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PubMed1989

[Primary myelofibrosis: description of a series of 53 patients].

The clinical and hematological profile of 53 patients in whom primary myelofibrosis (PMF) had been diagnosed during the last 15 years was evaluated. Median age was 64 years (range 17-86). Thirty-five patients were males and 18 females. The most frequent symptoms were associated with the hypermetabolic state, anemia and splenomegaly. The latter was found in 96% of patients, while 83% had hepatomegaly and 9% had lymphadenopathy. Thirty-three patients had anemia at the time of diagnosis. The leukocyte and platelet counts were normal or moderately high in most cases. Myelemia was found in 83% of patients, with circulating erythroblasts in 72%. The most common biochemical abnormalities were the increased serum LDH (84%) and hypocholesterolemia (62%). Bone marrow aspirate was not analyzable in most cases. Bone marrow biopsy showed myelofibrosis in hypercellular phase in 22 patients, myelofibrosis without osteosclerosis in 17, and myelofibrosis with osteosclerosis in 14. The median survival of the series was 3.8 years; 34 patients had died at the time of the analysis. The major causes of death were infection, cardiovascular complications and hemorrhage. In 4 patients the evolution from PMF to acute leukemia was observed.

Adolescent↗

PubMed1989

[Beneficial effect of 1,25-dihydroxyvitamin D3 in the treatment of myelofibrosis].

Two cases of myelofibrosis are reported, one corresponding to a chronic idiopathic myelofibrosis and another to an acute myelofibrosis or megakaryoblastic leukemia (AMGL). According to current knowledge, the origin of fibrosis in these disorders is a megakaryoblastic/megakaryocytic proliferation in the bone marrow. These megakaryocytic clonal populations result in an ineffective megakaryocytopoiesis and in an inability to store beta-thromboglobulin (BTG), platelet factor 4 (PlF4) and platelet derived growth factor (PDGF) in the alpha granules, whereby their release is increased. Both PDGF, a powerful stimulator of fibroblastic activity, and PlF4, a collagenase inhibitor, cooperate in the development of myelofibrosis. Owing to its action inducing cellular differentiation towards the monocytic-macrophagic line, which secretes collagenases and inhibits megakaryocyte proliferation, treatment with 1,25-dihydroxyvitamin D3 was attempted in both cases, 2.5 micrograms daily for 6 months. Satisfactory results were achieved.

Aged↗

PubMed1988

Zollinger-Ellison syndrome and myelofibrosis in a dog.

Zollinger-Ellison syndrome and myelofibrosis were diagnosed concurrently in a 10-year-old neutered female Brittany Spaniel. Documentation of gastric ulceration, hypergastrinemia, and gastrin-secreting islet cell tumor with splenic metastases facilitated the diagnosis of Zollinger-Ellison syndrome. Patchy long-bone medullary sclerosis, nonregenerative anemia and thrombocytopenia, multiple acellular bone marrow aspirates, marked splenic extramedullary hematopoiesis, and acellular core bone marrow biopsy with areas of necrosis and fibrosis supported the diagnosis of myelofibrosis. Despite the medical and surgical management attempted, the dog was euthanatized because of signs of severe intractable bone pain. Myelofibrosis has been documented in association with canine and human neoplastic disease. A direct causal relationship between gastrinoma and myelofibrosis was not clearly established in this instance.

Animals↗

PubMed1985

Secondary myelofibrosis in three dogs.

Myelofibrosis was diagnosed in 3 dogs. In each dog, there was evidence of concurrent bone marrow necrosis, suggesting that the myelofibrosis was a secondary change. This suggestion was supported by a lack of dysplastic changes in hematopoietic cells. Bone marrow necrosis in 2 of the dogs may have been the result of widespread malignancy. Reversal of the myelofibrosis in 1 dog suggested that myelofibrosis is not always a terminal disorder.

Adenocarcinoma↗

PubMed1994

[Idiopathic myelofibrosis transformed to acute myelomonocytic leukemia associated with non-Hodgkin's lymphoma].

