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PubMed1992

Polycythemia vera and myelofibrosis: correlation of MR imaging, clinical, and laboratory findings.

Magnetic resonance (MR) imaging was performed in 14 patients with biopsy-proved polycythemia vera (n = 4) or myelofibrosis (n = 10) to determine whether MR imaging findings can be correlated with the clinicopathologic diagnosis and established clinical parameters of severity (serum lactate dehydrogenase [LDH] and cholesterol levels) and chronicity (spleen size). Evaluation of marrow in the proximal femurs showed that patients could be categorized into three distinct groups based on anatomic patterns of normal fatty and abnormal low-signal-intensity (non-fatty) marrow in the femoral capital epiphysis (FCE) and greater trochanter (GT). Patients with nonfatty marrow in both the FCE and GT (n = 8) had significantly higher serum LDH (P less than .02) and lower serum cholesterol (P less than .02) levels than patients with fatty marrow in at least the GT (n = 6). Splenic volume, as measured from MR images, was significantly greater in the myelofibrosis group than in the polycythemia vera group (P less than .001). MR imaging provided a better understanding of these hematologic disorders and novel parameters for classification that are different from conventional histologic and laboratory data.

Adult↗
PubMed2005

Role for the nuclear factor kappaB pathway in transforming growth factor-beta1 production in idiopathic myelofibrosis: possible relationship with FK506 binding protein 51 overexpression.

The release of transforming growth factor-beta1 (TGF-beta1) in the bone marrow microenvironment is one of the main mechanisms leading to myelofibrosis in murine models and probably in the human idiopathic myelofibrosis (IMF). The regulation of TGF-beta1 synthesis is poorly known but seems regulated by nuclear factor kappaB (NF-kappaB). We previously described the overexpression of an immunophilin, FK506 binding protein 51 (FKBP51), in IMF megakaryocytes. Gel shift and gene assays show that FKBP51's overexpression in a factor-dependent hematopoietic cell line, induces a sustained NF-kappaB activation after cytokine deprivation. This activation correlates with a low level of IkappaBalpha. A spontaneous activation of NF-kappaB was also detected in proliferating megakaryocytes and in circulating CD34(+) patient cells. In normal cells, NF-kappaB activation was only detected after cytokine treatment. The expression of an NF-kappaB superrepressor in FKBP51 overexpressing cells and in derived megakaryocytes from CD34(+) of IMF patients revealed that NF-kappaB activation was not involved in the resistance to apoptosis after cytokine deprivation of these cells but in TGF-beta1 secretion. These results highlight the importance of NF-kappaB's activation in the fibrosis development of this disease. They also suggest that FKBP51's overexpression in IMF cells could play an important role in the pathogenesis of this myeloproliferative disorder.

Antigens, CD34↗
PubMed2000

Bilateral interstitial pneumonic shadows caused by perivascular fibrosis and extramedullary megakaryopoiesis of the lung in a case of advanced agnogenic myeloid metaplasia and myelofibrosis.

A 59-year-old man with progressive and advanced agnogenic myeloid metaplasia, also called idiopathic myelofibrosis, had complications showing bilateral interstitial pneumonic shadows. Pathological assessment of transbronchial biopsy revealed pulmonary perivascular fibrosis and infiltration of megakaryocytes. Autopsy 3 months later showed extramedullary megakaryopoiesis and fibrosis in lung, pleura, kidney, liver and spleen. Histopathological analysis for platelet-derived growth factor (PDGF) and PDGF-receptor revealed an abnormally high expression of the PDGF-receptor-beta gene in pulmonary fibroblasts. This is the first description of an association between pulmonary fibrosis and PDGF in idiopathic myelofibrosis.

Cell Movement↗
PubMed2002

Cytogenetic and molecular genetic aspects of idiopathic myelofibrosis.

