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Figure 1.
Thrombosis-free survival (TFS) among patients with essential thrombocythemia. A, Projected 10-year TFS. B, Effect of age (>60 years vs ≤60 years) on TFS (P = .07). C, Splenomegaly at diagnosis confers a higher TFS and thus protection against thrombosis (P = .02). D, Patients with thrombosis at diagnosis have a nonsignificant trend toward inferior TFS (P = .16).

Thrombosis-free survival (TFS) among patients with essential thrombocythemia. A, Projected 10-year TFS. B, Effect of age (>60 years vs ≤60 years) on TFS (P = .07). C, Splenomegaly at diagnosis confers a higher TFS and thus protection against thrombosis (P = .02). D, Patients with thrombosis at diagnosis have a nonsignificant trend toward inferior TFS (P = .16).

Figure 2.
Bleeding-free survival (BFS) among patients with essential thrombocythemia. A, Projected 10-year BFS. B, Male sex confers inferior BFS (P<.01). C, Age older than 60 years portends inferior BFS compared with age 60 years or younger (P = .07).

Bleeding-free survival (BFS) among patients with essential thrombocythemia. A, Projected 10-year BFS. B, Male sex confers inferior BFS (P<.01). C, Age older than 60 years portends inferior BFS compared with age 60 years or younger (P = .07).

Figure 3.
Overall survival (OS) among patients with essential thrombocythemia. A, Projected 10-year OS. B, Age older than 60 years portends inferior OS compared with age 60 years or younger (P<.01). C, Smoking confers inferior OS (P = .02).

Overall survival (OS) among patients with essential thrombocythemia. A, Projected 10-year OS. B, Age older than 60 years portends inferior OS compared with age 60 years or younger (P<.01). C, Smoking confers inferior OS (P = .02).

