|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3630-3636
Splenectomy and Risk of Blast Transformation in Myelofibrosis
With Myeloid Metaplasia
By
Giovanni Barosi,
Achille Ambrosetti,
Antonietta Centra,
Antonietta Falcone,
Carlo Finelli,
Paolo Foa,
Alberto Grossi,
Roberta Guarnone,
Serena Rupoli,
Luigiana Luciano,
Maria C. Petti,
Enrico Pogliani,
Domenico Russo,
Marco Ruggeri, and
Silvana Quaglini for
the Italian Cooperative Study Group on Myelofibrosis With Myeloid
Metaplasia
From the Laboratorio di Informatica Medica and Dipartimento di
Medicina Interna e Oncologia Medica, IRCCS Policlinico S. Matteo,
Pavia, Italy; the Cattedra di Ematologia, Policlinico Borgo Roma,
Verona, Italy; the Divisione di Ematologia, Ospedale S. Maria Goretti,
Latina, Italy; the Divisione di Ematologia Casa Sollievo della
Sofferenza, S. Giovanni Rotondo, Foggia, Italy; the Istituto di
Ematologia "Seragnoli", Bologna, Italy; the Servizio di
Ematologia Diagnostica, Istituto di Scienze Mediche, Milano, Italy; the
Divisione di Ematologia, Policlinico di Carreggi, Firenze, Italy; the
Clinica di Ematologia, Ospedale Generale Regionale, Torrette di Ancona,
Italy; the Divisione di Ematologia, Nuovo Policlinico, Napoli, Italy;
the Dipartimento di Biopatologia Umana, Università "La
Sapienza", Roma, Italy; the Cattedra di Medicina Interna II, Nuovo
Ospedale S. Gerardo, Monza, Italy; the Divisione di Ematologia,
Policlinico Universitario, Udine, Italy; the Divisione di Ematologia,
Ospedale S. Bortolo, Vicenza, Italy; and the Dipartimento di
Informatica e Sistemistica, Università di Pavia, Pavia, Italy.
 |
ABSTRACT |
An unexpectedly high incidence of blast transformation after
splenectomy has been reported in patients with myelofibrosis with
myeloid metaplasia. However, whether this was associated with spleen
removal after adjustment for risk factors was not determined. We
conducted a multicenter historical cohort study of patients with
myelofibrosis with myeloid metaplasia diagnosed from January 1970 through January 1994. A total of 549 patients (325 men and 224 women
from 22 to 92 years of age; median age, 63 years) were included in the
final data set. The Cox's proportional-hazards model was used to
identify factors associated with blast transformation and death. To
further adjust for factors related to spleen removal assignment, a
propensity score for splenectomy was estimated using recursive-partitioning analysis. Blast transformation developed in 78 patients (14.2%). Patients who underwent splenectomy developed more
blast transformations than those who were not splenectomized (23 of 87 [26.4%] v 55 of 462 [11.9%]; P < .001). The
cumulative incidence of blast transformation 12 years after diagnosis
was 27.0% in nonsplenectomized patients and 55.0% in splenectomized ones (P = .01). The risk factors independently predictive of
blast transformation included prior splenectomy (relative risk = 2.61), platelet count less than 100 × 109/L at diagnosis
(relative risk = 2.45), and the presence of blasts in peripheral
blood at diagnosis (relative risk = 2.31). The relative risk of blast
transformation in splenectomized patients increased from 2.2 at 48 months from diagnosis to 14.3 at 12 years. Patients with the same
propensity score for splenectomy showed a higher risk for blast
transformation on the basis of having undergone splenectomy (P
= .02). In conclusion, the risk of blast transformation is
significantly increased in subjects who underwent splenectomy and
appears to be independent of factors related to spleen removal assignment.
| |
INTRODUCTION |
BLAST TRANSFORMATION, ie, an accumulation
of blasts in bone marrow and peripheral blood associated with clinical
deterioration, is reported to occur in 5% to 30% of patients with
myelofibrosis with myeloid metaplasia.1-12 Erythroid
failure, severe anemia, a high number of circulating immature myeloid
cells or white blood cells at diagnosis, and chromosomal aberrations
have all been recognized as markers of leukemic
evolution.12-14
Two previous studies aimed at evaluating the outcome of splenectomy in
myelofibrosis with myeloid metaplasia reported an unexpectedly high
incidence of blast transformation in splenectomized patients. In one
study of 71 patients, blast transformation accounted for 42.8% of
deaths;15 in another study of 39 cases, blast
transformation occurred in 46.6% of surviving patients observed for
more than 2 years.16 However, the design of those studies
did not eliminate the possible bias related to whether the
splenectomized patients were inclined to proceed toward leukemic
evolution or whether it became clinically manifest with splenectomy.