We report a rare case of idiopathic myelofibrosis transformed to acute myelomonocytic leukemia associated with non-Hodgkin's lymphoma. A 64-year-old woman was admitted to our department because of anemia and leukocytosis. On admission, anemia and hepatosplenomegaly were noted. The hemoglobin content was 6.8 g/dl, and WBC count was 26,200/microliters with an increased number of immature neutrophils. Bone marrow biopsy revealed an increased amount of reticulin fiber. Because she had no disease which causes secondary myelofibrosis, idiopathic myelofibrosis was diagnosed, and she was treated with prednisolone, anabolic steroid and blood transfusion. Fifteen months after the diagnosis of myelofibrosis, blast increased in her peripheral blood and her spleen and liver enlarged remarkably. A tumor of right parotid region was recognized at the same time. The pathological diagnosis of biopsied tumor was non-Hodgkin's lymphoma. The cytochemical study of blasts in her peripheral blood showed that she had acute myelomonocytic leukemia. In spite of intensive chemotherapy, she died from heart failure, respiratory failure and renal insufficiency.

Female↗

PubMed1993

[Alpha interferon treatment of idiopathic myelofibrosis].

Idiopathic myelofibrosis is a chronic myeloproliferative syndrome for which there is no effective treatment. The good results obtained with interferon in other chronic myeloproliferative syndromes have led their being tested in idiopathic myelofibrosis, but to date the experience is scarce. Four patients out of a total of 12 diagnosed with idiopathic myelofibrosis over a period of 3 years were selected for interferon treatment. Patients with low leukocyte or platelet counts or with contraindication for administration of the drug were excluded. Alpha-2b interferon was administered at an initial dose of 3 MU/day which was increased at 4-6 weeks to 5 MU/day in cases of insufficient response and if tolerance so permitted. In patients in whom favorable response was observed a maintenance schedule was initiated with low doses of interferon. Treatment was discontinued in two patients due to bad tolerance at 6 and 8 weeks of initiation of treatment with no response having been observed until that time. In the other patients favorable response was reported to interferon after 5 months of treatment with disappearance of the symptomatology, normalization of the hemo-peripheral values and a marked reduction of splenomegaly. This responses was accompanied by a decrease in bone marrow fibrosis in one case and total disappearance of the same in the other patient. Alpha-2b interferon constitutes an effective therapy for a selected number of patients with idiopathic myelofibrosis. Greater experience would allow the identification of the subgroup of patients who may benefit from this type of treatment.

Adult↗

PubMed1996

A model of myelofibrosis and osteosclerosis in mice induced by overexpressing thrombopoietin (mpl ligand): reversal of disease by bone marrow transplantation.

We have previously shown that mice induced to overexpress thrombopoietin (TPO) by retroviral-mediated gene transfer into bone marrow (BM) cells develop myelofibrosis and osteosclerosis. It was speculated that these effects were secondary to TPO, resulting from high levels of megakaryocytes and platelets. Also, it was proposed that these mice represent a model for myelofibrosis and osteosclerosis. In this report, we show that levels of both transforming growth factor-beta 1 and platelet-derived growth factor are increased twofold to fivefold in the platelet-poor plasma of TPO overexpressing mice compared with control mice. These data suggest that the increased megakaryocytes produce elevated levels of these cytokines that lead to the pathogenesis of disease. Further, we retransplanted TPO overexpressing mice, at 40 to 42 weeks after primary transplantation, with normal BM cells. After the secondary transplantation, megakaryocytes and platelets returned to normal levels and the myelofibrosis and osteosclerosis were completely corrected. These data extend our initial studies of the effects of overexpression of TPO and show the potential use of this model to explore the underlying cause of myelofibrosis and osteosclerosis and potential treatments for these diseases.

Animals↗

PubMed1996

[A case of myelofibrosis that developed polycythemia vera following treatment with ranimustine and then acute myelogenous leukemia (M0)].

