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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2831-2838
Allogeneic Stem Cell Transplantation for Agnogenic Myeloid
Metaplasia: A European Group for Blood and Marrow Transplantation,
Société Française de Greffe de Moelle, Gruppo
Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson
Cancer Research Center Collaborative Study
By
Philippe Guardiola,
Jeanne E. Anderson,
Giuseppe Bandini,
Francisco Cervantes,
Volker Runde,
William Arcese,
Andrea Bacigalupo,
Donna Przepiorka,
Margaret R. O'Donnell,
Paola Polchi,
Agnès Buzyn,
Laurent Sutton,
Dominique Cazals-Hatem,
George Sale,
Theo de Witte,
H. Joachim Deeg, and
Eliane Gluckman for the
International Collaboration for Transplantation in Agnogenic Myeloid
Metaplasia
From the Department of Hematology, Bone Marrow Transplant,
Hôpital Saint-Louis, Paris, France; the Division of Hematology,
Department of Medicine, University of Texas Health Science Center, San
Antonio, TX; the Instituto of Hematology "Seragnoli," Hospital
San Orsola, Bologna, Italy; the Department of Hematology, Hospital
Clinic, Barcelona, Spain; the Department of Bone Marrow
Transplantation, University Hospital, Essen, Germany; GITMO-Roma,
Ematologia, Universita "La Sapienza," Rome, Italy; the Department
of Hematology, Ospedale San Martino, Genova, Italy; the Department of
Hematology, M.D. Anderson Cancer Center, Houston, TX; the Department of
Hematology, The City of Hope, Duarte, CA; the Department of Hematology,
Pesaro Hospital, Pesaro, Italy; Service d'Hématologie Adultes,
Hôpital Necker, Paris, France; Service d'Hématologie,
Groupe Hospitalier "La Pitié-Salpétrière,"
Paris, France; Laboratoire d'Anatomopathologie, Hôpital Beaujon,
Clichy, France; the Division of Clinical Research, Fred Hutchinson
Cancer Research Center, Seattle, WA; and the Division of Hematology,
University Hospital St Radboud, Nijmegen, The Netherlands.
 |
ABSTRACT |
Agnogenic myeloid metaplasia (AMM) is a chronic
myeloproliferative disorder in which patients with poor prognostic
features, receiving conventional treatments, have a median survival of
less than 3 years. In this retrospective multicenter study, we analyze the results and try to define the indications for allogeneic stem cell
transplantation in AMM. From January 1979 to November 1997, 55 patients
with a median age of 42 years were transplanted from HLA-matched
related (n = 49) or alternative (n = 6) donors for AMM. A
multivariate analysis was conducted to identify factors associated with
posttransplant outcome. The median posttransplant follow-up was 36 months (range, 6 to 223). The 5-year probability of survival was 47% ± 8% for the overall group, and 54% ± 8% for patients
receiving an unmanipulated HLA-matched related transplant. The 1-year
probability of transplant-related mortality was 27% ± 6%.
Hemoglobin level  100 g/L and osteomyelosclerosis before transplant
adversely affected the outcome. The probability of developing grade
III-IV acute graft-versus-host disease (GVHD) was 33% ± 8%. Sixteen of 45 patients developed extensive chronic GVHD. At last
follow-up, 22 patients were in complete histohematologic remission.
Treatment failure was observed in 13 cases. Age at transplant and
karyotype were predictors of treatment failure. Allogeneic stem cell
transplantation is an effective treatment leading to cure in a
substantial number of patients with AMM. A better characterization of
the variables affecting the posttransplant outcome should lead to a
decreased transplant-related mortality and an improvement in these results.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
AGNOGENIC MYELOID metaplasia (AMM) is a
clonal hematopoietic stem cell disorder characterized by bone marrow
fibrosis, extramedullary hematopoiesis, splenomegaly, and a
leukoerythroblastic blood picture.1,2 With median survival
ranging from 3 to 5 years, AMM has the worst outcome among the chronic
myeloproliferative disorders.3-11 Dupriez et
al11 recently proposed a scoring system, which identifies
three distinct prognostic groups. In the low-risk group (hemoglobin
level >100 g/L and leukocyte count between 4 and 30 × 109/L), patients had a median survival of 93 months,
whereas patients from the intermediate-risk (hemoglobin level 100 g/L
or leukocyte count <4 or >30 × 109/L) and
high-risk (hemoglobin level 100 g/L and leukocyte count <4 or >30 × 109/L) groups had median survivals of 26 and 13 months, respectively. To date, whether using hydroxyurea,
 -interferon, androgens or corticosteroids, standard therapies apart
from transfusions have not been shown to prolong the survival of
patients with AMM.12-17 Splenectomy can be performed when a
huge spleen is painful or implicated in the worsening of cytopenias.
