuCy-2,27 was
used for related-donor (RD) BMT patients. One RD-BMT patient was
conditioned with Cy/TBI and 1 patient requiring urgent UD-BMT received
BuCy-2. Patients receiving Bu-based conditioning routinely received
phenytoin as seizure prophylaxis.28 Uroepithelial
prophylaxis for all patients was with hyperhydration, except between
October 1987 and January 1990, when 14 patients were randomly assigned
to hyperhydration or mesna.29
BMT.
Thirty-seven patients received marrow from a histocompatible sibling
and 1 patient from a 1-antigen mismatched haploidentical relative.
Twenty-two patients received marrow from an unrelated donor; 16 pairs
were HLA A and B seroidentical and DRB1 matched on high resolution DR
DNA typing, 2 pairs were mismatched at one A locus, and 4 pairs
differed at a single DRB1 allele on high resolution typing. Bone marrow
was plasma- and/or erythrocyte-depleted30 when
necessitated by ABO incompatibility. In addition, 11 patients (9 with
unrelated and 2 with related donors) received marrow that was T-cell
depleted (TCD) as outlined below. The median nucleated cell dose for
all patients was 2.8 × 108/kg (range, 0.1 to 7.6 × 108/kg).
Supportive care.
Patients were treated on the Leukemia and Bone Marrow Transplantation
Unit at the VHHSC in rooms equipped with high-efficiency particulate
air (HEPA) filtration. Low bacterial content food and Hickman catheters
were used routinely. Empiric intravenous (IV) antibiotics, amphotericin
B, acyclovir, cytomegalovirus (CMV)-negative blood products, high-titer
CMV Ig products, ganciclovir, and total parenteral nutrition were
administered as required. Hepatic venocclusive disease prophylaxis with
low-dose IV heparin (100 U/kg/d) was administered routinely to the last
27 patients.31 IV fluconazole at 200 to 400 mg/d was
administered as standard antifungal prophylaxis to 18 patients between
June 1992 and December 1994; the final 10 patients on the study
received prophylactic IV amphotericin B at 10 mg/m2/d.
Growth factors were used only in instances of primary graft failure (1 patient) or drug-induced neutropenia (10 patients) and, beginning in
September 1995, in 7 patients receiving postengraftment ganciclovir as
part of a separate study.32
Graft-versus-host disease (GVHD).
During the 10-year study period, the GVHD prophylaxis regimen varied,
as outlined in Table 2. The majority of patients received cyclosporine
(CSP) and short-course methotrexate (MTX) with33-35 or
without36 other agents. In 10 patients, donor bone marrow underwent TCD by an immunomagnetic cell separation technique using iron-dextran particles cross-linked to anti-CD3
antibodies.37 One patient received a bone marrow that was
TCD using a CD34 avidin-biotin selection column (CellPro, Bothell,
WA).38 Treatment of established acute GVHD was with
high-dose methylprednisolone (MP); those with GVHD resistant to MP
received an anti-T-cell antibody, either anti-CD5/ricin immunotoxin
(XomaZyme; XOMA Corp, Berkeley, CA),35 interleukin-2 (IL-2)
receptor antibody (BT563 or B-B10; Biotest, Dreieich,
Germany),39 or anti-thymocyte globulin (either ATGAM [Upjohn, Kalamazoo, MI] or Thymoglobulin [Sangstat Medical Corp, Menlo Park, CA]). GVHD was graded according to standard
criteria.40,41
Statistical methods.
The actuarial EFS, NRM, GVHD, and relapse probabilities were calculated
using the product limit estimates of Kaplan and Meier.42 The following factors were analyzed with respect to EFS, NRM, and
relapse: recipient age and sex; marrow blast count; cytogenetic subgroup; disease duration; prior induction chemotherapy; donor type
(histocompatible sibling v other); GVHD prophylaxis; and the
development of acute and chronic GVHD. Univariate and multivariate analyses of prognostic factors were performed using a proportional hazards Cox regression model.43 For the purpose of the
analyses, patients were divided into 2 groups (<5% and 5%) based
on their highest marrow blast count at any point before BMT (ie, their highest grade of MDS). Chronic GVHD analyses included only patients event-free at day 100.
| |
RESULTS |
EFS.
