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PubMed1997

Thrombopoietin-responsive essential thrombocythaemia with myelofibrosis.

Platelet-derived growth factor (PDGF) and other cytokines released from megakaryocytes are thought to play a crucial role in the pathogenesis of myelofibrosis. We describe a patient with essential thrombocythaemia (ET) who developed myelofibrosis with an increased level of serum thrombopoietin (TPO). Recombinant human (rh) TPO stimulated the proliferation and spontaneous megakaryocyte colony formation of the neoplastic cells in the peripheral blood. Moreover, serum concentrations of PDGF, platelet factor 4, and beta-thromboglobulin were elevated and the production of these growth factors from the megakaryocyte progenitors was augmented with the addition of rhTPO in vitro. These results indicate that TPO may contribute to the development of myelofibrosis in ET.

Adult↗
PubMed1997

The role of transforming growth factor-beta in PEG-rHuMGDF-induced reversible myelofibrosis in rats.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) injected at a suprapharmacologic dose (100 microg/kg) daily for 5 d in normal rats caused marked increases in marrow megakaryocytes and platelet counts at 6-8 d followed by gradual decreases to control levels at 10-20 d. Interestingly, in addition to the expected thrombopoiesis, PEG-rHuMGDF was associated with myelofibrosis with a predominance of reticulin fibres at day 10 followed by complete normalization by day 20. At 6-8 d, the levels of transforming growth factor-beta1 (TGF-beta1) in the extracellular fluid of the marrow, the platelet poor plasma, and the platelet extract were increased 23-, 7- and 2-fold, respectively. The elevated levels of TGF-beta1 were gradually reduced to baseline levels at 13-20 d in accordance with the normalization of myelofibrosis and thrombopoiesis. An ultrastructural analysis showed that large fragments of megakaryocytes were deposited in the marrow parenchyma of PEG-rHuMGDF-treated rats at day 6. PEG-rHuMGDF administration at pharmacologic doses (1 and 10 microg/kg) did not induce the deposition of reticulin fibres in the marrow. These findings suggest that TGF-beta1 leaked from megakaryocytes is involved in the development of the PEG-rHuMGDF-induced myelofibrosis and that this is a reversible process related to the regulation of the excess production of platelets.

Animals↗
PubMed1999

Magnetic resonance imaging in myelofibrosis and essential thrombocythaemia: contribution to differential diagnosis.

To ascertain the value of magnetic resonance (MR) imaging in the differential diagnosis between myelofibrosis (MF) and essential thrombocythaemia (ET), 38 patients were analysed. 20 patients had MF (idiopathic myelofibrosis, 15 cases; post-ET myelofibrosis, four cases; post-polycythaemic MF, one case) and 18 ET. Mean age was 61.5 years (range 30-89) for patients with MF and 60.9 years (range 26-83) for ET patients. MR imaging was performed in the dorsal vertebrae in all cases, and also in both femurs in 2 5 of the patients. In most ET cases the MR signal of the dorsal vertebrae was not modified, whereas it was markedly reduced in MF (P=0.0000001). With regard to femoral marrow, it was usually fatty in ET, with an absent to moderate degree of reconversion seen in the 14 cases analysed, contrasting with the marked degree of reconversion noted in 10/11 patients with MF (P=0.000007). An inverse correlation was demonstrated between the vertebral signal and the degree of femoral reconversion. These differences were due to the fact that in ET the bone marrow adipose tissue is grossly preserved, whereas in MF it is usually markedly decreased or absent. The above results indicate that MR imaging is a useful tool for the differential diagnosis of ET and MF, with the usefulness of this technique increasing when vertebral and femoral bone marrow studies are combined.

Adult↗
PubMed2000

Long-term survival of infants with idiopathic myelofibrosis.

Idiopathic myelofibrosis can develop in children as well as adults. However, the disease appears to be much more aggressive in adults, being characterized by poor survival rates and a high frequency of malignant transformation. Here, we describe three cases of idiopathic myelofibrosis in infants, two of whom were followed for 16 and 22 years after diagnosis. Neither of these patients required more than minimal supportive care, and both have had spontaneous erythropoietic recovery as early as 2-3 years after diagnosis. There have been no indications of malignant transformation or clinical deterioration. Thus, idiopathic myelofibrosis may have a different pathogenesis and clinical course in infants from adults, requiring a more conservative approach to management.

