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PubMed1990

Acute myelofibrosis: response to recombinant human interferon alpha-2a.

Acute myelofibrosis is a rare myeloproliferative syndrome characterized by bone marrow proliferation of atypical megakaryocytes, poor response to conventional leukemic therapy, and a fulminant clinical course. Because alpha interferon exhibits potent antiproliferative effects against megakaryocyte progenitors and human fibroblast cell lines, we treated two patients with acute myelofibrosis or the related syndrome of acute myelodysplasia with myelofibrosis with recombinant human interferon alpha-2a. Patient 1 received a 12-week course of interferon alpha (1-6 x 10(6) IU/d) after failure of two cytarabine-based chemotherapy regimens. Interferon administration resulted in prompt improvement in symptoms, stabilization of leukocyte count, and a reduction in circulating blast forms. Primary treatment with interferon (1-3 x 10(6) IU/d x 4 weeks) in patient 2 produced complete hematologic recovery with restoration of marrow cellularity and reduced marrow fibrosis. Our findings suggest that interferon alpha may have significant activity in the treatment of patients with acute myelofibrosis.

Acute Disease↗
PubMed2006

Pathogenesis of myelofibrosis with myeloid metaplasia: Insight from mouse models.

Myelofibrosis with myeloid metaplasia or idiopathic myelofibrosis is a myeloproliferative disease. It is known to be a stem-cell disorder that leads to a secondary and reactive stromal reaction in the bone marrow microenvironment that is responsible for impaired haematopoiesis. Although progress has been made in the elucidation of the pathogenesis of idiopathic myelofibrosis, lack of suitable models has limited our understanding of the pathology. The aim of this chapter is to address recent inferred new insights in mouse models into the pathogenesis of osteomyelofibrosis. These insights outline the role of transforming growth factor-beta1 and osteoprotegerin in the promotion of myelofibrosis and osteosclerosis, respectively, paying special regard to the role of abnormal megakaryocyte proliferation and maturation.

Animals↗
PubMed1998

Translocation (1;20)(q32;q13.3) in myelofibrosis following polycythemia vera.

We report a novel chromosomal translocation (1;20)(q32;q13.3) in a patient with myelofibrosis following polycythemia vera. This 73-year-old woman developed myelofibrosis 6 years after the initial diagnosis of polycythemia vera (PV). The course of PV was uneventful. Subsequent to the diagnosis, the patient was treated with phlebotomy and low doses of hydroxyurea for 4 years. No therapy was delivered during the remaining 2 years. A bone-marrow biopsy and a karyotype analysis performed because of evolving anemia demonstrated myelofibrosis and a chromosomal aberration-t(1;20)(q32;q13.3). Aberrations in chromosomes 1 and 20 have been reported in myeloproliferative disorders, but a t(1;20) translocation has not been reported. Because a karyotype analysis was not performed at the time PV was diagnosed, whether this translocation is linked to the primary disease (PV) or to the transition to myelofibrosis is not known.

Aged↗
PubMed1993

Myelofibrosis in chronic myeloproliferative disorders. Incidence among subtypes according to the Hannover Classification.

The distribution and the development of fibrosis were evaluated from bone marrow biopsies of patients with chronic myeloproliferative disorders (CMPD), regarding two groups of patients: (1) 564 with follow-up biopsies over a period of up to twelve years observation time, and (2) 1.787 diagnostic bone marrow biopsies from CMPD patients. Fibrosis was divided into three grades of fiber increase: early myelosclerosis, myelofibrosis, and advanced myelofibrosis. The first group of sequential BMB showed a significant progress to myelofibrosis in so-called "Chronic Megakaryocytic-Granulocytic Myelosis"--CMGM-, which corresponds to Agnogenic Myeloid Metaplasia-AMM-in 72.4% (21/29 patients), as well as in CML with megakaryocytic increase-CML.MI-in 39.2% (20/51). In the second group of diagnostic biopsies, only 30% of CMGM cases showed no fibrosis. In P. vera, 16.2% (18/111) developed myelofibrosis up to twelve years later. This figure was 4.3% (2/46) in Primary Thrombocythemia. Increase of megakaryocytes in CML indicates a high risk for developing fibrosis, combined with reduced life expectancy.

Biopsy↗
PubMedDate not supplied

Magnetic resonance imaging of myelofibrosis. STIR and gadolinium-enhanced MR images.

