Published guidelines versus real‐life practice in the diagnosis and treatment of essential thrombocythemia
Authors: Erica A. Peterson, Leslie Zypchen, Vivian H. Y. Lee, Janet Nitta, Lynda M. Foltz
Journal: American Journal of Hematology (2011)

The discovery of the JAK2V617F gene mutation significantly altered the diagnostic approach to essential thrombocythemia (ET) as reflected in the revised 2008 World Health Organization (WHO) diagnostic criteria. However, both the previous and revised WHO criteria require a bone marrow assessment for diagnosis of ET. We reviewed 246 patients with a clinical diagnosis of ET made by a hematologist at two university teaching hospitals. Only 58% of patients had a bone marrow biopsy. There was a trend toward decreased frequency of bone marrow biopsies after testing for JAK2V617F became widely available, particularly in patients with a confirmed JAK2V617F mutation. Older patients were significantly less likely to undergo bone marrow biopsy. Treatment with hydroxyurea has been shown to reduce the risk of thrombosis in high-risk (age >60 or history of thrombosis) ET patients. Only 62% of high-risk ET patients in our cohort were prescribed hydroxyurea within 1 year of diagnosis. ASA was prescribed to 72% of high-risk and 44% of low-risk patients. This study shows that published recommendations for diagnosis and treatment of ET have not been widely adapted at a major teaching center. Further studies are required to assess the barriers to implementation. Essential thrombocythemia (ET) is a BCR-ABL-negative myeloproliferative neoplasm (MPN) characterized by persistent thrombocytosis. In 2005, an acquired point mutation in exon 14 of the JAK2 tyrosine kinase gene (JAK2V617F) was identified in a significant proportion of patients with BCR-ABL negative MPNs, including approximately 50% of patients with ET [1-4]. The discovery of the JAK2V617F gene mutation led to a revision of the diagnostic criteria for ET by the World Health Organization (WHO) in 2008 [5]. The 2008 WHO criteria, however, retained the requirement from previous criteria for a bone marrow biopsy showing megakaryocytic proliferation to make a diagnosis of ET (Table I) [6]. Patients with ET are at increased risk of arterial and venous thrombosis. The highest risk of thrombosis is seen in patients with a prior history of thrombosis or age over 60 years [7, 8]. Cytoreductive agents have been shown to reduce the incidence of thrombosis in these "high-risk" ET patients, with hydroxyurea being superior to anagrelide [9, 10]. Based on these studies, experts recommend cytoreduction for ET patients with previous history of thrombosis or age over 60 years. Low dose aspirin is recommended for most ET patients regardless of additional thrombotic risk factors [11, 12]. It is unclear whether physicians in clinical practice utilize the WHO diagnostic criteria for ET or follow expert treatment recommendation guidelines. We therefore conducted a retrospective chart review of patients with a clinical diagnosis of ET in an outpatient university hospital teaching center to determine what diagnostic tests and treatment strategies were being utilized. We identified all patients with a new clinical diagnosis of ET made by a hematologist at two university teaching hospitals in Vancouver, Canada between 1982 and 2008 (n = 246). A bone marrow biopsy was performed in only 58% of patients. As testing for JAK2V617F became widely available in 2006, patients were separated into cohorts of diagnosis pre-2006 and post-2006. Bone marrow biopsies were performed more frequently in patients diagnosed before 2006 compared with patients diagnosed after 2006 (60% vs. 50%), although this difference was not statistically significant (Table II). There was trend toward less frequent bone marrow assessment in patients with positive JAK2V617F mutation testing compared with patients with negative JAK2V617 mutation testing (42% vs. 58%). Increasing age was associated with a lower likelihood of bone marrow testing, with 38% of patients under 60 years, 34% of patients aged 60–69 years, 33% of patients aged 70–79 years, and 68% of patients ≥80 years not undergoing a bone marrow biopsy at diagnosis (P = 0.02 for ≥80 years compared with other groups). Before 2006, 72% of patients had molecular testing for the BCR-ABL gene product to exclude chronic myeloid leukemia (CML). Testing for BCR-ABL declined to 65% after JAK2V617F testing became available, primarily due to a laboratory policy to not routinely perform BCR-ABL testing in patients in whom JAK2V617F testing is positive. JAK2V617F testing was performed in 94% of patients after 2006, with 58% testing positive, 33% testing negative and 3% having equivocal results. The initial cohort of ET patients identified (n = 246) was reanalyzed by separating the patients into two risk groups