Idiopathic myelofibrosis is a chronic myeloproliferative disorder in which the characteristic fibroblast proliferation is thought to be a secondary phenomenon resulting from the inappropriate release of megakaryocyte- and/or monocyte-derived growth factors, including PDGF, TGF-beta, bFGF and calmodulin. In contrast, the haematopoietic cells are clonal, although the underlying pathogenetic mechanisms remain essentially unknown. Cytogenetic studies have highlighted that 13q-, 20q-, +8 and abnormalities of chromosomes 1, 7 and 9 constitute more than 80% of the chromosomal changes. A third of idiopathic myelofibrosis cases have abnormal karyotypes at diagnosis, a figure that increases if follow-up analyses are performed. Evolution to more complex karyotypes may accompany clinical progression, with abnormalities increasing to around 90% following acute leukaemic transformation. Cytogenetic abnormalities have been associated with prognosis and to a lack of treatment response to androgens. Oncogene mutations are rare and include point mutations in N-RAS, c-KIT and TP53.

Chromosome Aberrations↗
PubMed1996

Combination therapy with recombinant human erythropoietin, interferon-alpha-2b and granulocyte-macrophage colony-stimulating factor in idiopathic myelofibrosis.

Seven patients, 3 men and 4 women 48-72 years of age and suffering from idiopathic myelofibrosis were given a combination of recombinant human erythropoietin (r-hu-Epo), interferon-alpha-2b (IFN) and GM-CSF, in an attempt to treat their pancytopenia and marrow fibrosis. The dose of r-hu-Epo was 200 U/kg 3 times weekly, that of IFN was 3 x 10(6)/U 3 times weekly, and that of GM-CSF was 250 micrograms/m2/daily. The duration of therapy ranged from 3 to 6 months for r-hu-Epo and IFN and was 3 weeks for GM-CSF. The treatment regimen had a beneficial effect on all patients. The levels of hemoglobin increased in all patients but particularly in 5 (2 of whom had been dependent on red blood cell transfusions). Splenomegaly decreased significantly in 4 patients. Fibrosis in the bone marrow decreased in 2 patients. Three patients also had an increase in the number of white blood cells during the therapy with GM-CSF. We observed mild side effects in 6 of our patients. One patient had severe side effects from IFN and treatment was discontinued. In conclusion, the combination of r-hu-Epo, IFN and GM-CSF may improve the anemia (due to r-hu-Epo), increase the white blood cell count (due to GM-CSF) and reduce the marrow fibrosis (probably due to IFN) in patients with idiopathic myelofibrosis.

Aged↗
PubMed1991

Beneficial treatment with methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside in a patient with primary myelofibrosis.

We attempted treatment with methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), a novel nitrosourea derivative, in a 55-year-old man with advanced-stage primary myelofibrosis. MCNU was given intravenously at a dose of 50 mg once a month. Following MCNU treatment, his anemia and splenomegaly improved markedly. An increased dose of MCNU (100 mg, once a month) was even more effective for relieving the symptoms. Severe side effects resulting from this therapy, such as leukocytopenia or thrombocytopenia, were never observed. These observations indicate that MCNU treatment may be a beneficial management of advanced-stage primary myelofibrosis.

Antineoplastic Agents↗
PubMed1984

Elliptocytosis preceding myelofibrosis in a patient with polycythemia vera.

A patient with polycythemia vera showed marked elliptocytosis in the peripheral blood, 2 years after the diagnosis was established. 4 years later on, the patient developed myelofibrosis. The significance of elliptocytosis, which appears during the course of polycythemia vera, as an early indicator for the development of myelofibrosis is discussed.

Aged↗
PubMed1983

Peripheral blood cells in the study of chromosome aberrations of patients with chronic myeloid leukaemia or myelofibrosis.

Chromosome studies were performed on peripheral blood (PB) cells with and without stimulation, and/or on bone marrow (BM) cells from 21 patients with chronic myeloid leukaemia (CML), and 18 patients with myelofibrosis (MF). Our results show that almost all the patients with immature granulocyte precursors in PB also had mitotic cells in their unstimulated PB. In CML all unstimulated mitoses had the Philadelphia chromosome. In each patient the abnormal karyotype in the PB was the same as in the BM. Because of the high frequency of dry taps in myelofibrosis, the tissue of choice for chromosome study is peripheral blood.

