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PubMed2004

Allogeneic transplantation: a therapeutic option for myelofibrosis, chronic myelomonocytic leukemia and Philadelphia-negative/BCR-ABL-negative chronic myelogenous leukemia.

The role of allogeneic transplantation for myeloproliferative diseases other than chronic myeloid leukemia is not well established. In all, 20 patients with a median age of 51 years underwent allogeneic hematopoietic stem cell transplantation (HSCT) for myelofibrosis (n=5), chronic myelomonocytic leukemia (CMML) (n=8) and Philadelphia (Ph) chromosome-negative/BCR-ABL-negative chronic myeloid leukemia (CML) (n=7) in our institution. Patients who developed acute leukemia prior to HSCT were excluded from this analysis. A total of 15 patients received related and five patients received unrelated donor transplants. One patient failed to engraft. After a median follow-up of 17.5 months, actuarial survival at 2 years was 47% (95% CI 2%-67%), and disease-free survival 37% (95% CI 17-58%). Allogeneic transplantation may provide a therapeutic option for patients with myelofibrosis, CMML and Ph chromosome-negative/BCR-ABL-negative CML.

Adult↗
PubMed1998

Major effects of TPO delivered by a single injection of a recombinant adenovirus on prevention of septicemia and anemia associated with myelosuppression in mice: risk of sustained expression inducing myelofibrosis due to immunosuppression.

Adenoviral vectors may be useful tools to deliver a cytokine in vivo. A single intravenous injection of an adenovirus vector containing the human thrombopoietin (TPO) cDNA (AdRSVhuTPO) was able to induce a thrombocytosis for more than 6 weeks in SCID mice, associated with a megakaryocyte (MK) hyperplasia in different organs. A marrow and spleen fibrosis was observed at 6 weeks. In immunocompetent mice, a single AdRSVhuTPO injection led to a moderate and transient thrombocytosis without myelofibrosis. To evaluate the usefulness of TPO for the prevention of secondary side-effects during an aplastic period, mice were subjected to a myeloablative regimen 7 days after the intravenous AdRSVhuTPO injection. In this setting, TPO prevented mortality by accelerating hematological recovery. Survival was essentially related to an improvement in the leukopenia since all control mice died from septicemia. However, the effects of TPO may be potentiated by the release of inflammatory cytokines following the adenovirus infection; AdRSV beta galactosidase injected-mice had higher numbers of BFU-E and CFU-GM in the marrow than PBS-injected mice. Myelosuppression induced transient immunosuppression responsible for a sustained expression and elevation of platelet numbers for at least 5 months. These results further suggest that TPO may be an effective therapy in diminishing hematological complications related to myeloablative regimens, but emphasize that immunosuppression secondary to myelosuppression may lead to sustained expression associated with a risk of thrombosis and myelofibrosis when delivered by adenovirus vectors.

Adenoviridae↗
PubMed2006

Frequency and risk factors for thrombosis in idiopathic myelofibrosis: analysis in a series of 155 patients from a single institution.

Thrombosis is a frequent complication of polycythemia vera and essential thrombocythemia, but its incidence and predisposing factors in idiopathic myelofibrosis (IM) are unknown. In 18 (11.6%) of 155 patients diagnosed with IM in a single institution, 31 thrombotic events (19 arterial, 12 venous) were registered after a mean follow-up of 4.2 (s.d.: 4.5) years. In six patients, the thrombosis was simultaneous to or appeared a few months before IM diagnosis and 14 had one or more thrombotic episodes. When compared with the general population, a significant increase was observed in the incidence of venous thrombosis (odds ratio 17.5, 95% confidence interval: 10.3-31.4). At multivariate analysis, the initial variables associated with an increased risk of thrombosis were thrombocytosis (platelets >450 x 10(9)/l, P=0.001), presence of one cardiovascular risk factor (arterial hypertension, smoking, hypercholesterolemia, or diabetes, P=0.003), cellular phase of myelofibrosis (P=0.005), and Hb >11 g/dl (P=0.02). Considering post-diagnosis events, the 5-year thrombosis-free survival probability was 90.4% in the series, 80.6% for patients with platelets >450 x 10(9)/l, 82.6% for patients with one cardiovascular risk factor, and 85.1% for those in cellular phase. These results indicate an increased thrombotic risk for IM patients with hyperproliferative features and/or coexistent cardiovascular risk factors.

