International Journal of
HEMATOLOGY
Clinical Features of Polycythemia Vera and Essential Thrombocythemia in Japan: Retrospective Analysis of a Nationwide Survey by the Japanese Elderly Leukemia and Lymphoma Study Group Kazuo Dan,a Takashi Yamada,a Yukihiko Kimura,b Noriko Usui,c Shinichirou Okamoto,d Takashi Sugihara,e Kazue Takai,f Michihiko Masuda,g Mayumi Mori,h and the Japanese Elderly Leukemia and Lymphoma Study Group a
Department of Hematology, Nippon Medical School, Tokyo; bFirst Department of Internal Medicine, Tokyo Medical University, Tokyo; cDepartment of Hematology/Oncology, The Jikei University School of Medicine, Tokyo; d Department of Hematology, Keio University School of Medicine, Tokyo; eDepartment of Hematology, Kawasaki Medical School, Okayama; fDepartment of Hematology, Niigata City General Hospital, Niigata; g Department of Hematology, Tokyo Women’s Medical University, Tokyo; hDepartment of Hematology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan Received January 11, 2006; received in revised form February 27, 2006; accepted March 7, 2006
Abstract We conducted the first nationwide survey to clarify the clinical features, treatment methods, and prognoses for polycythemia vera (PV) and essential thrombocythemia (ET). A 1-page questionnaire was mailed to members of the Japanese Elderly Leukemia and Lymphoma Study Group (JELLSG). Surveys on 647 patients (PV, 266 patients; ET, 381 patients) were returned and analyzed. Thrombotic events at diagnosis and during follow-up occurred at rates of 15.4% and 8.5%, respectively, in PV cases and 17.6% and 8.7% in ET cases. Splenomegaly was observed in only 28.8% of PV patients and 10.8% of ET patients. The leukocyte alkaline phosphatase score was elevated in only 46.2% of PV patients. The incidences of abnormal karyotypes were less than 10% in both PV and ET cases. The rates of transformation to myelofibrosis were 2.6% in both PV and ET cases, and acute leukemia was noted in 1.1% of PV patients and 2.9% of ET patients. Prognostic factors were thrombotic history for PV and thrombotic history and age (60 years) for ET. The present study clearly demonstrated clinical differences between Japanese and Western patients for PV and ET. Concerning the treatment of PV and ET, the study revealed considerable variation among Japanese hematologists. These results suggest the necessity of developing treatment guidelines according to risk stratification that are suitable for Japanese PV and ET patients. Int J Hematol. 2006;83:443-449. doi: 10.1532/IJH97.06009 ©2006 The Japanese Society of Hematology Key words: Polycythemia vera; Essential thrombocythemia; Clinical features; Nationwide survey; Retrospective analysis
chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic idiopathic myelofibrosis, and CMPD not classifiable in the CMPD category. PV and ET are clonal disorders of unknown etiology involving multipotent hematopoietic stem cells [3,4] and are characterized by the excessive production of blood cells but with no diseasespecific cytogenetic or molecular markers, in contrast to the Philadelphia chromosome or BCR-ABL in chronic myelogenous leukemia. Recently reported for PV and ET have been some molecular findings, such as overexpression of PRV-1 in granulocytes from PV and ET patients [5,6], reduced expression of platelet c-mpl [7,8], and an acquired gain-of-function mutation of the Janus kinase 2 (JAK2) gene [9], although these findings are not of diagnostic value. Because of the absence of a disease-specific marker, diag-
1. Introduction Polycythemia vera (PV) and essential thrombocythemia (ET), previously recognized as “myeloproliferative syndromes,” are now classified as chronic myeloproliferative diseases (CMPD) according to the new World Health Organization (WHO) classification [1,2]. The current WHO classification also includes chronic myelogenous leukemia,
Correspondence and reprint requests: Kazuo Dan, MD, PhD, Department of Hematology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan; 03-5814-6322; fax: 035814-6322 (e-mail:
[email protected]).