A 60-year-old Japanese woman was admitted to our hospital because of fatigue, weight loss and abdominal distension. Myelofibrosis was diagnosed, based on anemia, huge hepatosplenomegaly, leukoerythroblastosis and bone marrow fibrosis. Following treatment with ranimustine, anemia and splenomegaly improved. Seven months after initial therapy of ranimustine, however, polycythemia (RBC 7.39 x 10(6)/microliter; Hb 19.1 g/dl, Ht 65.9%) developed gradually, then RBC decreased to normal level following venesection (total 1,200 ml). After 32 months, blastic transformation occurred. The blasts were negative for myeloperoxidase. By flow cytometric analysis, the cells were positive for CD2, CD13, CD33 and HLA DR. Thus, AML (M0) was diagnosed. Despite of treatment with multicytotoxic agents, she died of DIC 36 months after the initial diagnosis of myelofibrosis. The progression from myelofibrosis to polycythemia is rare and only 15 cases have been reported so far. In addition, although a chromosomal abnormality, 46, XX, t(3; 12) (q25; p11), was present at the time of first diagnosis of myelofibrosis, the development of an additional abnormality, del(11) (q-), might be related to the transformation to AML.

Antineoplastic Agents↗

PubMed1998

Analysis of clonality using X-linked polymorphisms in a patient with multiple myeloma and myelofibrosis.

We describe a patient who presented with a neutrophilic leukocytosis, normal karyotype, and IgA lambda multiple myeloma. One year after diagnosis she developed diffuse myelofibrosis as well as multiple lytic lesions of bone. Given the myeloproliferative features of her case, the clonality of her peripheral leukocytes was determined prior to treatment. Analysis of X-chromosome inactivation at the X-linked human androgen-receptor gene locus (HUMARA) proved that granulopoiesis was polyclonal. Subsequent treatment of the myeloma reversed with myelofibrosis and normalized her WBC count. This is the first case of multiple myeloma with myelofibrosis in which a concomitant clonal myeloproliferative disease was ruled out at a genetic level. The myeloproliferative features in this case are presumed to be induced by cytokines produced by the plasma cell clone.

Clone Cells↗

PubMed1976

Chromosome studies in "preleukemia". III. Myelofibrosis.

Cytogenetic studies were done on 18 patients with myelofibrosis or the closely related syndrome, undifferentiated myeloproliferative disorder (MPD). Clones of cells with chromosome abnormalities were demonstrated in the blood of eight individuals, including two with a history of radiation therapy and two with "acute myelofibrosis". Trisomy 8 was present in the latter two patients, but otherwise, there was no consistent cytogenetic pattern or correlation with specific hematologic findings. Sixteen of these patients have been followed for more than 1 year or until death; none has progressed to leukemia. The results indicate that chromosome abnormalities are relatively common in this disorder, but as with polycythemia vera, and unlike some other "preleukemic" states, the aberrant clones in myelofibrosis do not appear to indicate that clinical leukemia is imminent.

Adolescent↗

PubMed1979

Periostitis associated with myelofibrosis.

Two patients with myelofibrosis developed fever, leg pain and periostitis. The first patient had myelofibrosis with myeloid metaplasia and was symptomatic for months before x-rays showed periosteal new bone formation in the lower extremities. He subsequently developed periostitis of both upper extremities. Radiation of the lower extremities resulted in significant pain relief. The second patient had a past history of polycythemia vera and experienced painful periostitis of the tibiae and fibulae. 99mTechnetium pyrophosphate bone scans showed increased uptake in the involved bones in both patients. Asymptomatic or painful periostitis may be related to the increased bone blood flow associated with myelofibrosis. Radiation can afford successful palliation in the severely symptomatic patient.

Diagnosis, Differential↗

PubMed1983

Red cell aplasia in myelofibrosis with myeloid metaplasia. A distinct functional and clinical entity.

Three patients with myelofibrosis with myeloid metaplasia are described. All three presented with grave anemia and red cell aplasia. Erythroid failure was the functional characteristic of erythropoiesis as resulted from erythrokinetic studies. Bone marrow was hypercellular or normocellular with hyperplasia of granuloblasts and megakaryocytes. Despite absent or mild splenomegaly at diagnosis, massive splenomegaly associated with a leukoerythroblastic blood film developed during the course of the disease. A relative young age (42-47 years), a subacute course of the disease and terminal blast crisis in two of them were the prominent clinical features of the patients. The differentiation from acute or malignant myelofibrosis is discussed. The patients appear to be a distinct subset within myelofibrosis with myeloid metaplasia.

