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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Laboratory of Medical Informatics, the Unit of
Clinical Immunology and Immunohematology, the Transfusion Service, and
the Department of Internal Medicine and Clinical Oncology, Istituto di
Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo,
Pavia, Italy; and the Division of Hematology, Ospedale San Martino,
Genoa, Italy.
The absolute content of CD34+ cells in the peripheral
blood of 84 patients with myelofibrosis with myeloid metaplasia (MMM) and 23 patients with other Philadelphia-negative (Ph Chronic myeloproliferative disorders (CMDs)
encompass a heterogeneous array of diseases that are due to somatic
mutation and clonal proliferation of a pluripotent hematopoietic
progenitor cell. The functional derangement of the malignant
hematopoietic clone results in an increase of progenitor cells in the
bone marrow and an increased number of circulating hematopoietic
precursors, including pluripotent and committed
progenitors.1-12 In myelofibrosis with myeloid metaplasia
(MMM), a CMD characterized by bone marrow fibrosis and constitutive
myeloid metaplasia,13 the number of circulating
hematopoietic precursors has always been reported to be consistently
high, with the mean levels being from 8- to 167-fold higher than those
found in control subjects.1-9 When cells are measured by
flow cytometry, the average CD34+ cell recovery from
peripheral blood is higher in patients with MMM than in those with
other Philadelphia-negative (Ph The purpose of this study was to define the levels of CD34+
cells in a large, well-characterized population of patients with MMM.
Moreover, we wished to assess the ability of the number of circulating
CD34+ cells to distinguish MMM from other Ph Patients
The diagnosis of MMM was established according to the Italian Consensus
Conference criteria,14 by which the diagnosis holds if
diffuse bone marrow fibrosis is present and Philadelphia chromosome or
BCR-ABL rearrangement in peripheral blood cells is absent. In addition,
any 2 of the following criteria should be present when splenomegaly is
present and any 4 when splenomegaly is absent: anisopoikilocytosis with
teardrop erythrocytes, presence of circulating immature myeloid cells,
presence of circulating erythroblasts, presence of clusters of
megakaryoblasts and anomalous megakaryocytes in bone marrow sections,
myeloid metaplasia.
Sixty-five patients were classified as having primary MMM and 19 as
having secondary MMM (14 had post-polycythemia vera [PV] MMM, and 5 had post-essential thrombocythemia [ET] MMM). Twenty-two patients
(26.2%) were studied at the time of diagnosis and before any therapy
was started, while 62 were studied during the course of their disease.
Sixty-seven patients (79.7%) were studied before the start of any
cytoreductive treatment or when the cytoreduction had been stopped for
at least 3 months. Seventeen patients (20.2%) were on hydroxyurea
treatment at the time of the CD34+ analysis, and 8 (9.5%)
had also had a splenectomy. To analyze the change in CD34+
cells over time, blood was drawn from 7 patients at regular intervals over a period of at least 4 months.
At the time that blood was drawn for the measurement of
CD34+ cells, the patients also had a complete blood count
and a peripheral blood smear examination, and their spleen and liver
measurements were taken. White blood cell count was corrected for the
number of circulating erythroblasts. Circulating nucleated cells were classified as immature myeloid cells, erythroblasts, and blasts. Blasts
were defined as undifferentiated cells with an immature nucleolated
nucleus and basophilic cytoplasm with or without azurophilic granules.
The size of the spleen was measured by ultrasonography by measuring the
length from the splenic tip to the costal margin in centimeters and by
using the spleen index calculated by multiplying the length of the
longitudinal axis by that of the transverse axis, the latter defined as
the maximal width of the organ.15 Liver enlargement was
measured as the distance from the right costal margin in centimeters.
Patients were assigned a prognostic score on the basis of the findings
of Dupriez et al.16 A score of 0 was assigned to a
hemoglobin concentration of more than 100 g/L and a white blood cell
count between 4 × 109/L and 30 × 109/L; a
score of 1 was assigned to either a hemoglobin concentration lower than
100 g/L or a white blood cell count more than 30 × 109/L
or less than 4 × 109/L; and a score of 2 was assigned if
both the hemoglobin and the white blood cell values were in those
aberrant ranges.