Adult↗
PubMed2003

Bone marrow histopathology following cytoreductive therapy in chronic idiopathic myelofibrosis.

AIMS: To analyse systematically therapy-induced lesions of haematopoiesis in chronic idiopathic myelofibrosis (IMF). METHODS AND RESULTS: A total of 759 sequential bone marrow (BM) biopsies (median interval 32 months) were performed in 261 patients with IMF. Besides a control group (symptomatic treatment), monotherapies included busulfan, hydroxyurea and interferon. In all therapy groups hypoplasia of varying degree was a frequent finding and often accompanied by a patchy distribution of haematopoiesis. Most conspicuous was gelatinous oedema showing a tendency to develop discrete reticulin fibrosis (scleroedema). Minimal to moderate maturation defects of megakaryopoiesis and erythroid precursors occurred, but overt myelodysplastic features were most prominent following hydroxyurea and busulfan therapy. Acceleration and blastic crisis were characterized by the appearance of immature and CD34+ progenitor cells. Concerning the dynamics of fibrosis, no differences were observed between controls and the various therapy groups. In 143 patients (55%) without or with little reticulin at onset, an increase in myelofibrosis was detectable that progressed to overt collagen fibrosis. CONCLUSIONS: Therapy-related bone marrow lesions in IMF comprise a strikingly variable spectrum that may include aplasia with scleroedema and a patchy distribution of myelodysplastic haematopoiesis associated with progressive myelofibrosis.

Aged↗
PubMed2001

Acute renal failure secondary to spontaneous acute tumor lysis syndrome in myelofibrosis.

A 70-year-old man with myelofibrosis developed nonoliguric acute renal failure in association with acute uric acid nephropathy in the absence of chemotherapy or radiotherapy. The patient had an 18-month history of transfusion-dependent myelofibrosis and moderate chronic renal insufficiency. Admission laboratory findings were remarkable for severe hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia with acute deterioration of renal function, consistent with a diagnosis of acute uric acid nephropathy. Treatment, including hemodialysis and allopurinol administration, resulted in clinical improvement with normalization of serum uric acid concentrations and resolution of acute renal failure. With long-term allopurinol therapy, renal function has remained at his previous baseline, and there has been no transformation to acute leukemia. This case represents a rare instance of acute renal failure related to the occurrence of acute uric acid nephropathy associated with myelofibrosis and emphasizes the importance of early recognition and aggressive management, which can lead to recovery of renal function.

Acute Disease↗
PubMed2005

Idiopathic myelofibrosis.

Idiopathic myelofibrosis (IMF) is characterized by anemia, progressive splenomegaly, bone marrow fibrosis, and extramedullary hematopoiesis. However, patients with a transitional myeloproliferative disorder (MPD), a prefibrotic form of myelofibrosis, or myelofibrosis with a fatty bone marrow share many features of IMF but have clinical characteristics that deviate from the classical description of IMF. A phenomenon that serves as a unique biomarker of IMF is the constitutive mobilization of hematopoietic progenitor cells (HPCs) and/or endothelial progenitor cells (EPCs) from the bone marrow to the peripheral blood and other extramedullary sites. Using such parameters as hemoglobin level, white blood cell count, and number of blasts in the peripheral blood, prognostic scores can be developed by which to base therapeutic decisions. Androgens, recombinant human erythropoietin (rHuEpo), and thalidomide are effective modalities of treatment of the anemia of IMF. Systemic symptoms of excess myeloproliferation are the primary indication for treatment with chemotherapeutic agents. Hydroxyurea is the most commonly used drug. Ablation of the abnormal hematopoietic clone with high-dose chemotherapy and allogeneic stem cell transplantation offers an opportunity to cure patients with IMF. The use of fully myeloablative conditioning regimens, with or without total body irradiation, is associated with a high transplant-related mortality rate (27% to 48%), especially in patients with advanced disease and in the elderly. The use of reduced intensity conditioning (RIC) regimens has resulted in prolonged survival and lower transplant-related mortality.

Biomarkers↗
PubMed2006

Expression of TEL-JAK2 in primary human hematopoietic cells drives erythropoietin-independent erythropoiesis and induces myelofibrosis in vivo.