Adolescent↗
PubMed2001

Granulocytic sarcoma of megakaryoblastic differentiation in the lymph nodes terminating as acute megakaryoblastic leukemia in a case of chronic idiopathic myelofibrosis persisting for 16 years.

A 43-yr-old Japanese woman presented with mild anemia, leukocytosis and splenomegaly in May 1984. Splenomegaly and anemia gradually progressed. Sixteen years later, in October 2000, she developed inguinal lymphadenopathy. Biopsy of the lymph node revealed infiltration of blasts, megakaryocytes, fibroblasts and myeloid cells. Large blasts with basophilic cytoplasm with cytoplasmic projections appeared in the peripheral blood. These blasts were negative in peroxidase stain, positive in acid phosphatase and weakly positive in periodic acid-Schiff stain. Immunohistochemical staining with monoclonal antibodies revealed that these blasts were positive with anti-CD41 (glycoprotein IIb/IIIa) and negative with other monoclonal antibodies. So diagnosis of granulocytic sarcoma in megakaryoblastic transformation from chronic idiopathic myelofibrosis was made. A cytogenetic study revealed that bone marrow cells were 46,XX del(13)(q?) initially and additional abnormalities including der(5,5,11)(q11;q13)ins(5;?)(q11;?) were found when she developed megakaryoblastic transformation. Granulocytic sarcoma of megakaryoblastic transformation from chronic idiopathic myelofibrosis is a rare event. Immunophenotyping with monoclonal antibody for CD41(glycoprotein IIb/IIIa) confirmed the diagnosis.

Cell Differentiation↗
PubMed1996

Investigation of calmodulin and basic fibroblast growth factor (bFGF) in idiopathic myelofibrosis: evidence for a role of extracellular calmodulin in fibroblast proliferation.

The urinary concentration of calmodulin and basic fibroblast growth factor (bFGF) was determined in a total of 53 patients with various chronic myeloproliferative disorders (CMPD), including 22 patients with idiopathic myelofibrosis (IMF). Calmodulin excretion was significantly elevated in IMF (0.29 +/- 0.04 microgram/mmol creatinine) (P < 0.001), when compared to polycythaemia vera (PV) (0.14 +/- 0.02), essential thrombocythaemia (ET) (0.13 +/- 0.04), chronic myeloid leukaemia (CML) (0.16 +/- 0.02), unclassified myeloproliferative disorders (UMPD) (0.11 +/- 0.02) and age-matched controls (0.1 +/- 0.02) (P < 0.001). In contrast, bFGF was slightly elevated in all CMPD conditions when compared to age-matched controls. A neutralizing antibody to calmodulin was demonstrated to significantly influence the in vitro proliferation of normal human fibroblasts, an effect dependent on both cell density and the presence of fetal calf serum (FCS). Essentially, the antibody reduced FCS-induced proliferation of low-density fibroblasts but had little or no inhibitory effect on high-density fibroblasts in the absence of FCS. In addition, extracellular calmodulin was shown not to interact with known fibroblast mitogens, namely, IFG-1, EGF, bDGF and PDGF. We conclude that extracellular calmodulin should be considered, in addition to PDGF, TFG-beta and EGF, as a potential mitogen involved in the stromal reaction of idiopathic myelofibrosis.

Adult↗
PubMed1997

Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases.

The prognostic significance of cytogenetic abnormalities was determined in 106 patients with well-characterized idiopathic myelofibrosis who were successfully karyotyped at diagnosis. 35% of the cases exhibited a clonal abnormality (37/106), whereas 65% (69/106) had a normal karyotype. Three characteristic defects, namely del(13q) (nine cases), del(20q) (eight cases) and partial trisomy 1q (seven cases), were present in 64.8% (24/37) of patients with clonal abnormalities. Kaplan-Meier plots and log rank analysis demonstrated an abnormal karyotype to be an adverse prognostic variable (P<0.001). Of the eight additional clinical and haematological parameters recorded at diagnosis, age (P<0.01), anaemia (haemoglobin < or = 10 g/dl: P<0.001), platelet (< or = 100 x 10(9)/l, P<0.0001) and leucocyte count (> 10.3 x 10(9)/l; P=0.06) were also associated with a shorter survival. In contrast, sex, spleen and liver size, and percentage blast cells were not found to be significant. Multivariate analysis, using Cox's regression, revealed karyotype, haemoglobin concentration, platelet and leucocyte counts to retain their unfavourable prognostic significance. A simple and useful schema for predicting survival in idiopathic myelofibrosis has been produced by combining age, haemoglobin concentration and karyotype with median survival times varying from 180 months (good-risk group) to 16 months (poor-risk group).