We conducted a follow-up study of patients with myelofibrosis with
myeloid metaplasia that combined the results from Italian centers in an
attempt to reassess the risk factors for the development of blast
transformation and the effect of splenectomy on the outcome. The main
reason that brought us to address this problem with a large study was
that splenectomy in myelofibrosis with myeloid metaplasia is performed
with a critical balance between risks and benefits. Thus
postsplenectomy complications that could shorten the length and worsen
the quality of life should be perceived as particularly grave.
Moreover, the hypothesis of this study, with the reports on the effect
of splenectomy in increasing the risk of acute leukemia in Hodgkin's
disease17-23 and aplastic anemia,24 could
support a general role for splenectomy in the disruption of the
tumor-host relationship.
| |
MATERIALS AND METHODS |
A collaborative study group was formed comprising 13 large hospitals in
Italy. The centers were asked to include in this study all patients who
were diagnosed with myelofibrosis with myeloid metaplasia from January
1970 through January 1994. Confirmation of diagnosis required a bone
marrow biopsy demonstrating moderate to severe bone marrow fibrosis and
two of the following criteria: typical peripheral blood morphology
showing immature erythroid and myeloid cells with teardrop erythrocytes
in the absence of absolute monocytosis; signs of myeloproliferation
such as thrombocytosis or leukocytosis; and myeloid metaplasia
documented by splenomegaly, ferrokinetic evaluation, or extramedullary
tissue biopsy.25 Patients with postpolycythemia vera or
postessential thrombocythemia myelofibrosis were excluded.
The rate of disease progression was evaluated by three indices: anemia,
thrombocytopenia, and splenomegaly progression. They were defined as
the ratio of the change in one progression parameter to the time
interval from diagnosis to the change point. Change points were
established at the minimum value for hemoglobin concentration and
platelet count and at the maximum value for spleen size. Only the
period before splenectomy was considered in splenectomized patients.
Patients with fewer than three measurements for each parameter from
diagnosis to change points were excluded from this assessment.
Confirmation of a diagnosis of blast transformation required a
percentage of peripheral blood blasts greater than 20% of the white
blood cell count and/or a percentage of blasts in the bone
marrow greater than 40%.
Five hundred and sixty-four patients were recruited. Anyone with
clinical evidence of acute leukemia at diagnosis (n = 8) was excluded
from further analysis. Three patients were excluded because they had
undergone splenectomy from 5 to 20 years before diagnosis for reasons
other than a myeloproliferative disorder; 4 others were excluded for
insufficient data. Patients were censored from the analysis of blast
transformation risk factors if they died within 1 month after
splenectomy for causes related to surgery (n = 7). A total of 549 patients were included in the final data set.
Data from patient groups were compared using the Student's
t-test, Mann-Whitney U test, or  2 test as
appropriate. Actuarial blast transformation-free curves were calculated
using the method of Kaplan and Meier,26 with censoring at
death or at the last follow-up. The log-rank test was used to assess
differences between curves. We used the Cox's proportional-hazards
model27 to analyze the association between splenectomy and
blast transformation. The following baseline variables were included in
the univariate model: sex, age at diagnosis, white blood cell count
corrected for circulating erythroblasts, hemoglobin concentration,
platelet count, percentage of immature myeloid cell in peripheral blood
(excluding blasts), percentage of circulating erythroblasts, presence
of circulating blasts, and splenomegaly grade. Given the wide variation
in white blood cell counts and platelet counts at diagnosis, natural
logs were applied to these covariates before their evaluation in the
Cox's model. For the sake of homogeneity among different types of
measurements, the degree of splenomegaly was assessed
semiquantitatively on a scale of 0 to 3+ according to whether the
spleen was of normal size or detected over, at, or below the umbilical
line. Follow-up variables were the use of cytostatics, cumulative dose
of cytostatics (converted to an ordinal variable), the progression
indices, and splenectomy. Predictors with two-tailed P values
less than .05 were entered into the multivariate models, and a series
of models was constructed. To account for different times of
splenectomy, the operation was entered as a time-dependent covariate.