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nostic criteria were developed for PV [10] and ET [11]. Although PV and ET diagnoses are made by using these criteria, the clinical features for PV, ET, and idiopathic myelofibrosis show overlap in some patients, which makes a precise diagnosis difficult [12,13]. The causes of morbidity and mortality in PV and ET are thrombohemorrhagic events and progression to myelofibrosis or acute leukemia, although whether evolution to myelofibrosis or acute leukemia is part of the natural course of the disease or whether it is related to the cytoreductive agents used to control the overproduction of blood cells is uncertain. To date, there is no known treatment, except for hematopoietic stem cell transplantation, for eradicating the abnormal clone and improving the prognosis [14]. Thus, the objective of treatment for PV and ET is to prevent thrombohemorrhagic complications and to lower the risk of disease evolution to myelofibrosis or acute leukemia. For this purpose, risk-stratified management has been proposed [13], although the criteria used to allocate risk remain controversial; significant differences have been reported to exist among physicians with respect to the appropriate management of PV [13,15]. In Japan, no nationwide survey on PV and ET has been conducted until now; thus, there have been no data for Japanese patients concerning actual clinical features, such as the incidence of thrombosis or hemorrhage, or the rate of transformation to myelofibrosis or acute leukemia. Moreover, PV and ET treatment methods involving the use of cytoreductive agents and antiplatelet agents are also unknown in Japan. To clarify the clinical features of patients, treatment methods, and the prognoses for PV and ET, we conducted a nationwide survey of members of the Japanese Elderly Leukemia and Lymphoma Study Group (JELLSG) and analyzed the results retrospectively.
2. Methods 2.1. Questionnaire Survey A 1-page questionnaire on the clinical features, laboratory data, treatments, and prognoses for PV and ET was mailed to JELLSG members at 177 institutions. Patients who had received diagnoses between January 1994 and December 2003 and had met the diagnostic criteria for PV and ET were enrolled. Each questionnaire was sent with a short letter of introduction and the diagnostic criteria for PV [10] and ET [11], as well as return postage. All returned questionnaires were included in the data set and analyzed.
2.2. Statistical Analysis Statistical analyses were performed with the StatView for Windows software package, version 4.54 (Brain Power Inc, Calabasas, CA, USA). Comparisons of groups were conducted with the 2 test. Survival probabilities were estimated by the Kaplan-Meier method, and differences in survival distributions were evaluated by the log-rank test. For these analyses, P values were 2-tailed, and a P value <.05 was considered statistically significant.
3. Results 3.1. Subjects for Analysis Surveys were returned from 40 institutions (response rate, 22.6%) and included 647 PV and ET patients (PV, 266 patients; ET, 381 patients). Patient numbers were distributed evenly over the 10 years included in the investigation. At the time of the query, patients had been followed up for a median of 51 months for PV and 52 months for ET.
3.2. Clinical Features The clinical features of the patients are shown in Table 1. PV appeared to be somewhat more common in men than women, in contrast to ET. Patient ages ranged from 31 to 88 years in PV cases and 18 to 90 years in ET cases. The age distribution of ET patients tended toward younger patients than for PV cases (Figure 1). “Vasomotor” symptoms such as headache, dizziness, and tinnitus were more common than thrombotic and hemorrhagic events. The leukocyte alkaline phosphatase score was elevated in 46.2% of PV patients but only 15.4% of ET patients. The incidences of abnormal karyotype were less than 10% in both PV and ET groups. Although no karyotype abnormality specific for PV or ET was found, abnormalities in chromosomes 9 and 20 were conspicuous, a result similar to that of reports from Western countries.
3.3. Treatments for PV and ET Most patients received some kind of therapy (Table 2). Among antiplatelet agents, aspirin was used most frequently, followed by ticlopidine and then dipyridamole. Similarly, among myelosuppressive agents, hydroxyurea was used in more than two thirds of the PV and ET patients, followed by ranimustine and then busulfan. Interferon was used in only 1% of both PV and ET patients.
3.4. Commencement of Therapy Table 3 summarizes the patients’ clinical features at commencement of therapy. Both hematocrit values and platelet counts at the commencement of antiplatelet or myelosuppressive agent therapy were markedly different among patients. As for patient age, cytoreductive therapy was started before 60 years of age in more than one third of the patients.