Adult↗
PubMed1997

Elevated levels of basic fibroblast growth factor in megakaryocytes and platelets from patients with idiopathic myelofibrosis.

Idiopathic myelofibrosis, or agnogenic myeloid metaplasia, is a chronic myeloproliferative disorder characterized by clonal expansion and marrow fibrosis. Although marrow fibrosis appears to be a reactive process, it substantially contributes to impaired haemopoiesis. During the last few years the implication of megakaryocyte-derived growth factors in its pathogenesis has been documented. We previously reported increased expression of TGF-beta in patients with idiopathic myelofibrosis. In the present study we show that circulating megakaryocytic cells from such patients expressed high levels of basic fibroblast growth factor (bFGF). An increased expression of bFGF was also detected in patients' platelets. Under culture conditions, bFGF present in megakaryocytic cells was not exported into the medium. consistent with the fact that bFGF is devoid of a secretion peptide signal. Interestingly, this lack of bFGF secretion was observed in all patients but one, who was in an accelerated phase of the disease and presented an important percentage of circulating megakaryoblasts.

Aged↗
PubMed1999

The Italian Consensus Conference on Diagnostic Criteria for Myelofibrosis with Myeloid Metaplasia.

The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of patients with chronic myeloproliferative disorders or myelodysplastic syndromes. A list of 12 names for the disease and 37 diagnostic criteria were proposed to a Consensus Panel of 12 Italian experts who ranked them in order so as to identify a core set of criteria. The Panel was then asked to score the diagnosis of 46 patient profiles as appropriate or not appropriate for MMM. Using the experts' consensus as the gold standard, the performance of 90 possible definitions of the disease obtained through the core set was evaluated. 'Myelofibrosis with myeloid metaplasia' ranked as the preferred name of the disease. Necessary criteria consisted of 'diffuse bone marrow fibrosis' and 'absence of Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells'. The six optional criteria in the core set consisted of: splenomegaly of any grade; anisopoikilocytosis with tear-drop erythrocytes; the presence of circulating immature myeloid cells; the presence of circulating erythroblasts: the presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections; myeloid metaplasia. The definition of the disease with the highest final score was as follows: necessary criteria plus any other two criteria when splenomegaly is present or any four when splenomegaly is absent. The use of this definition will help to standardize the conduct and reporting of clinical studies and should help practitioners in clinical practice.

Humans↗
PubMed1999

A case of myelofibrosis with a t(4;13)(q25;q12): evidence for involvement of a second 13q12 locus in chronic myeloproliferative disorders.

Aberrations of 13q are frequently found in myeloproliferative disorders (MPD). In a case of primary proliferative polycythaemia which transformed to myelofibrosis, karyotype analysis at transformation revealed an acquired t(4;13)(q25;q12). FISH and Southern analysis demonstrated that the ZNF198 gene, disrupted in the t(8;13)(p11;q12) myeloproliferative syndrome, was unaffected by the t(4;13). FISH analysis mapped the 13q12 breakpoint to the genomic region flanked by the genetic markers D13S1126 and D13S1121. Physical mapping estimated this region to be <80 kbp. Our results suggest the possibility of a novel gene, distinct from ZNF198, that is located at chromosome 13q12 and involved in the pathogenesis of myelofibrosis.

Chromosomes, Human, Pair 13↗
PubMed2001

Locoregional intrasplenic chemotherapy for hypersplenism in myelofibrosis.

A 79-year-old patient with post-polycythaemic myelofibrosis presented with severe hypersplenism. After splenic artery catheterization, cytosine arabinoside was given intrasplenically from November 1999 to March 2000 for 5 d/month at 10 mg/m2 and increased each month by 10 mg/m2. It was then administered by continuous infusion until June 2000, starting at 20 mg/m2/d and tapering by 5 mg/m2 every 2 weeks to a final daily dose of 5 mg/m2/d. The drug was then stopped. The spleen had decreased to one third of the initial volume. Clinical conditions and haematological indices improved substantially. Intrasplenic therapy could be a new therapeutic tool for hypersplenism in chronic idiopathic and post-myeloproliferative myelofibrosis.

Aged↗
PubMed2003

Mutational analysis of class III receptor tyrosine kinases (C-KIT, C-FMS, FLT3) in idiopathic myelofibrosis.