Since there is no accepted definition of disease severity, we evaluated
a severity score by indexing leukocytosis, thrombocytosis, and
splenomegaly (myeloproliferation index) and anemia, leukopenia, and
thrombocytopenia (myelodepletion index). There were 3 grades for
splenomegaly or hepatomegaly in patients who had had a splenectomy (0, nonpalpable; 1, no more than 10 cm below the costal margin; 2, more
than 10 cm below the costal margin); 2 grades for leukocytosis (0, white blood cell count between 4 × 109/L and
15 × 109/L; 1, white blood cell count exceeding
15 × 109/L); and 2 grades for thrombocytosis (0, platelet count between 150 × 109/L and
500 × 109/L; 1, platelet count exceeding
500 × 109/L), making the myeloproliferation index range
from 0 to 4. There were 3 grades for anemia (0, hemoglobin level
exceeding 120 g/L; 1, from 100 to 120 g/L; 2, lower than 100 g/L or
under transfusion); 2 grades for leukopenia (0, white blood cell count
between 4 × 109/L and 30 × 109/L; 1, white blood cell count lower than 4 × 109/L); and 2 grades for thrombocytopenia (0, platelet count between 150 × 109/L and 500 × 109/L; 1, platelet
count lower than 150 × 109/L), making the myelodepletion
index range from 0 to 4. The severity score ranged from 0 to 6.
Patients were followed up to the end of the study with a median
follow-up of 11.5 months (range, 1-25 months), and death and evolution
toward blast transformation were recorded. A diagnosis of blast
transformation required the percentage of peripheral blood blasts to
exceed 20% of the white blood cell count and/or the percentage of
blasts in the bone marrow to exceed 40%.
For comparison, 20 patients with other Ph Control samples were obtained from 21 healthy individuals (15 males and
6 females; median age, 65 years).
All peripheral blood samples were collected after obtaining
informed consent.
Immunophenotype analysis
With this method, a between-assays coefficient of variation of 13.07% was obtained.21 Statistical methods Results were considered statistically significant when P < .05. Skewed variables were logarithmically transformed before entering a parametric analysis. Comparisons between groups were performed by the Mann-Whitney U test or chi-square test when appropriate. Associations between patient characteristics (covariates) were assessed for pairs of numerical variables by the Spearman correlation, and for categorical and continuous variables by Wilcoxon-Mann-Whitney statistics. The optimal cutoff point for CD34+ cell number for discriminating between MMM and other Ph CMDs was sought by constructing
receiver operating characteristic (ROC) curves, which were generated by
calculating the sensitivities and specificities of data at several
predetermined cutoff points.22 Logistic regression was
used to assess the ability of the patients' characteristics to predict
the number of CD34+ cells in the peripheral blood. We
examined the following covariates: sex, age at test examination, white
blood cell count corrected for circulating erythroblasts, hemoglobin
concentration, platelet count, percentage of immature myeloid cells in
peripheral blood (excluding blasts), percentage of circulating
erythroblasts, presence and number of circulating blasts, and spleen
and liver sizes. Multivariate logistic models were obtained by
performing a backward elimination with a cutoff of
P = .05, and then allowing any variable previously deleted
to enter the final model if it was P < .05. Survival
analysis and time to blast transformation curves were drawn by means of
the Kaplan-Meier procedure. Patients were censored from the analysis of
blast transformation risk factors if, at the time of CD34+
examination, their circulating blasts exceeded 10%. Multivariate analysis was performed on MMM patients to investigate independent variables predicting blast transformation rate. The following variables were analyzed: hemoglobin level, white blood cell
count, circulating blasts (both as a percentage of white blood cell
count and as an absolute value), time from diagnosis to examination, having had a splenectomy, or having received prior cytotoxic therapy, CD34 and CD34+CD38 expression. The relative
importance of each of the variables was estimated by means of the Cox
proportional regression model. All computations were performed with
Statistica software (Statsoft, Tulsa, OK).