However, its morbidity and mortality rates are not
negligible,18-20 and Barosi et al20 have shown
that this procedure might be associated with an increased risk of acute
transformation. In any case, palliative strategies are not satisfactory
for intermediate or high-risk patients less than 55 years of age, whose
median expected survival is less than 3 years.21
Allogeneic stem cell transplantation is a potential treatment approach
for AMM. We have recently reported encouraging results with the use of
this high-risk strategy in small series of selected patients,22,23 with apparent cure in some cases. However,
the small size of these studies precluded an analysis of factors
influencing engraftment, the occurrence of severe graft-versus-host
disease (GVHD), and treatment failure. Therefore, in this collaborative study, we have evaluated the results of 55 allogeneic stem cell transplants, determined the variables affecting the outcome, and tried
to define indications for this aggressive approach in patients with AMM.
| |
MATERIALS AND METHODS |
Patients.
Between January 1979 and November 1997, 55 consecutive patients (39 men
and 16 women) from the European Blood and Marrow Transplantation Registry, the Fred Hutchinson Cancer Research Center, and five other
non-European centers, representing 28 centers worldwide, were
allografted for AMM. All patients fulfilled the diagnostic criteria for
AMM proposed by the Polycythemia Vera Study Group.24 Patients with a previous history of polycythemia vera, bcr-abl rearrangement without Philadelphia chromosome, or acute transformation before transplant were not included. Two histopathologists performed a
centralized review of bone marrow biopsies performed at diagnosis and
before transplant to exclude frank acute transformation and other
causes of myelofibrosis, such as acute megakaryoblastic leukemia and
myelodysplastic syndromes with myelofibrosis. For the 12 patients in
whom it was not possible to review the biopsy specimens,
histopathological reports were obtained. Patient and disease
characteristics before transplant are listed in
Table 1. Eight patients had a previous
history of essential thrombocythemia. Median age at transplant was 42 years (range, 4 to 53) with two patients being less than 20 years of
age at that time. The median time from diagnosis to transplant was 21 months (range, 2 to 266). Immediately before transplant, 35 patients
had a hemoglobin level 100 g/L, 22 had leukocyte counts <4 × 109/L, and 21 had platelet counts <100×
109/L. Cytogenetic abnormalities were detected in 13 of the
45 assessable karyotypes (29%). Marrow fibrosis was graded using the
scale proposed by Sultan et al.25 Briefly, marrow fibrosis
was grade I if increased cellularity and reticulinic fibrosis were
observed, grade II if the overall cellularity was decreased with
collagen fibrosis, and grade III when there was osteomyelosclerosis. At
last bone marrow biopsy performed before transplant, grade I marrow
fibrosis was observed in 11 cases, grade II marrow fibrosis in 17 cases, and osteomyelosclerosis in 27 cases.
Transplant procedure.
Characteristics of the transplant procedures are listed in
Table 2. Thirty-five patients received a
conditioning regimen including fractionated or single-dose total body
irradiation. HLA matched related donors were used in 49 cases, and HLA
mismatched related or six loci matched unrelated donors in six cases.
According to institutional protocols, growth factors were used during
the early phase after graft infusion in seven cases.
The day of graft infusion was defined as day 0. The day of neutrophil
engraftment was defined as the first of 3 consecutive days with an
absolute neutrophil count of at least 0.5 × 109/L.
Primary graft failure was diagnosed if the neutrophil engraftment endpoint was not reached by day 50. The day of platelet engraftment was
defined as the first day with a platelet count of at least 50 × 109/L without transfusion for a week.
Acute and chronic GVHDs were graded according to the Seattle
criteria.26,27 Analysis involving chronic GVHD was based on patients who survived longer than 100 days from transplant, cases being
coded as limited or extensive.
Criteria of response.
Complete hematologic remission was defined as disappearance of all
clinical signs (including constitutional symptoms, splenomegaly, and
hepatomegaly), peripheral blood and cytogenetic abnormalities attributable to the disease. Complete histohematologic remission was
defined as the combination of a complete hematologic remission with
disappearance of marrow fibrosis, whereas partial histohematologic remission was considered when a complete hematologic remission was
achieved, but with partial regression of marrow fibrosis. Treatment
failure was considered when there was disease recurrence or persistence.
Statistical analysis.