Table 1. 
Comparison of Demographic Data and Clinical Features at Diagnosis Among Studies*
Comparison of Demographic Data and Clinical Features at Diagnosis Among Studies*
Table 2. 
Thrombosis and Bleeding Events at and After Diagnosis*
Thrombosis and Bleeding Events at and After Diagnosis*
Table 3. 
Univariate Analysis of Risk Factors for Thrombosis-Free Survival, Bleeding-Free Survival, and Overall Survival
Univariate Analysis of Risk Factors for Thrombosis-Free Survival, Bleeding-Free Survival, and Overall Survival
Table 4. 
Transformation to Myelofibrosis*
Transformation to Myelofibrosis*
Table 5. 
Transformation to Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Among Patients With vs Without Prior Myelofibrosis*
Transformation to Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Among Patients With vs Without Prior Myelofibrosis*
Table 6. 
Comparison of Myeloid Transformation to Myelofibrosis (MF), Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and Polycythemia Vera (PV) Among Studies*
Comparison of Myeloid Transformation to Myelofibrosis (MF), Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), and Polycythemia Vera (PV) Among Studies*
1.
Fialkow  PJFaguet  GBJacobson  RJVaidya  KMurphy  S Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood 1981;58916- 919
PubMed
2.
Spivak  JL The chronic myeloproliferative disorders: clonality and clinical heterogeneity. Semin Hematol 2004;41 ((suppl 3)) 1- 5
PubMedArticle
3.
Champion  KMGilbert  JGAsimakopoulos  FAHinshelwood  SGreen  AR Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. Br J Haematol 1997;97920- 926
PubMedArticle
4.
el-Kassar  NHetet  GBriere  JGrandchamp  B Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets. Blood 1997;89128- 134
PubMed
5.
Murphy  SPeterson  PIland  HLaszlo  J Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol 1997;3429- 39
PubMed
6.
Kessler  CM Propensity for hemorrhage and thrombosis in chronic myeloproliferative disorders. Semin Hematol 2004;41 ((suppl 3)) 10- 14
PubMedArticle
7.
Jensen  MKde Nully Brown  PNielsen  OJHasselbalch  HC Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol 2000;65132- 139
PubMedArticle
8.
Finazzi  GRuggeri  MRodeghiero  FBarbui  T Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial. Br J Haematol 2000;110577- 583
PubMedArticle
9.
Cervantes  FAlvarez-Larran  ATalarn  CGomez  MMontserrat  E Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients. Br J Haematol 2002;118786- 790
PubMedArticle
10.
Cortelazzo  SViero  PFinazzi  GD’Emilio  ARodeghiero  FBarbui  T Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990;8556- 562
PubMed
11.
Fenaux  PSimon  MCaulier  MTLai  JLGoudemand  JBauters  F Clinical course of essential thrombocythemia in 147 cases. Cancer 1990;66549- 556
PubMedArticle
12.
Tefferi  AFonseca  RPereira  DLHoagland  HC A long-term retrospective study of young women with essential thrombocythemia. Mayo Clin Proc 2001;7622- 28
PubMedArticle
13.
Sterkers  YPreudhomme  CLai  JL  et al.  Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. Blood 1998;91616- 622
PubMed
14.
Kwong  YLChiu  EKLiang  RHChan  VChan  TK Essential thrombocythemia with bcr/abl rearrangement. Cancer Genet Cytogenet 1996;8974- 76
PubMedArticle
15.
Kwong  YLLiang  RHChiu  EK  et al.  Essential thrombocythemia: a retrospective analysis of 39 cases. Am J Hematol 1995;4939- 42
PubMedArticle
16.
Tefferi  A Myelofibrosis with myeloid metaplasia. N Engl J Med 2000;3421255- 1265
PubMedArticle
17.
Barosi  G Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol 1999;172954- 2970
PubMed
18.
Bennett  JMCatovsky  DDaniel  MT  et al. French-American-British (FAB) Co-operative Group, Proposals for the classification of the acute leukaemias. Br J Haematol 1976;33451- 458
PubMedArticle
19.
Bennett  JMCatovsky  DDaniel  MT  et al.  Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51189- 199
PubMedArticle
20.
Thiele  JKvasnicka  HM Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients. Ann Hematol 2003;82148- 152
PubMed
21.
Thiele  JKvasnicka  HM Prefibrotic chronic idiopathic myelofibrosis: a diagnostic enigma? Acta Haematol 2004;111155- 159
PubMedArticle
22.
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53457- 481Article
23.
Cox  DR Regression models and life-tables. J R Statist Soc Series B 1972;34187- 220
24.
Chim  CSMa  SYAu  WY  et al.  Primary nasal natural killer cell lymphoma: long-term treatment outcome and relationship with the International Prognostic Index. Blood 2004;103216- 221
PubMedArticle
25.
Chim  CSLiang  RTam  CYKwong  YL Methylation of p15 and p16 genes in acute promyelocytic leukemia: potential diagnostic and prognostic significance. J Clin Oncol 2001;192033- 2040
PubMed
26.
Barbui  TBarosi  GGrossi  A  et al.  Practice guidelines for the therapy of essential thrombocythemia: a statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004;89215- 232
PubMed
27.
Colombi  MRadaelli  FZocchi  LMaiolo  AT Thrombotic and hemorrhagic complications in essential thrombocythemia: a retrospective study of 103 patients. Cancer 1991;672926- 2930
PubMedArticle
28.
Wolf  BCNeiman  RS Essential thrombocythemia. Neiman  SOrazi  Aeds.Disorders of the Spleen Philadelphia, Pa WB Saunders Co1999;173- 174
29.
Cortelazzo  SFinazzi  GRuggeri  M  et al.  Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;3321132- 1136
PubMedArticle
30.
Landolfi  R Bleeding and thrombosis in myeloproliferative disorders. Curr Opin Hematol 1998;5327- 331
PubMedArticle
31.
Georgii  ABuesche  GKreft  A The histopathology of chronic myeloproliferative diseases. Baillieres Clin Haematol 1998;11721- 749
PubMedArticle
32.
Barbui  T The leukemia controversy in myeloproliferative disorders: is it a natural progression of disease, a secondary sequela of therapy, or a combination of both? Semin Hematol 2004;41 ((suppl 3)) 15- 17
PubMedArticle
33.
Cervantes  FTassies  DSalgado  CRovira  MPereira  ARozman  C Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol 1991;85124- 127
PubMedArticle
34.
Ferster  ASariban  EMeuleman  NBelgian Registry of Sickle Cell Disease Patients Treated With Hydroxyurea, Malignancies in sickle cell disease patients treated with hydroxyurea. Br J Haematol 2003;123368- 369
PubMedArticle
35.
Wilson  S Acute leukemia in a patient with sickle-cell anemia treated with hydroxyurea. Ann Intern Med 2000;133925- 926
PubMedArticle
36.
de Montalembert  MDavies  SC Is hydroxyurea leukemogenic in children with sickle cell disease? Blood 2001;982878- 2879
PubMedArticle
37.
Hanft  VNFruchtman  SRPickens  CVRosse  WFHoward  TAWare  RE Acquired DNA mutations associated with in vivo hydroxyurea exposure. Blood 2000;953589- 3593
PubMed
38.
Najean  YRain  JD Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood 1997;903370- 3377
PubMed
39.
Census and Statistics Department, Hong Kong, Hong Kong Annual Digest of Statistics: Special Administrative Region.  Hong Kong Census and Statistics Dept2003;
40.
Anagrelide Study Group, Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med 1992;9269- 76
PubMedArticle
41.
Landaw  SA Acute leukemia in polycythemia vera. Semin Hematol 1986;23156- 165
PubMed
42.
Silverstein  MNBrown  AL  JrLinman  JW Idiopathic myeloid metaplasia: its evolution into acute leukemia. Arch Intern Med 1973;132709- 712
PubMedArticle
43.
Kimura  AFujimoto  TInada  T  et al.  Blastic transformation in essential thrombocythemia: in vitro differentiation of blast cells into granulocytic, erythroid, and megakaryocytic lineages. Cancer 1990;651538- 1544
PubMedArticle
44.
Emilia  GSacchi  STemperani  PLongo  RVecchi  A Progression of essential thrombocythemia to blastic crisis via idiopathic myelofibrosis. Leuk Lymphoma 1993;9423- 426
PubMedArticle
45.
Sedlacek  SMCurtis  JLWeintraub  JLevin  J Essential thrombocythemia and leukemic transformation. Medicine (Baltimore) 1986;65353- 364
PubMedArticle
46.
Yonemitsu  HOkuda  K Essential thrombocythemia terminating in myelofibrosis and myeloblastic transformation. Jpn J Med 1985;2457- 61
PubMedArticle
47.
Rozman  CGiralt  MFeliu  ERubio  DCortes  MT Life expectancy of patients with chronic nonleukemic myeloproliferative disorders. Cancer 1991;672658- 2663
PubMedArticle
48.
Bazzan  MTamponi  GSchinco  P  et al.  Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia. Ann Hematol 1999;78539- 543
PubMedArticle
49.
Kralovics  RPassamonti  FBuser  AS  et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;3521779- 1790
PubMedArticle
50.
James  CUgo  VLe Couedic  JP  et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;4341144- 1148
PubMedArticle
51.
Baxter  EJScott  LMCampbell  PJ  et al. Cancer Genome Project, Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;3651054- 1061
PubMedArticle
52.
Levine  RLWadleigh  MCools  J  et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7387- 397
PubMedArticle
Original Investigation
December 12/26, 2005