Patient characteristics The hematological and clinical characteristics of the population of MMM patients studied are summarized in Table 1. CD34+ cell analysis was performed at a median of 24 months (range, 0-204 months) after the diagnosis of MMM. Risk stratification according to the Dupriez-based prognostic scoring system showed a predominance of low- and intermediate-risk classes (85% of the patients). The severity score of the disease based on spleen size and hematological parameters measured at the time of CD34+ cell analysis ranged from 0 to 6, with a median value of 3. The myeloproliferation index (range, 0-4) had a median value of 3 and was no higher than 1 in 39 patients (46.4%), while the myelodepletion index (range, 0-4) had a median value of 2 and was no higher than than 1 in 34 patients (40.5%).
The level and phenotype profile of CD34+ cells in the peripheral blood of MMM patients The median absolute number of circulating CD34+ cells in the overall population of MMM patients was 91.6 × 106/L (range, 0-2460 × 106/L), 360 times higher than in healthy subjects (median, 0.25 × 106/L; range, 0.15-0.35 × 106/L). As shown in Table 2, there was no significant difference in the median CD34+ cell level between patients on chemotherapy and patients out of therapy. Likewise, there was no significant difference between primary MMM and post-PV or post-ET MMM. The highest median number of CD34+ cells was found in patients who had had a splenectomy (n = 8), in whom the median value was 616.2 × 106/L as compared with 232.2 × 106/L in patients who had not had a splenectomy (P = .016).
When cells were double-stained with anti-CD34 and anti-CD38, the median percentage of CD34+ cells in MMM that also expressed CD38 was 66%, but the range was from 23% to 99%. Sixty-four percent of the cases had more than 60% CD38+ cells. Differentiation between MMM and other Ph CMDs was 18 times lower than in patients with MMM
(Table 2). This number was independent of the clinical progression of
the diseases: the median number of CD34+ cells in patients
studied at disease diagnosis (n = 5) was 5.15 × 106/L
(range, 3.2-8.0 × 106/L); the median for patients
studied during the course of their disease (n = 12) was
8.25 × 106/L (range, 3.7-26.9 × 106/L);
and the median for patients who had had a splenectomy (n = 3) was
5.0 × 106/L (range, 4.4-6.7 × 106/L).
To study the power of CD34+ cell number to discriminate
between MMM and other Ph Correlation between circulating CD34+ cells and disease characteristics in MMM The analysis of correlation between circulating CD34+ cells and disease characteristics was restricted to MMM patients who were studied out of cytoreductive treatment (n = 67). In this series, 3 patients had a post-PV or post-ET MMM. There was no significant correlation between CD34+ cells in peripheral blood and patients' age, sex, hemoglobin concentration, or platelet count. By contrast, on comparing CD34+ cell levels with duration of disease, as measured from the time of diagnosis to the time of sample collection and analysis, we found a significant direct correlation (R = 0.28; P = .019). In 21 patients whose blood was drawn at diagnosis, the median number of CD34+ cells was 81.9 × 106/L (range, 2.04-349.4 × 106/L), lower than in patients (n = 45) whose blood was drawn more than 4 months after diagnosis (median CD34+ cell n = 305.6 × 106/L; range, 4.3-2460 × 106/L; P = .04). This suggests that CD34+ count increases as MMM progresses. According to the regression model, a value of 200 × 106/L CD34+ cells had to be expected after 36 months from diagnosis.Patients with higher numbers of CD34+ cells had a
significantly higher spleen volume index (R = 0.41;
P = .014) (Figure 1) and
spleen size measurement in centimeters (R = 0.41;
P = .002), liver volume (R = 0.51;
P = .000), percentage of immature myeloid cells
(R = 0.31; P = .020), and percentage of
circulating myeloid blasts (R = 0.68;
P = .000). Patients with blasts in peripheral blood
(n = 22) had a median CD34+ level of
282.8 × 106/L (range, 55.8-2460 × 106/L)
whereas patients without blasts (n = 36) had a median of
69.5 × 106/L (range, 2.04-722.5 × 106/L).
The median number of CD34+ cells in patients whose spleen
was enlarged more than 10 cm from the costal margin (n = 19) was
301.0 × 106/L (range 14.4-2460 × 106/L)
whereas this level was 70.0 × 106/L (range
2.04-1204.0 × 106/L) in patients with a smaller
spleen volume (n = 47).
