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PubMed1977

Portal hypertension complicating myelofibrosis: reversal following splenectomy.

Portal hypertension occurs in approximately 10% of patients with myelofibrosis. Increased portal blood flow secondary to splenomegaly has been proposed to explain its development. In a 60-year-old woman with proven myelofibrosis of 10 years' duration and gross splenomegaly, portal hypertension developed with esophageal varices and ascites. There was no demonstrable obstruction to portal blood flow. Following splenectomy the ascites and esophageal varices disappeared. Despite the presence of splenic myeloid metaplasia, splenectomy did not impair the patient's hematologic status. Portal hypertension complicating myelofibrosis has a poor prognosis, so careful attention should be given to its detection. Splenectomy may be preferable to portal-systemic shunting in the management of this complication.

Ascites↗

PubMed1977

Acute of fulminating myelofibrosis.

Patients who run a fulminating course in association with histologically proven myelofibrosis are distinctly unusual, since the natural history of this entity is characteristically one of slow progression. Because of its rarity and proteam manifestations, acute myelofibrosis may easily go unrecognized. We report 2 such patients. In one, rapid clinical deterioration was dominated by spreading skin lesions, and in the other by refractory intravascular haemolysis. There was no splenomegaly in the first patient, and it was minimal in the second. Although it is seen in frequently, it should be emphasized that myelofibrosis may arise de novo as an acute illness in which the usual degree of splenomegaly is absent.

Acute Disease↗

PubMed2006

Myelofibrosis and cytopenia are not always malignant.

Myelofibrosis (MF) is characterized by reticulin fibrosis of the bone marrow. It may occur in neoplastic disorders such as myelofibrosis with myeloid metaplasia (MMM) or other neoplasms involving the bone marrow. However, autoimmune phenomena have been described in patients with MF defining a distinct clinicopathological entity called autoimmune myelofibrosis (AIMF). We report two cases of AIMF and review the literature.

Journal Article↗

PubMed2026

Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target.

Splenomegaly is a defining feature of myelofibrosis, yet the contribution of splenic mesenchymal stroma to disease progression remains unclear. We combined spatial and single-nucleus transcriptomics of patient spleens with spatial and single-cell transcriptomics, as well as imaging analyses, of murine spleens to map extramedullary hematopoiesis niches. Activated red pulp reticular cells localize near hematopoietic stem and progenitor cells, and early disease is characterized by marginal zone disruption with lymphoid depletion preceding stromal remodeling. Trajectory analyses reveal a shift in reticular cells from hematopoiesis-supportive to inflammatory and pro-fibrotic states, driven by macrophage- and megakaryocyte-derived signals that activate complement and induce tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), extracellular matrix, and Thbs1 programs. Non-hematopoietic complement component C3 deficiency or pharmacological C3 inhibition suppresses these pathways, restores splenic architecture, and reduces splenomegaly and bone marrow fibrosis. These findings identify complement-dependent stromal reprogramming as a mechanism governing hematopoietic niches and as a targetable axis in myelofibrosis.

Animals↗

PubMed2003

Altered transcription of the stem cell leukemia gene in myelofibrosis with myeloid metaplasia.

An increased number of circulating CD34+ hematopoietic progenitors with a prominent proliferation of the megakaryocytic (MK) population are the hallmarks of the myeloproliferation in myelofibrosis with myeloid metaplasia (MMM). Analyzing the potential contribution of the stem cell leukemia (SCL) gene in MMM myeloproliferation was doubly interesting for SCL is expressed both in primitive-uncommitted progenitor cells and erythroid/MK cells, its transcription differentially initiating from promoter 1b and 1a, respectively. Our results show that: (i) the expression of SCL transcript is increased in peripheral blood mononuclear cells (PBMCs) from patients; (ii) SCL gene transcription is altered in MMM CD34+ progenitor cells sorted into CD34+CD41+ and CD34+CD41- subpopulations. Actually, in patients, SCL transcription initiated at promoter 1b is restricted to primitive CD34+CD41- progenitor cells, while it is detectable in both cell subsets from healthy subjects; (iii) the full-length isoform of SCL protein is present in patients' CD34+ cells and in PBMC; in the latter the SCL-expressing cells mainly belong to the MK lineage in which its sublocalization is both nuclear and cytoplasmic, which contrasts with the sole nuclear staining observed in normal MK cells. Our demonstration of altered expression and transcription of SCL in patients' hematopoietic cells emphasizes the possible contribution of this regulatory nuclear factor to the hematopoietic dysregulation, which is a feature of myelofibrosis with myeloid metaplasia.

