Page 1316 - Williams Hematology ( PDFDrive )

1291

CHAPTER 84 Arterial and venous thromboses are a major cause of morbidity and mortal-

POLYCYTHEMIA VERA ity in PV, and a small proportion of patients develop secondary myelofibrosis
(sometimes called the spent phase) and/or an invariably fatal acute leukemic
transformation. Myelosuppressive therapy has been an effective mode of ther-
apy, with drugs such as hydroxyurea, busulfan, pipobroman, and radioactive
Jaroslav F. Prchal and Josef T. Prchal phosphorus useful in controlling proliferation of all blood cell lineages. How-
ever, while myelosuppressive therapy controls the cellular proliferation and
decreases the incidence of thrombotic complications, many of these drugs
have leukemogenic potential. In contrast, pegylated interferon-α may lead to
SUMMARY complete hematologic remission and restoration of polyclonal hematopoiesis
and avoid the leukemogenic complications. Targeted therapy with JAK2 kinase
Polycythemia vera (PV) is classified in the group of Philadelphia chromosome– inhibitors is currently being evaluated in clinical trials and, thus far, have been
negative myeloproliferative neoplasms (MPNs) that also includes essential found effective in decreasing the need for phlebotomies, decreasing the num-
thrombocythemia (ET) and primary myelofibrosis (PMF). Chronic myelog- ber of white cells and splenomegaly, and improving the patient’s quality of life.
enous leukemia was historically classified as a MPN, but is now considered
a separate entity. PV is an acquired primary clonal polycythemic disorder.
Primary polycythemias result from abnormal intrinsic properties of erythroid
progenitors that proliferate independently or excessively in response to extrin- DEFINITION AND HISTORY
sic regulators; low serum erythropoietin is their hallmark. PV is the most The term polycythemia, denoting an increased amount of blood, has
common primary polycythemia. It arises from mutation(s) of a pluripotent traditionally been applied to those conditions in which the mass of ery-
hematopoietic stem cell, which results in excess production of erythrocytes throcytes is increased. In polycythemia vera (PV), an increase in the
and variable overproduction of granulocytes and platelets. It is often accompa- erythroid mass is frequently accompanied by an increase in neutrophils
nied by splenomegaly. Most patients with PV have a somatic mutation of the and platelets. For a classification of the polycythemias, see Chap. 57 and
Janus-type tyrosine kinase-2 gene (JAK2) that is detectable in blood myeloid Chap. 34, Table 34–2. Although several clinical stages of PV are recog-
cells. The mutation results in constitutive hyperactivity of JAK2 kinase stem- nized (masked PV, plethoric phase, stable phase, transformation, spent
ming from loss-of-function of its negative regulatory domain. The most com- phase, and acute leukemia), it is not clear whether these stages represent
mon mutation is JAK2 V617F , which is present in virtually all cases of PV; a small a sequential progression of the disease or whether all patients progress
through all stages.
minority of PV patients have a mutation in other parts of JAK2 (exon 12). The PV, the sole clonal form of primary polycythemia, was first
JAK2 V617F mutation is also found in many patients with ET and myelofibrosis described in 1892 by Vaquez. In 1903, Osler reviewed four of his own
1
(MF), albeit at lower frequency (55 percent in ET and 65 percent in MF). As with PV cases and an additional five cases from the literature and wrote,
other clonal hematologic disorders, PV can undergo a clonal evolution to PMF “The condition is characterized by chronic cyanosis, polycythemia, and
(JAK2 V617F -positive) or acute leukemia (either JAK2 V617F -negative or positive). variable moderate enlargement of the spleen. The chief symptoms have
2
In virtually all JAK2 V617F -positive PV patients, at least some progenitors exist been weakness, prostration, constipation, headache, and vertigo.” The
that become homozygous for the JAK2 V617F mutation by uniparental disomy- increased proliferation of granulocyte precursors and megakaryocytes
acquired mitotic recombination. The majority of these progenitors account for was first described by Türk in 1904. 3
the erythropoietin-independent erythroid colonies detected in vitro by clono-
genic burst-forming unit–erythroid assay. The JAK2 V617F mutation is often not EPIDEMIOLOGY
the initial cause of clonal proliferation, but may be preceded by other germline A recent analysis of 20 studies of PV patients from around the world
and somatic mutation(s) (e.g., TET2).
revealed an annual incidence rate of 0.84 cases per 100,000 people, with
4,5
no bias for gender. The true incidence may be higher, as many cases
are asymptomatic and thus not diagnosed. Testing for the Janus-type
tyrosine kinase 2 (JAK2) V617F mutation can uncover hidden cases of PV
among subjects with thrombosis or concomitant iron deficiency. The
incidence of PV may be higher among Ashkenazi Jews. 6,7
Acronyms and Abbreviations: AML, acute myelogenous leukemia; BFU-E, Although most patients with PV do not have a history of polycythe-
burst-forming unit–erythroid; ECLAP, European Collaboration on Low-Dose mia in the family, familial incidence of the disorder is known to occur 8–10
Aspirin in Polycythemia Vera; EEC, endogenous erythroid colony; ELN, Euro- and is very likely underreported. In a large Swedish study of more than
pean Leukemia Net; ET, essential thrombocytosis; HDAC, histone deacety- 25,000 first-degree relatives of 11,000 myeloproliferative neoplasm
lase; HU, hydroxyurea; IFN-α, interferon-α; IWG-MRT, International Working (MPN) patients, the incidence of MPNs were five to seven times higher
11
Group for Myeloproliferative Neoplasms Research and Treatment; JAK2, in relatives than in controls. In familial cases of PV, an inherited predis-
Janus-type tyrosine kinase 2; MDS, myelodysplastic syndrome; MF, myelo- position, perhaps in the form of a germline mutation, presumably facil-
9,12
itates the acquired somatic mutation(s) necessary for disease onset.
fibrosis; MPN, myeloproliferative neoplasm; PCR, polymerase chain reaction;
PEG-IFN, pegylated interferon; PFCP, primary familial and congenital poly-
cythemia; PMF, primary myelofibrosis; PV, polycythemia vera; SNP, single ETIOLOGY AND PATHOGENESIS
nucleotide polymorphism; UPD, uniparental disomy; TET2, a homologue of PV arises from the neoplastic transformation of a single normal hemato-
chromosome 10-11 translocation; WHO, World Health Organization. poietic pluripotent cell, which acquires a selective proliferative and
survival advantage, resulting in the development of a variable degree

Kaushansky_chapter 84_p1291-1306.indd 1291 9/21/15 11:10 AM