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PubMed1995

An unwanted side effect of hydroxyurea in a patient with idiopathic myelofibrosis.

A patient with idiopathic myelofibrosis is reported who developed a drug fever after treatment with hydroxyurea, a generally effective and well-tolerated drug in chronic myeloproliferative syndromes. Typically, this form of fever develops after a few weeks of exposure to the drug and disappears with discontinuation of the drug. Possible interactions with prostaglandin or leukotriene metabolism may play a role.

Aged↗
PubMed1994

Primary myelofibrosis: a detailed statistical analysis of the clinicopathological variables influencing survival.

In the present study we analyzed the prognostic significance of several clinical, hematological, and histological parameters recorded at diagnosis in a consecutive series of 72 patients with primary myelofibrosis (PMF). Univariate analysis showed that the most significant indicators of poor survival were the following: age greater than 60, splenomegaly, anemia (hemoglobin > 10 g/dl), leukopenia (WBC < 4 x 10(9)/l or leukocytosis > 14 x 10(9)/l), and any of these histological features: adipose tissue and megakaryocyte reduction, prominent osteoblastic rims along the trabecular bone, presence of peritrabecular megakaryocytes (Mk), absence of normal or giant Mk. The multivariate analysis showed that only the level of hemoglobin and the presence of both normal Mk and fever independently influenced the prognosis. These parameters were used to set up a prognostic scoring system, allowing a feasible prognosis to be made for each patient at the time of diagnosis and identifying those patients in urgent need of new therapeutic approaches.

Adult↗
PubMed1989

Systemic lupus erythematosus and myelofibrosis.

The coexistence of systemic lupus erythematosus and myelofibrosis is a rare occurrence. A review of the literature available to us revealed only five other patients with this combination. We have recently encountered a patient in whom these two diseases existed concomitantly, and in this report we shall describe the clinical course of our patient and discuss it in comparison with the patients described previously.

Female↗
PubMed1996

Endoscopic injection sclerotherapy for esophageal variceal hemorrhage in a patient with idiopathic myelofibrosis.

A 74-year-old female with idiopathic myelofibrosis (IMF) was admitted to our hospital because of massive hematemesis and melena. Immediate upper gastrointestinal endoscopy revealed an intermittent spurting hemorrhage from extensive esophageal varices. Endoscopic injection sclerotherapy (EIS) was carried out and the bleeding ceased. After five courses of EIS, all the esophageal varices were eradicated. About 15 months later, the patient died, due to a cerebral hemorrhage, without further variceal bleeding. A postmortem examination was carried out and the portal hypertension was considered to be due not only to extramedullary hematopoiesis in the sinusoids, but also to increased splenic blood flow. We are confident that EIS is an effective therapeutic procedure for patients with IMF showing esophageal variceal hemorrhage. EIS should be the preferred choice of treatment for esophageal varices in patients with IMF, since it is less invasive than splenectomy.

Aged↗
PubMed1993

Idiopathic myelofibrosis--an update with particular reference to clinical aspects and prognosis.

Idiopathic myelofibrosis (IMF) is characterized by excessive accumulation of connective tissue in the bone marrow as part of a clinical syndrome which in its classical form is featured by leukoerythroblastic anemia and huge splenomegaly at the time of diagnosis. An acute variant of the disease exists being featured by pancytopenia, nor or minimal splenomegaly and a rapidly fatal clinical course. This review describes the relationship of IMF to other chronic myeloproliferative disorders and highlights current concepts of the pathogenesis of bone marrow fibrosis, implicating the intramedullary release of various growth factors, including platelet-derived growth factor beta. In a subgroup of patients bone marrow fibrosis may develop consequent to autoimmune bone marrow damage. The clinical and laboratory findings in some of the larger series of patients are presented and the reasons for the highly variable clinical presentation and prognosis are critically discussed. It is proposed that studies on prognosis in IMF are based upon simple prognostic staging systems, which should include the Hb-concentration, platelet count, spleen size and the presence/absence of osteomyelosclerosis on X-ray. Using these parameters the patients are easily categorized into three prognostic groups with highly different survival times.

Female↗
PubMed1981

The association of carcinoid tumors of the rectum with myelofibrosis: report of two cases.

Two patients with myelofibrosis, a primary malignancy of the hematopoietic system, have developed carcinoid tumors of the rectum. This development is rare, as rectal carcinoids are more often associated with other carcinomas of the gastrointestinal tract. Rectal carcinoid tumors are, in general, less commonly associated with second malignancies than are carcinoid tumors of foregut and midgut origin.