The assumption of a constant risk ratio over time for the
proportional-hazards analysis was tested by the Schoenfeld residuals
method28 and found to be valid for all the variables
modeled except splenectomy. To accommodate risk time-dependency, a
separate approach was used by modelling a time-by-covariate interaction
as the product term in the Cox regression equation, and an exponential
function of time was modeled.
To further separate the influence of splenectomy assignment on the risk
for blast transformation, we used a propensity score adjustment.29 Recursive-partitioning analysis30
was used to discriminate between patients who were assigned to
splenectomy and those who were not. In addition to the variables
applied in the Cox's model for the risk of blast transformation, the
candidate predictor variables included the study center.
Mantel-Haenszel statistics31 were used to compare the
average incidence of blast transformation in splenectomized and
nonsplenectomized patients in each stratum. Two-sided P values
and 95% confidence intervals (CI) were used throughout. Statistical
analysis was performed with the STATISTICA package (StataSoft, Tulsa,
OK), except for the classification tree, for which implementation in
S-PLUS (Statistical Science Inc, Seattle, WA) was used.
| |
RESULTS |
The number of evaluable patients and data on clinical and hematologic
characteristics at diagnosis and during disease progression are
presented in Table 1. The median follow-up
period was 42.0 months (range, 1 to 297 months). Median follow-up
duration was not statistically different (P = .3) between
splenectomized (48 months; range, 2 to 297 months) and
nonsplenectomized patients (40 months; range, 1 to 236 months) in the
total patient population. This lack of difference was maintained when
the centers were analyzed separately. Information about medical therapy
was available in 516 patients (93.9%); a total of 305 (59.1%)
received some kind of chemotherapy: 54.1% received hydroxyurea (mean
total dose, 353 g; range, 1.50 to 1,500 g). Other patients received,
alone or in association, busulphan, melphalan, 6-mercaptopurine,
low-dose cytosine arabinoside, and pipobroman. Six patients underwent
splenic irradiation, one of them before splenectomy.
Eighty-seven patients (15.8%) were splenectomized from 1 to 190 months
after diagnosis (median, 19 months; first and third quartiles, 5 and 45 months). The main reasons for splenectomy were symptomatic splenomegaly
in 52 patients (59.7%) and transfusion-dependent anemia in 32 others
(36.8%). Three patients were splenectomized for isolated
thrombocytopenia in the absence of anemia and symptomatic splenomegaly.
The percentage of splenectomized patients appears to differ across the
study centers, ranging from 0% to 35.7% of the enrolled cases. The
reasons for performing splenectomy were different from center to
center. Transfusion-dependent anemia appeared to be the cause of spleen
removal in 0% to 77.8% of the patients from the 7 centers that
performed splenectomy in almost 10% of the cases. The cohort that
subsequently underwent splenectomy were diagnosed at a younger age, had
a lower white blood cell and platelet count, and a higher proportion of
patients with the highest degree of splenomegaly (Table 1). More
patients who were splenectomized received chemotherapy (62 of 86 [72.1%]) during the course of the disease and before the possible
occurrence of blast transformation than patients who did not undergo
splenectomy (240 of 430 [55.8%]; P < .005).
During the follow-up period, blast transformation occurred in 78 (43 men and 35 women) of 549 patients (14.2%) at 2 to 171 months after
diagnosis (median, 36 months; first and third quartiles, 19 and 63 months). The cumulative proportion of patients estimated to undergo
blast transformation 12 years after diagnosis was 36.7% (95% CI,
27.3% to 46.1%). Blast transformation was diagnosed in 47% of
patients on the basis of findings at peripheral blood examination only
and, in the remaining ones, on the results of bone marrow histologic
examination as well. Studies aimed at characterizing blasts cells were
available in 60 patients (76.9%). Forty-five blast transformations
were classified as myeloid type, 10 as monocyte type, and 5 as
megakaryocyte type.
At the time of diagnosis of blast transformation, the median percentage
of blasts in peripheral blood was 42%, ranging from 20% to 92%. In
82% of the patients, the appearance of blast transformation caused
death in 1 to 30 months (median, 2.7 months). The remaining 18% of the
patients were alive at follow-up 0 to 26 months (median, 4.0 months)
from the diagnosis of blast transformation.