Blood Cells↗
PubMed1983

Myelofibrosis in young adults.

3 young adults with myelofibrosis, a rare disease in this age-group, are presented. Their clinical course was distinguished by a virtually asymptomatic state at time of diagnosis and a stable, or very slowly progressive course over a 4- to 5-year follow-up. Myelofibrosis in young adults may pursue a more benign course than that usually noted in older populations.

Adult↗
PubMed1979

Endogenous erythroid colony formation by peripheral blood mononuclear cells from patients with myelofibrosis and polycythemia vera.

Peripheral blood mononuclear cells from patients with polycythemia vera or myelofibrosis with myeloid metaplasia were studied for their erythroid colony growth characteristics in plasma clot cultures. In both diseases, erythroid colonies formed early in culture in the absence of added erythropoietin (endogenous colonies). In no instance did early, endogenous colony formation occur with peripheral blood cells from normals or patients with secondary polycythemia. A normal response to erythropoietin was observed with both control and patients' peripheral blood cells. Spleen mononuclear cells obtained from one patient with myelofibrosis also produced endogenous colonies and showed a response to erythropoietin. This study suggests that culture of peripheral blood mononuclear cells might serve as a useful tool in discriminating polycythemia vera from secondary polycythemia.

Cells, Cultured↗
PubMed1988

Myelofibrosis and focal segmental glomerulosclerosis associated with toluene poisoning.

A 60-year-old man with long-term exposure to toluene presented with both myelofibrosis and focal segmental glomerulosclerosis. There was also evidence of other toluene-related complications to support the diagnosis of toluene toxicity. The toxic effects of toluene, particularly kidney disorders and haematotoxicity, suggest a relationship between toluene, myelofibrosis and focal segmental glomerulosclerosis.

Glomerulonephritis↗
PubMed2003

Allogeneic hematopoietic stem cell transplantation for myelofibrosis.

Fifty-six patients, 10 to 66 years of age, with idiopathic myelofibrosis (IMF) or end-stage polycythemia vera or essential thrombocythemia received allogeneic hematopoietic cell transplants from related (n = 36) or unrelated (n = 20) donors. Forty-four patients were prepared with busulfan plus cyclophosphamide and 12 with total body irradiation plus chemotherapy. The source of stem cells was marrow in 33 and peripheral blood in 23 patients. All but 3 patients achieved engraftment. While 50 patients showed complete donor chimerism, 3 patients were found to be mixed chimeras at 26, 48, and 86 months after transplantation, respectively. Two patients died from relapse/progressive disease, and 18 died from other causes. There are 36 patients surviving at 0.5 to 11.6 (median, 2.8) years, for a 3-year Kaplan-Meier estimate of 58% (CI, 43%-73%). Dupriez score, cytogenetic abnormalities, and degree of marrow fibrosis were the most significant risk factors for posttransplantation mortality. Patients conditioned with a regimen of busulfan targeted to plasma levels of 800 to 900 ng/mL plus cyclophosphamide had a higher probability of survival (76% [CI, 62%-91%]) than other patients. Results with unrelated donors were comparable with those with HLA-identical sibling transplants. Thus, allogeneic hematopoietic cell transplantation offers long-term relapse-free survival for patients with myelofibrosis.

Adolescent↗
PubMed2004

IL-8 and its CXCR1 and CXCR2 receptors participate in the control of megakaryocytic proliferation, differentiation, and ploidy in myeloid metaplasia with myelofibrosis.