Antigens, CD↗

PubMed2005

Stem cell dysregulation in myelofibrosis with myeloid metaplasia: current data on growth factor and transcription factor involvement.

Myelofibrosis with myeloid metaplasia (MMM), the rarest Philadelphia chromosome-negative chronic myeloproliferative disorder (MPD), is characterized by extramedullary hematopoiesis and myelofibrosis. The primary molecular defect leading to the clonal amplification of the hematopoietic progenitors is still unknown. In this review, we will focus on current data in favor of a pivotal role for hematopoietic and fibrogenic growth factors and of transcription factors in the dysregulation of the hematopoietic compartment. These data shed novel insight into the genesis of MMM myeloproliferation and led us to propose a model, integrating alterations in the expression and function of nuclear regulatory factors and in the hierarchical and complex network of interactions between hematopoietic cells and stroma in the pathogenetic mechanisms of the disease.

Chronic Disease↗

PubMed2026

Outcomes of patients with myelofibrosis treated with ruxolitinib and anemia-supporting medications.

OBJECTIVE: This post hoc analysis of the phase 3b JUMP trial evaluated addition of anemia-supporting medications to ruxolitinib in patients with myelofibrosis and anemia. METHODS: 101 patients with baseline hemoglobin <12.0 g/dL initiated an erythropoiesis-stimulating agent (ESA) or danazol <3 months post-enrollment and maintained ESA/danazol ≥3 months; 97% initiated ESAs. Patients enrolled in JUMP who had hemoglobin <12.0 g/dL but did not initiate ESAs/danazol within 3 months were evaluated as an unmatched comparator. Total JUMP population data were also analyzed for spleen length (≥50% reduction from baseline) and symptom response (≥6.5-point improvement in FACT-Lym score). RESULTS: Baseline characteristics were similar to comparator JUMP patients (no ESAs/danazol within 3 months, n = 1242). Mean total daily ruxolitinib dose remained >25 mg. Week 24 spleen length response was achieved by 37% of patients; 26% achieved symptom response, similar to the comparator population (28% and 26%, respectively) and comparable to the total JUMP population (N = 2233). Outcomes were similar between the hemoglobin <12.0 g/dL analysis population and patients with baseline hemoglobin <10.0 g/dL (n = 52). In all groups, hemoglobin levels increased after Week 4 following an expected initial decrease. DISCUSSION: This analysis suggests that patients treated with ruxolitinib and anemia-supporting care continued to receive optimal ruxolitinib dosing; spleen-length and symptom response rates in these patients were comparable to the overall JUMP population, the majority of whom did not have anemia. CONCLUSION: Results support use of anemia-supporting medications with ruxolitinib and may allow maintenance of ruxolitinib dose intensity in patients with myelofibrosis and anemia.

Humans↗

PubMed1998

Evidence for integrin receptor involvement in megakaryocyte-fibroblast interaction: a possible pathomechanism for the evolution of myelofibrosis.