Survival was assessed on the date of last patient contact and analyzed
on July 1, 1998. Deaths occurring the first year posttransplant, which
were not attributable to the disease, were considered as events for the
assessment of the 1-year transplant-related mortality. The
probabilities of hematopoietic recovery, acute GVHD, overall survival,
transplant-related mortality, and treatment failure were calculated
from date of transplant, according to the Kaplan-Meier product-limit
method.28 To determine factors affecting these endpoints,
variables found significant at a P value .05 in the two-tailed log-rank test were subsequently introduced in a Cox proportional hazards model.29 The Fisher's exact test was
used to individualize variables associated with the occurrence of
extensive chronic GVHD.
| |
RESULTS |
Hematopoietic recovery.
Fifty of the 55 patients had hematopoietic recovery. One of them,
because of nonstable engraftment, received a "boost" of peripheral blood stem cells without further immunosuppressive conditioning, followed by splenectomy, before achieving stable engraftment. Four patients died before day 50, between day 21 and day
32, without reaching the neutrophil engraftment endpoint, and one
patient had primary graft failure. The median time to reach the
neutrophil engraftment endpoint was 20 days (range, 11 to 50), with a
Kaplan-Meier estimated probability of 82% ± 5% to obtain
neutrophil recovery by day 30. In multivariate analysis, pretransplant
splenectomy (P < .001; relative risk, 3.6; 95% confidence interval, 1.8 to 7.2), absence of osteomyelosclerosis (P = .01; relative risk, 0.42; 95% confidence interval, 0.2 to 0.8), and a high
number of nucleated cells infused (P = .025; relative risk, 1.1; 95% confidence interval, 1 to 1.2) were the factors associated with a shorter time to neutrophil recovery. The median time to reach
the platelet engraftment endpoint was 28 days (range, 10 to 393).
Splenectomy (P < .0001; relative risk, 4.6; 95% confidence interval, 2.2 to 9.7) and absence of osteomyelosclerosis (P = .004; relative risk, 0.35; 95% confidence interval, 0.17 to 0.72) were
the factors associated with a shorter time to achieve platelet recovery
in multivariate analysis.
GVHD.
The probability of developing grade II-IV acute GVHD was 60% ± 7%
and grade III-IV acute GVHD, 33% ± 8% for the overall group of
patients. In univariate analysis, osteomyelosclerosis observed before
transplant was the only variable associated with the occurrence of
grade III-IV acute GVHD (P = .04). Twenty-seven of 45 assessable patients experienced chronic GVHD, which was extensive in 16 cases, and limited in 11. Extensive chronic GVHD was more frequently observed in patients who had developed grade III-IV acute GVHD (P < .001). Recipient age at transplant, time from diagnosis
to transplant, splenectomy before transplant, and total body
irradiation were not significantly associated with grade III-IV acute
GVHD or extensive chronic GVHD.
Survival.
The Kaplan-Meier estimate of survival at 5 years was 47% ± 8% for
the overall group and 54% ± 8% for patients receiving an unmanipulated HLA matched related graft (n = 44)
(Fig 1A). The median duration of follow-up
for the patients alive at that time was 36 months (range, 6 to 223),
with nine patients alive more than 5 years after transplant.
Twenty-five patients died of infection (n = 5), chronic GVHD (n = 5),
disease progression (n = 5), acute GVHD (n = 4), solid organ
failure (n = 3), lymphoproliferative disorder (n = 2), and graft
failure (n = 1). The Kaplan-Meier estimate of the 1-year
transplant-related mortality for the overall group of patients was 27% ± 6% and for the patients receiving an unmanipulated HLA
matched-related transplant, 22% ± 6%.
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| Fig 1.
(A) Kaplan-Meier estimates of the probability of survival
in 55 patients who received an allogeneic stem cell transplant for AMM.
The 5-year probability of overall survival was 47% for the overall
group, 54% for patients receiving an unmanipulated HLA matched related
transplant, and 26% for those receiving a T-cell-depleted graft or a
graft coming from an alternative donor (P = .18). (B) Outcome
according to the severity of myelofibrosis (MF) before transplant. The
5-year probability of survival was 55% if there was grade I or II
marrow fibrosis, and 38% if there was grade III marrow fibrosis
(osteomyelosclerosis) (P = .027). (C) Outcome according to
the score proposed by Dupriez et al before transplant. The 5-year
probability of survival was 83% for the patients in the low-risk
group, 43% for the patients in the intermediate-risk group, and 31%
for the patients in the high-risk group (P = .018). (D)
Outcome according to the hemoglobin level at transplant and the
requirement of RBC transfusions before transplant. The 5-year
probability of survival was 76% for patients with hemoglobin level
>100 g/L or with hemoglobin level 100 g/L and no RBC transfusion
before transplant, and 23% for patients with hemoglobin level 100
g/L receiving pretransplant RBC transfusions (P < .0001).