Twenty of 60 patients are alive without evidence of disease (9 RA, 2 RAEB, 7 RAEBIT, and 2 sAML), with a median follow-up of 70 months
(range, 18.5 to 134 months). The actuarial 7-year EFS for the entire
group (Fig 1) was 29% (CI, 16% to 43%);
EFS was identical for those undergoing related- (30%; CI, 14% to
47%) and unrelated- (32%; CI, 14% to 51%) donor BMT. Univariate
analysis (Table 3) showed that patient
variables predictive of EFS included the diagnosis of RA or RA with
ringed sideroblasts (RARS; Fig 2) and the use of CSP/MTX GVHD
prophylaxis. However, the most important variable in univariate analysis and the only significant variable in multivariate analysis (Table 4)
was cytogenetic subgroup, with the poor-risk patients having an EFS of
6% (CI, 0% to 24%), compared with an EFS of 40% (CI, 16% to 63%)
and 51% (CI, 30% to 69%) in the intermediate- and good-risk
patients, respectively (Fig 3). The
relative risks of treatment failure were 1.0 in the good-, 1.5 in the
intermediate-, and 3.5 in the poor-risk cytogenetic subgroups,
respectively (P = .004).
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| Fig 2.
EFS after allogeneic BMT for patients with refractory
anemia ± ringed sideroblasts (RA/RARS; n = 14) and all other
diagnoses (n = 46).
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| Fig 3.
EFS after allogeneic BMT for patients with good- (n = 25), intermediate- (n = 15), and poor- (n = 17) risk
cytogenetics.
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GVHD.
The actuarial probability of developing grades II-IV acute GVHD for all
patients was 59% (CI, 47% to 72%); for those undergoing related- and
unrelated-donor BMT, the probabilities were 52% (CI, 37% to 69%) and
71% (51% to 89%), respectively. The actuarial risk of developing
chronic GVHD was 54% (CI, 38% to 72%), with univariate and
multivariate analyses showing a significantly lower relapse rate in
patients who developed chronic GVHD (Tables 3 and 4).
NRM.
Twenty-seven patients died from causes other than relapse with the
actuarial risk of NRM in all patients being 50% (CI, 37% to 64%).
Nine deaths were attributed to acute GVHD and 6 deaths were a result of
chronic GVHD with (4 patients) or without (2 patients) accompanying
infection. Seven patients died of infection (6 pulmonary
Aspergillosis, 1 Candidemia), 2 from thrombocytopenic hemorrhage (1 gastrointestinal and 1 intracranial), and 1 from pulmonary regimen-related toxicity. Two patients died of complications relating to primary or secondary graft failure (1 candidemia and 1 intracranial hemorrhage). Univariate (Table 3) and multivariate analyses failed to show any variable that was a significant predictor of NRM.
Relapse.
Thirteen patients have experienced a relapse of MDS/AML at a median of
5.6 months (range, 3 to 83 months) post-BMT. The actuarial probability
of developing relapse for all patients was 42% (CI, 24% to 67%) and
for those undergoing related- and unrelated-donor BMT 47% (CI, 26% to
74%) and 23% (CI, 8% to 55%), respectively. None of the 13 patients
who relapsed became long-term survivors, although 2 patients had a
second BMT before dying of recurrent disease. There were 2 late
relapses (>12 months post-BMT); 1 of these patients had RAEBIT with
failed cytogenetics at diagnosis, but at the time of relapse 83 months
post-BMT had an abnormal marrow karyotype (+8 and +21). The second
patient with late relapse had a TCD-BMT for RAEB with normal
cytogenetics and relapsed 33 months post-BMT.
Risk factors for relapse.
