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PV is a clonal hematopoietic stem cell disorder in which phenotypically normal red cells, granulocytes, and platelets accumulate in the absence of a recognizable physiologic stimulus. The most common of the MPN, PV occurs in 2.5 per 100,000 persons, sparing no adult age group and increasing with age to rates over 10/100,000. Familial transmission is infrequent, and women predominate among sporadic cases.

ETIOLOGY

image Nonrandom chromosome abnormalities such as deletion 20q and deletion 13q or trisomy 9 occur in up to 30% of untreated PV patients, but unlike CML, no consistent cytogenetic abnormality has been associated with the disorder. However, a mutation in the autoinhibitory pseudokinase domain of the tyrosine kinase JAK2 that replaces valine with phenylalanine (V617F), causing constitutive kinase activation—appears to have a central role in PV pathogenesis.

JAK2 is a member of an evolutionarily well-conserved, nonreceptor tyrosine kinase family and serves as the cognate tyrosine kinase for the erythropoietin and thrombopoietin receptors. It also functions as an obligate chaperone for these receptors in the Golgi apparatus and is responsible for their cell-surface expression. The conformational change induced in the erythropoietin and thrombopoietin receptors following binding to their respective cognate ligands, erythropoietin or thrombopoietin, leads to JAK2 autophosphorylation, receptor phosphorylation, and phosphorylation of proteins involved in cell proliferation, differentiation, and resistance to apoptosis. Transgenic animals lacking JAK2 die as embryos from severe anemia. Constitutive activation of JAK2, on the other hand, explains the erythropoietin hypersensitivity, erythropoietin-independent erythroid colony formation, rapid terminal differentiation, increased Bcl-XL expression, and apoptosis resistance in the absence of erythropoietin that characterize the in vitro behavior of PV erythroid progenitor cells.

More than 95% of PV patients express this mutation, as do ∼50% of PMF and ET patients. Importantly, the JAK2 gene is located on the short arm of chromosome 9, and loss of heterozygosity on chromosome 9p involving the segment containing the JAK2 locus over time due to mitotic recombination (uniparental disomy), is the most common cytogenetic abnormality in PV. Loss of heterozygosity in this region leads to homozygosity for JAK2 V617F and occurs in ∼60% of PV patients and to a lesser extent in PMF but is rare in ET. Most PV patients who do not express JAK2 V617F express a mutation in exon 12 of the gene and are not clinically different from those who do, with the exception of a higher frequency of isolated erythrocytosis, nor do JAK2 V617F heterozygotes differ clinically from homozygotes. Importantly, the predisposition to acquire JAK2 mutations appears to be associated with a specific JAK2 gene haplotype, GGCC. JAK2 V617F is the basis for many of the phenotypic and biochemical characteristics of PV such as increased blood cell production and increased inflammatory cytokine production; however, it cannot solely account for the entire PV phenotype and is probably not the initiating lesion in any of the MPN. First, PV patients with the same phenotype and documented clonal disease can have mutations in LNK, a JAK2 inhibitor, or rarely, calreticulin (CALR), an ER chaperone. Second, ET and PMF patients have the same mutation but different clinical phenotypes. Third, familial PV can occur without the mutation, even when other members of the same family express it. Fourth, not all the cells of the malignant clone express JAK2 V617F. Fifth, inhibition of JAK2 V617F-expressing hematopoietic progenitor cells by the nonspecific JAK1/2 kinase inhibitor, ruxolitinib, does not affect the behavior of the involved hematopoietic stem cells. Finally, in some JAK2 V617F–positive PV or ET patients, acute leukemia can occur in a JAK2 V617F–negative progenitor cell, suggesting the presence of an ancestral precursor cell.

CLINICAL FEATURES

Isolated thrombocytosis, leukocytosis, or splenomegaly may be the initial presenting manifestation of PV, but most often the disorder is first recognized by the incidental discovery of a high hemoglobin, hematocrit, or red cell count. With the exception of aquagenic pruritus, no symptoms distinguish PV from other causes of erythrocytosis.

