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PubMed1993

[Bone marrow scintigraphy. Contribution to the diagnosis and the prognosis of myelofibrosis].

During the last three years 77 patients with myelofibrosis were studied by scintigraphy, using 99m Tc colloids and 111 In transferrin as tracers. Low axial uptake of the colloids, extension of the indium uptake beyond the axis towards the knees and sometimes the ankles and elbows, and splenic indium uptake are valuable diagnostic criteria, particularly useful to exclude myelofibrosis associated with a malignant disorder. The clinical severity of the disease, and in particular the disappearance of a physiologically active bone marrow (indium uptake) can be predicted from isotopic studies. Bone marrow scintigraphy could contribute to the difficult decision of splenectomy.

Adult↗
PubMed1995

[Essential thrombocythemia in transformation to smouldering megakaryoblastic leukemia with myelofibrosis].

Leukemic transformation in essential thrombocythemia (ET) is rare. We describe a patient with ET which transformed to megakaryoblastic leukemia with myelofibrosis after treatment with melphalan for 8 years. His course after transformation smouldered for 20 months without antileukemic chemotherapy. A 61-year-old man was referred by a local doctor to Niigata University Hospital due to nasal bleeding in June 1984. Complete blood count (CBC) was as follows; hemoglobin 12.4 g/dl, platelets 268.8 x 10(4)/microliters, and white blood cells 11,900/microliters, with differentials of 39% PMN, 1% basophils, 2% eosinophils, 4% monocytes, and 13% lymphocytes. Bone marrow examination revealed hyperplasia of megakaryocytes without increase of reticulin fibers. Neutrophil alkaline phosphatase activity and karyotype of marrow cells were normal. ET was diagnosed. He was followed up by local doctor. The platelet count was controlled at a level of approximately 40 x 10(4)/microliters with melphalan for eight years. In January 1992 he developed pain in his lower extremities. He was admitted to our hospital on May 29, 1992. CBC was as follows; hemoglobin 8.9 g/dl, platelets 14.3 x 10(4)/microliters, and white blood cells 3,500/microliters, with differentials of 25% PMN, 5% monocytes, 28% lymphocytes, and 24% blasts. Bone marrow aspiration was unsuccessful and bone marrow biopsy revealed increases in fibroblasts and collagen fibers. Circulating blasts were positive for CD4, CD7, CD25, CD13, CD33, CD34, and HLA-DR and partly positive for CD41 and CD36. In ultrastructural cytochemistry blasts were positive for platelet peroxidase but negative for myeloperoxidase. Cytogenetic study revealed 46, XY, +der (1) t(1:7) (p11;q11) in all of five metaphases. He was diagnosed with megakaryoblastic leukemia accompanied by myelofibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

[Myelofibrosis complicated by T-cell lymphoma followed by leukemic transformation].

A 37-year-old man was admitted because of pancytopenia with leukoerythroblastosis and anisocytosis in January 1986. Bone marrow aspiration resulted in a dry tap and biopsy showed marked myelofibrosis. Three months after admission, generalized lymph node swelling and multiple skin tumors were recognized. A biopsied lymph node revealed lymphoblastic lymphoma. The surface markers of lymphoma cells showed an immature T-cell phenotype, whereas T-cell receptor beta and gamma chain genes showed germ line configuration. The patient was treated with combination chemotherapy in June 1986. A month later, he developed leukemic transformation with features of acute myelocytic leukemia and he died of pneumonia. Autopsy disclosed extramedullary hematopoiesis in the liver and spleen. Primary myelofibrosis complicated by T-cell lymphoma is extremely rare.

Adult↗
PubMed1996

[Primary myelofibrosis with severe bone pain].

An 80-year-old man was admitted with bone pain, affecting both lower limbs and the dorsa of the feet, in September, 1991. Primary myelofibrosis was diagnosed. Bilateral x-ray films of the tibia, fibula, femur and vertebra revealed osteoporosis, but this was considered an unlikely source of the bone pain. The bone pain subsequently disappeared, but then became severe in both lower limbs and the dorsa of the feet and was accompanied by leukemic transformations in February, 1992. He died of aspiration pneumonia in July, 1992. Autopsy revealed microfractures with osteoporosis and infiltration of leukemic cells in the periosteum of the left tibia, which may have caused the bone pain. This case provides useful information to analyze the cause of bone pain in patients with myelofibrosis.

Aged↗
PubMed1996

[IgD (lambda) multiple myeloma associated with myelofibrosis: an isolated case of nuclear physicist].