Long-term Outcome of 231 Patients With Essential ThrombocythemiaPrognostic Factors for Thrombosis, Bleeding, Myelofibrosis, and Leukemia

Author Affiliations

Author Affiliations: Departments of Medicine (Drs Chim, Kwong, Lie, and Liang), Pathology (Dr Ma), and Clinical Oncology (Dr Law), Queen Mary Hospital, University of Hong Kong; Department of Medicine, Queen Elizabeth Hospital (Drs C.-C. Chan and C.-H. Chan); Department of Medicine, Tuen Mun Hospital (Drs Wong and Yeung); Department of Medicine, Pamela Youde Nethersole Hospital (Drs Kho, Sim, and J. C.-W. Chan); and Department of Medicine, Princess Margaret Hospital (Dr Lee); Hong Kong.

Arch Intern Med. 2005;165(22):2651-2658. doi:10.1001/archinte.165.22.2651
Abstract

Background  Essential thrombocythemia (ET) is a clonal myeloproliferative disease associated with thrombohemorrhagic complications and myeloid transformation to diseases such as myelofibrosis and acute myeloid leukemia.

Methods  A multicenter study was conducted among 231 consecutive Chinese patients with ET. The literature about leukemogenic risk associated with the use of hydroxyurea therapy was reviewed.

Results  The median patient age was 65 years. Thrombosis rates at and after diagnosis of ET were comparable to those of white patients, but bleeding rates at and after diagnosis were much lower. The projected 10-year thrombosis-free, bleeding-free, and overall survival rates were 66%, 83%, and 80%, respectively. There were no deaths among patients 60 years or younger during a maximum follow-up of 15 years, and splenomegaly at diagnosis of ET appeared to protect against thrombosis. In multivariate analysis, advanced age predicted inferior 10-year thrombosis-free and overall survival, and male sex predicted inferior bleeding-free survival. Half the deaths were related to ET. The probability of myelofibrosis transformation was 9.7% at 10 years. Prior myelofibrosis (P = .008) and the use of melphalan treatment (P = .002) were risk factors for acute myeloid leukemia evolution.

Conclusions  Essential thrombocythemia is a benign disease of older persons. Chinese patients have a low risk of bleeding, and prior myelofibrosis is a major risk factor for evolution to acute myeloid leukemia. Leukemic transformation with hydroxyurea therapy alone is rare and warrants further prospective studies.

Essential thrombocythemia (ET) is a clonal myeloproliferative disease involving a hemopoietic stem cell and manifesting predominantly as thrombocytosis.1,2 However, extreme skewing of X chromosome inactivation mimicking clonal hemopoiesis in healthy older women3 and polyclonal hematopoiesis in some patients with ET4 sometimes confound the diagnosis. Therefore, until a reliable clonal marker is available, ET remains a diagnosis by exclusion and has to be distinguished from reactive thrombocytosis5 and other chronic myeloproliferative diseases with prominent thrombocytosis and from myelodysplastic syndrome (MDS). In particular, ET should be distinguished from Philadelphia chromosome–positive chronic myeloid leukemia, which inevitably transforms into acute leukemia if not treated properly. Moreover, distinction from iron depletion in polycythemia vera (PV) is important, as iron deficiency may mask the polycythemia.

Essential thrombocythemia may transform into other Philadelphia chromosome–negative myeloproliferative diseases, including PV, myelofibrosis (MF), and acute myeloid leukemia (AML) or MDS.2,5 However, ET is generally considered a benign illness because it is associated with prolonged survival and a low risk of leukemic transformation. Thrombosis and, less frequently, bleeding are complications of the disease because of inherent platelet dysfunction.6 The long-term outcome of ET has been described largely among white patients but not among Chinese patients.5,712 Moreover, the leukemogenic potential of hydroxyurea, the main agent in the treatment of ET, has been controversial.5,8,9,12,13 In this study, we conducted a multicenter study to define the clinical characteristics, long-term outcome (survival and transformation to AML or MF), and risk factors for thrombosis among 231 Chinese patients with ET, most of whom were receiving hydroxyurea as the sole treatment.