Adult↗

PubMed1984

Therapy-related leukemia associated with myelofibrosis. Blast cell characterization in six cases.

Six patients exhibiting severe pancytopenia or overt leukemia associated with myelofibrosis after chemotherapy for malignant disease have been investigated by immunologic techniques and ultrastructural cytochemistry. Initially, five patients displayed severe thrombocytopenia contrasting with mild neutropenia and anemia. Bone marrow biopsies showed a clear megakaryocytic proliferation and an excess of immature mononuclear cells. The demonstration of peroxidase activities at the ultrastructural level and immunofluorescence labeling with a panel of monoclonal antibodies, including an antiplatelet glycoprotein Ib and an antiglycoprotein IIb-IIIa complex, on blood or marrow cells, permitted identification of otherwise unidentifiable promegakaryoblastic proliferation. In two patients, the use of an immunoperoxidase technique with an antifactor VIII-R-Ag antibody has allowed direct confirmation of this diagnosis on bone marrow sections. This megakaryoblastic proliferation was not pure and was variably associated with blasts of other cell lines (erythroblasts or myeloblasts). Changes in the population of blasts were observed during evolution in two patients. The sixth patient had a mild thrombocytopenia associated with severe neutropenia and anemia. Bone marrow biopsy displayed a myelofibrosis and immature cells, without megakaryocytic proliferation. Ultrastructural study revealed a pure basophil-mast cell proliferation. In conclusion, in five of six patients with secondary acute leukemia associated with myelofibrosis, a proliferation of promegakaryoblasts was demonstrated using both immunofluorescent and ultrastructural cytochemical techniques.

Aged↗

PubMed2003

Imatinib mesylate in idiopathic and postpolycythemic myelofibrosis.

Imatinib mesylate targets the adenosine triphosphate (ATP)-binding sites of the protein tyrosine kinase domains associated with Bcr-abl, the platelet-derived growth factor (PDGF) and c-kit. In idiopathic myelofibrosis (IMF) PDGF is considered to be one of the growth factors responsible for the development of bone marrow fibrosis. Recently, it has been shown that imatinib has antifibrogenic effect on bone marrow fibrosis in chronic myelogenous leukemia. Treatment with imatinib alone in IMF has been associated with significant side effects. In this study, the safety and efficacy of imatinib therapy in IMF, either administered as a single agent or in combination with hydroxyurea (HU) and/or alpha-interferon (IFN-alpha) are evaluated. Eleven patients (median age, 63 years; range, 33-82 years) with IMF (n = 8) or postpolycythemic myelofibrosis (PPMF) (n = 3) were studied All patients had been treated with HU (n = 9) and/or IFN (n = 7) before study entry. In all but one patient, treatment with these agents was discontinued when imatinib therapy was instituted. One patient continued IFN when treatment with imatinib was started. Imatinib was given at a dose of 400 mg/day. Nine patients were in an advanced disease phase. The patients have been followed for a median period of 2 months (range, 0.5-12 months). Treatment with imatinib has been stopped in six patients (55%), because of overt side effects (n = 4), recurrence of transitory dizziness and visual defects owing to a rising platelet count (n = 1), or the occurrence of an acute subdural hemorrhage that was evacuated without neurological deficits (n = 1). In nine patients imatinib treatment was followed by a rise in leukocyte and platelet counts that required combination with HU or IFN. The combined treatment modalities were followed by a rapid decrease in cell counts and were well tolerated apart from IFN side effects. A beneficial effect of imatinib was documented in three patients. It is concluded that leukocytosis and thrombocytosis are seen in most patients with myelofibrosis during treatment with imatinib. Combination therapy with HU or IFN seems safe and well tolerated and followed by a decrease in disease activity. A subgroup of patients in an early disease phase might benefit from imatinib therapy alone.

Adult↗

PubMed2005

Myelofibrosis-associated massive splenomegaly: a cause of increased intra-abdominal pressure, pulmonary hypertension, and positional dyspnea.