3.5. Complications and Transformation of the Disease Thrombohemorrhagic complications during the disease course were unexpectedly low in both PV and ET (Table 4). Likewise, the rates of disease transformation to myelofibrosis and acute leukemia were also low. However, these transformations tended to increase in patients who had received cytoreductive therapies. The rate of transformation to myelofibrosis in PV patients treated with cytoreductive therapy was 4.5%, which is significantly higher (P = .02) than that in all PV patients. In addition, the rate of leukemic transformation in ET patients treated with cytoreductive therapy
Clinical Features of PV and ET in Japan
445
Table 1. Clinical Features of the Patients* Characteristic Male-female ratio Age, y Symptoms at diagnosis, % None Thrombotic events Hemorrhagic events “Vasomotor” symptoms Splenomegaly Hepatomegaly Laboratory findings at diagnosis Peripheral blood Red blood cells, 104/L Hemoglobin, g/dL Hematocrit, % Platelets, 104/L White blood cells, /L Leukocyte alkaline phosphatase score, % High Normal Low Chromosome, % Abnormal Normal Vitamin B12, pg/mL
PV (n = 266)
ET (n = 381)
P
1.3:1 59.2 12.1
1:1.2 58.4 15.7
— NS
37.0 17.6 4.2 21.5 10.8 4.2
NS NS NS NS <.0001 NS
<.0001 <.0001 <.0001 <.0001 .007
32.7 15.4 6.4 27.1 28.8 4.9
661 8.0 55.6 53.1 13,500
103 2.3 6.4 33.2 7300
46.2 47.2 6.6 8.7 91.3 1622 5676
474 13.6 41.8 106.3 11,300
79 1.9 5.6 43.4 11,200
15.4 69.2 15.4
<.0001 <.0001 .006
6.4 93.6 878 723
NS NS NS
*Data are presented as the mean SD where applicable. PV indicates polycythemia vera; ET, essential thrombocythemia; NS, not statistically significant.
increased to 4.0%, compared with the rate for all ET patients, although this difference was not statistically significant (P = .07).
3.6. Prognosis Figure 2 shows the survival curves for the PV and ET patients. The probability of overall survival at 131 months was 72.8% for PV patients (Figure 2A) and 71.8% for ET patients (Figure 2B). When the survival curves of PV
patients aged 60 years and <60 years were compared, no difference was observed (Figure 2C). On the other hand, ET patients aged 60 years showed a poorer prognosis than younger patients (P = .021) (Figure 2D). As a risk factor, a history of thrombotic episodes had no influence on survival in either PV or ET patients; in addition, a platelet count of >150 104/L had no influence on the survival of ET patients (data not shown). The risks of thrombohemorrhagic complications during the clinical course of PV and ET were analyzed according to
Figure 1. Age distributions of polycythemia vera (PV) patients (n = 266) and essential thrombocythemia (ET) patients (n = 381).
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Table 2.
Table 4.
Treatments for Polycythemia Vera (PV) and Essential Thrombocythemia (ET)*
Complications and Transformation of Polycythemia Vera (PV) and Essential Thrombocythemia (ET)
Treatment
PV (n = 266), %
ET (n = 381), %
P
6.4 51.5 35.4 24.5 7.3 2.2 58.3 49.6 4.8 2.4
14.8 — 59.2 42.6 12.0 3.1 65.1 48.6 12.5 1.4
.001 — <.0001 <.0001 NS NS NS NS .0004 NS
No therapy Phlebotomy Antiplatelet agents Aspirin Ticlopidine Dipyridamole Myelosuppressive agents Hydroxyurea Ranimustine Busulfan
*NS indicates not statistically significant.
the history of thrombotic episodes. The rates of thrombohemorrhagic complications were significantly higher in patients with a history of thrombotic episodes in both the PV (P < .0001) and ET (P = .0018) groups (Figures 3A and 3B). Similarly, we analyzed the risks of thrombohemorrhagic complications by age group. In the PV cases, there was no significant difference between patients 60 years old and patients <60 years old in this risk (Figure 3C). On the other hand, an older age was a significant risk factor in the ET patients (P = .035; Figure 3D).