Anus Neoplasms↗
PubMed1987

Osteolytic lesions in idiopathic myelofibrosis.

A case of idiopathic myelofibrosis with the unusual finding of osteolytic lesions is presented. Biopsies from the lesions showed proliferation of fibroblasts, megakaryocytes and myeloid cells.

Biopsy↗
PubMed2001

Primary chronic myelofibrosis: clinical and prognostic evaluation in 336 Japanese patients.

We retrospectively analyzed 336 patients with primary chronic myelofibrosis from 203 medical institutes in Japan. Notwithstanding their heterogeneous treatments, the median survival in 298 patients that could be evaluated was 10.0 years. Average age at onset was 60.7 years. Men were affected 1.4 times more frequently than women. The factors associated with shorter survival included anemia, leukocytosis/leukocytopenia, thrombocytopenia, and increased blasts in the peripheral blood, and sex (male), age (>60), and the presence of symptoms. A new scoring system based on the peripheral blood findings (hemoglobin [Hb] level, platelet count, and rate of blast formation) at initial diagnosis clearly correlated with survival rate. Accordingly, patients could be categorized into 3 groups by severity grading. Through stepwise multivariate survival analysis, the significant prognostic factors were identified as the severity grading based on the new scoring system (P = .0002), age (P = .0024), sex (P = .0153), and Hb (P = .0198). Chromosomal abnormalities were found in 58 of 154 patients (38%), although these did not influence survival.

Actuarial Analysis↗
PubMed2001

A variant form of acute promyelocytic leukemia with marked myelofibrosis.

We describe a variant form, French-American-British (FAB) M3v, of acute promyelocytic leukemia (APL; FAB M3) with atypical morphocytochemical features, immature antigens (CD34 and HLA-DR) and marked myelofibrosis (MF). Usual APL cells do not express CD34 or HLA-DR antigens. MF may be more frequently observed in patients with M3v expressing CD34 and HLA-DR antigens than in patients with M3 lacking these antigens. Despite marked MF, recovery from the hypoplastic phase in the case we described was not delayed after remission induction chemotherapy consisting of enocitabine, 200 mg/mi2 intravenously; 6-mercaptopurine, 70 mg/m2 orally for 10 days; daunorubicin 40 mg/m2 intravenously for 4 days; and all-trans retinoic acid 45 mg/M2 orally between days 20 and 33. The promyelocytic leukemia-retinoic-acid receptor (PML-RAR) alpha fusion transcript, according to reverse transcriptase-polymerase chain reaction (RT-PCR), became negative in the bone marrow after the first course of consolidation chemotherapy. Autologous peripheral blood stem cell transplantation (autoPBSCT) was carried out after 3 courses of consolidation chemotherapy. There were no specific complications based on MF throughout the clinical course, including engraftment in autoPBSCT. The patient has been without MF and in molecular remission, defined as disappearance of the PML-RAR alpha fusion transcript according to RT-PCR, for 21 months. Longer follow-up will clarify the effects of autoPBSCT on prognosis in APL with MF.

Adolescent↗
PubMed2002

Clinical and pathological criteria for the diagnosis of essential thrombocythemia, polycythemia vera, and idiopathic myelofibrosis (agnogenic myeloid metaplasia).

A set of clinical and pathological criteria for the diagnosis and staging of Philadelphia chromosome-negative myeloproliferative disorders (Ph(1-)-MPDs) is presented by including bone marrow histopathology as a significant tool to identify the early, manifest, and advanced stages of essential thrombocythemia (ET), polycythemia vera (PV), and idiopathic myelofibrosis/agnogenic myeloid metaplasia (IMF/AMM). This combined approach provides a pathognomonic clue to each of the different subtypes of Ph(1-)-MPDs and further enables recognition of the various steps in the evolution of the myeloproliferative process Increase and clustering of giant to large megakaryocytes with mature cytoplasm and multilobulated staghorn-like nuclei in a normal or only slightly increased cellular bone marrow represent major hallmarks of ET. Loose assemblies of small to giant pleiomorphic megakaryocytes containing deeply lobulated nuclei together with a proliferation of erythro- and granulopoiesis (panmyelosis) are the specific lesions of PV. The initial prefibrotic and the overt and more advanced myelofibrotic stages of IMF/AMM show a pronounced proliferation of an abnormal megakaryo- and granulopoiesis dominated by clustered atypical medium-sized to giant megakaryocytes with cloud-like, bulbous, and often hyperchromatic nuclei, which are not seen in allied subtypes of MPDs including chronic myeloid leukemia (Ph(1+)-CML) and myelodysplastic syndromes (MDS). The presented clinical and pathological criteria modify the Polycythemia Vera Study Group (PVSG) proposals for the Ph(1-)-MPDs by including bone marrow histopathology and are in keeping with features outlined in the new World Health Organization classification. The latter allows the differentiation of true ET from reactive thrombocytosis and from thrombocythemias as an eventually presenting finding in PV, IMF/AMM, MDS, and Ph(1+)-CML. Moreover, these diagnostic guidelines are able to separate latent and early PV from secondary erythrocytosis and to detect the prefibrotic and early stages of IMF/AMM. Myelofibrosis is not a feature of ET and is rarely observed in PV at time of diagnosis, but it becomes apparent during long-term follow-up and constitutes a prominent lesion during the course of IMF/ AMM. Life expectancy is almost normal in ET and is also not significantly altered during the first, but compromised during the second, decade of follow-up in PV. On the other hand, survival is substantially shortened in IMF/AMM, even for patients with thrombocythemia as a frequent finding of prefibrotic and early stage IMF/AMM.