A new case of IgD (lambda) multiple myeloma associated with myelofibrosis is described and four from the literature are reviewed. A 66-year-old nuclear physicist who had been diagnosed of having multiple myeloma in 1992 was admitted to the hospital in 1995 because of pancytopenia. A bone marrow biopsy specimen showed nests of myeloma cells with marked fibrotic background. The association of IgD (lambda) multiple myeloma with myelofibrosis was characterized by marked marrow fibrosis and myeloma cell proliferation, without typical features of extramedullary hematopoiesis. Some increase in the bone marrow fibrous tissue is not uncommon in hematologic disorders in which there is a rapid proliferation of marrow cells. What distinguishes these five patients is that their marrow fibrosis was an order of magnitude more extensive. These patients were generally severely anemic and commonly leukopenic and thrombocytopenic. Radiation has been reported as a causal factor in multiple myeloma. In the present case, radiation exposure during his study may have been related to the development of his disease. The correct diagnosis in the case of Dr. Torahiko Terada (1878-1935; physicist, essayist) who died of disseminated bone tumor seems to be multiple myeloma.

Aged↗
PubMed1996

[Primary myelofibrosis with positive coombs' test responding to prednisolone].

Primary myelofibrosis was diagnosed in a 43-year-old female in 1991, who gradually became transfusion dependent. There was no evidence suggesting connective tissue diseases except for biological false positive STS. Because her direct Coombs' test was positive and serum haptoglobin level was extremely low (< 6mg/dl), intermediate dose (30mg/day) prednisolone therapy was started. Her hemoglobin level and platelet count increased dramatically to a normal level within 3 weeks after the initiation of prednisolone therapy. Bone marrow biopsy performed 6 months later revealed marked recovery of hematopoiesis. Though the effects of corticosteroid therapy in primary myelofibrosis still remain unclear, this therapy might be useful in the treatment of some groups of patients via the correction of immunological aberrations and/or the decrease of bone marrow fiber.

Adult↗
PubMed1996

[Transformation of aplastic anemia to acute myeloid leukemia with myelofibrosis following treatment with granulocyte colony-stimulating factor and erythropoietin].

A 67-year-old female was admitted with fatigue. Peripheral blood examination showed severe pancytopenia. Bone marrow biopsy revealed hypoplastic marrow. She was diagnosed as having aplastic anemia. Steroid pulse therapy was not effective. After treatment with erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF), blasts which were positive for CD13, CD33, CD34 and HLA-DR and negative for myeloperoxidase appeared in the peripheral blood. At this time, bone marrow biopsy revealed myelofibrosis with increased blasts. Chromosome analysis showed 46XX, add (1) (p36), add (1) (q44), -2, -5, del (7) (q11), -12, +3mar. She died of pneumonia despite chemotherapy with etoposide. Administration of EPO and G-CSF may have led to the rapid development of leukemia and myelofibrosis.

Aged↗
PubMedDate not supplied

Subtotal splenectomy for treatment of patients with myelofibrosis and myeloid metaplasia.

Idiopathic myelofibrosis is a chronic myeloproliferative disorder that may course with myeloid metaplasia involving several organs. Occasionally, the spleen reaches giant proportions and must be withdrawn. However, this procedure is followed by greater morbidity and mortality. Partial splenectomies, preserving the splenic pedicle, have been proposed in order to reduce postoperative complications. After an early postoperative improvement, some patients present symptomatic recurrence of their disease. This communication presents a new alternative for the treatment of complicated myeloid metaplasia: subtotal splenectomy, preserving the upper splenic pole supplied only by the splenogastric vessels. We performed this procedure in three patients. Their almost two years postoperative follow-up and health improvement suggest that this operation should be considered for the treatment of huge spleens due to myelofibrosis with myeloid metaplasia.

Adult↗
PubMed1996

[Cutaneous vasculitis during primary myelofibrosis].

A leukocytoclastic cutaneous vasculitis in the course of an idiopathic myelofibrosis is reported. The cutaneous lesions that might appear in this hematological disease are discussed, including cutaneous infections, myeloid metaplasia and cutaneous infiltration due to the myeloproliferative process. We point out the rarity of cutaneous vasculitis during the course of primary myelofibrosis.

Aged↗
PubMed1997

[Essential thrombocythemia in transformation to acute leukemia (FAB-M0) as a natural history from myelofibrosis with t(1;7)].

