Myeloproliferative Neoplasms

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Myeloproliferative Neoplasms

Ayalew Tefferi

Summary of Key Points

Incidence

• Each of the three classic BCR-ABL1 myeloproliferative neoplasms (MPNs)—that is, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)—are estimated to occur at the rate of 0.5 to 2.5 per 100,000 people per year.

Differential Diagnosis

• All three classic BCR-ABL1 MPNs may be considered as diagnoses of exclusion, because a specific diagnostic marker is currently lacking.

• The presence of a JAK2 mutation distinguishes PV from all other causes of polycythemia, and ET and PMF from reactive thrombocytosis or myelofibrosis, respectively.

Diagnostic Evaluation

• Evaluation of suspected PV should start with peripheral blood screening for JAK2V617F and serum erythropoietin (Epo) measurement.

• More than 90% of PV patients are expected to display the JAK2 mutation, whereas a low serum Epo level should capture most of the JAK2V617F cases, which might display other JAK2 mutations such as an exon 12 mutation.

• Bone marrow examination remains essential in the diagnosis of ET and PMF.

Risk Stratification

• Both PV and ET display a near-normal life expectancy in the first decade of the disease. The major problem during this period is thrombosis that may occur in as many as 30% of the patients.

• A history of thrombosis or age older than 60 years is associated with a high-risk of thrombosis.

• Platelet count by itself has not been significantly associated with thrombosis in either PV or ET.

• The presence of advanced age, anemia, red cell transfusion-dependency, thrombocytopenia, leukocytosis, severe constitutional symptoms, circulating blasts or unfavorable karyotype are all adverse risk factors in PMF.

Treatment

• Phlebotomy, to a hematocrit target of below 45%, remains the mainstay of therapy in PV.

• Low-risk patients (age younger than 60 years and no history of thrombosis) with either PV or ET have not been shown to benefit from cytoreductive therapy.

• Treatment with hydroxyurea has been shown to reduce thrombosis risk in high-risk patients with both ET and PV.

• Microvascular symptoms, including headache and erythromelalgia (painful and burning sensation of the feet or hands associated with erythema and warmth), are easily treated with low-dose aspirin, which is indicated in the absence of extreme thrombocytosis.

• Drug therapy in PMF is currently palliative, and effective agents include corticosteroids, erythropoiesis-stimulating agents (ESAs), androgen preparations, danazol, thalidomide, lenalidomide, hydroxyurea and ruxolitinib.

• Splenectomy continues to have a palliative role in PMF.

• Involved-field radiation therapy in PMF is most effective in the setting of nonhepatosplenic extramedullary hematopoiesis.

• Hematopoietic stem cell transplantation has a therapeutic role in high-risk PMF but is associated with substantial regiment-related toxicity including death and chronic morbidity.

Introduction

The World Health Organization (WHO) classification system for hematopoietic tumors recognizes five categories of myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), MDS/MPN overlap, and PDGFR/FGFR1-rearranged myeloid/lymphoid neoplasm with eosinophilia.1BCR-ABL1-negative MPN” is an operational subcategory of MPN that includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).2 In addition, the WHO MPN category includes chronic myeloid leukemia (CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia-not otherwise specified, mastocytosis, and MPN unclassifiable (MPN-U). The latter refers to a clinically and histologically MPN-like phenotype that does not fulfill the standard diagnostic criteria for the other seven MPN variants.

The WHO MDS/MPN category includes chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia, atypical CML-BCR-ABL1-negative, and “MDS/MPN, unclassifiable (MDS/MPN-U).”2 Atypical CML is characterized by the absence of BCR-ABL1 and the presence of left-shifted granulocytosis with granulocytic dysplasia. MDS/MPN-U refers to a clinical phenotype that displays histologic characteristics of both MDS and MPN without fulfilling the diagnostic criteria for CMML, juvenile myelomonocytic leukemia, or atypical CML-BCR-ABL1-negative.The WHO provisional entity of “refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T)” is included in the category of MDS/MPN-U.