Myeloproliferation, myelofibrosis, and neoangiogenesis are the 3 major intrinsic pathophysiologic features of myeloid metaplasia with myelofibrosis (MMM). The myeloproliferation is characterized by an increased number of circulating CD34+ progenitors with the prominent amplification of dystrophic megakaryocytic (MK) cells and myeloid metaplasia in the spleen and liver. The various biologic activities of interleukin 8 (IL-8) in hematopoietic progenitor proliferation and mobilization as well as in neoangiogenesis prompted us to analyze its potential role in MMM. We showed that the level of IL-8 chemokine is significantly increased in the serum of patients and that various hematopoietic cells, including platelets, participate in its production. In vitro inhibition of autocrine IL-8 expressed by CD34+ cells with either a neutralizing or an antisense anti-IL-8 treatment increases the proliferation of MMM CD34(+)-derived cells and stimulates their MK differentiation. Moreover, addition of neutralizing anti-IL-8 receptor (CXC chemokine receptor 1 [CXCR1] or 2 [CXCR2]) antibodies to MMM CD34+ cells cultured under MK liquid culture conditions increases the proliferation and differentiation of MMM CD41+ MK cells and restores their polyploidization. Our results suggest that IL-8 and its receptors participate in the altered MK growth that features MMM and open new therapeutic prospects for this still incurable disease.

Aged↗
PubMed2005

V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis.

Most patients with polycythemia vera and half with idiopathic myelofibrosis and essential thrombocythemia have an acquired V617F mutation in JAK2. Using sensitive polymerase chain reaction (PCR)-based methods, we genotyped 152 patients with idiopathic myelofibrosis to establish whether there were differences in presentation and outcome between those with and those without the mutation. Patients positive for V617F had higher neutrophil and white cell counts (P = .02) than did patients negative for V617F, but other diagnostic features were comparable between the 2 groups. Patients positive for V617F were less likely to require blood transfusion during follow-up (P = .03). Despite this, patients positive for V617F had poorer overall survival, even after correction for confounding factors (P = .01).

Aged↗
PubMed2006

Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model.

An acquired somatic mutation, Jak2V617F, was recently discovered in most patients with polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), and essential thrombocythemia (ET). To investigate the role of this mutation in vivo, we transplanted bone marrow (BM) transduced with a retrovirus expressing either Jak2 wild-type (wt) or Jak2V617F into lethally irradiated syngeneic recipient mice. Expression of Jak2V617F, but not Jak2wt, resulted in clinicopathologic features that closely resembled PV in humans. These included striking elevation in hemoglobin level/hematocrit, leukocytosis, megakaryocyte hyperplasia, extramedullary hematopoiesis resulting in splenomegaly, and reticulin fibrosis in the bone marrow. Histopathologic and flow cytometric analyses showed an increase in maturing myeloid lineage progenitors, although megakaryocytes showed decreased polyploidization and staining for acetylcholinesterase. In vitro analysis of primary cells showed constitutive activation of Stat5 and cytokine-independent growth of erythroid colony-forming unit (CFU-E) and erythropoietin hypersensitivity, and Southern blot analysis for retroviral integration indicated that the disease was oligoclonal. Furthermore, we observed strain-specific differences in phenotype, with Balb/c mice demonstrating markedly elevated leukocyte counts, splenomegaly, and reticulin fibrosis compared with C57Bl/6 mice. We conclude that Jak2V617F expression in bone marrow progenitors results in a PV-like syndrome with myelofibrosis and that there are strain-specific modifiers that may in part explain phenotypic pleiotropy of Jak2V617F-associated myeloproliferative disease in humans.

Amino Acid Substitution↗
PubMed1999

Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines.

PURPOSE: Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary hematopoiesis. Recent studies provide definite diagnostic criteria and prognostic classifications of the disease, and allogeneic stem-cell transplantation (SCT) now offers a chance of curing the disease. In order to put diagnostic criteria and prognostic classifications of the disease into the perspective of developing guidelines for treatment strategies, all studies published in the English literature over the last 30 years were reviewed. MATERIALS AND METHODS: Studies were identified through a MEDLINE search (1966 to present) and from the bibliographies of relevant articles. RESULTS: The Italian Consensus Conference on diagnostic criteria is a structured enterprise aimed at formulating a definition of MMM that will be used for enrolling patients onto clinical studies. It relies on the obligatory presence of myelofibrosis and on the exclusion of the BCR-ABL rearrangement or Philadelphia chromosome, in association with combinations of traditional features. Prognostic scores allow us to identify classes of patients on the basis of hemoglobin, age, WBC count, and chromosomal abnormalities. Several nonrandomized studies have indicated that allogeneic SCT for patients under the age of 55 is effective in prolonging survival in more than 50% of cases and in possibly curing the disease. Patients with the most severe prognosis are candidates. CONCLUSION: "Consensus" methodology offers a definition of MMM useful for conducting and reporting clinical studies. A detailed knowledge of prognostic factors can help to delineate guidelines for addressing patients with allogeneic SCT.