Genomic DNA from patients with idiopathic myelofibrosis (IMF) was screened by polymerase chain reaction (PCR) and conformation sensitive gel electrophoresis (CSGE) for mutations in the C-KIT gene (60 patients), as well as the C-FMS and FLT3 genes (40 patients). Intronic primers were used to amplify the entire coding region of both the C-KIT and C-FMS genes, and selected regions of the FLT3 gene. CSGE and direct DNA sequencing detected all previously reported as well as several novel polymorphisms in each of the genes. A novel c-fms exon 9 mutation (Gly413Ser) was detected in two patients. Its functional significance remains to be determined. The c-kit mutation Asp52Asn, previously described in two of six IMF patients in Japan, was not detected in this study. In addition, the reported c-fms mutations involving codons 301 and 969 were not identified. Therefore, in contrast to acute myeloid leukaemia, mutations in RTKs class III do not appear to play a significant pathogenetic role in idiopathic myelofibrosis.

DNA Mutational Analysis↗
PubMed1997

Pleural effusion secondary to extramedullary haemopoiesis in a patient with idiopathic myelofibrosis responding to pleurodesis and hydroxyurea.

A case of idiopathic myelofibrosis presenting with a pleural effusion secondary to extramedullary haemopoeisis is described. Approximately 2 years following the diagnosis of his myeloprolioferative disorder the patient presented with dyspnoea. Physical signs were consistent with a pleural effusion which was confirmed radiologically. Cytology of the effusion fluid demonstrated myeloid precursors, including megakaryocytes. The effusion required repeated draining and a pleurodesis was undertaken in an attempt to prevent reaccumulation of the fluid. The procedure was successful and follow up over a period of 5 months demonstrated no recurrence of the pleural effusion on that side of the chest. An effusion later occurred on the other side but was managed conservatively by drainage. Hydroxyurea was introduced at that stage, but shortly afterwards the patient died from an unrelated cause. We review the literature on this uncommon complication of myelofibrosis and discuss the options available to treat the disorder.

Hematopoiesis, Extramedullary↗
PubMed2002

Idiopathic myelofibrosis with extramedullary haemopoiesis involving the urinary bladder in a Chinese lady.

Extramedullary haemopoiesis (EMH) associated with idiopathic myelofibrosis most commonly involves the reticuloendothelial organs, such as the spleen and liver, although ectopic haemopoietic tissue has also been described rarely in the lymph nodes, skin, gastrointestinal tract, pleura, peritoneum, central nervous system, and genital and urinary tracts. We report on a 54-year-old Chinese lady with a long history of idiopathic myelofibrosis who presented with gross haematuria and left hydronephrosis due to EMH in the bladder trigone. Cystoscopic examination revealed a sessile necrotic papillary growth at the trigone, obstructing the left ureteric orifice. Transurethral resection of the bladder tumour was performed, and microscopic examination of the tumour chips demonstrated atypical megakaryocytes, immature granulocytes and normoblasts, confirming the presence of EMH. The residual bladder tumour responded well to low dose radiotherapy, with subsequent disappearance of haematuria and normalization of ultrasonogram findings.

Cell Lineage↗
PubMed2005

Pathogenesis of myelofibrosis with myeloid metaplasia: lessons from mouse models of the disease.

The primary genetic lesion(s), as well as the biological processes responsible for the typical structural changes of the bone marrow microenvironment in idiopathic myelofibrosis, are still poorly understood, although a central role in disease pathogenesis has been attributed to the clonal proliferation and defective maturation of megakaryocytes. Two animal models of the disease have been described, that in the last few years significantly contributed to the elucidation of some of the pathogenetic steps of the human disease; these are represented by mice genetically modified to overexpress thrombopoietin and by knock-down mice with defective GATA-1 expression in megakaryocytes (GATA-1(low) mice). This review will outline these murine models, both characterized by extensive accumulation of megakaryocytes in hematopoietic tissues, and illustrate how they provided insights into the identification of some of the molecules and mechanisms responsible for the development of fibrosis and osteosclerosis that present major similarities with those observed in patients with idiopathic myelofibrosis.

Animals↗
PubMed2005

Hematopathologic findings in chronic idiopathic myelofibrosis.

