Showing papers by "Giovanni Barosi published in 2003"

Chronic Myeloproliferative Disorders

Abstract: The Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF), have overlapping clinical features but exhibit different natural histories and different therapeutic requirements. Phenotypic mimicry amongst these disorders and between them and nonclonal hematopoietic disorders, lack of clonal diagnostic markers, lack of understanding of their molecular basis and paucity of controlled, prospective therapeutic trials have made the diagnosis and management of PV, ET and IMF difficult. In Section I, Dr. Jerry Spivak introduces current clinical controversies involving the CMPD, in particular the diagnostic challenges. Two new molecular assays may prove useful in the diagnosis and classification of CMPD. In 2000, the overexpression in PV granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Overexpression of PRV-1 mRNA appeared to be specific for PV since it was not observed in secondary erythrocytosis. At this time, it appears that overexpression of granulocyte PRV-1 in the presence of an elevated red cell mass supports a diagnosis of PV; absence of PRV-1 expression, however, should not be grounds for excluding PV as a diagnostic possibility. Impaired expression of Mpl, the receptor for thrombopoietin, in platelets and megakaryocytes has been first described in PV, but it has also been observed in some patients with ET and IMF. The biologic basis appears to be either alternative splicing of Mpl mRNA or a single nucleotide polymorphism, both of which involve Mpl exon 2 and both of which lead to impaired posttranslational glycosylation and a dominant negative effect on normal Mpl expression. To date, no Mpl DNA structural abnormality or mutation has been identified in PV, ET or IMF. In Section II, Dr. Tiziano Barbui reviews the best clinical evidence for treatment strategy design in PV and ET. Current recommendations for cytoreductive therapy in PV are still largely similar to those at the end of the PVSG era. Phlebotomy to reduce the red cell mass and keep it at a safe level (hematocrit < 45%) remains the cornerstone of treatment. Venesection is an effective and safe therapy and previous concerns about potential side effects, including severe iron deficiency and an increased tendency to thrombosis or myelofibrosis, were erroneous. Many patients require no other therapy for many years. For others, however, poor compliance to phlebotomy or progressive myeloproliferation, as indicated by increasing splenomegaly or very high leukocyte or platelet counts, may call for the introduction of cytoreductive drugs. In ET, the therapeutic trade-off between reducing thrombotic events and increasing the risk of leukemia with the use of cytoreductive drugs should be approached by patient risk stratification. Thrombotic deaths seem very rare in low-risk ET subjects and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1500000/mm(3) and with no additional risk factors for thrombosis. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia) it is wise to consider platelet-lowering agents on an individual basis. In Section III, Dr. Gianni Tognoni discusses the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study, a multi-country, multicenter project aimed at describing the natural history of PV as well as the efficacy of low-dose aspirin. Aspirin treatment lowered the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (relative risk 0.41 [95% CI 0.15-1.15], P =.0912). Total and cardiovascular mortality were also reduced by 46% and 59%, respectively. Major bleedings were slightly increased nonsignificnsignificantly by aspirin (relative risk 1.62, 95% CI 0.27-9.71). In Section IV, Dr. Giovanni Barosi reviews our current understanding of the pathophysiology of IMF and, in particular, the contributions of anomalous megakaryocyte proliferation, neoangiogenesis and abnormal CD34(+) stem cell trafficking to disease pathogenesis. The role of newer therapies, such as low-conditioning stem cell transplantation and thalidomide, is discussed in the context of a general treatment strategy for IMF. The results of a Phase II trial of low-dose thalidomide as a single agent in 63 patients with myelofibrosis with meloid metaplasia (MMM) using a dose-escalation design and an overall low dose of the drug (The European Collaboration on MMM) will be presented. Considering only patients who completed 4 weeks of treatment, 31% had a response: this was mostly due to a beneficial effect of thalidomide on patients with transfusion dependent anemia, 39% of whom abolished transfusions, patients with moderate to severe thrombocytopenia, 28% of whom increased their platelet count by more than 50 x 10(9)/L, and patients with the largest splenomegalies, 42% of whom reduced spleen size of more than 2 cm.

Myelofibrosis with myeloid metaplasia.

Abstract: MMM is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and neoangiogenesis, constitutive release ofa high number of CD34+ stem cells from the bone marrow, and extramedullary hematopoiesis. It presents with heterogeneous clinical features in which anemia and progression to symptomatic splenomegaly dominate. The pathogenesis is undefined, but the dual action of deregulation of the bFGF pathway may influence myeloproliferation, myelofibrosis, and neoangiogenesis. Animal models suggest that chronic exposure to high doses of thrombopoietin or impairment of the capacity of megakaryocytes to differentiate into platelets, as occurs in the GATA-1(low) mice, is a necessary event for myelofibrosis. Allogeneic stem cell transplantation offers a chance of cure, and low conditioning regimens may extend the age of transplantable patients with lower mortality. Autologus stem cell transplantation and splenectomy are risky procedures that may be considered in patients with advanced disease when conventional therapies for correcting anemia (danazol, recombinant human erythropoietin, or cyclosporine) or chemotherapy for splenomegaly and myeloproliferation (hydroxyurea or interferon alfa) have failed. Thalidomide has been tested in numerous series, and its capacity to improve anemia and thrombocytopenia while reducing splenomegaly has been documented.

Clinical and economic issues in the treatment of advanced breast cancer with bisphosphonates.

Abstract: An ideal palliative therapy for bone metastases would successfully reduce skeletal complications in several thousands of breast cancer patients. Second- and third-generation bisphosphonates are effective in reducing the overall skeletal complication rate and the time to first skeletal complication. Nevertheless, not enough evidence supports their benefit on quality of life. Furthermore, bisphosphonates are expensive (up to $US775 per month, 2002 value) and cost-effectiveness evaluations have been limited to pamidronate (pamidronic acid). In economic evaluations of pamidronate, resulting incremental dollar per quality-adjusted life year gained ranged from cost savings to $US108 000 per quality-adjusted life year. The data were quite sensitive to quality-of-life estimates and country-specific cost values. Because of the wide range of the cost-effectiveness ratio, it is uncertain whether the universal prescription of bisphosphonates in this setting represents an efficient use of healthcare resources. Probably, country- and drug-specific policies might increase the efficiency of this treatment. Further outcomes research is required to assess these agents more fully.