Table 100-1 represents an alternative semimolecular classification scheme for chronic myeloid neoplasms that uses the term “classic MPNs” to refer to the original four “MPD” variants including CML, PV, ET, and PMF.3 In this operational classification system, all remaining MPNs are assigned the term “nonclassic MPNs.”4 This chapter focuses on the classic BCR-ABL1 MPNs: PV, ET, and PMF.

Table 100-1

Modern Classification of Myeloproliferative Neoplasms

Main Categories Subcategories Molecular Signatures
Classic myeloproliferative disorders Chronic myeloid leukemia 100% BCR-ABL+
  Polycythemia vera ~95% JAK2V617F+
    ~4% JAK2 exon 12 mutations+
  Essential thrombocythemia ~50% JAK2V617F+
    ~1% MPLW515L/K+
  Primary myelofibrosis ~50% JAK2V617F+
    ~5% MPLW515L/K+
Nonclassic myeloproliferative neoplasms    
  Chronic neutrophilic leukemia ~20% JAK2V617F+
  Chronic eosinophilic leukemia, not otherwise specified
Mastocytosis
Myeloproliferative neoplasms-unclassifiable
 

Polycythemia Vera

Vaquez and Osler are credited for the initial description of PV, as a primary erythrocythemic process, in 1892 and 1903, respectively.5,6 Reported incidence figures in PV range from approximately 0.5 to 2.6 per 100,000 population.7,8 A higher disease incidence has been suggested in persons of Jewish ancestry,9 as well as among parent-offspring pairs.10 Median age at diagnosis of PV is approximately 60 years with a slight (1.2 : 1) male preponderance.11 Approximately 7% of patients are diagnosed before age 40 years,11 and there are rare cases of children affected with PV.12

Pathogenesis

PV is a clonal stem cell disease with trilineage myeloid involvement.13 In addition, some studies suggest clonal heterogeneity, including clonal involvement of B lymphocytes,14 as well as polyclonal granulopoiesis in certain cases.15 In vitro, erythroid colony formation in patients with PV does not require the addition of exogenous erythropoietin (Epo).16 This phenomenon is called endogenous erythroid colony growth and does not occur in either normal controls or in patients with nonclonal polycythemia. In addition, erythroid progenitor cells in PV display growth factor hypersensitivity to Epo, insulin-like growth factor (IGF)–1, and other cytokines.17,18 The consistently observed IGF1 hypersensitivity of erythroid cells in PV has been attributed to alterations in IGF1 binding proteins.19 However, several studies show that growth factor–independent or growth factor–hypersensitive colony formation is specific to neither PV nor erythroid progenitor cells.18

The Epo receptor gene as well as its protein are intact in PV.20 On the other hand, several postreceptor molecular abnormalities have been reported and include increased baseline phosphorylation of the IGF1 receptor,21 decreased activity of SH-PTP1 (a tyrosine phosphatase),22 increased activity of membrane-associated SH-PTP,23 constitutive activation of STAT3,24 upregulation of negative control elements of the cell cycle (p16/p14),25 and abundance, in erythroid precursors, of antiapoptotic proteins (Bcl-xL).26 However, these observations have not been always reproducible, and none of them have been shown to be specific to PV, as opposed to other MPNs.

In 2005, a novel Janus kinase 2 (JAK2) mutation (JAK2V617F) was described in association with PV, ET, and PMF.27 JAK2V617F occurs in approximately 95% of PV patients but also in approximately 50% of those with ET or PMF.2831 In addition, the mutation is found in a small proportion of patients with other myeloid neoplasms including nonclassic MPNs and MDS.32,33 Other JAK2 mutations (i.e., JAK2 exon 12 mutations) were subsequently described in the majority of patients with JAK2V617F PV or “idiopathic erythrocytosis,”34 thus raising the possibility that a JAK2 mutation is essential for the PV phenotype. On the other hand, neither JAK2V617F nor JAK2 exon 12 mutations have so far been reported in lymphoid disorders,3538 solid tumor,4141 or secondary myeloproliferation including congenital or acquired polycythemia.4444

JAK2V617F is a G-to-T somatic mutation, at nucleotide 1849, in exon 14, resulting in the substitution of valine by phenylalanine at codon 617.2831 JAK2 exon 12 mutations (F537-K539delinsL, H538QK539L, K539L, N542–E543del) include both in-frame deletions and tandem point mutations.34 Both exon 14 and exon 12 JAK2 mutations induce cytokine-independent/hypersensitive proliferation in Epo receptor–expressing cell lines and a PV-like phenotype in mice.34 Whereas homozygosity for JAK2V617F, which results from mitotic recombination, can be demonstrated in the majority of patients with PV,45 exon 12 JAK2 mutations are often heterozygous.34 The precise pathogenetic role of JAK2 mutations in PV and related MPNs continues to be investigated.