Megakaryocytes are assumed to be functionally linked with the evolution of myelofibrosis, complicating chronic myeloproliferative disorders. It has already been shown that megakaryocytes will promote fibroblast growth in vitro when in spatial proximity. Here, we demonstrate that the integrin receptors alpha3beta1 and alpha5beta1 are involved in this megakaryocyte-fibroblast interaction. Upon addition of anti-alpha3 and -alpha5 antibodies to megakaryocyte-fibroblast cocultures, fibroblast growth was significantly impaired, and megakaryocyte attachment to the fibroblast feederlayer was significantly reduced. Unilateral blocking of megakaryocytes with anti-alpha3 or -alpha5 antibodies resulted in a suppression of adhesion, probably reflecting the prominent function of fibronectin receptors on the megakaryocyte surface. Moreover, the oligopeptide RGDS (Asp-Gly-Asp-Ser) caused a significant reduction of fibroblast growth as well as megakaryocyte adhesion. This feature reinforces that fibronectin receptors are involved. In addition, fibroblast proliferation was impaired by the application of fibronectin antibodies recognizing the cell-binding domain. However, no effect was observable with respect to megakaryocyte adhesion. In conclusion, our in vitro studies demonstrate the involvement of beta1-integrins, in particular the fibronectin receptor in the megakaryocyte-dependent fibroblast proliferation and therefore suggest a pivotal role of megakaryocytes in the complex pathomechanism causing myelofibrosis.

Adult↗

PubMed1979

Idiopathic myelofibrosis without splenomegaly.

The patient described has had idiopathic myelofibrosis for 8 years. At the time of presentation, 12% of the circulating white cells were myeloblasts. In the past two years, the white blood count has been as high as 18,000/mm3 with 50% myeloblasts. Of significance is the absence of splenomegaly over the eight year period of observation. The rarity of the absence of significant splenomegaly and the presence of large numbers of circulating myeloblasts in idiopathic myelofibrosis are reviewed.

Aged↗

PubMed1980

Acute myelofibrosis terminating in an acute lymphoblastic leukemia: a case report.

A patient with acute myelofibrosis developed acute leukemia during the course of her disease. Light microscopic examination showed that the cells were lymphoblasts. The presence of terminal deoxynucleotidyl transferase and T- and B-lymphocyte markers suggested that the malignancy was of immature lymphoid cell origin. Terminal leukemic transformation in some cases of acute myelofibrosis may be of a lymphoid nature and, thus, less toxic chemotherapy could be used with a better prognosis.

Antigens, Surface↗

PubMed1980

Diffuse purely osteolytic lesions in myelofibrosis.

In myelofibrosis, the skeletal bones present radiologically as normal or with osteosclerotic or osteoporotic changes. Lytic lesions are very rare and when present are usually associated with osteosclerosis. We report on a case of a patient with myelofibrosis exhibiting diffuse purely osteolytic lesions.

Bone Neoplasms↗

PubMed1983

The role of myelofibrosis in malignant leukoerythroblastosis.

This study examined the relationship of bone marrow pathology to the presence of leukoerythroblastosis in 67 patients with biopsy-proven metastatic bone marrow tumor. Both extensive tumor involvement (greater than 25% of marrow space) and severe myelofibrosis were more common in solid tumors than lymphomas. Twenty-eight of 45 solid tumor biopsies versus only 4/21 lymphoma biopsies showed both features (P less than 0.005). The presence of leukoerythroblastosis was more common in solid tumors than lymphomas and was associated with fibrosis but not tumor extent. Myelofibrosis appears to be important in the pathogenesis of leukoerythroblastosis.

Anemia, Myelophthisic↗

PubMed1985

The pattern and clinical significance of karyotypic abnormalities in patients with idiopathic and postpolycythemic myelofibrosis.

Six of eight (75%) patients with postpolycythemic myelofibrosis (PPMF) and 11 of 20 (55%) patients with idiopathic myelofibrosis (MF), seen at the University of Chicago, had abnormal karyotypes in cells of bone marrow origin. The specific chromosomal findings and their clinical significance in these patients were analyzed. A review of the literature added the findings from abnormal karyotype studies in 10 patients with PPMF and 36 patients with MF to this series. The demonstration of an increased frequency of cytogenetic abnormalities after cytotoxic therapy in polycythemia vera (PV) implies that such therapy may have a role in the development of chromosomal changes seen in treated PV and PPMF. The cytogenetic abnormalities in MF appear to be unrelated to therapy except possibly for an association with partial or complete losses of chromosome 5 or 7. Trisomy 8 is the only finding that is more common in MF than in PPMF. Other abnormalities were more common in PPMF, particularly 20q-, loss of 7 or 7q-, and trisomy 9, and to a lesser extent trisomy 1q and 5q-. Cytogenetic abnormalities do not show a pattern that can be used to distinguish between PPMF and MF, nor are they useful in the prognosis of MF or in initial studies in PPMF. PPMF does appear to have a higher tendency toward leukemic transformation than does MF, and an evolution in karyotype appears to have serious prognostic implications in PPMF in regard to this transition.