at diagnosis. Patients >60 years of age or with a history of thrombosis before or at diagnosis were classified as high risk. Patients who did not fulfill these criteria were classified as low risk. Of the 246 patients identified, 166 (67.5%) were high risk (43.4% male, 56.6% female) and 80 (32.5%) were low risk (31.3% male, 68.6% female). Median age at diagnosis in the high-risk group was 71.4 years (range 31.7–98.4 years) and median follow-up was 5.7 years. Median age at diagnosis in the low-risk group was 42.7 years (range 19.1–60.9 years) and median follow-up was 8.1 years. Median values of hemoglobin and platelet count were similar between both groups; however extreme thrombocytosis (defined as a platelet count above 1500 × 109) was more common in low-risk patients (14.9% vs. 7.6%, P = 0.032). Mean white blood cell count (WBC) was marginally higher in high-risk patients (9.8 vs. 9.2 × 109 cells/L) whereas leukocytosis with a WBC over 15 × 109 was significantly more common in high-risk patients (11.9% vs. 1.6%, P = 0.015). The incidence of one or more cardiovascular (CV) risk factors defined as hypertension, diabetes, dyslipidemia, or personal or family history of coronary artery disease was significantly higher in high-risk patients (80.5% vs. 50%, P < 0.001). In contrast, rates of smoking were similar between the groups (P = 0.13). Among high-risk patients, arterial thrombotic complications at or before diagnosis of ET occurred in 47 (26.5%), and venous thrombotic events occurred in 17 (8.4%). Low-risk patients by definition did not have any prior thrombotic events. Significantly more patients in the high-risk group received treatment with ASA within 1 year of diagnosis (73% vs. 45%, P < 0.001). Throughout follow-up, ASA use increased in patients who were both high and low risk at diagnosis (Table III). Hydroxyurea was the most commonly used cytoreductive agent, initiated within 1 year of diagnosis in 62% of high-risk patients and 22% of low-risk patients (P < 0.01). During follow-up many of the initially low-risk patients were started on hydroxyurea, although the percentage remained lower than in the high-risk group (76% vs. 47%, P < 0.01). Use of anagrelide was similar in both groups at diagnosis and throughout follow-up (6.1% in high-risk patients vs. 2.5% in low-risk patients P = 0.21), although overall usage of anagrelide was much lower then hydroxyurea. Overall survival was superior for patients in the low-risk group at diagnosis (median not reached) compared with the high-risk group (median survival 14.0 years, P < 0.0001) (Table IV). During follow-up, 26 patients developed MF and 19 patients developed MDS/AML. The cumulative incidence of transformation to other myeloid disorders (MF, AML, MDS) at 10 years was 24% in high-risk patients and 14% in low-risk patients (P = 0.21). Arterial thrombosis occurred in 30 high-risk and 9 low-risk patients, while venous thrombosis occurred in three high-risk and seven low-risk patients. Thrombosis had occurred in 26% of high-risk and 24% of low-risk patients by 10 years (P = 0.29) (Table IV). When patients were excluded from the low-risk group upon reaching age 61 in follow-up, the incidence of thrombosis was reduced to 11% at 5 years and 21% at 10 years (P = 0.14 vs. high-risk group). Our study illustrates the challenges of translating published diagnostic criteria and treatment guidelines into day to day patient care. We found that a substantial number of patients with a clinical diagnosis of ET did not undergo bone marrow examination. This may be related to advanced age and comorbidities of patients at diagnosis. In our study, we did observe a correlation between age and a decreased likelihood of a bone marrow biopsy being performed, with patients ≥80 years old at diagnosis being half as likely to undergo this testing as their younger counterparts. Patient preference and the widespread availability of molecular testing may also play a role in the decision to forgo a bone marrow biopsy. We observed a trend toward a decreased rate of bone marrow biopsies in patients diagnosed after JAK2 testing was introduced. Indeed, all patients diagnosed after 2006 who did not have a bone marrow biopsy at diagnosis had tested positive for the JAK2V617F mutation. Although positivity for the JAK2V617F mutation does indicate the presence of an MPN and excludes a reactive cause for thrombocytosis, it is not specific for ET and cannot differentiate between ET and other myeloproliferative disorders such as prefibrotic primary myelofibrosis (PMF). During the time period of the study, many local hematologists did not feel that a bone marrow assessment in patients with JAK2V617F positivity would provide sufficient additional diagnostic information to justify the invasive procedure. More recently, however, Barbui et al. applied WHO morphological