Diagnosis

In clinical practice, the term polycythemia is used to indicate the possible occurrence of an increased erythrocyte volume or red blood cell mass (RCM). Such a perception might be either real (true polycythemia) or spurious (apparent polycythemia; Fig. 100-1).18 True polycythemia may represent either PV or a nonclonal increase in RCM that is often, but not always, mediated by Epo (secondary polycythemia; Fig. 100-2). Apparent polycythemia may result from either a reduction in plasma volume (relative polycythemia) or an inaccurate perception of an elevated RCM that results from not appreciating high normal values of hemoglobin/hematocrit.46 Inapparent polycythemia is the converse of apparent polycythemia and indicates a true increase in RCM that is masked by a normal hemoglobin/hematocrit value secondary to a concomitant increase in plasma volume (see Fig. 100-1).47

In 1975, the PV study group published a set of “diagnostic criteria” that were primarily used to ensure the exclusion, to treatment protocols, of patients with secondary or apparent polycythemia.48 These criteria required the demonstration of increased RCM by blood volume measurement using labeled erythrocytes as well as the demonstration of normal hemoglobin oxygen saturation. In 2001, the WHO published a refined diagnostic criteria for PV and related MPNs that recognized the value of both bone marrow histology and “MPN-specific” biological parameters.49 The recent discovery of the almost invariable association between PV and a JAK2 mutation has led to revised WHO diagnostic criteria for PV (Table 100-2)50 and a refined diagnostic algorithm (see Fig. 100-2),51 both of which incorporate JAK2 mutation screening.

Table 100-2

Revised World Health Organization Criteria for Polycythemia Vera

Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first major criterion together with two minor criteria.

MAJOR CRITERIA

Hemoglobin >18.5 g/dL in men, 16.5 g/dL in women, or other evidence of increased red cell volume*

Presence of JAK2V617F or other functionally similar mutation such as JAK2 exon 12 mutation

MINOR CRITERIA

Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent erythroid, granulocytic, and megakaryocytic proliferation

Serum erythropoietin level below the reference range for normal

Endogenous erythroid colony formation in vitro

*Hemoglobin or hematocrit >99th percentile of method-specific reference range for age, sex, and altitude of residence, or hemoglobin >17 g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at least 2 g/dL from an individual’s baseline value that cannot be attributed to correction of iron deficiency, or elevated red cell mass >25% above mean normal predicted value.

Data from Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytopenia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110:1092–1097.

Because more than 95% of patients with PV carry the JAK2V617F mutation, which is absent in both secondary and apparent polycythemia, it is most effective to initiate the workup of a patient with suspected PV with peripheral blood mutation screening for JAK2V617F (see Fig. 100-2). Furthermore, to minimize the consequences of false-positive or false-negative molecular test results, as well as capture the few cases of PV that are JAK2V617F, concomitant measurement of serum Epo level is recommended.52 If the results of both tests are suggestive of PV (i.e., mutation-positive and low serum Epo), then the diagnosis is likely and bone marrow examination is encouraged but not essential for making the diagnosis. If the JAK2V617F and serum Epo test results are both not consistent with the diagnosis of PV (i.e., mutation-negative and either normal or increased Epo), then further investigation for PV is not advised unless dictated otherwise by the clinical scenario.