A multiple linear regression was performed by forward selection of the above significantly correlated variables. The analysis yielded myeloid blasts and spleen volume as independent predictors of CD34+ cells with an adjusted R2 of 52%. An analysis of the more immature CD34+ cells, ie,
CD34+CD38 When the number of circulating CD34+ cells was correlated with risk stratification according to the Dupriez prognostic scoring system on the basis of white blood cell count and severity of anemia, the number of CD34+ cells increased significantly from low-risk (n = 29; median, 68.1 × 106/L; range, 2.04-448.9 × 106/L) to intermediate-risk (n = 30; median, 112.8 × 106/L; range, 5.0-1700 × 106/L) and high-risk patients (n = 7; median, 666.1 × 106/L; range, 14.4-2460 × 106/L) (F = 4.95; P = .009). When the number of CD34+ cells were correlated with the
severity score on the basis of both myeloproliferative and
myelodepletive characteristics of the disease, the number of
CD34+ cells proved to be associated with the severity score
(F = 4.28; P = .007), but a wide range of
CD34+ cell values was evidenced for any severity considered
(Figure 2). To account for this
variability, we separated the contribution given to the score by the
myeloproliferation index (spleen size, leukocytosis, and
thrombocytosis) and that given by the myelodepletion index (anemia,
thrombocytopenia, and leukopenia). Only the myeloproliferation index
was significantly associated with CD34+ cell number
(F = 5.7; P = .000) (Figure 2).
CD34+ and response to therapy As shown in Figure 3, in 7 patients the CD34+ cell levels were significantly lower after 2 to 4 months of treatment (daily dose range, 1000-1500 mg) with hydroxyurea (median, 135.3 × 106/L; range, 24.4-655.0 × 106/L) than before treatment (median, 223.2 × 106/L; range, 0-223 × 106/L; P = .02).
In one patient, consecutive blood samples were analyzed (Figure
4). This patient was followed up for 1 year and had mildly increased levels of CD34+ cells at the
first examination. He responded to hydroxyurea treatment, with a
decrease in spleen volume of more than 30% and a decrease in
CD34+ cells down to 16% of the initial value. Both
CD34+ cells and spleen volume remained low for 2 months
after termination of treatment. When spleen volume began to increase
again, CD34+ cells levels also rose. Thus,
CD34+ values in this patient tended to fluctuate in
accordance with the spleen volume as an effect of therapy.
Prognostic value of circulating CD34+ cell number in MMM By the follow-up, of the 84 patients with MMM studied, 13 (15.5%) had died. We compared the survival from the time of CD34+ cell measurement according to whether the number of CD34+ cells exceeded or fell below their median value (91.6 × 106/L). The overall survival was not significantly different in high CD34+ patients compared with low CD34+ patients. However, since it was possible that the relationship between CD34+ cell number and survival was more complicated, we used Martingale residual plots to examine the specific nature of this relationship. These plots suggested that as the number of CD34+ cells continued to increase to about 300 × 106/L, the difference in survival continued to increase. Hence, we compared survival in patients who had CD34+ levels above (n = 24) and below 300 × 106/L (n = 60). The death rate was 40% in the former group and 5.1% in the latter, and the difference in survival was significant (log-rank test, P = .005).Of the 84 patients with MMM studied, 12 (14.3%) developed blast
transformation, which was the cause of death in 8. After excluding one
patient who had more than 10% of blast cells in peripheral blood at
the time of CD34+ analysis, we compared the time to blast
transformation according to whether the number of CD34+
cells were greater or fewer than 300 × 106/L
CD34+ cells. The blast transformation rate was 40% in the
group with a high CD34+ cell count, but 3.4% in the group
with a low count, and the difference in time to blast transformation
was highly significant, as shown in Figure
5 (log-rank test,
P = .0005). Patients with high CD34+ cell
count had a 50% probability of developing blast transformation at 11 months from the evaluation.