MR images of myelofibrosis were assessed in twelve patients. Myelofibrosis showed low intensity in T1-weighted images, high intensity in STIR images, and enhancement after gadolinium injection. MR spectroscopy detected a large water resonance. MR imaging was consistent with histological findings and useful in evaluating the extracellular space in bone marrow of myelofibrosis, but it was of no value in differentiating between primary and secondary myelofibrosis.

Bone Marrow↗
PubMed1991

Defective erythropoiesis in primary myelofibrosis associated with a chromosome 11 abnormality.

A case of primary myelofibrosis was identified with a previously unreported complex karyotype with two abnormal clones in addition to a proportion of normal cells: 46,XY,-2,-11, + der(2)t(2;11) (q24/31;q13), + mar and 45,XY,-2,-11, + der(2)t(2;11)(q24/31;q13), + mar, -17, del(7q). Study of circulating committed progenitors from this patient consistently showed (1) an absence of erythroid progenitors which is uncommon and (2) greatly increased granulocyte-monocyte progenitors (CFU-GM) which is generally observed in myelofibrosis. Further study showed that peripheral blood mononuclear cells co-cultured with irradiated normal bone marrow stroma generated increased numbers of CFU-GM compared with controls but failed to generate erythroid progenitors, providing evidence for an intrinsic defect in erythropoiesis. Only once previously has the absence of erythroid progenitors in primary myelofibrosis been studied in relation to cytogenetic abnormalities. This case also revealed a complex karyotype which, however, shared with our case a defect on chromosome 11. The identification of two cases of primary myelofibrosis which lack committed erythroid progenitor cells and which show in common a chromosomal defect on chromosome 11 point to the existence of genes on this chromosome which play a key role during erythropoiesis.

Aged↗
PubMed2005

Acute panmyelosis with myelofibrosis: an entity distinct from acute megakaryoblastic leukemia.

The WHO criteria for diagnosing acute panmyelosis with myelofibrosis are somewhat distinct from those for acute megakaryoblastic leukemia. However, clinical and hematopathologic findings partially overlap. This has raised questions as to whether these are indeed separate, definable entities. To determine the potential importance of bone marrow biopsy supplemented by immunohistochemistry in distinguishing between these two conditions, we studied 17 bone marrow biopsies of well-characterized cases of acute panmyelosis with myelofibrosis (six cases) and acute megakaryoblastic leukemia (11 cases). We compared blast frequency, reticulin content, CD34 expression, and the degree of megakaryocytic differentiation of the blast cells in these two conditions. Our results demonstrate important differences. Acute panmyelosis with myelofibrosis is characterized by a multilineage myeloid proliferation with a less numerous population of blasts than acute megakaryoblastic leukemia (P<0.01). In the former condition, blasts are always positive with CD34, while in acute megakaryoblastic leukemia they express CD34 in 60% of the cases. The blasts in acute panmyelosis with myelofibrosis only rarely express megakaryocytic antigens. By contrast, acute megakaryoblastic leukemia has a significantly higher proportion of blasts expressing megakaryocytic antigens (P<0.01 with CD42b). Our results confirm that histology supplemented by immunohistochemistry permits the distinction of these conditions in routinely processed bone marrow biopsies.

Acute Disease↗
PubMed2000

Relevance and dynamics of myelofibrosis regarding hematopoietic reconstitution after allogeneic bone marrow transplantation in chronic myelogenous leukemia--a single center experience on 160 patients.

A retrospective single center study was performed on 516 trephine biopsies derived from 160 patients with stable phase Ph+-CML and allogeneic BMT. Following morphometric quantification of reticulin-collagen fibers we tried to elucidate (1) the dynamics of bone marrow fibrosis in the post-transplant period; and (2) the influence of manifest myelofibrosis on relevant engraftment parameters. An evaluation of fiber density at standardized endpoints after BMT was carried out on a selected cohort of 124 patients (399 biopsy specimens). A manifest myelofibrosis (more than a three-fold increase compared to the normal fiber content) before BMT was found in 26% of our patients. Concentrating on bone marrow areas with reconstituting hematopoiesis, several findings emerged. Pretransplant myelofibrosis was associated with an initial regression following BMT, but insidiously recurred in the areas of regenerating hematopoiesis or developed in a few patients without increased pregraft fibers during the post-transplant period (mean observation time more than 4 months). Severe acute GVHD (grades III and IV) was significantly correlated with a greater amount of reticulin fibers in the early post-transplant period (9 to 30 days after BMT). Regarding engraftment parameters, a significant delay was detectable in the time to achieve transfusion independence for the patients with manifest myelofibrosis compared to those without pre-transplant fiber increase.