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Factors assessed in univariate analysis for a potential impact on the
1-year transplant-related mortality and the 5-year overall survival are
listed in Table 3. Hemoglobin level 100
g/L, need for red blood cell (RBC) transfusions, osteomyelosclerosis,
and a high-risk score at transplant were the pretransplant variables associated with a worse outcome (Fig 1B and C). The prognostic value of
the hemoglobin level at transplant was neither supported by an older
recipient age at transplant (P = .76) nor by a higher incidence
of grade III-IV acute GVHD (P = .20). Among the patients with a
hemoglobin level 100 g/L before transplant, groups of different
prognosis were distinguished according to the number of RBC
transfusions required before transplant (Fig 1D). In the multivariate
analysis, the main pretransplant variable affecting the outcome at 5 years was hemoglobin level 100 g/L at transplant (Table 4). This variable, and the presence
of osteomyelosclerosis before transplant, were significantly associated
in the Cox model with the outcome of the 45 patients who received an
unmanipulated HLA matched-related transplant.
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Table 3.
Results of the Univariate Analysis for the 1-Year
Transplant-Related Mortality and the 5-Year Overall Survival
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Considering posttransplant variables, grade III-IV acute GVHD and
extensive chronic GVHD had the strongest effect on the outcome. GVHD
was the main cause of death for patients who had osteomyelosclerosis before transplant (8 of 16 deaths).
Posttransplant disease status.
Disease status assessment after transplant is summarized in
Table 5. Thirty-nine patients were in
complete hematologic remission at last follow-up time, 22 among them
were in complete histohematologic remission. Complete resolution of
marrow fibrosis was observed between 21 days and 23 months after
transplant (median, 6 months). Ten relapses were diagnosed between 4 and 67 months posttransplant (median, 12 months); and three patients
had persistent disease after transplant. The 5-year probability of
treatment failure was 36% ± 10% for the overall group and 28% ± 8% for the patients receiving an unmanipulated HLA matched
related graft. The 5-year probability of event-free survival (events
being death or treatment failure) was 39% ± 7% for the overall
group and 48% ± 8% when unmanipulated HLA matched transplants
were used. An older age at transplant, presence of a cytogenetic
abnormality before transplant, and absence of grade II-IV acute GVHD
were factors associated with treatment failure in multivariate analysis
(Table 6). Eight of the patients with
treatment failure were alive at last follow-up time, from 1 to 108 months after detection of treatment failure (median, 9 months), one in
complete remission after a second transplant. Five patients who
relapsed had died at a median of 9 months (range, 4 to 31).
| |
DISCUSSION |
This retrospective multicenter study of allogeneic stem cell
transplantation for AMM documents an important advance in the management of a disease otherwise uniformly fatal within a median of 5 years. First of all, this study confirms and extends previous reports showing that allogeneic stem cell transplanta-tion is the only
approach, which leads in the majority of cases to a complete hematologic remission, and for a substantial number of these, to
long-lasting complete histohematologic
remissions22,23,30-38 and probably to cure. The 5-year
overall survival of 54% for patients receiving an unmanipulated HLA
matched related graft is particularly encouraging, given the fact that
the 5-year actuarial survival rate reported in the largest series of
AMM patients treated by conventional, nonaggressive, but only
palliative, approaches was 40%.11
Second, this study is the first one to identify risk factors that are
significantly associated with posttransplant outcome. In particular,
using multivariate analysis, we found that the presence of
osteomyelosclerosis and hemoglobin level 100 g/L at the time of
transplant were independent predictors for decreased survival. The
reason for increased mortality in patients with osteomyelosclerosis is
unclear, as this group had similar characteristics and transplant
procedures as compared with the group of patients without
osteomyelosclerosis. The main reason might be the high incidences of
grade III-IV acute and extensive chronic GVHD seen in patients with
osteomyelosclerosis. The release of fibronectin and vitronectin from
the abnormal extracellular matrix of the bone marrow fibrotic
tissue39 after the conditioning regimen could explain this
relationship between severe GVHD and osteomyelosclerosis, as these
integrins can activate T cells via an antigen-independent pathway.40,41 The hemoglobin level at diagnosis has been
widely recognized as the main variable affecting the outcome of
patients with AMM receiving conventional treatments.4-11 We
also found that a hemoglobin level 100 g/L before transplant
adversely affected the outcome. Severe anemia might have been a marker
of a heavier pretransplant transfusional support, as the survival was
worse among anemic patients who received more than 10 RBC units
compared with less or nontransfused anemic patients.
