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Using a fluorescent technique intracellular immune complexes were found in the peripheral leucocytes in all of 12 patients with myelofibrosis studied. Fluorescent cells varied from 12% to 81%; with no relation to the total white count or any obvious clinical finding. Three of the patients with severe refractory anaemia benefited from immunosuppressive therapy.
Eighty-three patients with myelofibrosis have been studied by erythrokinetics and have been followed up until death or for at least 12 months. Because of a large plasma volume the venous haematocrit gives only a poor idea of the red blood cell volume. The red cell survival was reduced in the majority of cases but significant haemolysis was rare. The amount of haemolysis of autologous and isologous red cells was similar, suggesting an extra-corpuscular origin for the haemolysis. Plasma iron turnover was always increased, sometimes markedly, but red cell iron incorporation was reduced in 70% of cases, indicating ineffective erythropoiesis. Surface counting showed an absence on diminution of sacral iron fixation and a rapid and marked splenic uptake in more than 90% of the cases; uptake of iron by the liver occurred in half the cases, usually not very high; iron release from the spleen was absent or reduced in 67% of the cases. The degree of ineffective erythropoiesis as measured by radio-iron incorporation and release by the spleen, the amount of haemolysis, and the red cell volume were strongly correlated with prognosis. These factors enabled a more precise prediction to be made of the clinical outcome in the 2 years following the study, than the clinical data alone. A prospective study might show whether erythrokinetic studies are also useful in determining the choice of treatment.
A digital image processing technique has been used to quantitate bone marrow fibre in histological material (both biopsy and necropsy) from 17 cases of myelofibrosis. An attempt was made to correlate the results of these measurements with other diagnostically relevant parameters. Bone marrow fibre was found to correlate significantly with absolute neutrophil count, the absolute count of immature granulocytic cells and with the number of immature granulocytic cells expressed as a percentage of the total leucocyte count. There was no significant correlation between marrow fibre content and platelet count for the series as a whole, but for those cases in which measurements were made following splenectomy these parameters were highly correlated. Bone marrow fibre content did not appear to correlate with liver or spleen weight at necropsy, nor with the duration of clinical manifestations of the disease. The significance of these findings is discussed.
Total protein, collagen (hydroxyproline) and glycoproteins (hexosamine) content of control and myelofibrosis (MF) bone marrow samples was determined using a sequential extraction procedure. MF marrow extracts contained higher amounts of collagen than control extracts. The collagen content appeared to increase with the duration of the disease. In more recent MF cases (less than 2 years) at least 60% of the total collagen was extracted in 0.5 M NaCl. this proportion decreases to 33% in older cases (greater than 4 years), indicating a progressive insolubilization (crosslinking) of collagen. The hexosamine content of the extracts decreased in MF as compared to controls reflecting a decrease in glycosaminoglycans (and possibly of structural glycoproteins). The reticulin content of the same bone marrows was estimated by a quantitative morphometric procedure. There was a positive correlation between the morphometrically estimated reticulin surface and the total hydroxyproline content of the marrow samples. The slopes of the least square lines correlating increase of reticulin surface to hydroxyproline content were, however, significantly different in control and MF marrows, indicating a 44% higher increase in histochemically detectable reticulin per unit increase in hydroxyproline content than in the control marrows. This result may indicate a more efficient fibrogenetic process in MF marrow than in normal bone marrow. The above results confirm the collagenous nature of the fibrous reticulin like material deposited in MR marrows and suggests a correlation between the progression of the disease and the rate of synthesis and deposition of collagen fibres.
Eight patients with acute myelodysplasia and myelofibrosis are described. Four cases were secondary to long-term therapy with cytotoxic agents and four were idiopathic. All cases presented with an abrupt onset of the illness, absence of organomegaly and severe pancytopenia. Bone marrow aspirate yielded adequate material in four cases and showed myelodysplasic features. Study of histological sections indicated that the bone marrow was cellular in every case, including numerous dystrophic megakaryocytes, erythroblasts, immature cells of the granulocytic series and blast cells which were difficult to identify. The reticulin network was always increased. In each case the disease was rapidly fatal. No improvement was noted with chemotherapy. In three cases an overt leukaemia developed with marked pleomorphism of blast cells. The nosology of this syndrome is discussed.