Univariate analysis (Table 3) identified poor-risk cytogenetic subgroup
as an important predictor of relapse (Fig
4), with actuarial risk of relapse in the good-, intermediate- , and
poor-risk patients being 19% (CI, 6% to 49%), 12% (CI, 2% to
61%), and 82% (CI, 48% to 99%), respectively (P = .002).
Other factors found to be significant predictors of relapse in
univariate analysis included prior conventional chemotherapy,
non-CSP/MTX GVHD prophylaxis, marrow blast count, and the absence of
chronic GVHD. In multivariate analysis (Table 4), cytogenetic subgroup
remained significant as did prior conventional chemotherapy and absence
of chronic GVHD. Thirteen of 47 patients with diseases characterized by
5% marrow blasts (4 of 12 sAML, 6 of 23 RAEBIT, and 3 of 12 RAEB) have relapsed, compared with none of the 14 undergoing BMT for RA or
RARS (Fig 5). This variable could not be
included in multivariate analysis, because the proportional hazards
regression model does not converge trying to estimate an infinite
coefficient.
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| Fig 4.
Actuarial risk of relapse after allogeneic BMT for
patients with good- (n = 25), intermediate- (n = 15), and poor- (n
= 17) risk cytogenetics.
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| Fig 5.
Actuarial risk of relapse after allogeneic BMT for
patients with refractory anemia ± ringed sideroblasts (RA/RARS; n = 14) and all other diagnoses (n = 46).
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Prior conventional chemotherapy.
Four of 19 patients who had received conventional chemotherapy before
BMT remain alive and disease-free, including 3 of 4 patients
transplanted in CR1 (2 RAEBIT and 1 sAML). Of the 15 patients who
failed to enter CR1 or relapsed before BMT, 7 patients have died of
recurrent disease, 7 patients experienced NRM, and 1 patient remains
alive and well 7 years post-BMT.
Effect of TCD.
Only 1 of the 11 patients that received a TCD BMT is alive without
evidence of MDS/AML. There were 3 patients with sAML, 3 patients with
RAEBIT, 4 patients with RAEB, and 1 patient with RA in this cohort. Of
the 7 patients with good- or intermediate-risk karyotypes, 6 patients
died of NRM and 1 patient relapsed. One patient with poor-risk
cytogenetics is alive and well 2.5 years after BMT for sAML; 2 patients
with a poor-risk karyotype have relapsed and 1 patient experienced
primary graft failure, dying of Candidemia 18 days after a
non-TCD second BMT.
| |
DISCUSSION |
In our experience, treatment of primary MDS with allogeneic BMT has
resulted in an EFS, relapse rate, and NRM of 29%, 42%, and 50%,
respectively. This is similar to what other groups have reported with
both relapse rate and NRM contributing to inferior outcomes when
compared with other myeloid malignancies.16-20,44-47 Although certain pre-BMT patient variables (younger
age,16-19,23 shorter disease duration,17,23 and
diagnoses with <5% marrow blasts19,21,23) have been
associated with a superior EFS in MDS, the major finding in our current
analysis was the pivotal role that marrow karyotype had in predicting
outcome.