METHODS
PATIENTS AND DIAGNOSIS

Two hundred thirty-one consecutive Chinese patients with ET were identified from the patient record systems in 5 regional hospitals in Hong Kong. Patient records were reviewed for demographic data, initial symptoms, treatment, and subsequent clinical course, including thrombosis, bleeding, and conversion to MF, PV, or AML. Diagnosis of ET was based on the revised Polycythemia Vera Study Group5 criteria (Table 1), including persistent thrombocytosis with a platelet count higher than 600×103/μL and exclusion of reactive causes, MDS, Philadelphia chromosome–positive chronic myeloid leukemia, and other Philadelphia chromosome–negative myeloproliferative disorders (by hematocrit reading <40%, normal marrow iron store, and absent or minimal marrow fibrosis). In addition to evaluation of marrow iron, iron status was assessed by serum ferritin and serum iron levels and by total iron-binding capacity. The presence of the Philadelphia chromosome was detected by karyotyping, fluorescence in situ hybridization, or reverse transcription–polymerase chain reaction.14,15 A diagnosis of subsequent conversion to MF was based on the presence of marrow fibrosis and splenomegaly, a leukoerythroblastosis, and teardrop red cells, in addition to exclusion of secondary causes of MF.16,17 The diagnoses of AML and MDS were made according to the French-American-British classification.18,19 Recently, a prefibrotic phase of MF has been proposed that has a specific megakaryocyte morphologic structure, demonstrates a markedly increased propensity to MF, and is associated with inferior survival.20 For patients who developed MF, diagnostic bone marrow aspirates were reviewed to identify the characteristic morphologic features of abnormal megakaryopoiesis (grouping of cells containing compact bulbous nuclei, accompanied by bizarre features of differentiation).21 The initial treatment was according to the discretion of the attending physicians. In general, hydroxyurea would be started if patients were symptomatic or were initially seen with a platelet count higher than 1000×103/μL. The target platelet count was lower than 600×103/μL. Low-dose aspirin (100 mg/d) therapy would be started if there was a history of arterial events, including ischemic heart disease, thrombotic strokes, transient ischemic attacks, peripheral vascular disease, and erythromelalgia, or a history of venous thrombosis.

DEFINITIONS AND STATISTICAL ANALYSIS

Thrombotic events included arterial events (thrombotic strokes, transient ischemic attacks, and digital gangrene) and venous thrombosis (pulmonary embolism, deep venous thrombosis, retinal venous thrombosis, and portal vein thrombosis). The mean hemoglobin levels and platelet and leukocyte counts at diagnosis were compared between patients initially seen with erythromelalgia and patients who were asymptomatic. Bleeding events included gastrointestinal tract bleeding, intracerebral hemorrhage, and soft tissue hematoma. The mean platelet count was compared between patients who had and those who did not have bleeding at diagnosis. All thrombotic and bleeding episodes at diagnosis and during follow-up were counted as events. Age, sex, prior MF, and platelet and leukocyte counts at diagnosis of ET were analyzed for their association with the development of AML and MF. Categorical variables (sex, smoking history, splenomegaly at diagnosis, and prior MF) between subgroups were compared using the χ2 test or Fisher exact test, and the means of continuous variables (age and platelet and leukocyte counts at diagnosis) were compared using the t tests.

Thrombosis-free survival (TFS) and bleeding-free survival (BFS) were calculated from the date of diagnosis to the date of event. Overall survival (OS) was calculated from the date of diagnosis to the date of death or last follow-up. Survival curves were plotted by means of the Kaplan-Meier method22 and compared using the log-rank test. To study if thrombosis at diagnosis predicted subsequent thrombosis, TFS between patients initially seen with and those who did not have thrombosis was compared. Univariate analysis of age, sex, smoking history, splenomegaly at diagnosis, and high platelet count (>1200×103/μL) and high leukocyte count (>11 000/μL) at diagnosis was performed to assess the effect of these variables on TFS, BFS, and OS. Multivariate analysis of prognostic factors (age, male sex, smoking, splenomegaly at diagnosis, and high platelet and leukocyte counts at diagnosis) for TFS, BFS, and OS was performed by means of the Cox proportional hazards model2325 (using SPSS for Windows, version 12; SPSS Inc, Chicago, Ill). All P values were 2-sided, with P≤.05 considered statistically significant.

RESULTS
PATIENTS AND TREATMENT

Demographic data are given in Table 1. One hundred thirty-four patients (58.0%) were older than 60 years. Two hundred nine patients (90.5%) started hydroxyurea at diagnosis of ET, although all patients were eventually exposed to hydroxyurea for variable periods. Hydroxyurea was the sole cytoreductive treatment in all patients except 9, who were treated with radioactive phosphorus (3 patients), melphalan (4 patients for 6 months to 7 years), and anagrelide hydrochloride (2 patients) during their clinical course.