Uncontrolled erythrocytosis causes hyperviscosity, leading to neurologic symptoms such as vertigo, tinnitus, headache, visual disturbances, and transient ischemic attacks (TIA). Systolic hypertension is also a feature of the red cell mass elevation. In some patients, venous or arterial thrombosis may be the presenting manifestation of PV. Any vessel can be affected; but cerebral, cardiac, and mesenteric vessels are most commonly involved. Hepatic venous thrombosis (Budd-Chiari syndrome) is particularly common in young women and may be catastrophic if sudden and complete obstruction of the hepatic vein occurs. Indeed, PV should be suspected in any patient who develops hepatic vein thrombosis. Digital ischemia, easy bruising, epistaxis, acid-peptic disease, or gastrointestinal hemorrhage may occur due to vascular stasis or thrombocytosis. In the latter instance, absorption and proteolysis of high molecular weight von Willebrand multimers by the large platelet mass causes acquired von Willebrand disease. Erythema, burning, and pain in the extremities, a symptom complex known as erythromelalgia, is another complication of thrombocytosis in PV due to increased platelet stickiness. Given the large turnover of hematopoietic cells, hyperuricemia with secondary gout, uric acid stones, and symptoms due to hypermetabolism can also complicate the disorder.

DIAGNOSIS

When PV presents with erythrocytosis in combination with leukocytosis, thrombocytosis, or splenomegaly or any combination of these, the diagnosis is apparent. However, when patients present with an elevated hemoglobin, hematocrit, or red cell count alone, the diagnostic evaluation is more complex because of the many diagnostic possibilities (Table 99-2). Furthermore, unless the hemoglobin level is ≥20 g/dL (hematocrit ≥60%), it is not possible to distinguish true erythrocytosis from disorders causing plasma volume contraction. This is because uniquely in PV, in contrast to other causes of true erythrocytosis, there is expansion of the plasma volume, which can mask the elevated red cell mass, particularly in women; thus, red cell mass and plasma volume determinations are necessary to establish the presence of an absolute erythrocytosis and distinguish this from relative erythrocytosis due to a reduction in plasma volume alone (also known as stress or spurious erythrocytosis or Gaisböck’s syndrome). Figure 59-18 illustrates a diagnostic algorithm for the evaluation of suspected erythrocytosis. Assay for JAK2 mutations in the presence of a normal arterial oxygen saturation provides an alternative diagnostic approach to erythrocytosis when red cell mass and plasma volume determinations are not available; a normal serum erythropoietin level does not exclude the presence of PV, but an elevated erythropoietin level is more consistent with a secondary cause for the erythrocytosis.

TABLE 99-2Causes of Erythrocytosis

Other laboratory studies that may aid in diagnosis include the red cell count, mean corpuscular volume, and red cell distribution width (RDW), particularly when the hematocrit or hemoglobin levels are less than 60% or 20 g/dL, respectively. Only three situations cause microcytic erythrocytosis: β-thalassemia trait, hypoxic erythrocytosis, and PV. With β-thalassemia trait, the RDW is usually normal, whereas with hypoxic erythrocytosis and PV, the RDW may be elevated due to associated iron deficiency. Today, however, the assay for JAK2 V617F has superseded other tests for establishing the diagnosis of PV. Of course, in patients with associated acid-peptic disease, occult gastrointestinal bleeding may lead to a presentation with hypochromic, microcytic anemia, masking the presence of PV.

A bone marrow aspirate and biopsy provide no specific diagnostic information because these may be normal or indistinguishable from ET or PMF. Similarly, no specific cytogenetic abnormality is associated with the disease, and the absence of a cytogenetic marker does not exclude the diagnosis.