Sixteen patients with idiopathic myelofibrosis (IM) have been investigated with respect to the possibility that immune mechanisms may be of importance in the pathogenesis of bone marrow fibrosis. The following points appear relevant: (1) immune-complexes (IC) are detectable with different techniques in a high percentage of patients with IM. Their presence is associated with evidence of bone-marrow histological markers of immune activity. (2) IgG is the main Ig class in the composition of IM IC. The results obtained favour the hypothesis that autoimmune mechanisms are involved in IM patients.
A quantitative assessment of erythropoiesis was performed by means of a mathematical model of iron kinetics in 26 patients with myelofibrosis with myeloid metaplasia (MMM). A direct relationship between total erythropoiesis and red cell volume was revealed. This 'inverse' characteristic of erythropoietic control was the best marker of the proliferative nature of the disease. Three classes of patients were singled out by means of a cluster analysis of the erythrokinetic parameters. In class I (11 patients) the red cell volume was above the predicted normal in all but two patients. Erythropoiesis was sustained at 5--10 times the normal levels with a high degree of ineffective erythropoiesis. A fairly constant absence of erythroid activity over the sacral marrow was demonstrated. In class II most of the 12 patients had a decreased red cell volume. Erythropoiesis was sustained at 2--4 times the normal level with a high degree of peripheral haemolysis. Erythroid activity was recognized over the sacral area in all but two patients. The three patients of class III showed a pattern of erythroid failure and had the worst prognosis. It is suggested that these classes represent separate disease forms of MMM.
The ability of circulating progenitor cells from patients with polycythaemia vera (PV) and myelofibrosis with myeloid metaplasia (MMM) to develop erythroid colonies was studied in cultures with and without erythropoietin. In all normal controls, patients with secondary polycythaemia and MMM, erythroid colonies developed only after the addition of erythropoietin. Only in patients with PV, both in the active and spent phases of the disease, erythroid colonies developed in the absence of erythropoietin. The results indicate the perpetuation of erythropoietin-dependent, as well as erythropoietin-independent progenitors in both phases of this disease. Although spent PV often clinically resembles MMM, there is a basic difference in the behaviour of the circulating erythroid progenitors in these diseases which may serve as a useful tool in discriminating MMM from spent PV, when there is no history of active PV.
We have measured the numbers of myeloid progenitor cells in the circulation of patients with myelofibrosis (MF) and other myeloproliferative disorders. In general, progenitor cell numbers were increased in the circulation of patients with MF compared with controls. The mean increases were 9-fold for the multilineage progenitor cells (CFU-GEMM), 13-fold for the erythroid progenitor cells (BFU-E), 37-fold for the granulocyte-macrophage progenitor cells (CFU-GM) and 167-fold for the megakaryocyte progenitors (CFU-MK). Splenectomized patients generally had reduced numbers of circulating progenitor cells. In the CFU-MK assay, mature megakaryocytes cultured from patients with MF regularly showed large vacuoles in the nucleus and cytoplasm, unlike control cells. The increased colony formation in patients with MK, involving especially CFU-MK colonies, is consistent with the hypothesis that MF is a primary myeloproliferative disorder in which a megakaryocyte-derived factor predisposes to the formation of marrow fibrosis.
The distribution of laminin and collagen type IV in normal human bone marrow appeared to be limited to a small number of capillary and sinusoidal basement membranes. Cellular elements including megakaryocytes showed a negative staining reaction. In contrast, myelofibrotic bone marrow showed markedly increased quantities of both laminin and collagen type IV. This was consistent with a proliferation of endothelial cells within the marrow as confirmed by factor VIII RAG staining. It is suggested that in myelofibrosis in addition to a marked fibrous reaction proliferation of vascular elements is also prominent.