THROMBOHEMORRHAGIC EVENTS AND RISK FACTORS

Twenty-three patients (5.6%) initially had erythromelalgia at diagnosis (Table 2). There was no difference between the mean platelet count (934×103/μL vs 1001×103/μL, P = .28) and the mean leukocyte count (11 100/μL vs 12 000/μL, P = .55) at diagnosis for patients who had and those who did not have thrombosis at diagnosis. In particular, there was no significant difference in the mean platelet counts at diagnosis between patients with vs without erythromelalgia (1034 × 103/μL vs 988 × 103/μL, P = .66). The projected TFS was 66% at 10 years (Figure 1A). In univariate analysis, advanced age was associated with lower TFS (P = .07) (Figure 1B), and splenomegaly at diagnosis was negatively associated with thrombosis (P = .02) (Figure 1C) (Table 3). In multivariate analysis, only advanced age (>60 years) was associated with TFS (hazard ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .01). The projected 5-year TFS did not differ for patients who had and those who did not have thrombosis at diagnosis (90% vs 76%, P = .16) (Figure 1D). The projected 10-year BFS was 83% (Figure 2A). In univariate analysis, factors associated with bleeding included male sex (P<.01) (Figure 2B), advanced age (P = .07) (Figure 2C), and high platelet count (P = .07) and high leukocyte count (P = .07) at diagnosis (Table 3). In multivariate analysis, only male sex was associated with inferior BFS (hazard ratio, 3.74; 95% confidence interval, 1.22-11.47; P = .02).

MYELOID TRANSFORMATION AND RISK FACTORS
Myelofibrosis

Seven patients developed MF after a median latency of 8 years (latency range, 4-12 years), 2 of whom developed AML (Table 4). Age, sex, and mean platelet count at diagnosis did not significantly affect the risk. The cumulative probability of MF transformation was 9.7% at 10 years.

AML and MDS

Five patients developed AML (4 patients) or erythroblastic refractory anemia (1 patient) after a median latency of 10 years (latency range, 2-14 years) (Table 5). Three patients who developed AML received hydroxyurea only, and the other 2 received melphalan for variable periods in addition to hydroxyurea. Prior MF (P = .008) and melphalan exposure (P = .002) were risk factors for evolution to AML.

CAUSE OF DEATH, OVERALL SURVIVAL, AND RISK FACTORS

Twenty patients (age range, 62-90 years) died. Besides unknown causes in 2 patients, causes of death included AML or MDS (3 patients), MF (2 patients), bleeding (2 patients), thrombosis (2 patients), carcinoma (3 patients), and unrelated causes (4 patients from pneumonia and 2 patients from chronic obstructive airway disease). The projected 10-year OS was 80% (mean survival, 156 months) (Figure 3A). Univariate analysis showed that advanced age (P<.01) (Figure 3B) and smoking (P = .02) (Figure 3C) were risk factors predicting inferior OS. In multivariate analysis, advanced age was the sole risk factor predicting inferior OS (hazard ratio, 1.12; 95% confidence interval, 1.07-1.21; P<.001).

COMMENT

In contrast to other studies5,712 (Table 1) that reported a predominance of female patients, our study showed an equal sex prevalence among patients with ET. Moreover, a high percentage (54.1%) of our patients were asymptomatic at diagnosis, compared with 27% to 36% of patients in 3 other studies.911 Similar to other studies, our patients had an advanced median age, with 58.9% of our patients being older than 60 years. The mean platelet, leukocyte, and hemoglobin values at diagnosis of ET in our study were similar to those in other studies.5,79,11,12 Therefore, the clinical characteristics of Chinese patients with ET were similar to those of white patients with ET.5,712

Compared with other studies, our patients had a similar frequency of thrombosis at diagnosis but a lower rate of bleeding (Table 1). In an article evaluating 1850 patients enrolled in 21 retrospective studies, the frequency of thrombosis at diagnosis ranged from 9% to 84%, and the frequency of bleeding ranged from 4% to 63%.26 Similar to other studies, thrombosis was more common than bleeding among our patients (Table 2), and arterial thrombosis was more frequent than venous thrombosis.6,7,1012,27 Moreover, advanced age,6,10,12 but not smoking,7,10,12 was a risk factor for thrombosis. Although prior thrombosis is an important risk factor for recurrent thrombosis,10,27 our patients who initially had thrombosis had marginally inferior TFS. In univariate analysis (P = .02) but not in multivariate analysis, splenomegaly at diagnosis seemed to protect our patients against thrombotic events. The spleen in untransformed ET sequesters platelets28 and may protect against excessive platelet count increases. In support of this, a randomized controlled study29 showed that patients with ET achieving lower platelet counts had a decreased incidence of thrombosis.