Third, this study shows that the risk of treatment failure after an
allogeneic transplant for AMM is of concern because the 5-year
probability of treatment failure was 28% for patients receiving an
unmanipulated HLA matched related transplant. We found in multivariate analysis that recipient age at transplant, presence of a cytogenetic abnormality, and the absence of grade II-IV acute GVHD were associated with a higher risk of treatment failure. The significant association between grade II-IV acute GVHD and a low treatment failure rate leads
one to suspect a graft-versus-AMM effect. This hypothesis could be
supported in the near future by the results of donor lymphocyte
infusions recently performed in four patients with AMM (data not
shown). The identification of the pretransplant karyotype as a
predictor of treatment failure individualizes a group of patients with
cytogenetic abnormalities, for whom T-cell depletion, a procedure
usually associated with an increased risk of relapse in other
indications, should probably not be recommended.
Finally, the presence of severe marrow fibrosis and the absence of
splenectomy performed before transplant have been individualized as the
two main variables having a significant impact on the speed of
posttransplant hematopoietic recovery. However, it has to be emphasized
that osteomyelosclerosis was not associated with an increased incidence
of graft failure, even if total body irradiation was not used during
the conditioning regimen. Furthermore, marrow fibrosis was a reversible
process, with impressive regressions, most often complete, occurring
during the first year posttransplant. Splenectomy was also associated
with a faster hematopoietic recovery, without an increased rate of
severe GVHD. Therefore, splenectomy as an elective before transplant
might be an attractive option in case of spleen enlargement. However,
because of the significant morbidity and mortality of this procedure in
AMM and of the absence of survival benefit in our series, it seems
preferable to restrict splenectomy to patients with osteomyelosclerosis
or a huge spleen, eg, situations in which engraftment could be
significantly delayed.
As for patients with chronic myeloid leukemia in chronic phase,
physicians caring for patients with AMM face a difficult decision when
considering the optimal timing for a transplant. The prognostic score
recently described by Cervantes et al,42 which is derived from the analysis of a large cohort of patients less than 55 years of
age at diagnosis, and based on hemoglobin level, presence of blasts in
peripheral blood and/or constitutional symptoms, should be of some use.
This prognostic score identifies patients with a poor expected outcome
according to conventional approaches (median survival <33 months if
two of these factors are observed). For these patients, it seems
reasonable to consider a transplant shortly after diagnosis, as the
results of this curative approach in high-risk patients receiving less
than 10 RBC transfusions before transplant were at least similar to the
one reported in the study of Dupriez et al,11 where only
palliative treatments were given.
For asymptomatic patients with no cytogenetic abnormalities, no
significant cytopenias, and an expected median survival greater than 14 years with palliative treatments, "to be or not to be transplanted" early remains a dilemma. The identification in
multivariate analysis of the recipient age at transplant as the main
predictive factor of treatment failure could lead to consideration of
the transplant earlier in the course of the disease. Better results were obtained when transplants were performed before patients developed
poor prognostic features, and earlier transplants in younger patients
should decrease the incidence of severe GVHD. However, because
transplant-related mortality was 27% at 1 year in this series and
because the life expectancy of the low-risk patients receiving
palliative treatments, another less "straightforward" option
could be to propose a transplant when the hemoglobin level has fallen
below 100 g/L, or when an isolated cytogenetic abnormality, constitutional symptoms, or blasts in peripheral blood appear. Therefore, when considering low-risk patients, it is not currently possible to give a clear-cut message as to when a transplant should be
performed. Until larger series with longer follow-up time show that
early transplant is beneficial to low-risk patients, the proposal of
Clift et al43 regarding allogeneic transplantation for
chronic myeloid leukemia in chronic phase could be applied to low-risk
patients with AMM, in that "the ultimate decision should first
reflect the patient's approach to the disease."43
Drawing a parallel with the dramatic improvement of the allogeneic
transplant results for chronic myeloid leukemia, we can expect that,
with a more precise definition of the factors affecting the
posttransplant outcome, better results will be achieved with this
strategy in AMM over the next decade.