Adolescent↗
PubMed2003

Hemoglobin F in primary myelofibrosis and in myelodysplasia.

Our study investigated two groups of adult patients with established diagnoses of primary myelofibrosis (21 patients) and myelodysplastic syndromes (MDS) (21 patients). The objective was to assess fetal hemoglobin (HbF) concentration and to investigate correlations with organomegaly and extramedullary hematopoiesis and with the level of anemia and blood transfusion requirement. In all patients, the diagnosis was confirmed by histopathological examination. Patients with myelofibrosis were investigated by ferrokinetics using 59Fe. The percentage of marrow sideroblasts was assessed in patients with refractory anemia with ringed sideroblasts. Increased values of HbF were found to occur both in patients with myelofibrosis and with MDS, although a higher incidence and higher concentrations were evident in patients with myelofibrosis. Statistically significant increases in HbF concentration were found when there was accompanying organomegaly, as compared to patients without this feature. The average HbF concentration in both groups of patients under study was twice as high in cases with as in those without marrow fibrosis. The difference was statistically significant. Increased HbF levels appear to correlate with extramedullary hematopoiesis. HbF concentration did not correlate with the level of anemia or with requirement for blood transfusion.

Adult↗
PubMed2000

Splenectomy in chronic myeloid leukemia and myelofibrosis with myeloid metaplasia.

Myelofibrosis with myeloid metaplasia (MMM) is a collective term that describes the related disorders AMM, PPMM, and PTMM. The chronic myeloid disorders include chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and agnogenic myeloid metaplasia (myelofibrosis). These disorders display varying propensities for pathologic enlargement of the spleen which can lead to mechanical discomfort, hypercatabolic symptoms, anemia, thrombocytopenia, and portal hypertension. Splenectomy has been found to be of little benefit in the early stages of chronic myeloid leukemia. Similarly, the benefit of splenectomy in advanced cases is limited to symptomatic palliation and treatment of delayed engraftment after allogeneic bone marrow transplantation. Although polycythemia vera and essential thrombocythemia are also characterized by splenomegaly, splenectomy is not considered a therapeutic option in the absence of transformation of the disease into myelofibrosis with myeloid metaplasia. Splenectomy has been studied most in myelofibrosis with myeloid metaplasia. Although there is no clear survival advantage to splenectomy in this disorder, the surgical procedure can result in substantial palliation of mechanical discomfort, hypercatabolic symptoms, portal hypertension, and anemia. However, the procedure is associated with an approximately 9% mortality rate, and the postsplenectomy occurrence of extreme thrombocytosis, hepatomegaly, and leukemic transformation is of major concern.

Humans↗
PubMed2003

Peripheral T-cell lymphoma presenting with rapidly progressing myelofibrosis.

Myelofibrosis following peripheral T-cell lymphoma has rarely been reported. Described here is a case of peripheral T-cell lymphoma with myelofibrosis and elevated transforming growth factor beta (TGF-beta). A 69 years old male was admitted due to anemia and thrombocytopenia. His bone marrow showed fibrosis and was infiltrated with small lymphoid cells and a few residual normal hematopoietic cells. He had presented with hepatosplenomegaly and left inguinal lymph node swelling. Biopsy of the left inguinal lymph node revealed diffuse mature small lymphoid cells with atypical nuclei. Immunophenotyping of the small lymphoid cells were positive for CD3, CD8, TCR alphabeta and HLA-DR and were negative for CD4, CD19, CD20 and CD56. T-cell receptor beta-chain gene was rearranged in bone marrow cells. He was diagnosed as having peripheral T-cell lymphoma complicated with myelofibrosis. Chemotherapy was administrated which improved his pancytopenia and symptoms. Two years later, anemia and thrombocytopenia developed rather quickly, he died because of progression of myelofibrosis with severe pancytopenia.

Aged↗
PubMed2004

Acute panmyelosis with myelofibrosis.

