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200 American Society of Hematology
Chronic Myeloproliferative Disorders
Jerry L. Spivak, Giovanni Barosi, Gianni Tognoni, Tiziano Barbui, Guido Finazzi,Roberto Marchioli, and Monia Marchetti
The Philadelphia chromosome-negative chronicmyeloproliferative disorders (CMPD), poly-cythemia vera (PV), essential thrombocythemia(ET) and chronic idiopathic myelofibrosis (IMF),have overlapping clinical features but exhibitdifferent natural histories and different therapeuticrequirements. Phenotypic mimicry amongst thesedisorders and between them and nonclonalhematopoietic disorders, lack of clonal diagnosticmarkers, lack of understanding of their molecularbasis and paucity of controlled, prospectivetherapeutic trials have made the diagnosis andmanagement of PV, ET and IMF difficult.
In Section I, Dr. Jerry Spivak introducescurrent clinical controversies involving the CMPD,in particular the diagnostic challenges. Two newmolecular assays may prove useful in the diagno-sis and classification of CMPD. In 2000, theoverexpression in PV granulocytes of the mRNAfor the neutrophil antigen NBI/CD177, a member ofthe uPAR/Ly6/CD59 family of plasma membraneproteins, was documented. Overexpression ofPRV-1 mRNA appeared to be specific for PV sinceit was not observed in secondary erythrocytosis.At this time, it appears that overexpression ofgranulocyte PRV-1 in the presence of an elevatedred cell mass supports a diagnosis of PV; absenceof PRV-1 expression, however, should not begrounds for excluding PV as a diagnostic possibil-ity. Impaired expression of Mpl, the receptor forthrombopoietin, in platelets and megakaryocyteshas been first described in PV, but it has also beenobserved in some patients with ET and IMF. Thebiologic basis appears to be either alternativesplicing of Mpl mRNA or a single nucleotidepolymorphism, both of which involve Mpl exon 2and both of which lead to impaired posttransla-tional glycosylation and a dominant negativeeffect on normal Mpl expression. To date, no MplDNA structural abnormality or mutation has beenidentified in PV, ET or IMF.
In Section II, Dr. Tiziano Barbui reviews thebest clinical evidence for treatment strategydesign in PV and ET. Current recommendationsfor cytoreductive therapy in PV are still largelysimilar to those at the end of the PVSG era.
Phlebotomy to reduce the red cell mass and keepit at a safe level (hematocrit < 45%) remains thecornerstone of treatment. Venesection is aneffective and safe therapy and previous concernsabout potential side effects, including severe irondeficiency and an increased tendency to thrombo-sis or myelofibrosis, were erroneous. Manypatients require no other therapy for many years.For others, however, poor compliance to phle-botomy or progressive myeloproliferation, asindicated by increasing splenomegaly or very highleukocyte or platelet counts, may call for theintroduction of cytoreductive drugs. In ET, thetherapeutic trade-off between reducing thromboticevents and increasing the risk of leukemia withthe use of cytoreductive drugs should be ap-proached by patient risk stratification. Thromboticdeaths seem very rare in low-risk ET subjects andthere are no data indicating that fatalities can beprevented by starting cytoreductive drugs early.Therefore, withholding chemotherapy might bejustifiable in young, asymptomatic ET patientswith a platelet count below 1,500,000/mm3 andwith no additional risk factors for thrombosis. Ifcardiovascular risk factors together with ET areidentified (smoking, obesity, hypertension, hyper-lipidemia) it is wise to consider platelet-loweringagents on an individual basis.
In Section III, Dr. Gianni Tognoni discusses therole of aspirin therapy in PV based on the recentlycompleted European Collaboration on Low-doseAspirin in Polycythemia Vera (ECLAP) Study, amulti-country, multicenter project aimed at de-scribing the natural history of PV as well as theefficacy of low-dose aspirin. Aspirin treatmentlowered the risk of cardiovascular death, non-fatalmyocardial infarction, and non-fatal stroke (rela-tive risk 0.41 [95% CI 0.151.15], P = .0912). Totaland cardiovascular mortality were also reduced by46% and 59%, respectively. Major bleedings wereslightly increased nonsignificantly by aspirin(relative risk 1.62, 95% CI 0.279.71).
