Page 1279 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 70

PRIMARY MYELOFIBROSIS

John Mascarenhas, Vesna Najfeld, Marina Kremyanskaya, Alla Keyzner,
Mohamed E. Salama, and Ronald Hoffman

Primary myelofibrosis (PMF) is a chronic, malignant hematologic the chemical was first used in the leather and shoe industries during
disorder characterized by splenomegaly, cytopenias, systemic symp- the 1930s and 1940s. The average age at diagnosis of PMF is approxi-
toms, leukoerythroblastosis, teardrop poikilocytosis (i.e., dacryocytes), mately 65 years, and most patients are diagnosed between 50 and 69
ineffective hematopoiesis associated with megakaryocytic hyperplasia years of age. In several series, men have been affected more frequently
and dysplastic megakaryocytopoiesis, and the acquisition of a variety than women, but others have failed to confirm this male predomi-
of driver mutations (JAK2V617F, calreticulin exon 9 [CALR], and nance. Rarely, PMF has been reported in the pediatric age group.
the thrombopoietin receptor, MPL515L/K) along with varying Evidence of genetic transmission exists: a higher incidence has been
degrees of bone marrow (BM) fibrosis, increased BM microvessel reported in Ashkenazi Jews than in Arabs, who both live in Northern
density, and extramedullary hematopoiesis (EMH). The dysplastic Israel, and families where multiple members who suffer from a
megakaryocytes and clonal populations of myeloid cells elaborate number of the MPNs including PMF have been identified.
cytokines that are responsible for the development of BM fibrosis. PMF is a clonal hematologic malignancy originating in primitive
Fibrosis of the BM is not unique to PMF and may accompany many hematopoietic cells capable of producing lymphoid and myeloid cells,
other disorders (Table 70.1). The terms postpolycythemia vera (PV) while the BM fibrosis represents a secondary reaction of BM stromal
myelofibrosis (post-PV MF) and postessential thrombocythemia (ET) cells. The ability of primitive human hematopoietic cells to engraft
myelofibrosis (post-ET MF) have been developed to classify MF that sublethally irradiated immunodeficient mice is the standard surrogate
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is preceded by a history of PV or ET. In PMF, the BM fibrosis occurs in vivo assay for human HSCs. PMF CD34 cells are capable of
in response to the progeny of a clonal proliferation of hematopoietic engrafting non-obese non-diabetic/severe combined immune defi-
stem cells (HSCs). In 1951, Dameshek included PMF among a group cient (NOD/SCID) mice and generating myeloid and B cells that
of related disorders that he termed myeloproliferative disorders (MPDs). are clonal, JAK2V617F positive, and carry a patient-specific marker
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This hypothesis was largely based on clinical observations of patients chromosomal abnormality. The differentiation program of PMF
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with PV, chronic myeloid leukemia (CML), and ET who developed CD34 cells after transplant into NOD/SCID mice was also remark-
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BM fibrosis and a clinical picture resembling PMF. Dameshek also ably different from that of normal CD34 cells, producing greater
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noticed that each of these MPDs frequently evolve over time, chang- numbers of CD34 , CD33 , and CD41 cells but fewer CD19 cells.
ing their clinical phenotype, and frequently terminate in a leukemic This predisposition to produce greater numbers of megakaryocytes
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phase. In 2008, the World Health Organization (WHO) modified has been further explored by incubating PMF, PV, and CD34 cells
the terminology of MPDs to myeloproliferative neoplasms (MPNs) in vitro in the presence of stem cell factor and thrombopoietin. PMF
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to correctly reflect their malignant nature. 1 CD34 cells displayed a far greater proliferative capacity and produced
greater numbers of megakaryocytes that were characterized by a
resistance to undergo apoptosis in vitro caused by overexpression of
EPIDEMIOLOGY the antiapoptotic factor B-cell lymphoma-extra large (Bcl-XL). The
megakaryocyte hyperplasia in PMF, therefore, could be accounted for
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Few epidemiologic studies are available to estimate the incidence of by two factors—an increased ability of CD34 cells to generate
PMF. Previously published reports indicate an annual incidence rate megakaryocytes and the accumulation of megakaryocytes caused by
in European, Australian, and North American localities ranging from Bcl-xL overexpression. Although Bcl-xL overexpression has been
0.5 to 1.3 cases per 100,000 persons. The annual incidence rate of linked to JAK2V617F, PMF megakaryocyte Bcl-xL overexpression
PMF in Olmstead County (MN, USA) was reported to be 1.33 cases also occurred to a similar degree in megakaryocytes generated from
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per 100,000 persons, and in southeast England (UK), the annual CD34 cells isolated from individuals with both JAK2V617F-positive
incidence has been reported to be 0.37 per 100,000 persons. In Japan, and -negative disease. The role of megakaryocytes in the development
PMF is considered a rare disorder. The incidence of MF among of fibrosis in PMF is further supported by megakaryocytic hyperplasia
survivors who were 10,000 m or less from the hypocenter of the with dysplastic or necrotic megakaryocytes that characterizes this
atomic bomb explosion at Hiroshima, however, was 18 times the disorder; by the increased circulating megakaryocytes and mega-
incidence reported from the remainder of Japan. These patients karyocyte progenitors that are present in PMF; by the association of
became symptomatic an average of 6 years after the bomb blast. Such BM fibrosis and acute megakaryocytic leukemia; and by the presence
data indicate a strong link between excessive radiation exposure and of MF in gray platelet syndrome, an inherited disorder of platelet
development of PMF, which is further substantiated by the high α-granules. Ineffective megakaryocytopoiesis in PMF has been
incidence of MF in patients who have received the contrast material hypothesized to lead to the liberation of excessive amounts of such
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Thorotrast (which contains Th, a radioactive element with a half- growth factors, leading to BM fibroblast proliferation and collagen
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life of 1.41 × 10 years). Thorotrast is taken up and retained indefi- synthesis. PMF platelet-derived growth factor (PDGF) and trans-
nitely by cells of the reticuloendothelial system, which results in forming growth factor-β (TGF-β) levels have been found to be
continuous irradiation of the liver, spleen, lymph nodes, and BM. 2.0–3.0-fold and 1.5–3.0-fold higher, respectively, in PMF than in
Chronic exposure to several industrial solvents, including benzene normal control participants, but fibroblast growth factor (FGF) levels
and toluene, has also been associated with the development of PMF. in PMF were similar to those of control platelets. The roles of PDGF
Unlike PV, where clusters of patients have been identified in Eastern and TGF-β in the biogenesis of PMF probably are not restricted to
Pennsylvania, raising the concern for possible environmental effects promoting fibroblastic proliferation, but are also related to the effect
of waste-coal and Superfund sites, there are no definitive epidemio- of these two growth factors on synthesis, secretion, and degradation
logic studies supporting environmental exposures in PMF. PMF has of extracellular matrix components. TGF-β enhances fibronectin and
been reported as a complication of chronic benzene poisoning since collagens types I, III, and IV, as well as chondroitin or dermatan
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