Since there is a possible correlation between CD34+ cell
number and disease characteristics that may influence both survival and
blast transformation, we used multivariate analysis to assess the
influence on prognosis of each of the following: the number of
CD34+ cells; the CD34+CD38
CD34 is a surface antigen present on 1% to 3% of human bone
marrow cells and on 0.05% of nucleated circulating cells. It serves as
a marker for identifying and separating hematopoietic stem and
progenitor cells because it is not found on fully differentiated, or
mature, hematopoietic cells.23 The main finding in this
study was that the median number of CD34+ cells in
peripheral blood in a large, well-defined population of patients with
MMM is 360 times higher than in a healthy population and 18 to 30 times
higher than in a selected population of patients with other
Ph Since Ph By staining the CD34+ cells with other markers of differentiation, we found that the percentage of CD34+ cells in MMM that are CD38+ is widely variable, ranging from 23% to 99%. CD38 is a transmembrane molecule expressed heterogeneously during hematopoietic cell differentiation. Most human immature hematopoietic cells with high potential for self-renewal and multilineage differentiation express low levels of CD38 or no detectable CD38 at all.24 Thus, CD34+ cells that leave the bone marrow of MMM patients display different levels of differentiation. We have examined CD34+ measurements and how they correlate with hematological and clinical disease features to determine their usefulness as a clinical marker of disease progression. It was apparent that, on average, the number of circulating CD34+ cells tended to increase during progression of the disease. Moreover, the number of CD34+ cells reflected the number of immature myeloid and erythroid cells released into the peripheral blood, in particular, myeloid blasts. Patients with blasts in the peripheral blood had, on average, 4 times more CD34+ cells than patients without blasts. This agrees with data obtained in MDS,25 in which the existence of circulating blasts of at least 1% was accompanied by a high number of CD34+ cells compared with the number in patients with fewer than 1% blasts. Finally, the increasing CD34+ cell count was a determinant of splenomegaly progression. Together these observations establish that CD34+ cell number is related to the progression of the disease process and is a marker of myeloid metaplasia. In this study, we also examined whether CD34+ cell levels could be useful as a follow-up parameter. During hydroxyurea treatment, the standard cytoreductive treatment in MMM, CD34+ cell number was significantly lower than before treatment. To obtain more detailed information on the validity of the CD34+ levels during and after treatment, we analyzed a patient over a long period. There was a tendency for CD34+ cell levels to decrease in response to effective treatment. The data suggest that the blood levels of CD34+ may fluctuate in accordance with the tumor burden and that CD34+ is a candidate in the search for markers of disease activity. The possible prognostic relevance of measuring circulating CD34+ cells in hematologic malignancies has been appreciated in MDS.25,26 In the current study, we show that the extent of increased CD34+ cells in patients with MMM correlates with the Dupriez prognostic score and overall survival. However, the most relevant prognostic correlation we found in this study was between the number of circulating CD34+ cells and the development of blast transformation. Patients presenting more than 300 × 106/L CD34+ cells in peripheral blood have a 50% probability of developing blast transformation by 11 months. This prognostic factor was independent of other known predictors of blast transformation, such as hemoglobin level and the number of morphologically recognizable circulating blasts. This is in line with the results obtained in MDS, in which the presence of circulating CD34+ cells is associated with progression to acute myeloid leukemia and a shorter survival.26 Despite the foregoing, the role of CD34+ in the progression of MMM remains complex. In our whole population of MMM patients, disease progression, circulating myeloid cells, and spleen volume taken together justified only 52% of the variance in the number of CD34+ cells in the peripheral blood. This would suggest either that other, hidden factors intervene in determining the extent of circulating CD34+ or that MMM patients are heterogeneous in terms of the mechanisms of hematopoietic stem cell release from the bone marrow. The study of the relation to the severity of the disease contributed to clarification of this issue. In the absence of validated criteria for disease severity, we correlated the number of circulating hematopoietic cells to a construct of disease severity that included spleen size and hematological parameters. We showed that there was no relationship between CD34+ cells and the severity of disease, when indexed by anemia, thrombocytopenia, or leukopenia, while the correlation was strict when severity was indexed by leukocytosis, thrombocytosis, and splenomegaly. This documents that the release of hematopoietic stem cells from the bone marrow is higher in patients with a myeloproliferative pattern of disease than in patients with a myelodepletive pattern. Moreover, the demonstration that the number of circulating CD34+ cells better reflects the myeloproliferative characteristic of MMM than the myelodepletive pattern could be used to add to histological,27 clinical,13 or erythrokinetic28 features in the search for criteria for classifying the disease. Since a correlation between marrow angiogenesis and myeloproliferation has been reported,29 an important contribution could be to assess the influence increased angiogenesis exerts on the release of CD34+ cells from the bone marrow. In conclusion, we have shown a pronounced elevation of the number of
circulating CD34+ cells in MMM in contrast to other
Ph
Submitted December 7, 2000; accepted July 27, 2001.