If there is discrepancy between the molecular test result and serum Epo level, one should first repeat both tests and then proceed with bone marrow examination if the results are unchanged (see Fig. 100-2). In a patient with acquired erythrocytosis and a subnormal serum Epo level, the possibility of exon 12 JAK2 mutations should be entertained. In this regard it should be noted that some cases with JAK2 exon 12 mutation–associated PV might not display overt PV-characteristic features, even at the level of bone marrow histology.34

When congenital polycythemia is suspected, initial laboratory testing should include measurement of the oxygen tension at which hemoglobin is 50% saturated (i.e., p50).51 Left-shifted oxygen dissociation curve, suggested by decreased p50, suggests the presence of either high oxygen-affinity hemoglobinopathy (autosomal dominant)53 or 2,3-bisphosphoglycerate (2,3-BPG) deficiency, usually a consequence of BPG mutase mutation (autosomal recessive).54 If the p50 is normal, then the possibility of germline mutations of molecules that either enhance Epo effect (e.g., EPOR mutations)55 or govern intracellular oxygen sensing (e.g., mutations involving the von Hippel-Lindau [VHL] tumor suppressor or hypoxia-inducible factor 1a [HIF-1a] prolyl hydroxylase genes)56,57 should be considered (see Fig. 100-2). VHL mutations are usually associated with increased serum Epo level and constitute the most frequent mutations in congenital polycythemia (e.g., Chuvash polycythemia).58 In contrast, serum Epo level is often subnormal in patients with EPOR mutations.59

Bone marrow histology, to the experienced hematopathologist, is often revealing of characteristic changes of a MPN that include hypercellularity, increased number of megakaryocytes including cluster formation, the presence of giant megakaryocytes and pleomorphism in megakaryocyte morphology, mild reticulin fibrosis, and decreased bone marrow iron stores.60 In contrast, cytogenetic studies in PV disclose abnormalities (trisomies of chromosomes 9 and 8 and deletions of the long arms of chromosomes 13 and 20) in only 13% to 18% of patients at diagnosis, and hence have limited diagnostic value.61

Treatment

The natural history of PV is characterized by a lifelong propensity for thrombohemorrhagic complications, late-onset disease transformation into post-PV myelofibrosis and/or AML, and a shortened life expectancy.61 Specific treatment has been shown to positively influence the risk of both macrovascular and microvascular complications but not that of clonal evolution to post-PV myelofibrosis or AML.

Phlebotomy is the cornerstone of therapy in PV and is the only treatment modality that has improved survival in affected patients (Box 100-1). It is reported that median survival may be as low as 2 years in the absence of such treatment.63 Based on limited retrospective studies in PV that showed a progressive increase in the incidence of vascular occlusive episodes above a hematocrit level of 44%,64 as well as other studies that showed suboptimal cerebral blood flow in ranges of hematocrit values between 46% and 52%,65 the therapeutic target hematocrit level has, for a long time, been set at or below 45%. This particular practice is now further supported by the results of a recent randomized study where 365 adults with PV were treated with a target hematocrit, less than 45% or 45% to 50%.66 After a median follow-up of 31 months, the primary end point of thrombotic events or deaths from cardiovascular causes was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (P = 0.007). Furthermore, because of the physiological difference in hematocrit values between the two genders as well as among different races, it is reasonable, though not evidence-based, to target an even lower hematocrit level (i.e., 42%) in women and African-Americans.67

Role of Drug Therapy in Polycythemia Vera

Observations from Randomized Studies

In the first controlled study in PV, the PV study group randomized 431 patients to treatment with either phlebotomy alone or phlebotomy supplanted by either oral chlorambucil or intravenous radioactive phosphorus (32P). The results favored treatment with phlebotomy alone with a median survival of 12.6 years as compared with 10.9 and 9.1 years for treatment with 32P and chlorambucil, respectively (P = 0.008). The difference in survival was attributed to an increased incidence of AML in patients treated with chlorambucil or 32P compared with those treated with phlebotomy alone (13.2% vs. 9.6% vs. 1.5% over a period of 13 to 19 years).68 Furthermore, 3.5% of the patients treated with chlorambucil developed large cell lymphoma, and the incidence of gastrointestinal and skin cancer was increased in those patients treated with either chlorambucil or 32P.