To clarify the lineage involvement of haemopoietic progenitor cells in idiopathic myelofibrosis (MF), simultaneous analysis of morphology and chromosomes were performed on single colonies from a 70-year-old Japanese woman with typical presentation of MF. The cytogenetic analysis of unstimulated peripheral blood cells revealed three cell lines 47,XX,-6,+9,+der(6)t (1;6)(1qter----1q21::6p21----6qter), 46,XX,-6,+der(6) and 46,XX. Of 91 metaphases examined, the numbers of each cell line were 43, 41 and 7, respectively. Blood mononuclear cells were plated at 2 X 10(3) or 1 X 10(4)/ml in methylcellulose medium containing phytohaemagglutinin-stimulated leucocyte conditioned medium and erythropoietin. On days 10, 12 and 14 of culture, 47 individual colonies were lifted and served for morphological and cytogenetic examination. Morphological examination revealed that the colonies contained neutrophils (n), macrophages (m), basophils (b), erythrocytes (E) and megakaryocytes (M). Twenty-two of the 47 colonies had analysable metaphases, yielding totally 158 metaphases. Twelve colonies contained three or more metaphases. Eight colonies (3bE, 1E, 2b, 1nEM, 1bEM) were of the abnormal cell line 46,XX,-6,+der(6), and four colonies (2E, 1bE, 1mE) were of the karyotypically normal cell line 46,XX. The other abnormal cell line 47,XX,-6,+9,+der(6) was not detected in any of the metaphases obtained from single colonies. These results provided direct evidence that the pluripotent stem cells were involved in MF.
The granulopoiesis-supporting effects of marrow adherent cells from seven patients with primary myelofibrosis (PMF) were studied by a continuous allogeneic co-culture system in which the survival of donor granulocyte-macrophage colony-forming cells (CFU-GM) depends upon the supporting ability of adherent cells. Marrow adherent cells from all these seven patients were able to sustain the same number of CFU-GM as those from control subjects. Cytochemical studies showed that colonies grown from cells sustained on fibrous marrow adherent cell layers were predominantly neutrophilic, as were those in control cultures, although many eosinophil colonies grew from patients' bone marrow. These results indicate that marrow stromal cells from PMF patients function normally in their ability to support granulopoiesis.
Factors regulating the interaction between bone marrow haemopoietic cells, stromal elements and bone growth are poorly understood. Disturbance in the equilibrium between these elements can occur as the result of metabolic bone disease, haematologic disorders, neoplasia and infections. The present report concerns a child with myelofibrosis, hypoplastic/dyserythropoietic anaemia, osteoblast proliferation and increased bone formation. A positive tuberculin skin test and elevated EB virus titre indicated previous exposure to Mycobacterium tuberculosis and Epstein-Barr virus. No active focus of infection was identified and no improvement occurred following anti-tuberculous therapy. A dramatic improvement occurred on corticosteroid therapy. Reticulocytosis was followed by an increase in haemoglobin and platelets and a decrease in ESR. Bone marrow fibrosis resolved and the marrow was repopulated with normal haemopoietic tissue. The bone abnormalities improved both radiologically and histomorphometrically. Relapse occurred when steroids were discontinued. Bone marrow tissue culture supernate from the patient during the active phase of the disease inhibited colony formation by normal marrow mononuclear cells. This was reversed by steroid therapy. It is postulated that EB virus may have triggered osteoblast proliferation with resultant bony and haematologic changes. Response to corticosteroids could be explained on the basis of suppression of osteoblast activity and correction of fibroblast mediated suppression of haemopoiesis.
The presence of lymphoid nodules in bone marrow biopsy was investigated at diagnosis in 200 patients with chronic myeloproliferative disorders (MPD). Twelve out of 51 patients with idiopathic myelofibrosis (IM) showed such a feature (23.5%), versus two out of 100 with Ph1-positive chronic myeloid leukaemia, two of 32 with polycythaemia vera, and one of 17 with essential thrombocythaemia, the difference between IM and the remaining MPD being statistically significant (P less than 0.0001). When IM patients were compared for their initial characteristics according to the presence or not of bone marrow lymphoid nodules, patients with such a histological finding showed significantly lower values for either WBC counts, number of primitive cells in the blood, and serum lactic dehydrogenase levels. Moreover, it was observed that virtually all patients with lymphoid nodules were in the nonmyelosclerotic phases of IM. Finally, among the 14 of 32 IM patients (44%) investigated for circulating immune complexes who gave a positive test, a significant association between this immunological abnormality and bone marrow lymphoid nodules was found. The above results reinforce the immunological significance of the finding of bone marrow lymphoid nodules in IM and give support to the hypothesis of an immune component in the pathogenesis of the disorder.