There were 22 episodes of bleeding in the present study, mostly from the gut (Table 2), with 2 fatalities. A high platelet count at diagnosis was predictive of bleeding at diagnosis (P = .06), an observation that was previously reported.30 In univariate analysis, advanced age (P = .005) and male sex (P = .07) predicted bleeding, but only male sex remained significant in multivariate analysis.

Although conversion to PV can occur,5 none of our patients developed PV. However, because PV may present with thrombocytosis and because hydroxyurea suppresses erythropoiesis, misdiagnosis of patients with PV and prominent thrombocytosis as having ET may have occurred. Seven patients developed MF after a median latency of 8 years, and 2 of them developed AML. Unlike PV, in which a phase of MF with myeloid metaplasia is well recognized, data on conversion of ET to MF are scant. In an extensive retrospective histopathologic study31 of chronic myeloproliferative disease, the risk of conversion to MF was 10% at 10 years. Another study9 showed the risk of MF to be 8.3% at 10 years, with a median latency of 8 years. Our results demonstrated a similar cumulative probability of MF conversion (9.3% at 10 years), with the same median latency of 8 years.

Five of 231 patients developed AML or MDS after a median latency of 120 months. Four patients received melphalan, 3 patients received radioactive phosphorus, and the remaining 224 patients received hydroxyurea only (at diagnosis or during follow-up). Therefore, the frequency of leukemic or MDS transformation among those receiving hydroxyurea as the sole treatment was 3 occurrences (1.3%) among 224 patients. In the literature, variable rates (1.3%-13.1%) of AML or MDS transformation have been reported (Table 6).5,7,8,12,13 The rates were confounded by the inherent risk of leukemic transformation in ET32 and the variable use of alkylating agents, radioactive phosphorus,33 and hydroxyurea.5,32Table 6 summarizes the transformation to leukemia or MDS among patients with ET receiving hydroxyurea as the sole treatment, with the frequency varying between 1.3% and 4.5%.5,7,8,12,13 Similar to these studies, our data showed a low frequency of AML or MDS transformation, with a prolonged latency in patients treated with hydroxyurea alone.34 In all of these studies,5,7,8,12,13 the use of alkylating agents or radioactive phosphorus was the only risk factor for AML or MDS transformation. Similarly, the present study showed a strong association between the use of melphalan and the development of AML (P = .002). However, AML has been reported in patients with sickle cell anemia treated solely with hydroxyurea.3537 The leukemogenic potential of hydroxyurea is further implicated by the increased rate of “illegitimate” variable diversity joining in patients with sickle cell anemia who receive prolonged hydroxyurea treatment.38 Furthermore, previous investigations of PV showed that the risk of acute leukemia was not significantly increased until after 8 years of hydroxyurea exposure.39 This is particularly relevant because a substantial proportion of patients with ET (42.0% in our series) were 60 years or younger. Given that the median survival of the population in Hong Kong in 2003 was about 80 years (78.6 years for men and 84.3 years for women),40 hydroxyurea therapy may be required for more than a decade in younger patients who are diagnosed as having ET. Therefore, prospective studies are needed to address the leukemogenic potential of hydroxyurea therapy in ET, especially because anagrelide, a nonmutagenic platelet-lowering agent, is available as an alternative.41

Two of our patients with AML or MDS transformation had prior conversion to MF. Previous findings have demonstrated higher rates (up to 20%) of leukemic transformation among patients with MF. Similarly, among patients with PV, patients who developed MF had a higher rate of leukemic transformation.42 This is further illustrated by a study43 in which almost half of the patients with acute leukemia evolving from PV had prior myeloid metaplasia. The frequency of AML or MDS transformation is much higher among patients who develop MF (P = .008). In contrast to the well-documented conversion of ET to MF or AML, sequential evolution of ET to AML after prior transformation to MF has only been reported in 6 cases.7,12,4447 Although the platelet count at diagnosis was not associated with development of AML (P = .39), a high leukocyte count at diagnosis seemed to be associated with the subsequent development of AML or MDS (P = .002).

The mean survival in our series was 13 years, demonstrating the benign nature of ET. Moreover, despite a maximum follow-up of 15 years, there were no deaths among our patients 60 years or younger, suggesting that young patients with ET are likely to have a survival rate similar to that of age-matched control subjects. One study48 demonstrated that survival of patients with ET was comparable to that of age- and sex-matched healthy controls; however, another study7 showed that a high platelet count at diagnosis of ET negatively affected OS. Age, not platelet count, was the significant prognostic factor in our study. Moreover, death from thrombosis only occurred in 2 patients, which is much fewer than the rate of 29.8% reported previously.30

Because of the lack of an identified pathognomonic mutation, ET is largely diagnosed by exclusion. However, several independent researchers recently identified a somatic gain-of-function mutation in JAK2, a nonreceptor tyrosine kinase, in 65% to 97% of patients with PV and in 23% to 57% of patients with ET, resulting in a valine to phenylalanine substitution at position 617 (V617F).4952 Because this mutation was found in patients but not in healthy controls, it serves as a specific marker of clonal myeloproliferative disease. Moreover, this mutation in a mouse model has been shown to result in constitutive activation of JAK2, leading to cytokine hypersensitivity and erythrocytosis,50 and is thus functionally important. The availability of this marker will facilitate future definitive diagnosis of ET.