In another controlled study, the European Organization for Research on Treatment of Cancer randomized 293 patients to treatment with either 32P or oral busulfan. The results favored busulfan in terms of both first-remission duration (median: 4 years vs. 2 years) and overall survival (10-year survival rates of 70% vs. 55%; P = 0.02). At a median follow-up period of 8 years, there was not a significant difference in the risk of leukemic transformation (2% vs. 1.4%), nonhematologic malignancy (2.8% vs. 5%), vascular complications (27% vs. 37%), or transformation into post-PV myelofibrosis (4.8% vs. 4.1%) between the busulfan and 32P arms, respectively.69

Other randomized studies in PV have compared hydroxyurea against pipobroman (a significant difference favoring pipobroman in the incidence of transformation into post-PV myelofibrosis but no difference in survival, incidence of thrombosis, or the rate of leukemic conversion),70 and 32P alone against 32P plus hydroxyurea (no difference in survival, incidence of thrombosis, or risk of transformation into post-PV myelofibrosis, but 32P alone was associated with significantly fewer incidences of both acute leukemia and other cancers).71 More importantly, in the final analyses from the aforementioned French study that compared hydroxyurea to pipobroman in 285 patients younger than age 65 years,72 after a median follow-up of 16.3 years, median survival was 20.3 years for the hydroxyurea arm, and 15.4 years for the pipobroman arm (P = 0.008). At 10, 15, and 20 years, cumulative incidence of AML/MDS was 6.6%, 16.5%, and 24% in the hydroxyurea arm, and 13%, 34%, and 52% in the pipobroman arm (P = 0.004). Cumulative myelofibrosis incidence at 10, 15, and 20 years according to main treatment received was 15%, 24%, and 32% with hydroxyurea versus 5%, 10%, and 21% with pipobroman (P = 0.02). These results suggest a leukemogenic potential for pipobroman.

Randomized studies involving aspirin therapy include one study where 32P plus phlebotomy was compared to phlebotomy plus high-dose aspirin (900 mg/day) in combination with dipyridamole (225 mg/day); the addition of antiplatelet agents provided no benefit in terms of thrombosis prevention but increased the risk of gastrointestinal bleeding.73 However, a more recent randomized study of PV (112 patients) using lower doses of aspirin (40 mg/day) did not show an increased bleeding diathesis.74 Furthermore, the results of the PV study group aspirin study may have been influenced by the fact that 27% of the patients randomized to the phlebotomy-aspirin-dipyridamole arm had a prior history of thrombosis compared with 13% in the other arm. This contention was confirmed by the most recent European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study that showed safety as well as antithrombotic activity of low-dose aspirin in a randomized study.75

Observations from Nonrandomized Studies

In a nonrandomized study by the PV study group, treatment with hydroxyurea was associated with a lower incidence of early thrombosis compared with a historical cohort treated with phlebotomy alone (6.6% vs. 14% at 2 years). Similarly, the incidence of AML in patients treated with hydroxyurea, compared with a historical control treated with either chlorambucil or 32P, was significantly lower (5.9% vs. 10.6% vs. 8.3%, respectively, in the first 11 years of treatment).76 Other studies have confirmed the low incidence of AML in PV patients treated with hydroxyurea (1% to 5.6%).7979

Many studies have reported on the use of pipobroman as a single agent in PV.80,81 In one of these studies involving 163 patients, the drug was effective in more than 90% of the patients and median survival exceeded 17 years.80 In the first 10 years, the incidences of thrombotic events, acute leukemia, post-PV myelofibrosis, and other malignancies were 16%, 5%, 4%, and 8%, respectively. Favorable outcome has also been reported in single-arm studies using oral busulfan.82,83 In 65 busulfan-treated patients with PV followed between 1962 and 1983, overall median survival was 11.1 years and 19 years in patients whose disease was diagnosed before age 60 years.82 Only two patients (3.5%) treated with busulfan alone developed acute leukemia.