Bone Marrow↗
PubMed2003

Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis.

The Wilms tumor gene, WT1, is overexpressed not only in leukemias and myelodysplastic syndrome (MDS) but also in various types of solid tumors, including lung and breast cancer, and the WT1 protein is a tumor antigen for these malignancies. In clinical trials of WT1 peptide-based cancer immunotherapy, patients with overt leukemia from MDS or MDS with myelofibrosis were injected intradermally with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant. Only a single dose of WT1 vaccination resulted in an increase in WT1-specific cytotoxic T-lymphocytes, which was followed by a rapid reduction in leukemic blast cells. Severe leukopenia and local erythema at the injection sites of WT1 peptide were observed as adverse effects. These results have provided us with the first clinical evidence suggesting that WT1 peptide-based immunotherapy is an attractive treatment for patients with leukemias or MDS.

Aged↗
PubMed2002

Allogeneic hemopoietic stem cell transplantation in patients with myelodysplastic syndrome or myelofibrosis.

Myelodysplastic syndrome (MDS) and myeloproliferative disorders associated with myelofibrosis (MF) are stem cell disorders, and hemopoietic stem cell transplantation (HSCT) is currently the only therapy with curative potential. Among patients with less advanced MDS, 3 year survivals of 65% to 70% are achievable with HLA-identical related and HLA-matched unrelated donors. The probability of relapse is < 5%. Among patients with advanced disease (> or = 5% marrow blasts), about 35 to approximately 45% and 25 to approximately 30%, respectively, are surviving in remission after transplantation from related or unrelated donors. The incidence of post-transplant relapse is 1035%. Criteria of the International Prognostic Scoring System (IPSS), originally developed for nontransplanted patients, also predict survival following transplantation. Patients with MF, either idiopathic or on the basis of pre-existing disorders, are also transplanted successfully with stem cells from related or unrelated donors. Transplants early in the disease, before leukemic transformation, are successful in 60 to approximately 80% of patients. Success rates are lower in patients who have developed MDS or leukemia. New conditioning regimens have permitted successful HSCT even in patients in the seventh decade of life. Results with a regimen using a combination of busulfan (targeted to predetermined plasma levels) and cyclophosphamide are particularly encouraging. Improved survival with transplants from unrelated volunteer donors may, in part, reflect selection of donors on the basis of high resolution (allele-level) HLA typing. Nevertheless, transplant-related morbidity and mortality, including graft- vs. -host disease, remain challenges that need to be addressed with innovative approaches.

Hematopoietic Stem Cell Transplantation↗
PubMed2002

CD34+ progenitor cells in idiopathic (primary) myelofibrosis: a comparative quantification between spleen and bone marrow tissue.

Previous studies on idiopathic (primary) myelofibrosis (IMF) are in keeping with the finding of an increased number of circulating CD34+ progenitor cells. However, dependent on the fibrosclerotic changes, little knowledge exists about quantitative relationships of this precursor cell population in spleen and bone marrow. The purpose of this study was to determine the number of CD34+ cells at these sites by applying immunohistochemistry and morphometry. In seven patients with IMF and a control group without hematopathology (14 patients), CD34+ progenitors were identified in the red pulp of the spleen and also in bone marrow trephine biopsies by the monoclonal antibody QBEND10. Histological analysis showed no differences regarding size or cytological details of these cells at both sites in patients with IMF as well as in the controls. On the other hand, in the IMF group there was an unequal distribution with an approximate twofold increase in precursor cells in the spleen compared to the bone marrow. This result is opposed to corresponding values of the control group. Considering the quantity of progenitor cells in the normal bone marrow, no significant increase was revealed in IMF, but a marked pooling (more than fourfold of the normal value) in the spleen. In conclusion, our findings are in keeping with a increased number of splenic CD34+ progenitor cells and therefore support the hypothesis of a pronounced filtration and trapping of this precursor cell population by the spleen in IMF.