| |
APPENDIX |
Additional participating institutions and their principal
investigators. Inderjeet Dokal (Hammersmith Hospital, London, UK), Norbert Ifrah (C.H.R.U. Angers, Angers, France),
Jean-Pierre Jouet (Hôpital Claude Huriez, Lille, France), Manuel
Abecasis (Instituto Portugues Oncologia, Lisboa,
Portugal), Jane F. Apperley (Hammersmith Hospital, London,
UK), J.J. Cornellissen (Dr Daniel Den Hoed Cancer Center, Rotterdam,
The Netherlands), Maher K. Gandhi (Addenbrooke's Hospital, Cambridge,
UK), John M. Goldman (Hammersmith Hospital, London, UK), Nicole
Gratecos (Hôpital de l'Archet I, Nice, France), Shunro Kai
(Hyogo College of Medicine, Nishinomiya, Japan), Mathieu Kuentz (Hôpital Henri Mondor, Créteil, France), Bruno
Lioure (Hôpital Haute-Pierre, Strasbourg, France), Per Ljungman
(Huddinge Hospital, Huddinge, Sweden), Aleksandaar Mijovic
(King's College School of Medicine and Dentistry, London, UK), Ricardo
Pasquini (Hospitale de Clinicas, Curitiba, Brazil),
Raymond L. Powles (Royal Marsden Hospital, Sutton Surrey, UK),
Christoph H. Rossbach (St Petersburg, FL), Tapani Ruutu (Helsinki
University Central Hospital, Helsinki, Finland), Norbert
Schmitz (Christian-Albrechts-University, Kiel, Germany), Hervé
Tilly (Centre Anti-Cancéreux Henri Becquerel, Rouen, France),
Eric Deconinck (Hôpital Jean Minjoz, Besançon, France),
Paolo Di Bartolomeo (Ospedale Civile, Pescara, Italy), Augustin Ferrant
(Cliniques Universitaires St Luc, Brussels, Belgium), François
Guilhot (Hôpital la Miletrie, Poitiers, France), Gerald Marit
(Hôpital du Haut-Lévêque, Pessac, France), Mauricette Michallet (Hôpital Edouard Herriot, Lyon, France), M. Mistrik (University Hospital, Bratislava, Slovakia), H. Grant
Prentice (Royal Free Hospital, Hampstead London, UK), John D. Shepherd (Vancouver Hospital and Health Sciences Centre, Vancouver, Canada), Harry Shouten (University Hospital Maastricht, Maastricht, The Netherlands), Anne M. Smith (London Hospital, London, Ontario, Canada).
| |
ACKNOWLEDGMENT |
The authors thank Prof Claude Chastang for his advice concerning the
statistical analysis and Anja van Biezen for her help in collecting the
data from the European centers.
| |
FOOTNOTES |
Submitted August 27, 1998; accepted December 29, 1998.
Additional participating institutions and their principal investigator
are listed in the Appendix.
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 Philippe Guardiola, MD, Service de Greffe
de Moelle "Trèfle 3," Hôpital Saint-Louis, 1 avenue
Claude Vellefaux, F-75475 Paris Cedex 10, France; e-mail:
Phguardiol{at}aol.com.
| |
REFERENCES |
1.
Dameshek W:
Some speculations on the myeloproliferative syndromes.
Blood
6:372, 1951[Free Full Text]
2.
Silverstein MN:
Agnogenic Myeloid Metaplasia. Acton, MA, Publishing Sciences, 1975.
3.
Rozman C, Giralt M, Feliu E, Rubio D, Cortes MT:
Life expectancy of patients with chronic nonleukemic myeloproliferative disorders.
Cancer
67:2658, 1991[Medline]
[Order article via Infotrieve]
4.
Cervantes F, Pereira A, Esteve J, Rafel M, Cobo F, Rozman C, Montserrat E:
Identification of `short-lived' and `long-lived' patients at presentation of idiopathic myelofibrosis.
Br J Haematol
97:635, 1997[Medline]
[Order article via Infotrieve]
5.
Kvasnicka HM:
Prognostic factors in idiopathic (primary) osteomyelofibrosis.
Cancer
80:708, 1997[Medline]
[Order article via Infotrieve]
6.
Hasselbalch H:
Primary myelofibrosis: A clinical study of 80 patients.
Am J Hematol
34:291, 1990[Medline]
[Order article via Infotrieve]
7.
Varki A, Lottenberg R, Griffith R, Reinhard E:
The syndrome of primary myelofibrosis. A clinicopathologic review with emphasis on the prognostic variables predicting survival.
Medicine
62:353, 1983[Medline]
[Order article via Infotrieve]
8.