Age Factors↗
PubMed2003

Diagnostic differentiation of essential thrombocythaemia from thrombocythaemias associated with chronic idiopathic myelofibrosis by discriminate analysis of bone marrow features--a clinicopathological study on 272 patients.

Until now diagnosis of essential thrombocythaemia (ET) is generally performed by following the criteria of the Polycythaemia Vera Study Group (PVSG) that only marginally regards morphological features. Bone marrow biopsies were studied from 272 patients with ET in strict accordance with the PVSG guidelines and also from 35 control patients with reactive thrombocytosis. To define morphological features of distinctive impact more accurately, we performed a stepwise discriminant analysis of 16 morphological parameters based on histochemical staining reactions and semiquantitative grading of standardized features. A clear-cut separation into three distinctive histological patterns was accomplished that showed in more than 96% a correct predicted classification. Variables of significant impact included fibre content, quantity and cytological abnormalities of megakaryopoiesis like bulbous (cloud-like) nuclei, degree of nuclear lobulation and presence of giant forms. These changes were not detectable in the control group. The different constellations of histopathological features could be assigned to true ET (98 patients) and false ET, i.e. 136 patients with prefibrotic and 38 patients with early fibrotic chronic idiopathic myelofibrosis (IMF) accompanied by thrombocythaemia. A re-evaluation of clinical findings was in keeping with this classification into three categories that exerted significant differences to develop myelofibrosis during observation time and also different survival patterns. Contrasting IMF true ET is characterized by a pronounced proliferation of the megakaryocyte lineage showing large to giant cells without maturation defects and no relevant increase in reticulin fibres. Discrimination between these entities is warranted, because of a significant difference in presenting haematological data, follow-up and life expectancy.

Bone Marrow Cells↗
PubMed2006

Myelofibrosis in chronic myeloproliferative disorders--dynamics and clinical impact.

In chronic myeloproliferative disorders, presenting or evolving myelofibrosis (MF) is associated with significant morbidity and mortality. A systematically conducted evaluation of previous studies and data from our own material reveals a strikingly expressed heterogeneity of findings. Assessment of MF should be performed by a recently established semiquantitative scoring system regarding quantity and quality (reticulin versus collagen). It is important to differentiate between a fiber increase in bone marrow specimens and the clinical diagnosis that is explicitly based on extramedullary hematopoiesis (myeloid metaplasia). For this reason, prodromal stages of (reticulin) fibrosis are overlooked by the clinicians. Up to 30% of patients with chronic myelogenous leukemia show a minimal to advanced MF that is significantly associated not only with corresponding clinical parameters but more importantly with prognosis. In polycythemia vera about 20% of patients may display some degree of reticulin fibrosis at diagnosis, depending on stage of the disease. Transformation into (collagen) MF after more than 10 years is accompanied by clinical signs of myeloid metaplasia (spent phase). Essential thrombocythemia (ET) is characterised by the absence of increased reticulin at onset and an insignificant progression into MF, provided diagnosis is performed by the WHO criteria. Discrimination of prefibrotic and early stages of chronic idiopathic myelofibrosis (CIMF) from ET is relevant, especially concerning the rate and time usually required for the development of MF with myeloid metaplasia (full-blown CIMF). In conclusion, more elaborate evaluations including standardized grading of MF is warranted by regarding bone marrow biopsy specimens in association with clinical parameters including follow-up examinations.

Bone Marrow Examination↗