Until now scant knowledge was available about the dynamics of chronic idiopathic myelofibrosis (CIMF). However, follow-up studies are in keeping with a stepwise evolution starting with a prefibrotic (hypercellular) phase that progressively transforms into the classical fibro-osteosclerotic endstage with myeloid metaplasia. Prefibrotic CIMF is characterized by a granulocytic and megakaryocytic myeloproliferation lacking an increase in reticulin. Most conspicuous are abnormalities of megakaryopoiesis with regard to their histotopography and maturation. There is a more than 65% probability of progression from an early to advanced CIMF accompanied by increasing anemia, splenomegaly, and leuko-erythroblastosis. A significant relationship is recognizable among frequency, tortuosity, and luminal dilation of the microvessels and the extent of myelofibrosis. Quantity of CD34(+) progenitor cells in the bone marrow (BM) reveals a close association with advancement of disease (fibrosis, splenomegaly, anemia, peripheral blasts) and therefore prognosis. Cell kinetic studies show increased proliferation associated with a higher rate of apoptosis in initial (hypercellular) stages, as well as a reduced endoreduplicative activity of megakaryopoiesis and a blocked synthesis phase of the erythroid precursors. It is noteworthy that prefibrotic and early CIMF often present with a marked thrombocytosis mimicking essential thrombocythemia. Regarding prognosis, early CIMF is associated with a significantly more favorable survival than advanced stages.

Antigens, CD34↗
PubMed2004

Myelofibrosis secondary to hyperparathyroidism.

We report on a young female who had presented with fatigue, bilateral knee pain and gait disturbance. Primary hyperparathyroidism was diagnosed together with splenomegaly and anemia. Bone marrow biopsy revealed myelofibrosis. A parathyroid adenoma was excised during surgical intervention. As early as three months after the operation, hematologic parameters improved along with bone markers without any other intervention. The control bone marrow biopsy demonstrated well marked regression in marrow fibrosis. Her spleen has also gradually decreased in size. These findings indicate that her myelofibrosis was the result of primary hyperparathyroidism. Anemia associated with primary hyperparathyroidism may be due to bone marrow fibrosis.

Anemia↗
PubMed2006

The impact of clinicopathological studies on staging and survival in essential thrombocythemia, chronic idiopathic myelofibrosis, and polycythemia rubra vera.

In chronic myeloproliferative disorders (MPDs), varying results regarding staging of disease and assessment of outcome have been reported. Risk classification is mainly based on clinical data; however, in those disorders associated with an elevated platelet count, discrimination of (true) essential thrombocythemia (ET) may be difficult without the possibility to recognize characteristic histopathological bone marrow patterns according to the World Health Organization (WHO) guidelines. Patients with ET reveal no relevant reduction of life expectancy and the impact of disease is significantly higher in elderly patients, especially in chronic idiopathic myelofibrosis (IMF) and polycythemia rubra vera (PV). In high-risk ET, the overall incidence of myelofibrotic transformation after 36 months of follow-up is 2.8% when considering the Polycythemia Vera Study Group guidelines. In contrast, classification according to WHO fails to show a relevant transformation into myelofibrosis either by clinical or morphological standards in (true) ET. Early stages of IMF show a more favorable outcome, but in multivariate risk classification, signs of myeloid metaplasia have the most important impact on prognosis. In PV, the risk for thrombosis increases with age, and furthermore, signs of generalization are generally associated with a worsening of prognosis. It has been shown that examination of bone marrow specimens enhances the diagnostic reliability and also enables the recognition of evolving myelofibrotic transformation in MPDs.

Adult↗
PubMed1994

[Reversible myelofibrosis in angioimmunoblastic lymphadenopathy].

Ankle oedema and abdominal swelling suddenly developed in a 55-year-old woman who also had lymphadenopathy in the neck, axillae and groin. Ultrasonography demonstrated hepatosplenomegaly, ascites and pleural effusions. Histological examination of some lymph-nodes from the axilla and groin revealed angioimmunoblastic lymphadenopathy (low-malignant peripheral T cell lymphoma). Bone-marrow biopsy was undertaken because of a normocytic anaemia (haemoglobin 4.9 g/dl) requiring blood transfusion, thrombocytopenia (5000/microliters) and monoclonal IgG gammopathy. This showed lymphoma-associated secondary myelofibrosis. Treatment with prednisone (2 mg/kg daily for 8 weeks) and vincristine (1 mg/m2 once weekly for 4 weeks) brought about partial remission of the angioimmunoblastic lymphadenopathy with normalization of the clinical and laboratory findings, the splenohepatomegaly regressed, and there was only a small amount of ascites. Four months after onset of the illness bone-marrow biopsy also showed regression of the myelofibrosis.

Biopsy, Needle↗