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.