A 34-year-old man was found to have leukocytosis and thrombocytosis in 1983. In 1988, his leukocyte count was 10,400/microliter, Hb 16.5g and a platelet was 73 x 10(4)/microliter. A bone marrow examination showed megakaryocyte hyperplasia. Essential thrombocythemia (ET) was diagnosed but no treatment was given. In February 1993, anemia and hepatosplenomegaly developed and cytogenetic study of the peripheral blood demonstrated t(1;7) (q10;p10). Myelofibrosis was diagnosed as by bone marrow biopsy. The patient was treated with blood transfusion, oxymetholone and prednisolone, but without effect. In 1995, acute myeloid leukemia developed, and he died in December 1995 due to septicemia. We report here a case of the ET developed myelofibrosis with t(1;7) (q10;p10) anomaly and acute leukemia.

Acute Disease↗
PubMed1998

Splenectomy and risk of blast transformation in myelofibrosis with myeloid metaplasia. Italian Cooperative Study Group on Myeloid with Myeloid Metaplasia.

An unexpectedly high incidence of blast transformation after splenectomy has been reported in patients with myelofibrosis with myeloid metaplasia. However, whether this was associated with spleen removal after adjustment for risk factors was not determined. We conducted a multicenter historical cohort study of patients with myelofibrosis with myeloid metaplasia diagnosed from January 1970 through January 1994. A total of 549 patients (325 men and 224 women from 22 to 92 years of age; median age, 63 years) were included in the final data set. The Cox's proportional-hazards model was used to identify factors associated with blast transformation and death. To further adjust for factors related to spleen removal assignment, a propensity score for splenectomy was estimated using recursive-partitioning analysis. Blast transformation developed in 78 patients (14.2%). Patients who underwent splenectomy developed more blast transformations than those who were not splenectomized (23 of 87 [26.4%] v 55 of 462 [11.9%]; P < .001). The cumulative incidence of blast transformation 12 years after diagnosis was 27.0% in nonsplenectomized patients and 55.0% in splenectomized ones (P = . 01). The risk factors independently predictive of blast transformation included prior splenectomy (relative risk = 2.61), platelet count less than 100 x 10(9)/L at diagnosis (relative risk = 2.45), and the presence of blasts in peripheral blood at diagnosis (relative risk = 2.31). The relative risk of blast transformation in splenectomized patients increased from 2.2 at 48 months from diagnosis to 14.3 at 12 years. Patients with the same propensity score for splenectomy showed a higher risk for blast transformation on the basis of having undergone splenectomy (P = .02). In conclusion, the risk of blast transformation is significantly increased in subjects who underwent splenectomy and appears to be independent of factors related to spleen removal assignment.

Adult↗
PubMed1998

rHuEpo for the treatment of anemia in myelofibrosis with myeloid metaplasia. Experience in 6 patients and meta-analytical approach.

BACKGROUND AND OBJECTIVE: Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is slight up to now. We present our results of the treatment of 6 patients and a review of the literature in search of possible parameters predicting response to this treatment. DESIGN AND METHODS: From January 1994 to June 1996 all transfusion-dependent patients with MMM diagnosed in our hospital were included in this study. We established a minimum period of 4 weeks of treatment and a maximum of 12 if no response was observed. Initial dosages used were 100 U/kg s.c. 3 times weekly, increasing by 50 U/kg every 4 weeks where no response was observed. Response was defined as a reduction > or = 30% of the previous transfusional needs. The review of the literature was made using a MEDLINE search (January 1990-December 1996) on the keywords erythropoietin, myelofibrosis, and agnogenic myeloid metaplasia. A statistical study was made in search of possible parameters to predict response. The parameters studied include age, sex, hemoglobin, serum erythropoietin (sEPO) levels, transfusional dependency, transfusional requirements per month prior to treatment, maximum dosages used and dosage at which response was obtained. RESULTS: Only 2 of our 6 patients responded, both at a dosage of 600 U/kg/week (200 U/kg 3 times weekly s.c.). In addition to our 6 patients we have found only 28 other patients in the literature. For statistical calculation 2 of our patients were not considered as they did not complete the period of study. The overall rate of response was 17/32 (53.1%). In the univariate analysis comparing responders and non-responders we found a tendency to significance with respect to sex (p = 0.07), sEPO (p = 0.07) and transfusional needs in units of packed red blood cells per month (PRBC/m) (p = 0.13). In this way patients with low sEPO, females and those with low transfusional needs (< 3 PRBC/m) respond better. This better response in females could be explained by the fact that their disease situation was more stable (with both lower sEPO levels and transfusional dependency). The best cut-off point in the sEPO to predict response was 123 mU/mL. No important side-effects have been observed except three cases of aggravation of splenomegaly. In two cases this condition improved when the rHuEPO was discontinued. The association of rHuEPO with hydroxyurea or interferon does not seem to affect the response. INTERPRETATION AND CONCLUSIONS: Though the number of patients is low, our data suggest that some MMM patients, in particular females and individuals with low sEPO levels and with low transfusional needs, might benefit from rHuEPO in terms of elevation of hemoglobin levels. Unfortunately, transfusion dependent-patients, i.e. those in whom a beneficial effect of rHuEPO would be most welcome, are unlikely to respond, and more generally, treatment is not cost effective in medically responsive patients.