Aged↗
PubMed2001

Ineffectiveness of interferon-gamma in the treatment of idiopathic myelofibrosis: a pilot study.

It has been proposed that interferon-gamma (IFN) inhibits collagen synthesis in myeloproliferative disorders through an inhibitory effect on PDGF and TGF-beta. We therefore evaluated the role of IFN-gamma on bone marrow fibrosis in idiopathic myelofibrosis (IMF). After a 3-month observation period, nine patients (five female, four male), median age 64 years (range 43-72 years), received 3 x 3 mU IFN-gamma/week over 6 months and were monitored after withdrawal of IFN-gamma for further 3 months. Three out of nine patients have completed the study according to the protocol. Six patients had to be withdrawn from IFN-gamma due to the following reasons: bacterial infection (three patients), splenic infarction or deterioration of splenomegaly (one patient, each) and refusal to continue IFN-gamma (one patient). Results from seven patients treated for at least 8 weeks were considered measurable. Leukopenia, initially present in one of the evaluated patients, deteriorated during IFN-gamma treatment. This patient died during the observation period shortly after withdrawal of the therapy as a result of septicemia. Transfusion-dependent anemia, initially observed in two of the evaluated patients, deteriorated during the IFN-gamma treatment. Bone marrow fibrosis increased in three patients, whereas it remained unchanged in another and improved in a further patient. Splenomegaly improved in two patients but deteriorated markedly in one. Taking these observations together, four patients had disease progression during IFN-gamma treatment, two had stable disease and one could be qualified as a partial responder. According to these data IFN-gamma cannot be considered as a treatment option for patients with IMF.

Adult↗
PubMed1998

Neutrophil 5-nucleotidase reaction in chronic myelogenous leukemia, myelofibrosis with myeloid metaplasia, and polycythemia vera.

A readable and reproducible 5-nucleotidase (5N) cytochemical reaction was developed for blood smear preparation, after modification of the technique of Wachstein and Meisel. The reaction was applied to normal polymorphonuclear neutrophils (NPN) and to neutrophils from patients with chronic myelogenous leukemia (CML), myelofibrosis with myeloid metaplasia (MMM), and polycythemia vera (PV). The following observations were made: (a) 5N was present in NPN, with a mean score of 83.2+/-15.7. (b) In patients with MMM and PV an increased 5N score was observed (mean score 111+/-63.8 and 178.3+/-83.3, respectively). (c) In CML the mean score was 4.9+/-2.2. (c) A statistical comparison of neutrophil 5-nucleotidase (N5N) between CML and MMM and PV patients demonstrated a highly significant difference (p<0.0001). In the present study, we showed that the N5N activity parallels that of NAP in chronic myeloproliferative disorders such as CML, MMM, and PV. It appears that, apart from the already known activity of NAP in myeloproliferative disorders, other enzymes (e.g., N5N) can present a similar behavior with increased or decreased activity.

5'-Nucleotidase↗
PubMed1999

The role of interferon-alpha in the treatment of idiopathic myelofibrosis.

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by fibrosis of the bone marrow, varying degrees of extramedullary hematopoiesis, splenomegaly, anemia, and a leukoerythroblastic peripheral blood smear. Bone marrow fibrosis develops as a secondary phenomenon and is caused by increased intramedullary activity of mitogens such as platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and calmodulin. Because of the variable clinical course of IMF, attempts have been made to define prognostic parameters that can be helpful in detecting patients with a shortened life expectancy. The most important adverse prognostic parameters that have been reported are hemoglobin concentration, age, leukocyte count, number of thrombocytes, and cytogenetic abnormalities. However, no standardized prognostic score for IMF has yet been established. Therapeutic strategies in IMF remain predominantly supportive. The most common are blood transfusions, androgens, and cytoreductive agents such as hydroxyurea. Bone marrow transplantation is increasingly being taken into consideration, but it still has to be regarded as an experimental approach. Interferon-alpha (IFN-alpha) has shown promising results in early hyperproliferative stages of IMF but has no or only very little effect in more advanced stages of the disease. Whether IFN-alpha is able to postpone marrow fibrosis if administered in early disease stages remains to be determined in future clinical trials.

Humans↗