COMPLICATIONS

Many of the clinical complications of PV relate directly to the increase in blood viscosity associated with red cell mass elevation and indirectly to the increased turnover of red cells, leukocytes, and platelets with the attendant increase in uric acid and inflammatory cytokine production. The latter appears to be responsible for constitutional symptoms. Peptic ulcer disease can also be due to Helicobacter pylori infection, the incidence of which is increased in PV, while the pruritus associated with this disorder may be a consequence of mast cell activation by JAK2 V617F. A sudden increase in spleen size can be associated with painful splenic infarction. Myelofibrosis appears to be part of the natural history of the disease but is a reactive, reversible process that does not itself impede hematopoiesis and by itself has no prognostic significance. In ∼15% of patients, however, myelofibrosis is associated with hematopoietic stem cell failure, manifested by substantial extramedullary hematopoiesis in the liver and spleen and transfusion-dependent anemia. The organomegaly can cause significant mechanical discomfort, portal hypertension, and progressive cachexia. Although the incidence of acute myeloid leukemia is increased in PV, the incidence of acute leukemia in patients not exposed to chemotherapy or radiation therapy is low. Interestingly, chemotherapy, including hydroxyurea, has been associated with acute leukemia in JAK2 V617F–negative stem cells in some PV patients. Erythromelalgia is a curious syndrome of unknown etiology associated with thrombocytosis, primarily involving the lower extremities and usually manifested by erythema, warmth, and pain of the affected appendage and occasionally digital infarction. It occurs with a variable frequency and is usually responsive to salicylates. Some of the central nervous system symptoms observed in patients with PV, such as ocular migraine, appear to represent a variant of erythromelalgia.

Left uncontrolled, erythrocytosis can lead to thrombosis involving vital organs such as the liver, heart, brain, or lungs. Patients with massive splenomegaly are particularly prone to thrombotic events because the associated increase in plasma volume masks the true extent of the red cell mass elevation measured by the hematocrit or hemoglobin level. A “normal” hematocrit or hemoglobin level in a PV patient with massive splenomegaly should be considered indicative of an elevated red cell mass until proven otherwise.

TREATMENT

TREATMENT Polycythemia Vera

PV is generally an indolent disorder, the clinical course of which is measured in decades, and its management should reflect its tempo. Thrombosis due to erythrocytosis is the most significant complication and often the presenting manifestation; maintenance of the hemoglobin level at ≤140 g/L (14 g/dL; hematocrit <45%) in men and ≤120 g/L (12 g/dL; hematocrit <42%) in women is mandatory to avoid thrombotic complications. Phlebotomy serves initially to reduce hyperviscosity by reducing the red cell mass to normal while further expanding the plasma volume. Periodic phlebotomies thereafter serve to maintain the red cell mass within the normal range and induce a state of iron deficiency that prevents accelerated reexpansion of the red cell mass. In most PV patients, once an iron-deficient state is achieved, phlebotomy is usually only required at 3-month intervals. Neither phlebotomy nor iron deficiency increases the platelet count relative to the effect of the disease itself, and neither thrombocytosis nor leukocytosis are correlated with thrombosis in PV, in contrast to the strong correlation between erythrocytosis and thrombosis. The use of salicylates to prevent thrombosis in PV patients is not only potentially harmful if the red cell mass is not controlled by phlebotomy, but is also an unproven remedy. Anticoagulants are indicated when a thrombosis has occurred and can be difficult to monitor if the red cell mass is substantially elevated owing to the artifactual imbalance between the test tube anticoagulant and plasma that occurs when blood from these patients is assayed for prothrombin or partial thromboplastin activity. Asymptomatic hyperuricemia (<10 mg/dL) requires no therapy, but allopurinol should be administered to avoid further elevation of the uric acid when chemotherapy is used to reduce splenomegaly or leukocytosis or to treat pruritus. Generalized pruritus intractable to antihistamines or antidepressants such as doxepin can be a major problem in PV; the JAK1/2 inhibitor, ruxolitinib, pegylated interferon α (IFN-α), psoralens with ultraviolet light in the A range (PUVA) therapy, and hydroxyurea are other methods of palliation. Asymptomatic thrombocytosis requires no therapy unless the platelet count is sufficiently high to cause bleeding due to acquired von Willebrand’s disease, but bleeding in this situation is not usually spontaneous and is responsive to ε-aminocaproic acid. Symptomatic splenomegaly can be treated with either ruxolitinib or pegylated IFN-α. Pegylated IFN-α has the advantage over recombinant IFN-α of being better tolerated and requiring only weekly administration and produced complete hematologic and molecular remissions in ∼20% of PV patients; its role in this disorder is currently under investigation. Anagrelide, a phosphodiesterase inhibitor, can reduce the platelet count and, if tolerated, is preferable to hydroxyurea because it lacks marrow toxicity and is also protective against venous thrombosis while hydroxyurea is not. A reduction in platelet number may be necessary for the treatment of erythromelalgia or ocular migraine if salicylates are not effective or if the platelet count is sufficiently high to increase the risk of hemorrhage, but only to the degree that symptoms are alleviated. Alkylating agents and radioactive sodium phosphate (32P) are leukemogenic in PV, and their use should be avoided. If a cytotoxic agent must be used, hydroxyurea is preferred, but this drug does not prevent either thrombosis or myelofibrosis in PV, is itself leukemogenic, and should be used for as short a time as possible. Previously, PV patients with massive splenomegaly unresponsive to reduction by chemotherapy or interferon required splenectomy. However, with the introduction of the nonspecific JAK2 inhibitor ruxolitinib, it has been possible in the majority of patients with PV complicated by myelofibrosis and myeloid metaplasia to reduce spleen size while at the same time alleviating constitutional symptoms and pruritus due to cytokine release and reducing the phlebotomy requirement. Ruxolitinib has also been demonstrated in a phase three clinical trial to be effective in PV patients without myelofibrosis who are intolerant or refractory to hydroxyurea or best available supportive therapy. In some patients with end-stage disease, pulmonary hypertension may develop due to fibrosis or extramedullary hematopoiesis. A role for bone marrow transplantation, either allogeneic or haploidentical, in PV has not been defined.