In an unadjusted comparison, patients who underwent splenectomy
developed more blast transformations than those who were not splenectomized (23 of 87 [26.4%] v 55 of 462 [11.9%];
P < .001). Higher crude blast transformation incidences in
splenectomized patients also resulted when patients were stratified by
centers according to the proponent of the study (Pavia v all
others), to the total number of cases enrolled (more or less than 50 patients per center), and according to the frequency with which
splenectomy was performed (more or less than 10% of patients
splenectomized). The Kaplan-Meier estimate of developing blast
transformation after diagnosis was significantly higher among patients
who had been splenectomized. By 12 years, the estimates were 27.0%
(95% CI, 16.3% to 37.3%) among patients who had not been
splenectomized and 55.0% (95% CI, 37.8% to 72.2%) among those who
had (P = .01). In patients splenectomized within 5 years from
diagnosis, ie, homogeneous with respect to risk time-dependence (73 cases; 83.9% of splenectomies), the estimated incidence of blast
transformation by 12 years was 72.0% (95% CI, 53.6% to 92.2%;
P = .001; Fig 1). In the
splenectomized group, the estimated cumulative hazard of developing
blast transformation after surgery showed a constant steep increase
that began 3 months after the operation and increased to 43.4% (95%
CI, 27.6% to 59.2%) at 6 years and 63.0% (95% CI, 43.0% to 83.2%)
at 10 years (Fig 1, left upper corner).
View larger version (24K):
[in this window]
[in a new window]
| Fig 1.
Cumulative incidence of blast transformation in 73 patients who had been splenectomized within 5 years from diagnosis and in the 462 nonsplenectomized patients. The vertical lines represent 95% CIs. Actuarial data beyond 144 months were not reported because the number of patients remaining in each group was too small. The
incidence of blast transformation from the time of splenectomy is also
represented in the upper left corner.
|
|
In univariate analysis, the factors associated with blast
transformation included prior splenectomy, the presence of blast cells
in peripheral blood at diagnosis, a platelet count less than 100 × 109/L at diagnosis, and a hemoglobin concentration
less than 9 g/dL at diagnosis. Prior therapy with hydroxyurea,
considering any dose, was not significantly correlated to blast
transformation, but considering only patients who had received doses
greater than 300 g, was marginally correlated (P = .07). At
multivariate analysis (Table 2), prior
splenectomy, low platelet count, and the presence of blasts at
diagnosis remained independently correlated with blast transformation.
At subgroup analysis, patients splenectomized for symptomatic
splenomegaly had a higher risk of blast transformation than the ones
splenectomized for transfusion-dependent anemia, but the risk ratio was
not significant. Also, the combination of splenectomy and hydroxyurea
therapy significantly was not correlated with blast
transformation. The time-dependent evolution of the relative risks of blast transformation according to prior splenectomy is represented in Fig 2. The relative risk
was 2.2 at 4 years, 5.2 at 8 years, and 14.3 at 12 years from
diagnosis.
View larger version (11K):
[in this window]
[in a new window]
| Fig 2.
Relative risk of blast transformation according to
whether splenectomy had been performed. Observed ( ) and calculated
risks ( ) using a time-dependent function in the Cox's model are
represented.
|
|
Three hundred nineteen candidates with a complete set of covariates
were assigned by the recursive partitioning algorithm to one of seven
groups according to propensity to be splenectomized, from null to high
(64.1%; Fig 3). The model indicated that
the age was the primary determinant of assignment to splenectomy. Among
the patients in both groups, the next division was according to the
clinical Center, and additional factors that were important were the
hemoglobin concentration at diagnosis and the anemia progression index.
The seven groups were aggregated in six strata with the same propensity
score, and the stratum-specific incidence of blast transformation was
plotted by splenectomized and nonsplenectomized groups
(Fig 4). Patients who had been
splenectomized showed a higher incidence of blast transformation than
the nonsplenectomized patients in the same propensity score stratum
(P = .008).
View larger version (17K):
[in this window]
[in a new window]
| Fig 3.
Derivation of the seven propensity groups for splenectomy
on the basis of data available at the time of diagnosis and the progression indices. The recursive partitioning model shows the variables used to discriminate between subgroups according to the
likelihood of the patients' undergoing splenectomy. Hb, hemoglobin at
diagnosis in grams per deciliter; Anemia progr., anemia progression index hemoglobin per month. The size of the subgroup relative to the
total population and the percentage of patients in that subgroup in
whom splenectomy was performed are represented in each circle.
|
|
View larger version (17K):
[in this window]
[in a new window]
| Fig 4.