We describe a patient with myelofibrosis, giant splenomegaly, and pulmonary hypertension related to increased intra-abdominal pressure. Focusing on alterations in hemodynamic studies, we conclude that in patients with myelofibrosis, dyspnea, and hypoxemia, the measurement of intra-abdominal pressure should be included in the initial evaluation. It is an inexpensive, non-invasive diagnostic tool that can provide crucial information about the cause of dyspnea and disclose the pathogenetic link between massive splenomegaly and pulmonary compromise in myelofibrosis.

Abdomen↗

PubMed1983

Increased serum procollagen III aminoterminal peptide in myelofibrosis.

Myelofibrosis has been shown to involve an increase in type III collagen in the marrow. The aminoterminal procollagen III (PC III) peptide fragment is released during the production of PC III by fibroblasts and its serum level is therefore a marker for type III collagen synthesis. Using a recently developed sensitive radioimmunoassay, serum levels of PC III peptide were measured in 30 patients with myeloproliferative disease and 23 normal volunteers. Levels were found to be elevated above normal values in patients with polycythemia vera, even more elevated in patients with polycythemia and evidence of secondary myelofibrosis with myeloid metaplasia, and most strikingly elevated in patients with agnogenic myeloid metaplasia and severe marrow fibrosis. There was a significant association between serum levels of PC III peptide and the extent of reticulin fibrosis in bone marrow biopsies. Serum PC III level appears to be a quantitative marker for myelofibrosis.

Adult↗

PubMed1989

Ferrokinetic study of splenic erythropoiesis: relationships among clinical diagnosis, myelofibrosis, splenomegaly, and extramedullary erythropoiesis.

Splenic erythropoiesis was demonstrated by surface counting of 59Fe in 129 of 1,350 ferrokinetic studies performed over a 15 year period. These 129 studies were carried out in 108 patients, including 40 with chronic myelogenous leukemia (CML), 24 with agnogenic myeloid metaplasia (AMM), 18 with polycythemia vera (PV), six with a myelodysplastic syndrome, five with acute leukemia, three with prostate or breast carcinoma, two each with aplastic anemia or Hodgkin's disease, and one each with idiopathic thrombocythemia, multiple myeloma, chronic renal failure, or treated hypopituitarism. Splenomegaly was present in 83% of the studies and hepatomegaly in 72%. Grade II-III myelofibrosis was demonstrated in 62% of the cases. Hepatic erythropoiesis was present in 77% of the studies (only 38% in PV), and marrow erythropoiesis was undetectable in 33%. Total erythropoiesis was about twice normal (range 0.2 to 8 times normal) but was ineffective to varying degrees in 86% of the studies. Relationships between organomegaly, myelofibrosis, and extramedullary erythropoiesis, as well as differences among clinical disorders, are discussed. Differences observed between CML in chronic or blastic phase suggested that the erythroid cell line was involved in the proliferative process. It is concluded that splenic erythropoiesis 1) is encountered in a variety of clinical conditions; 2) is not necessarily associated with splenomegaly or myelofibrosis, even in the myeloproliferative disorders; 3) is part of a predominantly extramedullary (in the liver as well as in the spleen), expanded, and largely inefficient total erythropoiesis; and 4) can be evaluated in a semiquantitative manner by surface counting.

Erythropoiesis↗

PubMed1990

Neutrophilic myelofibrosis presenting as Philadelphia chromosome negative BCR non-rearranged chronic myeloid leukemia.

Chronic myeloid leukemia consists of Philadelphia chromosome positive disease in 90% of cases, and a further 5%, although Philadelphia chromosome negative, exhibit bcr gene rearrangements consistent with the disease. The remaining 5% of cases have a heterogeneous clinical picture with a course unlike that of classical chronic myeloid leukemia, and may belong to different pathologic entities. We report five cases belonging to the latter group, initially identified as Philadelphia chromosome negative, bcr non-rearranged chronic myeloid leukemia, that developed progressive leucocytosis, absolute monocytosis, myelodysplasia, extramedullary hematopoiesis, and had evidence of myelofibrosis. These cases may represent a distinct clinical entity characterized by neutrophilic myelofibrosis, which can be identified prospectively by clinical and pathologic criteria. Standard therapy for treating chronic myeloid leukemia or idiopathic myelofibrosis may not be appropriate for this group.

Adult↗