Activation of JAK2 by chromosomal translocation or point mutation is a recurrent event in hematopoietic malignancies, including acute leukemias and myeloproliferative disorders. Although the effects of activated JAK2 signaling have been examined in cell lines and murine models, the functional consequences of deregulated JAK2 in the context of human hematopoietic cells are currently unknown. Here we report that expression of TEL-JAK2, a constitutively active variant of the JAK2 kinase, in lineage-depleted human umbilical cord blood cells results in erythropoietin-independent erythroid differentiation in vitro and induces the rapid development of myelofibrosis in an in vivo NOD/SCID xenotransplantation assay. These studies provide functional evidence that activated JAK2 signaling in primitive human hematopoietic cells is sufficient to drive key processes implicated in the pathophysiology of polycythemia vera and idiopathic myelofibrosis. Furthermore, they describe an in vivo model of myelofibrosis initiated with primary cells, highlighting the utility of the NOD/SCID xenotransplant system for the development of experimental models of human hematopoietic malignancies.

Animals↗
PubMed1997

Tuberculosis and myelofibrosis in children: a report.

Seven children, six boys and a girl, aged from 2 to 15 years with proven myelofibrosis are reported. The clinical presentation in each of them was more or less similar with weight loss, moderate or low-grade fever, and abdominal distension with pain or discomfort for some months. They had hepatosplenomegaly. The spleens, enlarged to more than 6 cm below the costal margin, were smooth, firm and not tender. There was a variable degree of generalized lymphadenopathy. They were diagnosed as myelofibrosis associated with tuberculosis. The clinical response to anti-tuberculous chemotherapy was remarkable. Extensive search should be made for evidence of tuberculosis in children presenting with myelofibrosis.

Adolescent↗
PubMed1982

Cytogenetic studies of peripheral myeloblasts and bone marrow fibroblasts in acute myelofibrosis.

Chromosome analysis with giemsa-trypsin banding was performed on circulating myeloblasts and cultured bone marrow fibroblasts from a patient with acute myelofibrosis. Major karyotypic abnormalities were found in the myeloblasts involving chromosomes #1, 3, 5, 13, and 16; no chromosome abnormalities were detected in the fibroblasts. In addition, a pericentric inversion of number 7 was present in the circulating blasts but not the fibroblasts. Pericentric inversions have not previously been associated with acquired abnormalities of malignant cells. These findings support the concept that acute myelofibrosis is a primary malignancy of hematopoietic cells associated with secondary marrow fibrosis. The entity of acute myelofibrosis is discussed and the results of cytogenetic studies of previous reports are reviewed.

Acute Disease↗
PubMed1987

Acute myelofibrosis. Immunohistochemical study of four cases and comparison with acute megakaryocytic leukemia.

Four cases of acute myelofibrosis are contrasted to three cases of acute megakaryocytic leukemia. The cases were clinically indistinguishable. Light microscopic examination of hematoxylin and eosin-stained bone marrow biopsy specimens from the cases of acute myelofibrosis showed a trilinear proliferation of mature and immature hematopoietic cells, increased numbers of mature magakaryocytes, and marked fibrosis. In contrast, the blast cells in the cases of acute megakaryocytic leukemia showed a continuous spectrum of differentiation from small blasts to megakaryoblasts. Immunoperoxidase staining showed the blast cells in all three cases of acute megakaryocytic leukemia to be strongly positive for Factor VIII, a marker of megakaryocytic differentiation. These same blasts did not stain with markers of myelomonocytic (lysozyme), lymphocytic (Hle), and myeloid (Leu-Ml) differentiation. In contrast, the blast cells in all four cases of acute myelofibrosis were Factor VIII, Hle, and Leu-Ml negative but did occasionally stain with anti-lysozyme.

Acute Disease↗
PubMed1988

Myelodysplastic syndrome with acquired hemoglobin H disease. Evolution through megakaryoblastic transformation into myelofibrosis.

A 64-year-old man was found to have a hemolytic anemia with a hematocrit of 0.28 (28%) during a routine evaluation. One month before this his hematocrit had been normal. Further studies revealed a myelodysplastic syndrome and acquired hemoglobin H disease. Eighteen months later this transformed into acute megakaryoblastic leukemia with disappearance of hemoglobin H, and shortly thereafter he had myelofibrosis develop. Acquired hemoglobin H disease, which is an alpha-thalassemia-like syndrome, results in the formation of an unstable hemoglobin composed of beta chain tetramers. This condition has been associated with preleukemia, sickle cell anemia, and hematologic malignancies. Although idiopathic myelofibrosis also has been described as a setting in which this thalassemic syndrome occurs, the present case is unusual in that the myelofibrosis was preceded by refractory anemia with leukemic transformation.