The incidence of blast transformation plotted by
propensity score stratum for splenectomized and nonsplenectomized
patients. The six propensity score strata were indexed in order of
increasing probability of splenectomy.
|
|
Data on current status (living or dead) was obtained for 409 patients
(74.5% of the entire cohort). A total of 210 subjects (38.2%) died
during follow-up. The median length of survival after diagnosis was 90 months (95% CI, 78 to 110 months). At Cox's multivariate analysis,
mortality corrected for age, hemoglobin concentration, and presence of
blasts at diagnosis was associated with both blast transformation (risk
ratio = 2.94; 95% CI, 1.99 to 4.34; P < .001) and
splenectomy (risk ratio = 1.59; 95% CI, 1.02 to 2.48; P = .03). Patients who developed blast transformation had a median survival
of 51.9 months (95% CI, 35.5 to 64.0 months) as compared with 113.5 months (95% CI, 93.2 to 189.5 months) for patients who did not develop
blast transformation (P < .001).
| |
DISCUSSION |
In this cohort of patients, the incidence of blast transformation
progressively increased from diagnosis and the cumulative incidence at
12 years was 36.7%. Disease presentation with detectable blasts in
peripheral blood or with thrombocytopenia was predictive of the
transformation. Others found that erythroid failure, a high percentage
of myeloid precursors, or a high white blood cell count and abnormal
karyotype were associated with the conversion.12-14 Extreme
heterogeneity of features and outcomes in myelofibrosis with myeloid
metaplasia and the low number of patients in individual series may
justify these differences in results. However, these risk factors,
taken together, lead to the conclusion that high proliferation of the
myeloid lineage with defective maturation associated with the failure
of other hemopoietic series is the prime characteristic at presentation
that predisposes to blast transformation.
The present study provided evidence that splenectomy is an adjunctive
strong independent risk factor for blast transformation. The crude
blast transformation rate in splenectomized patients was 26.4%,
whereas it was 11.9% in nonsplenectomized patients, and the cumulative
actuarial transformation rate at 12 years after diagnosis was 55.0% in
splenectomized and 27.0% in nonsplenectomized patients. We found that
the cumulative incidence of blast transformation after splenectomy
began to increase from 3 months after surgery and at the 12 years of
follow-up it had not reached a plateau. The overall relative risk of
blast transformation was 2.61 times higher among patients who had been
submitted to splenectomy, even when all contributing factors were
corrected, and being splenectomized carried the highest risk of blast
transformation during the late phase of follow-up, where it reached
14.3 times that of nonsplenectomized patients.
We were especially careful to separate the influence of splenectomy
assignment in the analysis of risk for blast transformation. In
addition to multivariate Cox regression analysis, we used the propensity score approach31 on the grounds that the two
methodologies are conceptually different.32 Through the use
of recursive partitioning analysis, the relatively young age retained
major importance in selecting patients for splenectomy. The clinical
center, anemia at diagnosis, and worsening of anemia during disease
progression were the additional factors that played an independent role
in choosing patients for spleen removal. When these factors were considered in a propensity score and when the occurrence of blast transformation was adjusted for it, splenectomized patients retained on
average an increased risk of blast transformation. In conclusion, both
methodological approaches used in this study served to exclude that
splenectomy and blast transformation shared the same causes and
contrasted the hypothesis of a selection bias in previous studies15,16 that showed a high incidence of blast
transformation after splenectomy.
Our study is limited by its reliance on data drawn from clinical
records, but there is no reason to believe that there was a systematic
bias in the identification of MMM patients or in their follow-up. In
particular, the slightly but significantly shorter survival of patients
who had been submitted to splenectomy reduced the risk of a duration
bias, ie, that splenectomy afforded additional survival time for a
blast crisis to occur.
An additional important problem concerns the possibility of
misdiagnosis of blast transformation. We used the definition of blast
conversion reported in studies on chronic myeloproliferative disorders,12,33 but our most important reason for
confidence in its accuracy derives from the fact that in our cohort of
patients this diagnosis was associated with hematologic and clinical
deterioration that substantiated an acute and terminal event of the
disease.
The most compelling link between splenectomy and malignant diseases
derives from clinical studies. Although not universally demonstrated,34-39 studies have reported that, in patients
with Hodgkin's disease, the risk of secondary leukemia or solid tumors is higher in splenectomized patients.17-23 Moreover,
splenectomy was found to correlate with increased risk for both acute
leukemia and myelodysplastic syndromes in patients treated for aplastic anemia.24 There is no evident reason to justify an
association between splenectomy and tumors; nevertheless, certain
features may help us to understand the role of the spleen in the
leukemia-host relationship in myelofibrosis with myeloid metaplasia.