Most recently, alfa-interferon (IFN-α) was shown to control erythrocytosis in approximately 76% of the patients with PV receiving subcutaneous drug in doses ranging from 4.5 to 27 million units per week (usual dose is 3 million units subcutaneously 3 times a week).84,85 A similar degree of benefit is appreciated in terms of reduction in spleen size or relief from intractable pruritus. Furthermore, a variable degree of JAK2V617F allele burden reduction was recently associated with IFN-α therapy, but the relevance in overall outcome of the disease is not known.86 A randomized study (which is currently ongoing) is needed to determine if IFN-α is superior to hydroxyurea as a cytoreductive agent in PV, especially in view of its higher cost and toxicity profile. Finally, anagrelide, an oral imidazoquinazoline derivative that inhibits platelet aggregation at higher than therapeutic drug concentrations but displays a species-specific platelet-lowering effect in humans at therapeutic concentrations, controls thrombocytosis in PV.87 However, the drug is currently not recommended in the treatment of PV, because it was associated with increased incidence of arterial thrombosis and post-ET myelofibrosis, when compared with hydroxyurea, in patients with ET.88

In summary, the results from single-arm studies support those of the randomized studies and show that busulfan is a valuable treatment agent in PV and might be considered as an alternative to hydroxyurea. Pipobroman is currently not available in the United States and a recent French study suggested a leukemogenic potential for the particular drug.72 It is currently not clear what additional value is gained by substituting the aforementioned traditional cytoreductive agents by the newer drugs (i.e., IFN-α and anagrelide), especially in view of their unfavorable toxicity and cost profile (Table 100-3), but randomized studies are currently ongoing, in this regard.89

Table 100-3

Clinical Properties of Popular Cytoreductive Agents Used in Polycythemia Vera or Essential Thrombocythemia

Drug (class) Hydroxyurea Anagrelide Alfa interferon Phosphorus-32 Pipobroman
  Myelosuppressive Platelet-specific Myelosuppressive Myelosuppressive Myelosuppressive
Mechanism of action Antimetabolite Unknown Biological agent Radionuclide Alkylating agent
Pharmacology Half-life ≡ 5 hours, renal excretion Half-life ≡ 1.5 hours, renal excretion Kidney is main site of metabolism Half-life ≡ 14 days Insufficient information
Starting dose 500 mg PO BID 0.5 mg PO TID 5 million units SC TIW 2.3 mCi/m2 IV 1 mg/kg per day PO
Onset of action ≡ 3 to 5 days ≡ 6 to 10 days 1 to 3 weeks 4 to 8 weeks ≡ 16 days
Frequent side effects Leukopenia, oral ulcers, anemia, hyperpigmentation, nail discoloration, xerodermia Headache, palpitations, diarrhea, fluid retention, anemia Flulike syndrome, fatigue, anorexia, weight loss, lack of ambition, alopecia Transient mild cytopenia Nausea, abdominal pain, diarrhea
Infrequent side effects Leg ulcers, nausea, diarrhea, alopecia, skin atrophy Arrhythmias, lightheadedness, nausea Confusion, depression, autoimmune thyroiditis, myalgia, arthritis Prolonged pancytopenia in elderly patients Leukopenia, thrombocytopenia, hemolysis
Rare side effects Fever, cystitis, platelet oscillations Cardiomyopathy Pruritus, hyperlipidemia, transaminasemia Leukemogenic  

image

Thrombohemorrhagic Risk Factors in Polycythemia Vera

The series of studies performed by the PV study group revealed the following: (a) a significantly higher incidence of thrombotic events, in the first 3 years, in patients treated with phlebotomy alone; (b) a lack of correlation between thrombosis and either platelet count or hematocrit value; and (c) a significant association between thrombosis risk and either age older than 70 years or a prior history of thrombosis. In addition, in patients treated with phlebotomy alone, thrombosis risk was associated with an increased frequency of phlebotomy (maintenance phlebotomy of more than once every 3 months). Other studies have confirmed the detrimental effect of advanced age (>60 years) and thrombosis history in PV.18 As such, patients who are 60 years old or older or have a history of thrombosis are considered at high-risk (Table 100-4). In contrast, the degree of thrombocytosis has never been correlated with thrombosis risk. However, some patients with extreme thrombocytosis (platelet count at or above 1 million platelets/µL), carry an acquired bleeding diathesis that results from an abnormal adsorption and catabolism of large-molecular-weight von Willebrand factor.90 The prognostic influence of extreme thrombocytosis, in the absence of acquired von Willebrand disease, is unknown. Equally uncertain is the prognostic relevance of cardiovascular risk factors.