In Section IV, Dr. Giovanni Barosi reviews ourcurrent understanding of the pathophysiology ofIMF and, in particular, the contributions of anoma-lous megakaryocyte proliferation, neoangio-
Hematology 2003 201
genesis and abnormal CD34+ stem cell traffickingto disease pathogenesis. The role of newer thera-pies, such as low-conditioning stem cell transplan-tation and thalidomide, is discussed in the contextof a general treatment strategy for IMF. The resultsof a Phase II trial of low-dose thalidomide as asingle agent in 63 patients with myelofibrosis withmeloid metaplasia (MMM) using a dose-escalationdesign and an overall low dose of the drug (TheEuropean Collaboration on MMM) will be pre-
sented. Considering only patients who completed4 weeks of treatment, 31% had a response: thiswas mostly due to a beneficial effect of thalido-mide on patients with transfusion dependentanemia, 39% of whom abolished transfusions,patients with moderate to severe thrombocytope-nia, 28% of whom increased their platelet count bymore than 50 109/L, and patients with the largestsplenomegalies, 42% of whom reduced spleensize of more than 2 cm.
I. CLINICAL CONTROVERSIES INVOLVING THECHRONIC MYELOPROLIFERATIVE DISORDERS
Jerry L. Spivak, MD*
Polycythemia vera (PV), idiopathic myelofibrosis(IMF), and essential thrombocytosis (ET) have beentraditionally classified under the rubric the chronicmyeloproliferative disorders1 because they share thefollowing features: involvement of a multipotent he-matopoietic progenitor cell2; dominance of the trans-formed clone over nontransformed hematopoietic pro-genitor cells3; overproduction of one or more of theformed elements of the blood in the absence of a defin-able stimulus; growth factorindependent colony for-mation in vitro4; marrow hypercellularity; megakaryo-cyte hyperplasia and dysplasia; abnormalities predomi-nantly involving chromosomes 1, 8, 9, 13, and 205,6;thrombotic and hemorrhagic diatheses; exuberant ex-tramedullary hematopoiesis; and spontaneous transfor-mation to acute leukemia7 or the development of mar-row fibrosis but at a low rate compared with the rate inchronic myelogenous leukemia (CML).
This classification scheme, of course, implies thatwe know more about these disorders than we actuallydo. In fact, among hematologic disordersparticularlymalignant onesPV, IMF, and ET are among the leastwell understood and most understudied. For example,we do not know which multipotent hematopoietic stemcell is involved in these disorders, the significance ofclonality or the lack of it, whether the disorders areinterrelated to any extent, or how to reconcile their treat-ment with their clinical and clonal heterogeneity.
The recent World Health Organization classifica-tion of the chronic myeloproliferative diseases includesin addition to PV, IMF, and ET, the following disor-ders: CML (BCR/ABL positive), chronic neutrophilic
leukemia, chronic eosinophilic leukemia and thehypereosinophilic syndrome, and chronic myeloprolif-erative disease-unclassifiable,8 but only PV, IMF, andET will be considered here.
There are many reasons for this unsatisfactory situ-ation. First, while not rare, the chronic myeloprolifera-tive disorders are sufficiently uncommon that most phy-sicians, including hematologists, encounter very fewsuch patients in the course of their practice. Second,these disorders are not only chronic, but their clinicalmanifestations also vary during the course of the ill-ness, making it difficult for any one physician to ob-serve their full clinical scope. Third, the chronic my-eloproliferative disorders exhibit significant phenotypicmimicry, not only with respect to other benign andmalignant blood diseases but also, and most important,among themselves. As a consequence, since molecularmarkers for these disorders are lacking, attempts to dis-tinguish them on clinical grounds can be misleading.For example, approximately 10% of patients in onestudy of IMF actually had PV,9 while many of the pa-tients initially described as having ET had PV instead.10
Indeed, PV can present as isolated leukocytosis,11 iso-lated thrombocytosis,12 or myelofibrosis with myeloidmetaplasia,13 while IMF can also present with isolatedthrombocytosis. Fourth, ironically, because the chronicmyeloproliferative disorders were among the earliestrecognized hematologic diseases, it is commonly per-ceived that these diseases have been well characterized,when in fact the bulk of clinical information about themis not evidence based but both anecdotal and distortedbecause of the confounding issues cited above that areintrinsic to these disorders. For example, the clinicalphenotype for PV was derived from 13 case studiesselected from a group of 75 patients,14 while ET wasinitially designated hemorrhagic thrombocythemia10
although current clinical concerns about this disorderfocus on its thrombotic rather than its hemorrhagicmanifestations.15 Fifth, investigator bias has contributedsubstantially to our lack of knowledge or confusionabout the optimal treatment of the chronic myelopro-liferative disorders. For example, the perceived efficacy
* Johns Hopkins University School of Medicine, Departmentof Medicine, 720 Rutland Ave., Traylor 924, Baltimore MD21205-2109
202 American Society of Hematology
of 32P combined with lack of appreciation of the patho-physiology and natural history of PV led to the initialadoption of 32P as the treatment of choice for this dis-ease without the type of clinical trials that would bemandatory today and despite caveats about its toxic-ity.16,17,