Adult↗

PubMed1986

Myelofibrosis following treatment with a nitrosourea for malignant glioma.

Nitrosoureas are alkylating agents that have been associated with the development of a preleukemic syndrome, secondary acute nonlymphocytic leukemia and a variety of acute and delayed toxicities. Nitrosoureas have activity in the treatment of primary malignant brain tumors. The authors report a patient who developed bone marrow myelofibrosis three years following treatment with radiation therapy and oral CCNU. This is the first case of marrow fibrosis associated with the use of a nitrosourea. Bone marrow myelofibrosis may be another delayed treatment effect of this class of drugs.

Brain Neoplasms↗

PubMed1988

Down's syndrome and acute myelofibrosis. Time study of DNA content during the progression to leukemia.

Flow cytometry (FCM) for the determination of cellular DNA content was performed on multiple bone marrow biopsy specimens from a 3-year-old boy with Down's syndrome and myelofibrosis. A rapidly fatal acute nonlymphocytic leukemia developed within 3 months after initial bone marrow evaluation. The clinical and morphologic changes corresponded to the development of aneuploidy as determined by FCM and cytogenetic analysis. These findings support the clinical observations of the premalignant potential of myelofibrosis in Down's syndrome.

Antibodies, Monoclonal↗

PubMed1988

Meningeal hematopoiesis causing exophthalmus and hemiparesis in myelofibrosis: effect of radiotherapy. A case report.

Meningeal myeloid metaplasia (MM) is very rarely observed in patients with myelofibrosis. We report the occurrence of meningeal MM causing exophthalmus and fever in a patient with myelofibrosis secondary to polycythemia vera. A computerized tomography (CT) scan showed multiple intracranial and intraorbital enhancing masses. A needle aspirate of retrobulbar space confirmed the diagnosis of extramedullary hematopoiesis. The patient subsequently developed a rapidly worsening tumor-like syndrome with hemiparesis, aphasia, and loss of sphinteric control. The administration of radiotherapy caused a complete and stable regression of clinical symptoms and a marked reduction of MM masses.

Adult↗

PubMed2002

Successful treatment of anemia in idiopathic myelofibrosis with recombinant human erythropoietin.

Thirteen patients with idiopathic myelofibrosis (5 osteomyelosclerosis) were treated with recombinant human erythropoietin (rHuEpo) for transfusion-dependent anemia. All but 7 patients were concomitantly treated with alpha interferon, and 5 patients also received a interferon before the start of erythropoietin (EPO) treatment. All but two patients became transfusion independent. The highly positive results of the present study of transfusion-dependent patients with idiopathic myelofibrosis calls for further studies to delineate more precisely in larger series those patients who are likely to respond to rHuEpo.

Aged↗

PubMed2007

Clearance of the Janus kinase 2 (JAK2) V617F mutation after allogeneic stem cell transplantation in a patient with myelofibrosis with myeloid metaplasia.

A patient with myelofibrosis with myeloid metaplasia displaying the V617F mutation of the JAK2 gene was given an allogeneic stem cell transplantation using a reduced-intensity conditioning regimen. The patient engrafted, and as he became a chimera, the expression of the V617F mutation of the JAK2 gene decreased progressively until its disappearance. Accordingly, the concept of "molecular remission" of the myelofibrosis with myeloid metaplasia could be entertained and added to the categories of response to treatment which have been recently described.

Biomarkers↗