4. Discussion This report presents the results of the first nationwide survey of JELLSG members concerning the clinical features, treatment methods, and prognoses for PV and ET. We have to take account of the relatively low response rate of 22.6% in the analysis of the data. However, it is important that the present survey and our analyses have revealed actual Japanese data on the clinical features and prognoses for PV and ET, which have been lacking in Japanese textbooks on hematology until now. Although a more comprehensive survey might have been preferable, we felt that a longer questionnaire would have adversely affected the response rate. Thus,
Table 3. Clinical Features at Commencement of Therapy for Polycythemia Vera (PV) and Essential Thrombocythemia (ET)
Feature Hematocrit, % Platelet, 104/L Patient Age, % <29 y 30-39 y 40-49 y 50-59 y 60-69 y 70-79 y >80 y
Antiplatelet Agents PV ET
Myelosuppressive Agents PV ET
35.5-73.2 12-144
— 32-247
32.6-73.4 14-223
— 35-352
— — — — — — —
— — — — — — —
0 4.3 10.6 27.7 35.5 18.4 3.5
2.1 5.1 13.1 18.1 32.1 21.5 8.0
Thrombosis Hemorrhage Transformation (all patients) Myelofibrosis Acute leukemia Transformation (in patients with cytoreductivetherapy) Myelofibrosis Acute leukemia
PV (n = 266), %
ET (n = 381), %
8.5 5.5
8.7 6.5
2.6 1.1
2.6 2.9
4.5* 1.3
3.6 4.0†
*P = .02, compared with the incidence for all PV patients. †P = .07, compared with the incidence for all ET patients.
we were able to analyze data from 266 PV patients and 381 ET patients. The clinical features, age distributions, and male-female ratios of the Japanese PV and ET patients were similar to those reported in Western countries [16,17]. On the other hand, the incidences of thrombotic events were much lower in Japanese patients. The incidences of thrombotic events for the PV patients at diagnosis and during follow-up were 15.4% and 8.5%, respectively, compared with the corresponding incidences of 13% to 39% [14,18] and 10.3% to 25% [14,18] reported in Western countries. The incidences of thrombotic events for the ET patients at diagnosis and during follow-up were 17.6% and 8.7%, respectively, compared with the incidences of 15% to 25% [13,18,19] and 11% to 22.3% [18-20] for the corresponding Western data. In the present survey, thrombotic events tended to be frequent in patients treated with antiplatelet or cytoreductive agents. These findings may simply reflect the fact that more aggressive cases are more likely to be treated. We could not establish the hematocrit values and platelet counts at the times of thrombotic events from the present survey. With regard to the physical examination findings, the incidences of splenomegaly (28.8% for PV and 10.8% for ET) were also much lower than the figures (45%-70% for PV and 20%59% for ET) reported in Western countries [16,17,21]. With respect to the laboratory findings at diagnosis, the leukocyte alkaline phosphatase score and the incidence of chromosomal abnormality in the present Japanese PV patients were very low compared with the results from Western countries presented in previous reports [17,22,23]. In the present survey of Japanese PV and ET patients, the rates of transformation to myelofibrosis and acute leukemia were relatively low. Although there is a wide range in the reported incidences among studies in Western countries, many reports suggest much higher rates. The incidence of transformation from PV to acute myeloid leukemia/ myelodysplastic syndrome (AML/MDS) was reported to be 5% to 15% after 10 years of the disease, with the risk increasing over time [21], and the 15-year risks for clonal evolution into myelofibrosis or AML were reported to be 6% and 7%, respectively [24]. In ET, the actual probability of myelofibrotic transformation was reported to be 8.3% at 10 years
Clinical Features of PV and ET in Japan
447
Figure 2. Survival curves of polycythemia vera (PV) and essential thrombocythemia (ET) patients. Probabilities of overall survival for PV (A) and ET (B) patients. Survival curves according to age group for PV (C) and ET (D) patients. NS indicates not statistically significant.
[25], whereas leukemic conversion rates ranged from 0.5% to 5% [24,26,27]. However, we have to be aware that it is impossible to distinguish between the level of risk of hematologic transformation due to the natural course of the disease and that due to the long-term use of cytoreductive agents. Even the effect of hydroxyurea, which is the most commonly
administered agent in PV and ET and is thought to be less leukemogenic than other agents, on the occurrence of AML/ MDS remains controversial. Our present survey showed the tendency of the transformation rate to increase when PV and ET patients underwent treatment with hydroxyurea in combination with other cytoreductive agents.
Figure 3. Risk of thrombohemorrhagic complications. Rates of thrombohemorrhagic complications according to history of thrombotic episodes in polycythemia vera (PV) patients (A) and essential thrombocythemia (ET) patients (B). Rates of thrombohemorrhagic complications by age group for PV (C) and ET (D) patients. NS indicates not statistically significant.