After splenectomy, a progressive increase in circulating mature and
immature myeloid cells with massive liver enlargement due to myeloid
metaplasia has been reported.15 These features may be
associated with a progressive increase in blast cells in peripheral
blood (data not evaluated in this study) preceding the evolution toward
blast transformation.15 These observations, along with the
finding that splenectomies in both healthy population40,41
and animal models42,43 did not increase the risk of acute
leukemia, indicate a direct effect of splenectomy in accelerating
preexisting myeloid proliferation.
The results of the present investigation have little chance of being
confirmed by additional prospective randomized studies due to the
rarity of the disease and lack of a consensus about the indications for
splenectomy. Given the observational nature of the present study, we
are aware of the possibility of bias in patient selection and of
confounding due to splenectomy indication or duration of
postsplenectomy disease. However, in this study, two different
methodologies of data analysis yielded the same result, providing
sufficient evidence that splenectomy adds to the chances of blast
transformation. The knowledge that, using splenectomy, we provide the
patient with an additional chance for blast transformation and survival
reduction, when considered together with his or her specific clinical
profile, may influence the clinician's judgment about whether that
person will benefit from splenectomy.
| |
FOOTNOTES |
Submitted August 4, 1997;
accepted January 13, 1998.
Address reprint requests to Giovanni Barosi, MD,
Laboratorio di Informatica Medica, IRCCS Policlinico S. Matteo, 27100 Pavia, Italy.
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.
| |
REFERENCES |
1.
Pitcock JA,
Reinhard EH,
Justus BW,
Mendelsohn RS:
A clinical and pathological study of seventy cases of myelofibrosis.
Ann Intern Med
57:73,
1962
2.
Bouroncle BA,
Doan CA:
Myelofibrosis: Clinical, hematologic and pathologic study of 110 patients.
Am J Med Sci
243:697,
1962
3.
Silverstein MN,
Gomes MR,
ReMine WH,
Elvebach LR:
Agnogenic myeloid metaplasia. Natural history and treatment.
Arch Intern Med
120:546,
1967[Medline]
[Order article via Infotrieve]
4.
Rosenthal DS,
Moloney WC:
Myeloid metaplasia. A study of 98 cases.
Postgrad Med
45:136,
1969
5. Ward HP, Block MH: The natural history of agnogenic myeloid
metaplasia (AMM) and a critical evaluation of its relationship with the
myeloproliferative syndrome. Medicine (Baltimore) 50:357, 1971
6.
Chelloul N,
Briere J,
Leval-Jeantet M,
Najean Y,
Vorhauer W,
Jacquillat C:
Prognostic of myeloid metaplasia with myelofibrosis.
Biomedicine
24:272,
1976[Medline]
[Order article via Infotrieve]
7.
Meytes D,
Katz D,
Ramot B:
Prognostic parameters in myeloid metaplasia: Agnogenic vs post polycythaemia.
Isr J Med Sci
12:534,
1976[Medline]
[Order article via Infotrieve]
8.
Manoharan A,
Smart RC,
Pitney WR:
Prognostic factors in myelofibrosis.
Pathology
14:455,
1982[Medline]
[Order article via Infotrieve]
9.
Varki A,
Lottenberg R,
Griffith R,
Reinhard E:
The syndrome of idiopathic myelofibrosis. A clinicopathologic review with emphasis on the prognostic variables predicting survival.
Medicine
62:353,
1983[Medline]
[Order article via Infotrieve]
10. Lopez-Guillermo A, Cervantes F, Rovira M, Pereira A, Quinteros
L, Rozman C: Myelofibrosis idiopatica: Patrones evolutivos, supervivencia y causas de muerte en una serie de 60 pacientes. Sangre 35:114, 1990
11.
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,
Tura S:
Myelofibrosis with myeloid metaplasia: clinical and haematologic parameters predicting survival in a series of 133 patients.
Br J Haematol
75:4,
1990[Medline]
[Order article via Infotrieve]
12.
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]
13.
Bentley SA,
Murray KH,
Lewis SM,
Roberts PD:
Erythroid hypoplasia in myelofibrosis: A feature associated with blastic transformation.
Br J Haematol
36:41,
1977[Medline]
[Order article via Infotrieve]
14.