Cell Transformation, Neoplastic↗
PubMed1995

Myelofibrosis and benzene exposure.

Petrol station attendants are exposed to benzene, a well-known carcinogen for blood malignancies. A case of myelofibrosis in a petrol station attendant is presented, along with other reports of myelofibrosis after benzene exposure obtained from the Swedish Cancer Environment Register. Findings of an increased risk for myelofibrosis in the transport sector also suggest a causal relationship with benzene.

Benzene↗
PubMedDate not supplied

Lupus anticoagulant in myelofibrosis.

A patient with myelofibrosis who also demonstrates a lupus anticoagulant is reported. The presence of a circulating anticoagulant adds to the list of potential hemorrhagic diatheses in myelofibrosis and also demonstrates myelofibrosis to involve a system that may be separate from the myeloid elements of the bone marrow.

Blood Coagulation↗
PubMed1988

Remission of chronic idiopathic myelofibrosis to busulfan treatment.

Three patients with chronic idiopathic myelofibrosis have responded to busulfan treatment with an excellent hematologic remission and reversal of myelofibrosis and myeloid metaplasia. Four months after busulfan therapy all three patients showed an improvement of hematocrit and hemoglobin and reduction of the number of leukoerythroblasts. Cellular bone marrow was re-established in two patients. A decrease of hepatomegaly and splenomegaly also occurred and was well correlated with the hematologic response. In one patient, when busulfan was discontinued for about 2 years after achieving an excellent remission, hematologic relapse was accompanied by increase of hepatomegaly and splenomegaly. When busulfan treatment was resumed, hematologic response and decrease of hepatomegaly and splenomegaly reoccurred. This observation has demonstrated the beneficial effect of busulfan in chronic idiopathic myelofibrosis; therefore, the role of busulfan in the management of this disease should be further investigated.

Aged↗
PubMed1999

Massive ascites caused by peritoneal extramedullary hematopoiesis as the initial manifestation of myelofibrosis.

An 83-year-old man presented with massive ascites. Cytological examination of the ascites revealed primitive hematopoietic cells. The specimen of bone marrow biopsy disclosed diffuse fibrosis, which suggested myelofibrosis with extramedullary hematopoiesis as the cause of ascites. His symptoms resolved dramatically after administration of hydroxyurea. Ascites formation in myelofibrosis is often attributed to presinusoidal portal hypertension and occurs in the context of well-established disease. This case demonstrates that myelofibrosis may manifest as massive ascites caused by peritoneal implants of myeloid tissues. Extramedullary hematopoiesis should be included in the differential diagnosis of ascites.

Aged↗
PubMed2005

Idiopathic myelofibrosis with generalized periostitis in a 4-year-old girl.

Idiopathic myelofibrosis, a chronic myeloproliferative disorder of unknown origin, is characterized by splenomegaly, extramedullary hematopoiesis, leukoerythroblastosis, teardrop erythrocytes, and myelofibrosis. It is a rare disorder in childhood. The authors describe a 4-year-old girl with features consistent with idiopathic myelofibrosis, who also had generalized solid laminated periosteal reaction involving all long bones. The presence of thrombocytopenia at the onset and lack of leukocytosis were in contrast to the reported features seen in children. Recent case reports describe a relatively indolent course in children. Spontaneous remissions have also been described in pediatric cases. The fulminant course of this patient without any features of malignant transformation was noteworthy in this regard.

Bone Marrow↗
PubMed1977

Erythroid hypoplasia in myelofibrosis: a feature associated with blastic transformation.

Four cases of myelofibrosis have shown a pattern which is usually found only where there is erythroid hypoplasia and in none of these was there evidence of extramedullary erythropoiesis. Three of these cases terminated in a blastic phase. The findings suggest that the occurrence of erythroid hypoplasia in myelofibrosis may be associated with blastic transformation--whether as a predisposing factor or as a secondary event is still speculative. This phenomenon is discussed in relation to the natural history of myelofibrosis.

Bone Marrow↗