Supported by funds from the Italian Association for Cancer Research (AIRC).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Giovanni Barosi, Laboratorio di Informatica Medica, IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy; e-mail: barosig{at}smatteo.pv.it.
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Blood.
2000;96:3374-3380
Members of the Italian Registry for MMM who contributed with cases to this study (person responsible, department, center city, listed by alphabetical order): Gerli Giancarla, Divisione di Medicina I, Ospedale San Paolo, Milan; Cirasino Lorenzo, Divisione Medica "Vergani," Ospedale Ca' Granda Niguarda, Milan; Colonna Alberto, Divisione di Medicina Interna, Ospedale "F. Ferrari," Casarano, Lecce; Comotti Benedetto, UO Medicina Interna e Servizio Ematologia-Oncologia, Policlinico San Pietro, Ponte San Pietro, Bergamo; Custodi Pietro, Medicina Interna, Ospedale San Biagio, Domodossola, Verbania. D'Arco Alfonso, Divisone Medicina Generale, Sezione Ematologia, Cava dei Tirreni, Salerno; Giordano Monica, Servizio di Oncologia Medica, Ospedale Sant'Anna, Como; Minetti Bruno, Divisione di Medicina, Ospedale Civile San Biagio, Clusone, Bergamo; Morandi Sergio, Ematologia, Istituti Ospedalieri, Cremona; Negri Maria, Divisione di Medicina Interna, Ospedale Civile di Voghera, Pavia; Pogliani Enrico, Divisione di Ematologia, Unità TMO, Ospedale San Gerardo, Monza; Scrinzi Luigi, UO Medicina Interna, Ospedale Civile San Bonifacio, Verona; Turpini Chiara, Divisione di Medicina Generale, Fondazione Maugeri, Pavia.
© 2001 by The American Society of Hematology.
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  F. Cervantes, B. Dupriez, A. Pereira, F. Passamonti, J. T. Reilly, E. Morra, A. M. Vannucchi, R. A. Mesa, J.-L. Demory, G. Barosi, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment Blood, March 26, 2009; 113(13): 2895 - 2901. [Abstract] [Full Text] [PDF]
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J.-J. Lataillade, O. Pierre-Louis, H. C. Hasselbalch, G. Uzan, C. Jasmin, M.-C. Martyre, M.-C. Le Bousse-Kerdiles, and on behalf of the French INSERM and the European EU Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence Blood, October 15, 2008; 112(8): 3026 - 3035. [Abstract] [Full Text] [PDF]
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 C. Bogani, V. Ponziani, P. Guglielmelli, C. Desterke, V. Rosti, A. Bosi, M.-C. Le Bousse-Kerdiles, G. Barosi, A. M. Vannucchi, and for the Myeloproliferative Disorders Research Cons Hypermethylation of CXCR4 Promoter in CD34+ Cells from Patients with Primary Myelofibrosis Stem Cells, August 1, 2008; 26(8): 1920 - 1930. [Abstract] [Full Text] [PDF]
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J. L. Spivak and R. T. Silver The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: an alternative proposal Blood, July 15, 2008; 112(2): 231 - 239. [Full Text] [PDF]
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E. O. Hexner, C. Serdikoff, M. Jan, C. R. Swider, C. Robinson, S. Yang, T. Angeles, S. G. Emerson, M. Carroll, B. Ruggeri, et al. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders Blood, June 15, 2008; 111(12): 5663 - 5671. [Abstract] [Full Text] [PDF]
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F. Passamonti, E. Rumi, M. Caramella, C. Elena, L. Arcaini, E. Boveri, C. Del Curto, D. Pietra, L. Vanelli, P. Bernasconi, et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis Blood, April 1, 2008; 111(7): 3383 - 3387. [Abstract] [Full Text] [PDF]
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C. Vener, N. S. Fracchiolla, U. Gianelli, R. Calori, F. Radaelli, A. Iurlo, S. Caberlon, G. Gerli, L. Boiocchi, and G. L. Deliliers Prognostic implications of the European consensus for grading of bone marrow fibrosis in chronic idiopathic myelofibrosis Blood, February 15, 2008; 111(4): 1862 - 1865. [Abstract] [Full Text] [PDF]