In summary, ET among Chinese patients is a disease of older persons and has a benign clinical course. Advanced age is associated with inferior TFS, BFS, and OS. Conversion to PV and MF is uncommon. Leukemic transformation with hydroxyurea therapy alone is rare and has a long latency.

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Article Information

Correspondence: Chor-Sang Chim, MD, FRCP, FACP, Department of Medicine, Queen Mary Hospital, University of Hong Kong, 102 Pokfulam Rd, Hong Kong (jcschim@hkucc.hku.hk).

Accepted for Publication: June 27, 2005.

Financial Disclosure: None.

Acknowledgment: We thank Li-Chong Chan, PhD, FRCPath, FRCP; Clarence Lam, FRCPath; Kit-Fai Wong, FRCP, FRCPath; Raymond Chu, FRCPath; and S. C. Szeto, FRCP, FRCPath, for their help in ET diagnosis, and Stanley Yeung for his statistical advice.

References
1.
Fialkow  PJFaguet  GBJacobson  RJVaidya  KMurphy  S Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood 1981;58916- 919
PubMed
2.
Spivak  JL The chronic myeloproliferative disorders: clonality and clinical heterogeneity. Semin Hematol 2004;41 ((suppl 3)) 1- 5
PubMedArticle
3.
Champion  KMGilbert  JGAsimakopoulos  FAHinshelwood  SGreen  AR Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. Br J Haematol 1997;97920- 926
PubMedArticle
4.
el-Kassar  NHetet  GBriere  JGrandchamp  B Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets. Blood 1997;89128- 134
PubMed
5.
Murphy  SPeterson  PIland  HLaszlo  J Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol 1997;3429- 39
PubMed
6.
Kessler  CM Propensity for hemorrhage and thrombosis in chronic myeloproliferative disorders. Semin Hematol 2004;41 ((suppl 3)) 10- 14
PubMedArticle
7.
Jensen  MKde Nully Brown  PNielsen  OJHasselbalch  HC Incidence, clinical features and outcome of essential thrombocythaemia in a well defined geographical area. Eur J Haematol 2000;65132- 139
PubMedArticle
8.
Finazzi  GRuggeri  MRodeghiero  FBarbui  T Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial. Br J Haematol 2000;110577- 583
PubMedArticle
9.
Cervantes  FAlvarez-Larran  ATalarn  CGomez  MMontserrat  E Myelofibrosis with myeloid metaplasia following essential thrombocythaemia: actuarial probability, presenting characteristics and evolution in a series of 195 patients. Br J Haematol 2002;118786- 790
PubMedArticle
10.
Cortelazzo  SViero  PFinazzi  GD’Emilio  ARodeghiero  FBarbui  T Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol 1990;8556- 562
PubMed
11.
Fenaux  PSimon  MCaulier  MTLai  JLGoudemand  JBauters  F Clinical course of essential thrombocythemia in 147 cases. Cancer 1990;66549- 556
PubMedArticle
12.
Tefferi  AFonseca  RPereira  DLHoagland  HC A long-term retrospective study of young women with essential thrombocythemia. Mayo Clin Proc 2001;7622- 28
PubMedArticle
13.
Sterkers  YPreudhomme  CLai  JL  et al.  Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: high proportion of cases with 17p deletion. Blood 1998;91616- 622
PubMed
14.
Kwong  YLChiu  EKLiang  RHChan  VChan  TK Essential thrombocythemia with bcr/abl rearrangement. Cancer Genet Cytogenet 1996;8974- 76
PubMedArticle
15.
Kwong  YLLiang  RHChiu  EK  et al.  Essential thrombocythemia: a retrospective analysis of 39 cases. Am J Hematol 1995;4939- 42
PubMedArticle
16.
Tefferi  A Myelofibrosis with myeloid metaplasia. N Engl J Med 2000;3421255- 1265
PubMedArticle
17.
Barosi  G Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol 1999;172954- 2970
PubMed
18.
Bennett  JMCatovsky  DDaniel  MT  et al. French-American-British (FAB) Co-operative Group, Proposals for the classification of the acute leukaemias. Br J Haematol 1976;33451- 458
PubMedArticle
19.
Bennett  JMCatovsky  DDaniel  MT  et al.  Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51189- 199
PubMedArticle
20.
Thiele  JKvasnicka  HM Chronic myeloproliferative disorders with thrombocythemia: a comparative study of two classification systems (PVSG, WHO) on 839 patients. Ann Hematol 2003;82148- 152
PubMed
21.
Thiele  JKvasnicka  HM Prefibrotic chronic idiopathic myelofibrosis: a diagnostic enigma? Acta Haematol 2004;111155- 159
PubMedArticle
22.
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53457- 481Article
23.
Cox  DR Regression models and life-tables. J R Statist Soc Series B 1972;34187- 220
24.
Chim  CSMa  SYAu  WY  et al.  Primary nasal natural killer cell lymphoma: long-term treatment outcome and relationship with the International Prognostic Index. Blood 2004;103216- 221