Aged↗
PubMed1998

[Pachydermoperiostosis with extramedullary hematopoiesis without myelofibrosis].

BACKGROUND: In three previous reports of primary hypertrophic osteoarthropathy, an associated extramedullary hematopoiesis was related to myelofibrosis. CASE REPORT: A 44-year-old male patient with primary hypertrophic osteoarthropathy diagnosed when he was 34-year-old was referred to our hospital with an abdominal mass fortuitously detected. DISCUSSION: The present case is unique for the patient developed an extramedullary hematopoïesis without associated myelofibrosis. It suggests the possible intervention of growth factors common to the skin fibroblasts and the blood progenitor cells in the pathogenesis of primary osteoarthropathy.

Abdomen↗
PubMed1999

Autonomous megakaryocyte growth in essential thrombocythemia and idiopathic myelofibrosis is not related to a c-mpl mutation or to an autocrine stimulation by Mpl-L.

Essential thrombocythemia (ET) and idiopathic myelofibrosis (PMF) are two myeloproliferative diseases characterized by a marked megakaryocytic (MK) involvement. The pathogenesis of these two diseases is unknown. Recently it has been shown that overexpression of Mpl-ligand (Mpl-L) in mice induces thrombocytosis and myelofibrosis. In this study, we investigated whether Mpl-L was responsible for the pathogenesis of ET and PMF. Using in vitro cultures of blood or marrow CD34(+) cells, we investigated whether MK growth was abnormal in these two diseases. Spontaneous MK growth involving only a fraction (20%) of the MK progenitors, as compared with growth in the presence of pegylated recombinant human megakaryocyte growth and development factor (PEG-rhuMGDF), was found in both diseases (21ET and 14PMF) using serum-free semisolid and liquid cultures, including cultures at one cell per well. We first searched for a c-mpl mutation/deletion by sequencing the entire coding region of the gene by polymerase chain reaction (PCR) in nine ET patients and five PMF patients, but no mutation was found. We subsequently investigated whether an autocrine stimulation by Mpl-L could explain the autonomous MK growth. Addition of different preparations of soluble Mpl receptor (sMpl) containing a Fc domain of IgG1 (sMpl-Fc) markedly inhibited MK spontaneous growth in both ET and PMF patients. This effect was specific for sMpl because a control soluble receptor (s4-1BB-Fc) had no inhibitory effect and an sMpl devoid of the Fc fragment had the same inhibitory efficacy as the sMpl-Fc. This inhibition was reversed by addition of PEG-rhuMGDF or a combination of cytokines. The sMpl-Fc markedly altered the entry into cell cycle of the CD34(+) cells and increased the apoptosis that occurs in most patient CD34(+) cells in the absence of exogenous cytokine, suggesting an autocrine stimulation. In contrast, a neutralizing antibody against Mpl-L did not alter the spontaneous MK growth, whereas it totally abolished the effects of 10 ng/mL PEG-rhuMGDF on patient or normal CD34(+) cells. Mpl-L transcripts were detected at a very low level in the patient CD34(+)cells and MK and only when a highly sensitive fluorescent PCR technique was used. By quantitative reverse-transcription (RT)-PCR, the number of Mpl-L transcripts per actin transcripts was lower than detected in human Mpl-L-dependent cell lines, suggesting that this synthesis of Mpl-L was not biologically significant. In favor of this hypothesis, the Mpl-L protein was not detected in culture supernatants using either an enzyme-linked immunosorbent assay (ELISA) or a biological (Ba/F3hu c-mpl) assay, except in one PMF patient. Investigation of Mpl-L signaling showed an absence of constitutive activation of STATs in spontaneously growing patient MKs. Addition of PEG-rhuMGDF to these MKs activated STATs 3 and 5. This result further suggests that spontaneous growth is neither related to a stimulation by Mpl-L nor to a c-mpl mutation. In conclusion, our results show that Mpl-L or Mpl are not directly implicated in the abnormal proliferation of MK cells from ET and PMF. The mechanisms by which the sMpl mediates a growth inhibition will require further experiments.

Adult↗
PubMed1998

Fatal myelofibrosis following fludarabine administration in a patient with indolent lymphoma.