Acute panmyelosis with myelofibrosis (APMF) is an ill-defined disorder that may either evolve as a clonal hematopoietic condition or as a sequel of toxic exposure to the bone marrow (BM). Therefore, controversy and discussion continues as to whether APMF may be considered as a hyperfibrotic (de novo) myelodysplastic syndrome (MDS), as acute myeloid leukemia (AML) or as a severe toxic myelopathy with accompanying myelofibrosis. In this context scant knowledge exists about BM findings, but especially evolution of this disorder according to sequential examinations. Clinically patients present with pancytopenia, a very few blasts in the peripheral blood and no or little splenomegaly. Initially BM histopathology is characterized by different degrees of reticulin-collagen fibrosis and wide ranges of cellularity with a prominent left-shifted and often macrocytic erythropoiesis associated with a reduction and maturation defects of the neutrophil series. Most conspicuous are abnormalities of the megakaryocytes including loose clustering, dislocation towards the endosteal border and appearance of atypical microforms with compact nuclei. Moreover, besides myelofibrosis in a number of patients the interstitial compartment displays a remarkable inflammatory reaction with lymphoid nodules, abundant iron-laden macrophages, perivascular plasmacytosis and increase in microvessels. Repeatedly performed BM biopsies reveal an accumulation of dispersed or clustered CD34+ and lysozyme-expressing blasts in keeping with the insidious transformation into acute leukemia. Prognosis is unfavorable with a median survival of less than 1 year. In conclusion, APMF has to be regarded as a condition that shows considerable overlappings with primary hyperfibrotic MDS, AML and toxic myelopathy (secondary MDS) with accompanying myelofibrosis and therefore can not be considered as a definite clinical entity.

Acute Disease↗
PubMed2005

Peripheral T-cell lymphoma together with myelofibrosis with elevated plasma transforming growth factor-beta1.

Myelofibrosis is usually observed in myeloproliferative disorders, such as chronic myeloid leukemia. However, there are only a few reports showing an association between T-cell lymphoma and myelofibrosis. We report a case of peripheral T-cell lymphoma, unspecified (diffuse large cell) type, involving the bone marrow that was associated with severe myelofibrosis. In the present case, the plasma concentration of transforming growth factor-beta1 (TGF-beta1) was increased to 8.95 ng/ml (normal range: 1.56-3.24 ng/ml). No lymphadenopathy or skin lesions were observed during the entire clinical course. Although the mechanism of secondary myelofibrosis is still unclear, elevated plasma TGF-beta1 might be involved in the pathogenesis of bone marrow fibrosis in the present case.

Aged↗
PubMed2006

Allogeneic hematopoietic stem cell transplantation for myelofibrosis.

PURPOSE OF REVIEW: This review summarizes the current status and new developments in allogeneic hemopoietic stem cell transplantation strategies for patients with myelofibrosis with myeloid metaplasia, focusing on novel concepts of allogeneic transplantation with reduced-intensity conditioning. RECENT FINDINGS: No substantial progress has been made in the conventional management of myelofibrosis with myeloid metaplasia. Allogeneic hemopoietic stem cell transplantation represents the only treatment modality with proven curative potential. Standard-dose conditioning regimes followed by allogeneic transplantation are associated with a relatively high transplant-related mortality. Reduced-intensity conditioning regimens have substantially reduced treatment-related mortality. This result is from three studies on myelofibrosis with myeloid metaplasia including more than 60 patients overall. The optimal conditioning regimen for this condition is unknown, in particular the utility of using T-cell depleted stem cells to reduce graft versus host disease is not documented. Emerging concepts include new risk classification for a better provision of the transplant outcome, and splenectomy before transplantation for reducing tumor burden. SUMMARY: The data on hemopoietic stem cell transplantation with reduced-intensity conditioning in myelofibrosis with myeloid metaplasia are encouraging. An accurate risk stratification is a pivotal procedure for selecting patients who will receive the greatest benefit for transplantation. Reduced-intensity conditioning should be further evaluated within clinical trials, in particular for assessing the role of splenectomy and for testing the optimal conditioning regimen.

Graft vs Host Disease↗
PubMed1979

Splenic irradiation in myelofibrosis: effect on circulating myeloid progenitor cells.