Table 100-4

Risk Stratification in Polycythemia Vera and Essential Thrombocythemia

Low-risk Age younger than 60 years
  and
  No history of thrombosis
  and
  Platelet count <1 million cells/µL
Low-risk with extreme thrombocytosis Age younger than 60 years
and
  No history of thrombosis
  but
  Platelet count ≥1 million cells/µL
High-risk Age 60 years or older
  or
  Positive history of thrombosis

image

Current Treatment Recommendations

The mainstay of therapy in PV remains phlebotomy for all patients to keep hematocrit at or below 45% in male whites and the appropriate corresponding value for females and other races.66 Additional drug therapy depends on an individual patient’s risk for thrombohemorrhagic complications (see Table 100-4). In general, there is good evidence to advocate the use of cytoreductive agents in high-risk patients (Table 100-5). In this regard, and based on the results of the aforementioned studies, my current choice of chemotherapy is hydroxyurea (starting dose of 500 mg twice daily) or busulfan (starting dose of 4 mg/day) in case of nontolerance to hydroxyurea. Side effects of hydroxyurea that might necessitate the use of an alternative agent include neutropenia and mucocutaneous changes such as ulcers in the mouth and lower extremities. In using busulfan, one should recognize the potential, but infrequent, toxicity to the lungs (pulmonary fibrosis)91 and the bone marrow (aplasia).92 Intermittent treatment with drug holidays and withholding treatment for impending cytopenia are recommended.

Table 100-5

Treatment Algorithm in Polycythemia Vera

Risk Category Age <60 Years Age ≥60 Years Women of Childbearing Age
Low-risk Phlebotomy + low-dose aspirin Not applicable Phlebotomy + low-dose aspirin
Low-risk with extreme thrombocytosis Phlebotomy + low-dose aspirin* Not applicable Phlebotomy + low-dose aspirin*
High-risk Phlebotomy + hydroxyurea + Phlebotomy + hydroxyurea + Phlebotomy + IFN-α*
  low-dose aspirin low-dose aspirin* + low-dose aspirin

image

*Screening for acquired von Willebrand disease is encouraged before the use of aspirin in patients with extreme thrombocytosis (platelet count ≥1 million cells/µL). Use of aspirin is discouraged if ristocetin cofactor activity is <50%.

Based on anecdotal evidence of safety.

In the younger but high-risk patient group, some investigators are concerned about drug leukemogenicity associated with long-term treatment with either hydroxyurea or busulfan. However, there is currently not hard evidence to support this particular concern.79 Regardless, IFN-α (starting dose of 3 million units subcutaneously 3 times a week) or pegylated IFN is a reasonable alternative in this instance.84 IFN-α is also the treatment of choice in women of childbearing age (see Table 100-5) because of the theoretical risk of teratogenicity associated with the use of other cytoreductive agents.85

It is currently unclear whether any specific drug therapy influences clonal evolution in PV. Under current treatment strategies, the incidences of transformation into post-PV myelofibrosis or AML, in the first decade of disease, are estimated at 10% and 5%, respectively.68 The risk beyond the first decade increases progressively.93

Treatment of Non–Life-Threatening Complications in Polycythemia Vera

Additional clinical features of PV include microvascular disturbances, aquagenic pruritus, and constitutional symptoms. Microvascular disturbances in PV and related disorders are thought to represent transient inflammation-based occlusive phenomenon that is a result of interaction between clonal platelets and the endothelium of arterioles. The corresponding clinical manifestations include headache, lightheadedness, transient neurological or ocular disturbances, tinnitus, atypical chest discomfort, paresthesias, and erythromelalgia. Aspirin produces prompt (within hours) alleviation of symptoms in the majority of patients with PV-associated microvascular disturbances.