PubMedArticle
25.
Chim  CSLiang  RTam  CYKwong  YL Methylation of p15 and p16 genes in acute promyelocytic leukemia: potential diagnostic and prognostic significance. J Clin Oncol 2001;192033- 2040
PubMed
26.
Barbui  TBarosi  GGrossi  A  et al.  Practice guidelines for the therapy of essential thrombocythemia: a statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica 2004;89215- 232
PubMed
27.
Colombi  MRadaelli  FZocchi  LMaiolo  AT Thrombotic and hemorrhagic complications in essential thrombocythemia: a retrospective study of 103 patients. Cancer 1991;672926- 2930
PubMedArticle
28.
Wolf  BCNeiman  RS Essential thrombocythemia. Neiman  SOrazi  Aeds.Disorders of the Spleen Philadelphia, Pa WB Saunders Co1999;173- 174
29.
Cortelazzo  SFinazzi  GRuggeri  M  et al.  Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;3321132- 1136
PubMedArticle
30.
Landolfi  R Bleeding and thrombosis in myeloproliferative disorders. Curr Opin Hematol 1998;5327- 331
PubMedArticle
31.
Georgii  ABuesche  GKreft  A The histopathology of chronic myeloproliferative diseases. Baillieres Clin Haematol 1998;11721- 749
PubMedArticle
32.
Barbui  T The leukemia controversy in myeloproliferative disorders: is it a natural progression of disease, a secondary sequela of therapy, or a combination of both? Semin Hematol 2004;41 ((suppl 3)) 15- 17
PubMedArticle
33.
Cervantes  FTassies  DSalgado  CRovira  MPereira  ARozman  C Acute transformation in nonleukemic chronic myeloproliferative disorders: actuarial probability and main characteristics in a series of 218 patients. Acta Haematol 1991;85124- 127
PubMedArticle
34.
Ferster  ASariban  EMeuleman  NBelgian Registry of Sickle Cell Disease Patients Treated With Hydroxyurea, Malignancies in sickle cell disease patients treated with hydroxyurea. Br J Haematol 2003;123368- 369
PubMedArticle
35.
Wilson  S Acute leukemia in a patient with sickle-cell anemia treated with hydroxyurea. Ann Intern Med 2000;133925- 926
PubMedArticle
36.
de Montalembert  MDavies  SC Is hydroxyurea leukemogenic in children with sickle cell disease? Blood 2001;982878- 2879
PubMedArticle
37.
Hanft  VNFruchtman  SRPickens  CVRosse  WFHoward  TAWare  RE Acquired DNA mutations associated with in vivo hydroxyurea exposure. Blood 2000;953589- 3593
PubMed
38.
Najean  YRain  JD Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood 1997;903370- 3377
PubMed
39.
Census and Statistics Department, Hong Kong, Hong Kong Annual Digest of Statistics: Special Administrative Region.  Hong Kong Census and Statistics Dept2003;
40.
Anagrelide Study Group, Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med 1992;9269- 76
PubMedArticle
41.
Landaw  SA Acute leukemia in polycythemia vera. Semin Hematol 1986;23156- 165
PubMed
42.
Silverstein  MNBrown  AL  JrLinman  JW Idiopathic myeloid metaplasia: its evolution into acute leukemia. Arch Intern Med 1973;132709- 712
PubMedArticle
43.
Kimura  AFujimoto  TInada  T  et al.  Blastic transformation in essential thrombocythemia: in vitro differentiation of blast cells into granulocytic, erythroid, and megakaryocytic lineages. Cancer 1990;651538- 1544
PubMedArticle
44.
Emilia  GSacchi  STemperani  PLongo  RVecchi  A Progression of essential thrombocythemia to blastic crisis via idiopathic myelofibrosis. Leuk Lymphoma 1993;9423- 426
PubMedArticle
45.
Sedlacek  SMCurtis  JLWeintraub  JLevin  J Essential thrombocythemia and leukemic transformation. Medicine (Baltimore) 1986;65353- 364
PubMedArticle
46.
Yonemitsu  HOkuda  K Essential thrombocythemia terminating in myelofibrosis and myeloblastic transformation. Jpn J Med 1985;2457- 61
PubMedArticle
47.
Rozman  CGiralt  MFeliu  ERubio  DCortes  MT Life expectancy of patients with chronic nonleukemic myeloproliferative disorders. Cancer 1991;672658- 2663
PubMedArticle
48.
Bazzan  MTamponi  GSchinco  P  et al.  Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia. Ann Hematol 1999;78539- 543
PubMedArticle
49.
Kralovics  RPassamonti  FBuser  AS  et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;3521779- 1790
PubMedArticle
50.
James  CUgo  VLe Couedic  JP  et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005;4341144- 1148
PubMedArticle
51.
Baxter  EJScott  LMCampbell  PJ  et al. Cancer Genome Project, Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;3651054- 1061
PubMedArticle
52.
Levine  RLWadleigh  MCools  J  et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7387- 397
PubMedArticle
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