Visani G, Finelli C, Castelli U, Petti MC, Ricci P, Vianelli N, Gianni L, Zuffa E, Aloe Spiriti MA, Latagliata R, Pileri S, Magrini U, Gugliotta L, Morra E, Bernasconi C, Mandelli F:
Myelofibrosis with myeloid metaplasia: Clinical and haematological parameters predicting survival in a series of 133 patients.
Br J Haematol
75:4, 1990[Medline]
[Order article via Infotrieve]
9.
Ward HP, Block MH:
The natural history of primary myelofibrosis (AMM) and a critical evaluation of its relationship with the myeloproliferative syndrome.
Medicine
50:357, 1971[Medline]
[Order article via Infotrieve]
10.
Barosi G, Berzuini C, Liberato LN, Costa A, Polino G, Ascari E:
A prognostic classification of myelofibrosis with myeloid metaplasia.
Br J Haematol
70:397, 1988[Medline]
[Order article via Infotrieve]
11.
Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I, Bauters F:
Prognostic factors in agnogenic myeloid metaplasia: A report on 195 cases with a new scoring system.
Blood
88:1013, 1996[Abstract/Free Full Text]
12.
Besa EC, Nowell PC, Geller NL, Gardner FH:
Analysis of the androgen response of 23 patients with primary myelofibrosis.
Cancer
49:308, 1982[Medline]
[Order article via Infotrieve]
13.
Löfvenberg E, Wahlin A, Roos G, Öst A:
Reversal of myelofibrosis by hydroxyurea.
Eur J Haematol
44:33, 1990[Medline]
[Order article via Infotrieve]
14.
Silver RT:
Interferons in the treatment of myeloproliferative diseases.
Semin Hematol
27:6, 1990[Medline]
[Order article via Infotrieve] (suppl 4)
15.
Sacchi S:
The role of -interferon in essential thrombocythaemia, polycythaemia vera and myelofibrosis with myeloid metaplasia (MMM): A concise update.
Leuk Lymphoma
19:13, 1995[Medline]
[Order article via Infotrieve]
16.
Reilly JT:
Idiopathic myelofibrosis: Pathogenesis, natural history and management.
Blood Rev
11:233, 1997[Medline]
[Order article via Infotrieve]
17.
Tefferi A, Silverstein MN, Noel P:
Agnogenic myeloid metaplasia.
Semin Oncol
22:327, 1995[Medline]
[Order article via Infotrieve]
18.
Silverstein MN, ReMine WH:
Splenectomy in myeloid metaplasia.
Blood
53:515, 1979[Abstract/Free Full Text]
19.
Ben-Bassat I, Gilon D, Penchas S:
The choice between splenectomy and medical treatment in patients with advanced primary myelofibrosis.
Am J Hematol
33:128, 1990[Medline]
[Order article via Infotrieve]
20.
Barosi G, Ambrosetti A, Buratti A, Finelli C, Liberato NL, Quaglini S, Ricetti MM, Visani G, Tura S, Ascari E:
Splenectomy for patients with myelofibrosis with myeloid metaplasia: Pretreatment variables and outcome prediction.
Leukemia
7:200, 1993[Medline]
[Order article via Infotrieve]
21.
Morel P, Demory JL, Dupriez B:
Relevance of prognostic features in myeloid metaplasia to selection of patients for bone marrow transplantation.
Blood
89:2219, 1997[Free Full Text]
22.
Guardiola Ph, Espérou H, Cazals-Hatem D, Ifrah N, Jouet JP, Buzyn A, Sutton L, Gratecos N, Tilly H, Lioure B, Gluckman E:
Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia.
Br J Haematol
98:1004, 1997[Medline]
[Order article via Infotrieve]
23.
Anderson JE, Sale G, Appelbaum FR, Chauncey TR, Storb R:
Allogeneic marrow transplantation for primary myelofibrosis and myelofibrosis secondary to polycythemia vera or essential thrombocytosis.
Br J Haematol
98:1010, 1997[Medline]
[Order article via Infotrieve]
24.
Laszlo J:
Myeloproliferative disorders (MPD): Myelofibrosis, myelosclerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia.
Semin Hematol
12:409, 1975[Medline]
[Order article via Infotrieve]
25.
Sultan C, Scoazec JY, Imbert M:
Histopathologie de la moelle osseuse. Paris, France, Masson, 1991.
26.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED:
Clinical manifestations of graft-versus-host disease in human recipient of marrow from HLA-matched sibling donors.
Transplantation
18:295, 1974[Medline]
[Order article via Infotrieve]
27.
Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD:
Bone-marrow transplantation.
N Engl J Med
292:832, 1975[Medline]
[Order article via Infotrieve]
28.
Kaplan EL, Meier P:
Nonparametric estimation from incomplete observations.
J Am Stat Assoc
53:457, 1958
29.
Cox DR:
Regression models and life tables.
J R Stat Soc
34:187, 1972
30.
Singhal S, Powles R, Treleaven J, Pollard C, Lumley H, Mehta J:
Allogeneic bone marrow transplantation for primary myelofibrosis.
Bone Marrow Transplant
16:743, 1995[Medline]
[Order article via Infotrieve]
31.
Schmitz N, Suttorp M, Schlegelberger B, Weber-Matthiesen K, Tiemann M, Sonnen R:
The role of the spleen after bone marrow transplantation for primary myelofibrosis.
Br J Haematol
81:616, 1992[Medline]
[Order article via Infotrieve]
32.
O'Donnell MR, Nademanee AP, Snyder DS, Schmidt GM, Parker PM, Bierman PJ, Fahey JL, Stein AS, Krance RA, Stock AD, Forman SJ, Blume KG:
Bone marrow transplantation for myelodysplastic and myeloproliferative syndromes.
J Clin Oncol
5:1822, 1987[Abstract/Free Full Text]
33.
Creemers GJ, Löwenberg B, Hagenbeek A:
Allogeneic bone marrow transplantation for primary myelofibrosis.
Br J Haematol
82:772, 1992[Medline]
[Order article via Infotrieve]
34.
Dokal I, Jones L, Deenmamode M, Lewis SM, Goldman JM:
Allogeneic bone marrow transplantation for primary myelofibrosis.
Br J Haematol
71:158, 1989[Medline]
[Order article via Infotrieve]
35.
Ifrah N, Gardembas-Pain M, Hunault M, Saint-André JP, Foussard C, Boasson M:
Allogeneic bone marrow transplantation for primary myelofibrosis.
Br J Haematol
73:575, 1989[Medline]
[Order article via Infotrieve]
36.
Przepiorka D, Giralt S, Khouri I, Champlin R, Bueso-Ramos C:
Allogeneic marrow transplantation for myeloproliferative disorders other than chronic myelogenous leukemia: Review of forty cases.
Am J Hematol
57:24, 1998[Medline]
[Order article via Infotrieve]
37.
Iwata N, Inoue N, Tamura A, Miyazaki E, Fujimori Y, Okamoto T, Takemoto Y, Kosaki M, Kanamaru A, Kakishita E:
Primary myelofibrosis successfully treated with allogeneic bone marrow transplantation.
Jpn J Clin Hematol
33:1703, 1992
38.
Rossbach HC, Grana NH, Chamizo W, Barrios NJ, Barbosa JL:
Successful allogeneic bone marrow transplantation for agnogenic myeloid metaplasia in a 3-year-old boy.
J Pediatr Hematol Oncol
18:213, 1996[Medline]
[Order article via Infotrieve]
39.
Reilly JT, Nash JR:
Vitronectin (serum spreading factor): Its localisation in normal and fibrotic tissue.
J Clin Pathol
41:1269, 1988[Abstract/Free Full Text]
40.
Sturmhofel K, Brando C, Martinon F, Shevach EM, Coligan JE:
Antigen-independent, integrin-mediated T cell activation.
J Immunol
154:2104, 1995[Abstract]
41.
Moulder K, Roberts K, Shevach EM, Coligan JE:
The mouse vitronectin receptor is a T cell activation antigen.
J Exp Med
173:343, 1991[Abstract/Free Full Text]
42.
Cervantes F, Barosi G, Demory JL, Reilly JT, Guarnone R, Dupriez B, Pereira A, Montserrat E:
Myelofibrosis with myeloid metaplasia in young individuals: Disease characteristics, prognostic factors and identification of risk-groups.
Br J Haematol
102:684, 1998[Medline]
[Order article via Infotrieve]
43.
Clift RA, Buckner CD, Thomas ED, Doney K, Fefer A, Neiman PE, Singer J, Sanders J, Stewart P, Sullivan KM, Deeg J, Storb R:
Treatment of chronic granulocytic leukaemia in chronic phase by allogeneic marrow transplantation.
Lancet
2:621, 1982[Medline]
[Order article via Infotrieve]
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|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
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[Full Text]
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|
|
|
|
|
|
|
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|
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[Full Text]
|
|
|
|
|
|
|
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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[Abstract]
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|
|
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ABSTRACT
INTRODUCTION