Most patients with PV can live long lives without functional impairment when their red cell mass is effectively managed with phlebotomy alone. Chemotherapy is never indicated to control the red cell mass unless venous access is inadequate.

PRIMARY MYELOFIBROSIS

Chronic PMF (other designations include idiopathic myelofibrosis, agnogenic myeloid metaplasia, or myelofibrosis with myeloid metaplasia) is a clonal hematopoietic stem cell disorder associated with mutations in JAK2, MPL or CALR and characterized by marrow fibrosis, extramedullary hematopoiesis, and splenomegaly. PMF is the least common MPN, and establishing its diagnosis in the absence of a specific clonal marker is difficult because myelofibrosis and splenomegaly are also features of both PV and CML. Furthermore, myelofibrosis and splenomegaly also occur in a variety of benign and malignant disorders (Table 99-3), many of which are amenable to specific therapies not effective in PMF. In contrast to the other MPN and so-called acute or malignant myelofibrosis, which can occur at any age, PMF primarily afflicts men in their sixth decade or later.

TABLE 99-3Disorders Causing Myelofibrosis

ETIOLOGY

Nonrandom chromosome abnormalities such as 9p, 20q−, 13q−, trisomy 8 or 9, or partial trisomy 1q are common in PMF, but no cytogenetic abnormality specific to the disease has been identified. JAK2 V617F is present in ∼50% of PMF patients, and mutations in the thrombopoietin receptor, MPL, occur in about 8%. Most of the rest have mutations in the calreticulin gene (CALR) that alter the carboxy-terminal portion of the protein, permitting it to bind and activate MPL. The degree of myelofibrosis and the extent of extramedullary hematopoiesis are not related. Fibrosis in this disorder is associated with overproduction of transforming growth factor β and tissue inhibitors of metalloproteinases, while osteosclerosis is associated with overproduction of osteoprotegerin, an osteoclast inhibitor. Marrow angiogenesis occurs due to increased production of vascular endothelial growth factor. Importantly, fibroblasts in PMF are polyclonal and not part of the neoplastic clone but can be induced by it to produce inflammatory cytokines.