The prognostic significance of bone marrow cytogenetic findings in MDS
patients on standard therapy was first described by Mufti et
al.2 This inital report suggested that a complex karyotype was associated with an inferior EFS but did include patients with both
primary MDS and tMDS. This and another similar study3 devised prognostic scores (Bournemouth and Spanish, respectively) that
combined marrow blast percentage and severity of cytopenias without
including the less uniformly available bone marrow
cytogenetics. In a French study that focused on primary MDS
patients receiving Ara-C and anthracycline induction therapy, a normal
karyotype was predictive of an improved EFS.9 In a
follow-up to this study8 and in a report from Toyama et
al,10 it was concluded that cytogenetic findings in MDS
were critical in determining prognosis; the former study incorporated
marrow karyotype into the Lille risk score. The data from a number of
the aforementioned risk-based studies were combined for the purpose of
developing the IPSS that defined the novel cytogenetic subgroups on
which our present analysis is based.11
It has been suggested in previous studies that MDS karyotypes also
influence the results of BMT.19,21,22,48 An earlier analysis of MDS patients that underwent BMT at our center showed a
better prognosis for those individuals with a normal karyotype versus
any chromosomal abnormality.16 This conflicted with other studies that failed to show an association between MDS karyotype and
EFS,49,50 although small patient numbers may have limited these analyses. An initial report from Seattle found that MDS patients
with a normal karyotype actually had an inferior outcome with
BMT.21 Longer follow-up led to the conclusion that this finding was likely artefactual,51 and more recently the
same group have found that a normal karyotype appears to be linked with
an improved EFS in patients with advanced MDS.48 The
Société Française de Greffe de Moelle have reported
that patients with primary MDS and an intermediate karyotype had
superior outcomes to those patients with either normal or complex
karyotypes.19 It is worth noting that for most of the BMT
results published in MDS, cytogenetics were not consistently available
and a variety of different methods were used to categorize marrow
karyotypes.19,21,22,48-50
Our report is the first BMT study to use the cytogenetic subgroups
recently defined in the IPSS.11 This system appears to be
particularly well suited for assessing the prognosis of MDS patients
before BMT. It recognizes that certain karyotypic abnormalities, such
as del (5q)23 or other single anomalies,19,23
have been found to be associated with a superior EFS after BMT.
Conversely, abnormalities of chromosome 7 have been noted to be
predictive of a poor prognosis with BMT,22 and these
patients are placed in an IPSS subgroup that is more representative of
expected outcome.
The results of our analysis suggest that, in accord with what has been
reported for AML,52 the IPSS cytogenetic categories have a
similar impact on outcome after BMT as after conventional therapy.
Virtually all (95%) of our patients had successful marrow cytogenetics
performed before BMT, with EFS in the good-, intermediate-, and
poor-risk subgroups being 51%, 40%, and 6%, respectively. In
multivariate analysis, cytogenetic category was the only significant variable influencing EFS. It should be emphasized that the inferior outcome of patients in the poor-risk cytogenetic subgroup was not due
to a difference in NRM but was rather a result of a higher actuarial
relapse rate (82% at 1 year).
The need for pre-BMT conventional chemotherapy in patients with MDS
remains a contentious issue. The use of standard AML induction regimens
in MDS has been reported to produce remission rates similar to those
observed in de novo AML, particularly in younger
patients.53 Furthermore, a subsequent survey performed by
the EBMTG showed that EFS was far superior in patients with MDS
undergoing BMT in a chemotherapy-induced CR1 (60%) as compared with
those patients in partial remission (18%) or with relapsed/refractory
disease (0%).54 However, these results were recently
countered by those from a French multicenter study in which pre-BMT
conventional chemotherapy yielded a low remission rate in MDS patients
(<50%) and a high post-BMT relapse rate (57%), even when BMT was
performed in CR1.19 Both studies reported poor results in
patients for whom pre-BMT induction chemotherapy failed. In
multivariate analysis, we found that the administration of conventional
cytoreductive therapy before BMT was predictive of relapse. This may
have been due to the fact that patients who received pre-BMT induction
chemotherapy were exclusively those with an excess of marrow blasts, a
variable that was excluded from multivariate analysis. However, we also observed a low remission rate in patients receiving standard AML induction (50%), and less than half of these patients remained in CR
until BMT. Our experience with BMT in patients failing to respond to or
relapsing after conventional chemotherapy was similar to that reported
by the EBMTG and the French study, with only 1 long-term survivor.
It is interesting to note that alternative donor BMT did not result in
inferior outcome, a finding consistent with previous reports.17 This has been suggested to be due to a lower
relapse rate,17 perhaps because of an enhanced
graft-versus-leukemia (GVL)-like effect. This notion is supported by
the fact that the presence of chronic GVHD was predictive for a reduced
risk of relapse in our analysis, underscoring the important role that the graft plays in determining outcome after BMT.