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 A. Rambaldi, T. Barbui, and G. Barosi From Palliation to Epigenetic Therapy in Myelofibrosis Hematology, January 1, 2008; 2008(1): 83 - 91. [Abstract] [Full Text] [PDF]
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G. Barosi, G. Bergamaschi, M. Marchetti, A. M. Vannucchi, P. Guglielmelli, E. Antonioli, M. Massa, V. Rosti, R. Campanelli, L. Villani, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis Blood, December 1, 2007; 110(12): 4030 - 4036. [Abstract] [Full Text] [PDF]
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S. O. Ciurea, D. Merchant, N. Mahmud, T. Ishii, Y. Zhao, W. Hu, E. Bruno, G. Barosi, M. Xu, and R. Hoffman Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis Blood, August 1, 2007; 110(3): 986 - 993. [Abstract] [Full Text] [PDF]
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 J. Shi, Y. Zhao, T. Ishii, W. Hu, S. Sozer, W. Zhang, E. Bruno, V. Lindgren, M. Xu, and R. Hoffman Effects of Chromatin-Modifying Agents on CD34+ Cells from Patients with Idiopathic Myelofibrosis Cancer Res., July 1, 2007; 67(13): 6417 - 6424. [Abstract] [Full Text] [PDF]
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 D. P. Steensma and R. E. Richard Myeloproliferative disorders ASH Self-Assessment Program, January 1, 2007; 2007(1): 172 - 227. [Full Text] [PDF]
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P. Guglielmelli, R. Zini, C. Bogani, S. Salati, A. Pancrazzi, E. Bianchi, F. Mannelli, S. Ferrari, M.-C. Le Bousse-Kerdiles, A. Bosi, et al. Molecular Profiling of CD34+ Cells in Idiopathic Myelofibrosis Identifies a Set of Disease-Associated Genes and Reveals the Clinical Significance of Wilms' Tumor Gene 1 (WT1) Stem Cells, January 1, 2007; 25(1): 165 - 173. [Abstract] [Full Text] [PDF]
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 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]
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A. Tefferi, G. Barosi, R. A. Mesa, F. Cervantes, H. J. Deeg, J. T. Reilly, S. Verstovsek, B. Dupriez, R. T. Silver, O. Odenike, et al. International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT) Blood, September 1, 2006; 108(5): 1497 - 1503. [Abstract] [Full Text] [PDF]
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F. Passamonti, E. Rumi, D. Pietra, M. G. D. Porta, E. Boveri, C. Pascutto, L. Vanelli, L. Arcaini, S. Burcheri, L. Malcovati, et al. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders Blood, May 1, 2006; 107(9): 3676 - 3682. [Abstract] [Full Text] [PDF]
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U. Popat, A. Frost, E. Liu, Y. Guan, A. Durette, V. Reddy, and J. T. Prchal High levels of circulating CD34 cells, dacrocytes, clonal hematopoiesis, and JAK2 mutation differentiate myelofibrosis with myeloid metaplasia from secondary myelofibrosis associated with pulmonary hypertension Blood, May 1, 2006; 107(9): 3486 - 3488. [Abstract] [Full Text] [PDF]
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 G. Gerli, C. Vanelli, O. Turri, M. Erario, A. Gardellini, M. Pugliano, and M. L. Biondi SDF1-3'A Gene Polymorphism Is Associated with Chronic Myeloproliferative Disease and Thrombotic Events Clin. Chem., December 1, 2005; 51(12): 2411 - 2414. [Full Text] [PDF]
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 A. Tefferi Pathogenesis of Myelofibrosis With Myeloid Metaplasia J. Clin. Oncol., November 20, 2005; 23(33): 8520 - 8530. [Abstract] [Full Text] [PDF]
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 M. Xu, E. Bruno, H. Ni, V. Rosti, M. Massa, G. Barosi, and R. Hoffman SDF-1/CXCR4 Interactions in Idiopathic Myelofibrosis. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 3504 - 3504. [Abstract]