Barosi G,
Baraldi A,
Cazzola M,
Spriano P,
Magrini U:
Red cell aplasia in myelofibrosis with myeloid metaplasia.
Cancer
52:1290,
1983[Medline]
[Order article via Infotrieve]
15.
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]
16.
Lafaye F,
Rain JD,
Clot P,
Najean Y:
Risks and benefits of splenectomy in myelofibrosis: An analysis of 39 cases.
Nouv Rev Fr Hematol
36:359,
1994
17.
van Leeuwen FE,
Somers R,
Hart AAM:
Splenectomy in Hodgkin's disease and second leukemias.
Lancet
2:210,
1987[Medline]
[Order article via Infotrieve]
18.
van der Velden JW,
van Putten WLJ,
Guinee VF,
Pfeiffer R,
van Leeuwen FE,
van der Linden EA,
Vardomskaya I,
Lane W,
Durand M,
Lagarde C:
Subsequent development of acute-nonlymphocytic leukemia in patients treated for Hodgkin's disease.
Int J Cancer
42:252,
1988[Medline]
[Order article via Infotrieve]
19.
van Leeuwen FE,
Somers R,
Taal BG,
van Heerde P,
Coster B,
Dozeman T,
Huisman SJ,
Hart AA:
Increased risk of lung cancer, non-Hodgkin's lymphoma, and leukemia following Hodgkin's disease.
J Clin Oncol
7:1046,
1989[Abstract]
20.
Meadows AT,
Obringer AC,
Marrero O,
Oberlin O,
Robison L,
Fossati-Bellani F,
Green D,
Voute PA,
Morris-Jones P,
Greenberg M:
Second malignant neoplasms following childhhood Hodgkin's disease: Treatment and splenectomy as risk factors.
Med Pediatr Oncol
17:477,
1989[Medline]
[Order article via Infotrieve]
21.
Kaldor JM,
Day NE,
Clarke EA,
Van Leeuwen FE,
Henry-Amar M,
Fiorentino MV,
Bell J,
Pedersen D,
Band P,
Assouline D:
Leukemia following Hodgkin's disease.
N Engl J Med
322:7,
1990[Abstract]
22.
Tura S,
Fiacchini M,
Zinzani PL,
Brusamolino E,
Gobbi PG:
Splenectomy and the increasing risk of second acute leukemia in Hodgkin's disease.
J Clin Oncol
11:925,
1993[Abstract/Free Full Text]
23.
Dietrich P-Y,
Henry-Amar M,
Cosset J-M,
Bodis S,
Bosq J,
Hayat M:
Second primary cancers in patients continuously disease-free from Hodgkin's disease: A protective role of the spleen.
Blood
84:1209,
1994[Abstract/Free Full Text]
24.
Socie G,
Henry-Amar M,
Bacigalupo A,
Hows J,
Tichelli A,
Ljungman P,
McCann SR,
Frickhofen N,
Van't Veer Korthof E,
Gluckman E:
Malignant tumor occurring after treatment of aplastic anemia.
N Engl J Med
329:1152,
1993[Abstract/Free Full Text]
25.
Laszlo J:
Myeloproliferative disorders (MPD): Myelofibrosis, myelosclerosis, extramedulllary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia.
Semin Hematol
4:409,
1975
26. Kaplan EL, Meier P: Non parametric estimation from incomplete
observations. J Am Stat Assoc 53:457, 1958
27.
Cox DR:
Regression models and life-tables.
J R Stat Soc [B]
34:187,
1972
28.
Schoenfeld D:
Chi-squares goodness-of-fit tests for the proportional hazards regression model.
Biometrika
67:145,
1980[Abstract/Free Full Text]
29.
Rosenbaum PR,
Rubin DB:
The central role of the propensity score in observational studies for causal effects.
Biometrika
70:41,
1983[Abstract/Free Full Text]
30. Breiman L, Friedman JH, Olshen RA, Stone CJ: Classification and
regression trees. Belmont, CA, Wadsworth International Group, 1984
31.
Mantel N,
Haenszel W:
Statistical aspects of the analysis of data from retrospective studies of disease.
J Natl Cancer Inst
22:719,
1959
32.
Drake C,
Fosher L:
Prognostic models and the propensity score.
Int J Epidemiol
24:183,
1995[Abstract/Free Full Text]
33.