CLINICAL FEATURES

No signs or symptoms are specific for PMF. Many patients are asymptomatic at presentation, and the disease is usually detected by the discovery of splenic enlargement and/or abnormal blood counts during a routine examination. In contrast to its companion MPN, night sweats, fatigue, and weight loss are common presenting complaints. A blood smear will show the characteristic features of extramedullary hematopoiesis: teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes; myeloblasts may also be present (Fig. 99-1). Anemia, usually mild initially, is common, whereas the leukocyte and platelet counts are either normal or increased, but either can be depressed. Mild hepatomegaly may accompany the splenomegaly but is unusual in its absence; isolated lymphadenopathy should suggest another diagnosis. Both serum lactate dehydrogenase and alkaline phosphatase levels can be elevated. Marrow is usually inaspirable due to the myelofibrosis (Fig. 99-2), and bone x-rays may reveal osteosclerosis. Exuberant extramedullary hematopoiesis can cause ascites; portal, pulmonary, or intracranial hypertension; intestinal or ureteral obstruction; pericardial tamponade; spinal cord compression; or skin nodules. Splenic enlargement can be sufficiently rapid to cause splenic infarction with fever and pleuritic chest pain. Hyperuricemia and secondary gout may ensue.

FIGURE 99-1

Teardrop-shaped red blood cells indicative of membrane damage from passage through the spleen, a nucleated red blood cell, and immature myeloid cells indicative of extramedullary hematopoiesis are noted. This peripheral blood smear is related to any cause of extramedullary hematopoiesis.

FIGURE 99-2

This marrow section shows the marrow cavity replaced by fibrous tissue composed of reticulin fibers and collagen. When this fibrosis is due to a primary hematologic process, it is called myelofibrosis. When the fibrosis is secondary to a tumor or a granulomatous process, it is called myelophthisis.

DIAGNOSIS

While the clinical picture described above is characteristic of PMF, all of these clinical features can be observed in PV or CML. Massive splenomegaly commonly masks erythrocytosis in PV, and reports of intraabdominal thrombosis in PMF most likely represent instances of unrecognized PV. In some PMF patients, erythrocytosis has developed during the course of the disease. Furthermore, because many other disorders have features that overlap with PMF but respond to distinctly different therapies, the diagnosis of PMF is one of exclusion, which requires that the disorders listed in Table 99-3 be ruled out.

The presence of teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes establishes the presence of extramedullary hematopoiesis, while the presence of leukocytosis, thrombocytosis with large and bizarre platelets, and circulating myelocytes suggests the presence of an MPN as opposed to a secondary form of myelofibrosis (Table 99-3). Marrow is usually inaspirable due to increased marrow reticulin, but marrow biopsy will reveal a hypercellular marrow with trilineage hyperplasia and, in particular, increased numbers of megakaryocytes in clusters and with large, dysplastic nuclei. However, there are no characteristic bone marrow morphologic abnormalities that distinguish PMF from the other MPN. Splenomegaly due to extramedullary hematopoiesis may be sufficiently massive to cause portal hypertension and variceal formation. In some patients, exuberant extramedullary hematopoiesis can dominate the clinical picture. An intriguing feature of PMF is the occurrence of autoimmune abnormalities such as immune complexes, antinuclear antibodies, rheumatoid factor, or a positive Coombs’ test. Whether these represent a host reaction to the disorder or are involved in its pathogenesis is unknown. Cytogenetic analysis of the blood is useful both to exclude CML and for prognostic purposes because the development of complex karyotype abnormalities portends a poor prognosis in PMF. For unknown reasons, the number of circulating CD34+ cells is markedly increased in PMF (>15,000/μL) compared to the other MPN, unless they too develop extramedullary hematopoiesis.