The dependence of survival time on a set of prognostic factors was explored by means of Cox's regression model in 137 cases of myelofibrosis with myeloid metaplasia (MMM). The following parameters recorded at diagnosis proved to be important independent indicators of a poor prognosis: a higher value for age, a lower value for Hb concentration, a higher value for immature myeloid cells in peripheral blood (IMC), a lower value for total erythroid iron turnover (TEIT), and a bone marrow red cell aplasia (RCA). A prognostic classification tree was constructed whose terminal nodes (risk groups), described by simple logical conditions upon important indicators, were characterized by significantly different expected survival. The two extreme risk groups lend themselves to a simple, but complete description. The low-risk group (19.7% of the sample) comprises cases who had the diagnosis of MMM before age 45 and a number of IMC constantly lower than 24%. The actuarial proportion of patients surviving at 15 years was 100%. The high-risk group (29.9% of cases) comprises patients with age greater than 45 and Hb lower than 13 g/dl, associated with RCA, or with a relatively decreased erythropoiesis (TEIT lower than 2 times the normal) or with IMC greater than 24%. Seven out of the 11 who died within this group developed blastic crisis. Median survival time of the group was 69 months.
In 78 patients with myelofibrosis with myeloid metaplasia (MMM) the serum procollagen III peptide activity (s-PIIIP) had a higher mean value than in 22 normal adult volunteers (22.5 v. 10 ng/ml). Nevertheless, 21.8% of the patients had s-PIIIP within the 95th percentile of the normal control group (16 ng/ml): with respect to those whose concentrations exceeded this limit, patients with normal s-PIIIP levels were younger (55.8 v. 61.2 years), had a higher Hb value (12.3 v. 10.5 g/l), a lower serum ferritin level (106 v. 464 micrograms/l) and a higher platelet count (390 v. 216 x 10(9)/l). In the overall patient population, s-PIIIP was significantly higher in those with symptoms of active disease (fever, sweating, weight loss) than in subjects with non-active disease (28 v. 16.9 ng/ml). At univariate analysis s-PIIIP correlated (at the 5% level) with increasing WBC, serum ferritin and number of transfusions and with decreasing Hb and platelet count. At multivariate analysis increasing WBC, serum ferritin and age proved to be independently associated with s-PIIIP. No relationship was found between the s-PIIIP level and morphometric grading of bone marrow fibrosis, megakaryocyte number, or lymphoid infiltration. Longitudinal studies showed that s-PIIIP increased with disease progression. The conclusion of the study is that s-PIIIP correlates more with overall disease activity than with the extent of bone marrow fibrosis.
The prognostic value of 12 clinical and haematological parameters, recorded at diagnosis, in myelofibrosis with myeloid metaplasia (MMM) was retrospectively analysed in a consecutive series of 133 patients followed for a minimum of 60 months. Multivariate analysis showed that the following features were associated with a significantly shorter survival: (1) short period of time (less than 13 months) between first symptoms and diagnosis; (2) anaemia (haemoglobin less than 10 g/dl); (3) leucocyte count greater than 12 x 10(9)/l; (4) peripheral blood granulocyte precursors greater than 10%. Age, splenectomy and percentage of peripheral blood metamyelocytes were found significantly to affect survival only from univariate analysis, whereas sex, size of spleen, thrombocytopenia and thrombocytosis were of no prognostic significance. These data suggest that a more intensive chemotherapy might be useful for younger patients with bad prognostic factors at diagnosis.
We previously reported high platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta) levels in platelets from patients with myelofibrosis with myeloid metaplasia. We report here the effects of in vivo administration of recombinant human interferon-gamma on these growth factor levels. Of six patients who entered this study in our institution, four completed the 6-month therapy trial with interferon-gamma PDGF and TGF-beta levels in platelets were evaluated before and after treatment. PDGF levels were determined using a radioimmunoassay and TGF-beta activity was measured using an inhibition growth assay on CC164 cells. In these four patients, IFN-gamma therapy led to a reduction of the increased PDGF and TGF-beta levels in platelets towards the normal range. PDGF and TGF-beta values decreased by 25-45% and 32-46%, respectively. An acute deterioration was observed in one patient 5 months after the end of IFN-gamma therapy. In this patient, the deterioration of his clinical state correlated with an increase in intraplatelet PDGF and TGF-beta levels.