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G. Barosi, D. Bordessoule, J. Briere, F. Cervantes, J.-L. Demory, B. Dupriez, H. Gisslinger, M. Griesshammer, H. Hasselbalch, R. Kusec, et al. Response criteria for myelofibrosis with myeloid metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET) Blood, October 15, 2005; 106(8): 2849 - 2853. [Abstract] [Full Text] [PDF]
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 A. M. Vannucchi, A. Pancrazzi, P. Guglielmelli, S. Di Lollo, C. Bogani, G. Baroni, L. Bianchi, A. R. Migliaccio, A. Bosi, and F. Paoletti Abnormalities of GATA-1 in Megakaryocytes from Patients with Idiopathic Myelofibrosis Am. J. Pathol., September 1, 2005; 167(3): 849 - 858. [Abstract] [Full Text] [PDF]
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M. Massa, V. Rosti, I. Ramajoli, R. Campanelli, A. Pecci, G. Viarengo, V. Meli, M. Marchetti, R. Hoffman, and G. Barosi Circulating CD34+, CD133+, and Vascular Endothelial Growth Factor Receptor 2-Positive Endothelial Progenitor Cells in Myelofibrosis With Myeloid Metaplasia J. Clin. Oncol., August 20, 2005; 23(24): 5688 - 5695. [Abstract] [Full Text] [PDF]
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M. Xu, E. Bruno, J. Chao, S. Huang, G. Finazzi, S. M. Fruchtman, U. Popat, J. T. Prchal, G. Barosi, R. Hoffman, et al. Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases Blood, June 1, 2005; 105(11): 4508 - 4515. [Abstract] [Full Text] [PDF]
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M. Xu, E. Bruno, J. Chao, H. Ni, V. Lindgren, R. Nunez, N. Mahmud, G. Finazzi, S. M. Fruchtman, U. Popat, et al. The constitutive mobilization of bone marrow-repopulating cells into the peripheral blood in idiopathic myelofibrosis Blood, February 15, 2005; 105(4): 1699 - 1705. [Abstract] [Full Text] [PDF]
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S. Emadi, D. Clay, C. Desterke, B. Guerton, E. Maquarre, A. Charpentier, C. Jasmin, M.-C. Le Bousse-Kerdiles, and for the French INSERM Research Network on MMM IL-8 and its CXCR1 and CXCR2 receptors participate in the control of megakaryocytic proliferation, differentiation, and ploidy in myeloid metaplasia with myelofibrosis Blood, January 15, 2005; 105(2): 464 - 473. [Abstract] [Full Text] [PDF]
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M. Massa, V. Rosti, M. Ferrario, R. Campanelli, I. Ramajoli, R. Rosso, G. M. De Ferrari, M. Ferlini, L. Goffredo, A. Bertoletti, et al. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction Blood, January 1, 2005; 105(1): 199 - 206. [Abstract] [Full Text] [PDF]
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B. Arora, S. Sirhan, J. D. Hoyer, R. A. Mesa, and A. Tefferi Blood CD34 Count in Myelofibrosis with Myeloid Metaplasia: A Prospective Evaluation of Prognostic Value in 94 Patients. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 662 - 662. [Abstract]
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K. van Besien Transplantation for myelofibrosis: yes! But for whom? Blood, December 1, 2003; 102(12): 3857 - 3857. [Full Text] [PDF]
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H. J. Deeg, T. A. Gooley, M. E. D. Flowers, G. E. Sale, J. T. Slattery, C. Anasetti, T. R. Chauncey, K. Doney, G. E. Georges, H.-P. Kiem, et al. Allogeneic hematopoietic stem cell transplantation for myelofibrosis Blood, December 1, 2003; 102(12): 3912 - 3918. [Abstract] [Full Text] [PDF]
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J. L. Spivak, G. Barosi, G. Tognoni, T. Barbui, G. Finazzi, R. Marchioli, and M. Marchetti Chronic Myeloproliferative Disorders Hematology, January 1, 2003; 2003(1): 200 - 224. [Abstract] [Full Text] [PDF]
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| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
cells in lymphohematopoiesis.
Leuk Lymphoma.
1998;31:285-293