Importantly, ∼50% of PMF patients, like patients with its companion MPN, express the JAK2 V617F mutation, often as homozygotes. Such patients are usually older and have higher hematocrits than patients with MPL (8%) or CALR (30%) mutations; PMF patients expressing an MPL mutation tend to be more anemic and have lower leukocyte counts than JAK2 V617F-positive patients. Somatic mutations (due to deletions [type 1] or insertions [type 2]) in exon 9 of CALR have been found in a majority of patients with PMF who lack mutations in either JAK2 or MPL. In some studies, type 1 mutations, the most common CALR mutation in PMF, had a survival advantage compared to JAK2 or MPL mutations but not with respect to leukemic transformation. PMF patients who lack a known driver mutation have the worst prognosis.

COMPLICATIONS

Survival in PMF varies according to specific risk factors at diagnosis (Tables 99-4 and 99-5) but is shorter than in PV and ET patients. The natural history of PMF is one of increasing marrow failure with transfusion-dependent anemia and increasing organomegaly due to extramedullary hematopoiesis. As with CML, PMF can evolve from a chronic to an accelerated phase with constitutional symptoms and increasing marrow failure. About 10% of patients spontaneously transform to an aggressive form of acute leukemia for which therapy is usually ineffective. Additional important prognostic factors for disease acceleration during the course of PMF include the presence of complex cytogenetic abnormalities, thrombocytopenia, and transfusion-dependent anemia. Mutations in the ASXL1, EZH2, SRSF2, and IDH1/2 genes have been identified as risk factors for early death or transformation to acute leukemia and may prove to be more useful for PMF risk assessment than clinical scoring systems.

TABLE 99-4Three Current Scoring Systems for Estimating Prognosis in PMF Patients
TABLE 99-5IPSS and DIPSS Risk Stratification Systems

TREATMENT

TREATMENT Primary Myelofibrosis

No specific therapy exists for PMF. The causes for anemia are multifarious and include ineffective erythropoiesis uncompensated by splenic extramedullary hematopoiesis, hemodilution due to splenomegaly, splenic sequestration, blood loss secondary to thrombocytopenia or portal hypertension, folic acid deficiency, systemic inflammation, and autoimmune hemolysis. Neither recombinant erythropoietin nor androgens such as danazol have proven to be consistently effective as therapy for anemia. Erythropoietin may worsen splenomegaly and will be ineffective if the serum erythropoietin level is >125 mU/L. Given the inflammatory milieu that characterizes PMF, glucocorticoids can ameliorate anemia as well as constitutional symptoms such as fever, chills, night sweats, anorexia, and weight loss, and combining these with low-dose thalidomide has proved effective as well. Thrombocytopenia can be due to impaired marrow function, splenic sequestration, or autoimmune destruction and may also respond to low-dose thalidomide and prednisone.

Splenomegaly is by far the most distressing and intractable problem for PMF patients, causing abdominal pain, portal hypertension, easy satiety, and cachexia, whereas surgical removal of a massive spleen is associated with significant postoperative complications including mesenteric venous thrombosis, hemorrhage, rebound leukocytosis and thrombocytosis, and hepatic extramedullary hematopoiesis with no amelioration of either anemia or thrombocytopenia when present. For unexplained reasons, splenectomy also increases the risk of blastic transformation. Splenic irradiation is, at best, temporarily palliative and associated with a significant risk of neutropenia, infection, and subsequent operative hemorrhage if splenectomy is attempted. Allopurinol can control significant hyperuricemia, and bone pain can be alleviated by local irradiation. Pegylated IFN-α can ameliorate fibrosis in early PMF, but in advanced disease, it may exacerbate the bone marrow failure. The JAK2 inhibitor, ruxolitinib, has proved effective in reducing splenomegaly and alleviating constitutional symptoms in a majority of advanced PMF patients while also prolonging survival, although it does not significantly influence the JAK2 V617F neutrophil allele burden. Although anemia and thrombocytopenia are its major side effects, these are dose-dependent, and with time, anemia stabilizes and thrombocytopenia may improve. Allogeneic bone marrow transplantation is the only curative treatment for PMF and should be considered in younger patients and older patients with high risk disease; nonmyeloablative conditioning regimens may permit hematopoietic cell transplantation to be extended to older individuals, and is currently under investigation.

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