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As for the prognoses for PV and ET patients in Japan, the 10-year overall survival rate was 72.8% for PV patients and 71.8% for ET patients. The overall mortality rate in PV patients was reported to be 1.6 to 1.7 times that of an ageand sex-matched healthy population [14,24], whereas the life expectancy of patients with ET was not affected significantly by the disease, reflecting the more indolent nature of the proliferation [24]. The present analyses revealed that the risk factors were a history of thrombosis in PV and an older age (60 years) and a history of thrombosis in ET. Age (60 years) as a risk factor for ET may be related to the high incidence of thrombohemorrhagic complications in older ET patients (Figure 3D). The present study has clearly demonstrated the differences between Japanese and Western patients with PV and ET concerning clinical features, laboratory data, and disease transformation. With respect to the reasons for these differences, although we should take into account the low tendency toward thrombosis in the general Japanese population compared with the Caucasian population, we think it is important to consider the pathogenetic aspect of the disease itself. Mutation of the JAK2 gene has recently been reported to be a strong candidate for causing clonal expansion of hematopoietic progenitors in myeloproliferative disorders [28], and evaluation of the clinical data has revealed significant correlations between the presence of a JAK2 mutation (V617F) and the frequency of complications, ie, secondary fibrosis, hemorrhage, and thrombosis [9]. These findings have prompted us to perform an investigation into the occurrence of the JAK2 V617F mutation in Japanese PV and ET patients. Our survey, the first nationwide assessment of treatment methods for PV and ET, has convincingly demonstrated that considerable variation exists among Japanese hematologists in the treatment of PV and ET. The criteria for starting therapy with antiplatelet or cytoreductive agents vary remarkably among physicians. It is intriguing that cytoreductive therapy was started before 60 years of age in more than one third of the patients. These realities imply the necessity of developing treatment guidelines according to risk stratifications that are suitable for Japanese PV and ET patients.
Acknowledgments The authors thank the members of JELLSG for their efforts in filling out and returning the questionnaire survey. We are grateful to the following participating institutions: Hokkaido University, Third Department of Internal Medicine; Hokkaido University, Department of Hematology; Asahikawa Medical College, Third Department of Internal Medicine; Sapporo Medical University, Fourth Department of Internal Medicine; Sapporo Teishin Hospital, First Department of Internal Medicine; Akita University School of Medicine, Third Department of Internal Medicine; Kamaishi City General Hospital, Internal Medicine; Niigata City General Hospital, Department of Hematology; Niigata Prefectural Central Hospital, Department of Hematology; Kitafukushima Medical Center, Department of Hematology; Usui Hospital, Department of Internal Medicine; Saitama Medical School, Department of Hematology; Nippon Med-
ical School, Department of Geriatrics; Nippon Medical School, Third Department of Internal Medicine; Tokyo Medical University, Department of Geriatrics; Tokyo Medical University, First Department of Internal Medicine; Tokyo Medical University, Third Department of Internal Medicine; Tokyo Women’s Medical University, Department of Hematology; Showa University School of Medicine Fujigaoka Hospital, Department of Hematology; The Jikei University School of Medicine, Department of Hematology/Oncology; Tokyo Metropolitan Geriatric Hospital, Department of Hematology; Keio University School of Medicine, Department of Hematology; Aiiku Hospital, Department of Internal Medicine; Kanazawa University School of Medicine, Third Department of Internal Medicine; Osaka University, Department of Hematology/Oncology; Osaka Medical College, Department of Hematology; Kobe University School of Medicine, Department of Hematology/Oncology; Kobe City General Hospital, Department of Immunology/Hematology; Okayama Rosai Hospital, Department of Internal Medicine; Kawasaki Medical School, Department of Hematology; Hiroshima City Hospital, Department of Internal Medicine; Masuda Red Cross Hospital, Department of Hematology; Kochi Medical School, Third Department of Internal Medicine; Fukuoka University School of Medicine, First Department of Internal Medicine; Saiseikai Hita Hospital, Department of Internal Medicine; Sawara Hospital, Department of Internal Medicine; Kyushu University School of Medicine, Third Department of Internal Medicine; Kyushu Cancer Center, Department of Hematology; National Kokura Hospital, Department of Internal Medicine; Saga University, Department of Hematology.
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