Muehleck SD,
McKenna RW,
Arthur DC,
Parkin-JL,
Brunning RD:
Transformation of chronic myelogenous leukemia: Clinical, morphologic and cytogenetic features.
Am J Clin Pathol
82:1,
1984[Medline]
[Order article via Infotrieve]
34.
Andrieu J-M,
Ifrah N,
Payen C,
Fermanian J,
Coscas Y,
Flandrin G:
Increased risk of second acute nonlymphocytic leukemia after extended-field radiation therapy combined with MOPP chemotherapy for Hodgkin's disease.
J Clin Oncol
8:1148,
1990[Abstract]
35. Abrahamsen JF, Andersen A, Hannisdal E, Nome O, Abrahamsen AF,
Kvaloy S, Host H: Second malignancies after tretament of Hodgkin's
disease: The influence of treatment, follow-up time, and age. J Clin
Oncol 11:255, 1993
36.
Rodriguez MA,
Fuller LM,
Zimmerman SO,
Allen PK,
Brown BW,
Munsell MF,
Hagemeister FB,
McLaughlin P,
Velasquez WS,
Swan F Jr:
Hodgkin's disease: Study of treatment intensities and incidences of second malignancies.
Ann Oncol
4:125,
1993[Abstract/Free Full Text]
37.
van Leeuwen FE,
Klokman WJ,
Hagenbeek A,
Noyon R,
van den Belt Dusebout AW,
van Kerkhoff EH,
van Heerde P,
Somers R:
Second cancer risk following Hodgkin's disease: A 20 year follow-up study.
J Clin Oncol
12:312,
1994[Abstract]
38.
Beaty O III,
Hudson MM,
Greenwald C,
Luo X,
Fang L,
Wilimas JA,
Thompson EI,
Kun LE,
Pratt CB:
Subsequent malignancies in children and adolescents after treatment for Hodgkin's disease.
J Clin Oncol
13:603,
1995[Abstract/Free Full Text]
39. Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G,
Fossati-Bellani F, Meadows AT: Breast cancer and other second neoplasms
after childhood Hodgkin's disease. N Engl J Med 334:745, 1996
40.
Linet MS,
Nyren O,
Gridley G,
Mellemkjaer L,
McLaughlin JK,
Olsen JH,
Adami HO,
Fraumeni JF Jr:
Risk of cancer following splenectomy.
Int J Cancer
66:611,
1996[Medline]
[Order article via Infotrieve]
41.
Robinette CD,
Fraumeni JF Jr:
Splenectomy and subsequent mortality in veterans of the 1939-45 war.
Lancet
2:127,
1977[Medline]
[Order article via Infotrieve]
42.
Moloney WC,
King VP:
Reduction of leukemia incidence following splenectomy in the rat.
Cancer Res
33:573,
1973[Abstract/Free Full Text]
43.
Nason-Burchenal K,
Wolff L:
Involvement of the spleen in preleukemic development of a murine retrovirus-induced promonocytic leukemia.
Cancer Res
52:5317,
1992[Abstract/Free Full Text]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
D. P. Steensma and R. E. Richard
Myeloproliferative disorders
ASH Self-Assessment Program,
January 1, 2007;
2007(1):
172 - 227.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Arana-Yi, A. Quintas-Cardama, F. Giles, D. Thomas, A. Carrasco-Yalan, J. Cortes, H. Kantarjian, and S. Verstovsek
Advances in the Therapy of Chronic Idiopathic Myelofibrosis
Oncologist,
September 1, 2006;
11(8):
929 - 943.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. A. Mesa, C.-Y. Li, R. P. Ketterling, G. S. Schroeder, R. A. Knudson, and A. Tefferi
Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases
Blood,
February 1, 2005;
105(3):
973 - 977.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Spivak
Polycythemia vera: myths, mechanisms, and management
Blood,
December 15, 2002;
100(13):
4272 - 4290.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tefferi
Myelofibrosis with Myeloid Metaplasia
N. Engl. J. Med.,
April 27, 2000;
342(17):
1255 - 1265.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Tefferi, R. A. Mesa, D. M. Nagorney, G. Schroeder, and M. N. Silverstein
Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients
Blood,
April 1, 2000;
95(7):
2226 - 2233.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Barosi
Myelofibrosis With Myeloid Metaplasia: Diagnostic Definition and Prognostic Classification for Clinical Studies and Treatment Guidelines
J. Clin. Oncol.,
September 1, 1999; | |
Abstract
Introduction
Abstract