We report a case of fulminant myelofibrosis after administration of fludarabine in a patient diagnosed as having refractory low-grade lymphoma, progressing fatally. Myelofibrosis in the setting of an indolent lymphoma is very rare; this fact, and the short period between drug administration and fibrosis suggest an etiopathogenic link, although this potential and severe adverse effect of fludarabine has not been previously reported in the literature.

Antimetabolites, Antineoplastic↗
PubMed1979

Megakaryoblastic leukaemia (acute myelofibrosis): a report of three cases.

Three patients with megakaryoblastic leukaemia are described. All three presented with pancytopenia, a few blast cells in the peripheral blood and absence of overt hepatosplenomegaly. In two of them bone marrow aspiration yielded a dry tap. Histological investigation of the bone marrow indicated that the megakaryocytic cell line was the dominant proliferating lineage. Cytochemical and EM investigation supported these findings. The isomorphic isoenzyme pattern of the elevated serum lactic dehydrogenase might be of diagnostic importance. Despite chemotherapy, there was a rapidly fatal terminal leukaemic phase with high blast cell counts. The differentiation from other haematological malignancies, especially acute (aleukaemic) leukaemias and the accelerated phase of primary (chronic) myelofibrosis, is discussed. The picture appears to be identical with acute (malignant) myelofibrosis.

Acute Disease↗
PubMed1985

Characterization of blast cells in chronic granulocytic leukaemia in transformation, acute myelofibrosis and undifferentiated leukaemia. II. Studies with monoclonal antibodies and terminal transferase.

A panel of 19 monoclonal antibodies (McAb) and the enzyme terminal transferase (TdT) have been applied to the characterization of poorly differentiated blasts from 50 patients with chronic granulocytic leukaemia (CGL) and myelofibrosis in blast crisis (BC), acute myelofibrosis and undifferentiated leukaemia. These cells were also extensively studied by transmission electron microscopy (TEM) (see Polli et al, 1985a). McAb against platelet glycoproteins (GP) showed a high specificity for megakaryoblasts, in particular those reactive with the GPIIb/IIIa complex (J15) and GPIIIa (C15 and C17), which were positive in a higher proportion of blasts than the McAb to GPIb (AN51 and FMC25). Findings with these anti-platelet McAb paralleled those of the platelet-peroxidase (PPO) reaction in 76% of cases studied simultaneously. The PPO reaction was always positive in cases in which two or more of the McAb were reactive with the blast cells. The differences observed suggest, nevertheless, that PPO is more sensitive for megakaryoblasts than the McAb and that this TEM technique should be reserved for cases which are negative with the platelet specific McAb. Of the McAb against myeloid antigens used in this series OKM1 was positive in 50% of cases but the others failed to demonstrate early features of differentiation in myeloblasts and monoblasts. In only three cases were erythroid precursors demonstrated by TEM and these were the only ones reactive with a McAb to glycophorin-A (LICR LON/R10). TdT and the McAb J5 helped in the identification of lymphoblasts which were seen as a 'pure' proliferation in 23% of CGL-BC and as part of blast cell mixtures in another 17% of cases. The McAb reactive to haemopoietic precursor cells (RFB1, FMC8 and OKIa), on the other hand, were of no practical value for the classification of blast cell types. The lineage specificity of several of the McAb used in this study, confirmed by TEM, suggest that these reagents are valuable tools for the characterization of immature blast cells.

Acute Disease↗
PubMed2003

Myelofibrosis in a cat (abstract).

A 2-year-old female domestic shorthair cat was presented with ill-health and marked ascites. Clinically, there was marked pallor of mucous membranes. Two haematological examinations and transudate-exudate analyses of peritoneal fluid were conducted 1 week apart, as well as a coagulation screen and routine serum biochemistry. The haematological examinations revealed a severe persistent non-regenerative anaemia. There were no abnormalities within the neutrophil and lymphocyte cell lines. Very occasional nucleated red blood cells (RBCs) in peripheral circulation and some RBC agglutination were seen. Analysis of peritoneal fluid disclosed a modified transudate, and small numbers of erythroid and myeloid precursors were observed on the second occasion. The cat was FIV/FeLV-negative, and there were no coagulation abnormalities. Following necropsy and histopathological examination, myelofibrosis and extramedullary haematopoiesis were seen. Thoracic masses were hyperplastic lymph nodes in which there was evidence of extramedullary haematopoiesis. The exact cause of the myelofibrosis was not obvious but it may have been a case of myeloid metaplasia, however not all the characteristics of this entity were present.

Journal Article↗