Generalized pruritus that is often exacerbated by hot bath is a characteristic feature of PV and occurs in 48% of patients either at diagnosis or at a later stage of the disease.94 Etiology of PV-associated pruritus remains to be determined and treatment responses to antihistamines have been both unpredictable and variable.94 Interestingly, a recent study demonstrated a greater than 80% response rate in PV-associated pruritus treated with paroxetine, which is a selective serotonin reuptake inhibitor.95 Other treatment modalities that have been used in PV-associated pruritus include IFN-α, psoralen photochemotherapy, cholestyramine and ruxolitinib.5,18

Essential Thrombocythemia

Among the classic BCR-ABL1 MPNs, ET is the most recently described.96 Reported incidence figures range from 0.2 to 2.5 per 100,000 population.9,9799 With a median age at diagnosis of 60 years, approximately 20% of the patients with ET are diagnosed before age 40 years and in the young age group of patients, the incidence is higher in women than in men.100,101 There are well-documented cases of ET in children, although some of the reported cases may have represented familial thrombocytosis.102,103

Pathogenesis

Trilineage clonal myeloproliferation has been demonstrated in the majority of patients with ET using X chromosome–linked DNA or gene product analysis.104,105 However, X-linked clonal assays have revealed both polyclonal hematopoiesis in a substantial minority of patients with ET106 and “monoclonal” hematopoiesis in normal elderly controls.107 Furthermore, in some cases, the clonal process in ET was shown to include lymphocytes14 or be restricted to megakaryocytes.105 The clonal basis of ET was recently underlined by JAK2V617F mutation analysis that revealed the presence of the mutation even in those patients who feature “polyclonal” hematopoiesis by X-linked clonality studies.106,108 However, the primary clonogenic event in ET remains undefined despite the recent descriptions of two gain-of-function mutations that occur in 50% (JAK2V617F)109 and 1% (MPLW515L/K)110 of patients with ET, respectively.

Other biological features in ET include in vitro growth factor independence/hypersensitivity of both erythroid and megakaryocyte progenitor cells,111,112 low serum Epo level,113 altered megakaryocyte/platelet Mpl expression,114,115 increased neutrophil PRV-1 expression,116,117 and decreased platelet serotonin content.118 Laboratory studies in ET have demonstrated myeloid growth factor hypersensitivity to interleukin-3119 as well as thrombopoietin (Tpo).112 Growth factor independence of myeloid progenitor cells in ET and related myeloproliferative disorders has now been attributed to mutations involving molecules of the JAK-STAT pathway including the aforementioned JAK2V617F and MPLW515L/K. In patients with ET,120 PV,121 and myelofibrosis,122 serum Tpo levels are usually normal or elevated despite an increased megakaryocyte mass. This has been attributed to the markedly decreased megakaryocyte/platelet expression of myeloproliferative leukemia (MPL), although the extent of this particular phenotypic abnormality is significantly less in ET as compared with PV or PMF.114,115,123,124

In addition to clonal myeloproliferation, ET is also characterized by microvascular symptoms (e.g., headaches and erythromelalgia) as well as an increased risk of both thrombosis and bleeding.125 Pathogenesis in the former might involve abnormal thromboxane A2 generation and small vessel–based platelet-endothelial interactions that are inhibited by aspirin therapy.126,127 On the other hand, there is increasing information that implicates granulocytes but not platelets as the thrombogenic culprit in ET.88,128130 Consistent with these observations, a recent study has identified leukocytosis as an independent risk factor for thrombosis in ET.131 Bleeding diathesis in ET is currently believed to involve an acquired von Willebrand syndrome that becomes apparent in the presence of extreme thrombocytosis.90 The mechanism of acquired von Willebrand syndrome in ET is currently believed to involve a platelet count-dependent increased proteolysis of high-molecular-weight von Willebrand protein.90 Other qualitative platelet defects in ET are believed to play a minor role in disease-associated hemorrhage and include defects in epinephrine-, collagen-, and adenosine diphosphate–induced platelet aggregation, decreased adenosine triphosphate secretion, and acquired storage pool deficiency that results from abnormal in vivo platelet activation.125

Diagnosis

Although thrombocytosis is the hallmark of ET, more than 85% of cases with thrombocytosis seen in routine clinical practice are reactive (secondary thrombocytosis) and associated with other comorbid conditions (Table 100-6).132 The degree of thrombocytosis is a poor discriminator of ET from secondary thrombocytosis. However, the clinical scenario is often helpful in distinguishing ET from secondary thrombocytosis. In routine clinical practice, it is important to exclude the contribution of either iron-deficiency anemia or a hyposplenic state as possible causes of an otherwise unexplained thrombocytosis (Box 100-2

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