We could not confirm age or disease duration as predictors of EFS in
our study through either univariate or multivariate analysis. This may
relate to the finding that none of the patient variables was
significantly associated with NRM, an outcome to which age and disease
duration have been most closely linked.17,19,20 Our
experience in patients without excess marrow blasts (no relapses in 14 patients), like other reports,19-21,23 strongly supports that these individuals have a superior EFS due to a very low relapse rate.
It is apparent that, if further improvements are to be made in
allogeneic BMT for MDS, relapse rate and/or NRM must be
reduced. Conventional intensification of conditioning regimens is
unlikely to be beneficial, because any advantage gained in terms of
disease eradication would be offset by an expected increase in
NRM.19,48,55,56 However, the addition of targeted
hematopoietic irradiation, eg, using 131I-labeled
monoclonal antibody,57 could reduce relapse rates without
increase in toxicity. An alternative strategy might focus on reduction
of NRM, particularly in patients at low risk of relapse (RA/RARS
and/or good/intermediate-risk cytogenetics) through the use of
either nonmyeloablative conditioning, eg, using purine
analogs58 or TCD of the allograft.59,60 Another
approach would be to enhance the GVL effect by the use of
immunomodulatory therapies. There have been reports of successful treatment of MDS with IL-2,61 and patients with MDS in
relapse post-BMT have re-entered remission after administration of
donor leukocyte infusions (DLI).62-64 One possibility would
be the use of prophylactic DLI early after BMT in patients without
evidence of chronic GVHD but at high risk of relapse due to a poor-risk karyotype.
Allogeneic BMT offers long-term EFS to a significant proportion of
patients with MDS. However, our results show that marrow cytogenetic
abnormalities have a similar impact on outcome after BMT as after
conventional therapy. Patients with MDS and poor-risk cytogenetics are
at great risk of relapse after BMT and, if their prognosis is to be
improved, novel treatment strategies will have to be incorporated.
| |
FOOTNOTES |
Submitted December 23, 1997;
accepted April 23, 1998.
Address reprint requests to Thomas J. Nevill, MD, Department of
Medicine, Vancouver Hospital and Health Sciences Centre, 910 W 10th
Ave, Vancouver, BC, Canada V5Z 4E3.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors acknowledge the contribution of the medical and nursing
staff of East 6 Ward and Medical Day Care at the Vancouver Hospital and
Health Sciences Centre as well as Shawna Lumer for assistance with
manuscript preparation.
| |
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M. Benesch and H. J. Deeg
Hematopoietic Cell Transplantation for Adult Patients With Myelodysplastic Syndromes and Myeloproliferative Disorders
Mayo Clin. Proc.,
August 1, 2003;
78(8):
981 - 990.
[Abstract]
[PDF]
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D. A. Wells, M. Benesch, M. R. Loken, C. Vallejo, D. Myerson, W. M. Leisenring, and H. J. Deeg
Myeloid and monocytic dyspoiesis as determined by flow cytometric scoring in myelodysplastic syndrome correlates with the IPSS and with outcome after hematopoietic stem cell transplantation
Blood,
July 1, 2003;
102(1):
394 - 403.
[Abstract]
[Full Text]
[PDF]
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G. Mufti, A. F. List, S. D. Gore, and A. Y.L. Ho
Myelodysplastic Syndrome
Hematology,
January 1, 2003;
2003(1):
176 - 199.
[Abstract]
[Full Text]
[PDF]
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E. M. Sloand, S. Kim, M. Fuhrer, A. M. Risitano, R. Nakamura, J. P. Maciejewski, A. J. Barrett, and N. S. Young
Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities
Blood,
December 15, 2002;
100(13):
4427 - 4432.
[Abstract]
[Full Text]
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J. Sierra, W. S. Perez, C. Rozman, E. Carreras, J. P. Klein, J. D. Rizzo, S. M. Davies, H. M. Lazarus, C. N. Bredeson, D. I. Marks, et al.
Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia
Blood,
August 28, 2002;
100(6):
1997 - 2004.
[Abstract]
[Full Text]
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H. J. Deeg, B. Storer, J. T. Slattery, C. Anasetti, K. C. Doney, J. A. Hansen, H.-P. Kiem, P. J. Martin, E. Petersdorf, J. P. Radich, et al.
Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome
Blood,
July 30, 2002;
100(4):
1201 - 1207.
[Abstract]
[Full Text]
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P. Guardiola, V. Runde, A. Bacigalupo, T. Ruutu, F. Locatelli, M. A. Boogaerts, A. Pagliuca, J. J. Cornelissen, H. C. Schouten, E. Carreras, et al.
Retrospective comparison of bone marrow and granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells for allogeneic stem cell transplantation using HLA identical sibling donors in myelodysplastic syndromes
Blood,
May 29, 2002;
99(12):
4370 - 4378.
[Abstract]
[Full Text]
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H. Castro-Malaspina, R. E. Harris, J. Gajewski, N. Ramsay, R. Collins, B. Dharan, R. King, and H. J. Deeg
Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program
Blood,
March 15, 2002;
99(6):
1943 - 1951.
[Abstract]
[Full Text]
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P. L. Greenberg, N. S. Young, and N. Gattermann
Myelodysplastic Syndromes
Hematology,
January 1, 2002;
2002(1):
136 - 161.
[Abstract]
[Full Text]
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L. Nilsson, I. Astrand-Grundstrom, I. Arvidsson, B. Jacobsson, E. Hellstrom-Lindberg, R. Hast, and S. E. W. Jacobsen
Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level
Blood,
September 15, 2000;
96(6):
2012 - 2021.
[Abstract]
[Full Text]
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I. N. M. Micallef, D. M. Lillington, J. Apostolidis, J. A. L. Amess, M. Neat, J. Matthews, T. Clark, J. M. Foran, A. Salam, T. A. Lister, et al.
Therapy-Related Myelodysplasia and Secondary Acute Myelogenous Leukemia After High-Dose Therapy With Autologous Hematopoietic Progenitor-Cell Support for Lymphoid Malignancies
J. Clin. Oncol.,
March 1, 2000;
18(5):
947 - 947.
[Abstract]
[Full Text]
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I. Yakoub-Agha, P. de La Salmoniere, P. Ribaud, L. Sutton, E. Wattel, M. Kuentz, J. P. Jouet, G. Marit, N. Milpied, E. Deconinck, et al.
Allogeneic Bone Marrow Transplantation for Therapy-Related Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Long-Term Study of 70 Patients--Report of the French Society of Bone Marrow Transplantation
J. Clin. Oncol.,
March 1, 2000;
18(5):
963 - 963.
[Abstract]
[Full Text]
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H. J. Deeg, H. M. Shulman, J. E. Anderson, E. M. Bryant, T. A. Gooley, J. T. Slattery, C. Anasetti, A. Fefer, R. Storb, and F. R. Appelbaum
Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age
Blood,
February 15, 2000;
95(4):
1188 - 1194.
[Abstract]
[Full Text]
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E. Hellstrom-Lindberg, C. Willman, A. J. Barrett, and Y. Saunthararajah
Achievements in Understanding and Treatment of Myelodysplastic Syndromes
Hematology,
January 1, 2000;
2000(1):
110 - 132.
[Abstract]
[Full Text]
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J. W. Friedberg, D. Neuberg, R. M. Stone, E. Alyea, H. Jallow, A. LaCasce, P. M. Mauch, J. G. Gribben, J. Ritz, L. M. Nadler, et al.
Outcome in Patients With Myelodysplastic Syndrome After Autologous Bone Marrow Transplantation for Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
October 1, 1999;
17(10):
3128 - 3135.
[Abstract]
[Full Text]
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M. L. Heaney and D. W. Golde
Myelodysplasia
N. Engl. J. Med.,
May 27, 1999;
340(21):
1649 - 1660.
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Abstract
Introduction
Abstract