We have investigated the mechanism of splenic irradiation-induced granulocytopenia in two patients with myelofibrosis and marked splenomegaly. Serial assays were performed for circulating granulocyte-monocyte progenitors capable of colony formation in vitro (CFU-C). For comparison, similar studies were performed on two patients receiving whole brain irradiation for glioma. Splenic irradiation caused a significant decrease in circulating CFU-C in the myelofibrosis patients. There was no decrease in circulating CFU-C in the brain-irradiated patients. No radiation-induced humoral inhibitor of granulopoiesis and no increased CFU-C radiosensitivity could be demonstrated in the myelofibrosis patients. These observations, taken together with previous data on splenic blood flow and pooling, suggest that the major mechanism of irradiation-induced granulocytopenia in myelofibrosis is destruction of proliferating precursor cells in the splenic tissue and sinusoids.

Aged↗
PubMed1992

Cytogenetic studies of bone marrow fibroblasts cultured from patients with myelofibrosis and myeloid metaplasia.

Cytogenetic studies of bone marrow fibroblasts and blood cells from peripheral blood or bone marrow were performed in 19 patients with myelofibrosis with myeloid metaplasia (group 1), nine patients with other myeloproliferative syndromes without myelofibrosis (group 2), and 12 patients with anaemia secondary to iron deficiency or chronic inflammatory disease (group 3). Clonal cell populations with abnormal karyotypes were seen in the bone marrow or blood in five of 14 (36%) group 1 patients, one of nine (11%) group 2 patients and none (0%) of the group 3 patients. Abnormal karyotypes of bone marrow fibroblasts were found in three of 16 (19%) of patients of group 1, and in two of nine (22%) and two of 12 (17%) patients each of groups 2 and 3, respectively. Since abnormal karyotypes can be found in bone marrow fibroblasts cultured from normal subjects, and since the abnormalities seen in the bone marrow fibroblasts differed from those found in bone marrow or blood cells, it is suggested that abnormal karyotypes found in bone marrow fibroblasts cultured from patients with primary myelofibrosis do not necessarily reflect neoplasia. The results of this study are compatible with the widely accepted hypothesis that in patients presenting with 'primary' myelofibrosis, the fibrosis is a secondary reactive process.

Aged↗
PubMed1993

Antibodies against terminal galactosyl alpha(1-3) galactose epitopes in patients with idiopathic myelofibrosis.

Sera from patients with myelofibrosis were analysed for circulating antibodies against an antigenic determinant characterized by two molecules of galactose in alpha 1-3 linkage (anti-Gal antibodies). 50% of patients were found to have values above the 90th percentile of the values of control sera chosen as a cut-off. The median level of the antibodies was significantly higher than the value detected in normal controls, but no difference could be found between patients with idiopathic myelofibrosis and those with myelofibrosis associated to a chronic myeloproliferative disorder. Anti-Gal antibodies were found to correlate with disease activity and with platelet count whereas no correlation was detected with other haematological parameters. Furthermore, for evaluation of disease activity, determination of serum anti-Gal antibodies was a sensitive and specific parameter. We conclude that humoral immunity against Gal alpha 1-3Gal may provide a sensitive tool to detect disease activity in patients with idiopathic myelofibrosis and may be important for understanding its pathogenesis.

Aged↗
PubMed2005

Modern management of myelofibrosis.

The conventional treatment of myelofibrosis involves a wait-and-see approach for asymptomatic patients, oral chemotherapy for the hyperproliferative forms of the disease, androgens or erythropoietin for the anaemia, and splenectomy in selected patients. Low-dose thalidomide plus prednisone is a well-tolerated therapy for the anaemia and the thrombocytopenia of myelofibrosis, whereas imatinib has shown little efficacy. Allogeneic stem cell transplantation (allo-SCT) is the only curative therapy for myelofibrosis. Its standard modality has an associated mortality of about 30% and can be applied to younger patients with high-risk disease or resistant to conventional treatment. Reduced-intensity conditioning allo-SCT involves a low mortality and is a promising therapy for patients aged 45-70 years old with the above characteristics. Autologous SCT is a palliative therapy for patients resistant to conventional treatment who lack a suitable donor. The next candidates for the treatment of myelofibrosis are the thalidomide derivatives, the proteasome inhibitors, and vascular endothelial growth factor neutralizing antibodies.

Adult↗