criteria to the bone marrow biopsies of cohort of patients diagnosed with and treated as ET. Patients who on review were found to have a bone marrow biopsy consistent with early PMF had higher rates of leukemic transformation and inferior overall survival compared with patients whose bone marrow biopsies were consistent with ET [13]. It will be interesting to observe whether this newly published prognostic data leads to an increase in the number of bone marrow biopsies performed in clinical practice. It is concerning that only 61% of patients in our cohort at high risk for thrombotic events at diagnosis (age >60 or previous thrombosis) were treated with cytoreductive therapy. Possible reasons for withholding cytoreductive therapy in high risk older individuals may have included concerns regarding medical comorbidities, medication side effects and higher pill burden. Indeed, side effects of hydroxyurea such as cytopenias may be more pronounced in older patients with diminished bone marrow reserve. Forty-four percent of low-risk patients received antiplatelet agents within 1 year of diagnosis and 22% received hydroxyurea. In our study, a large number of patients in our low-risk group did have CV risk factors (50%), smoking (32.5%) or extreme thrombocytosis (17.4%) which may explain the observed initiation of cytoreductive therapy. In our study, there were no significant differences in the incidence of transformation or thrombosis between patients in the high and low-risk groups. This may be in part related to sample size and duration of follow-up. However, the risk classification scheme used in this study is based on risk of thrombotic events, so this risk grouping may not optimally stratify patients based on risk of transformation. Transformation events were somewhat more frequent in our cohort than what has been reported in other studies [8, 13], possibly reflecting a more heterogenous population including prefibrotic myelofibrosis as bone marrow biopsies were not performed in 42% of patients. Risk of thrombosis was comparable with previously published reports [9, 10], but interestingly was similar between the high- and low-risk groups. Hydroxyurea use was more common in the high-risk group and this likely contributed to the normalization of thrombosis rates between the groups. As with any retrospective study, the retrospective nature of information gathering is a weakness of this study, as data was missing for some patients for certain diagnostic tests and treatments. The main strength of this study is that is describes how clinicians diagnose and treat ET in a "real world" setting, outside of a specialized center. In conclusion, this study demonstrates diversity in clinical practice in the diagnosis and treatment of ET. Further studies are required to identify the barriers to translating diagnostic and treatment recommendations into clinical practice. A retrospective chart review of all patients diagnosed with ET at two tertiary centers in Vancouver, Canada between 1982 and 2008 was completed. Data collected included demographic information, thrombosis history, diagnostic tests performed, treatment administered, arterial and venous thrombotic complications, and transformation to other myeloid disorders. For analysis of diagnostic strategies utilized, patients were separated into two groups, based on diagnosis pre- or post 2006 (when JAK2V167F testing became available). This yielded 210 patients diagnosed before 2006 and 36 patients after 2006. Bone marrow biopsy testing at diagnosis was unavailable for 15 patients in the pre-2006 cohort, and BCR-ABL testing was unavailable for 18 patients in the pre-2006 cohort and one patient in the post-2006 group. For analysis of treatment and outcomes, patients were separated into risk categories and were considered high risk if they were over 60 years of age or they had a history of thrombosis at the time of diagnosis. All other patients were considered low risk. Treatment information at diagnosis was unavailable for 49 patients for ASA, three patients for anagrelide and 13 patients for hydroxyurea. Therapy during follow-up was missing for three patients for ASA, one patient for anagrelide and two patients for hydroxyurea. Therapy during follow-up was missing for three patients for ASA, one patient for anagrelide, and two patients for hydroxyurea. Three and five patients respectively were excluded from the Kaplan Meier analysis for cumulative risk of thrombosis and cumulative risk of transformation as the exact date of the event was not available. Baseline characteristics, diagnostic tests performed, and treatment received were compared between high- and low-risk patients with the use of Chi-squared tests. Cumulative risk of thrombosis, cumulative risk of transformation, and overall survival were calculated using the Kaplan-Meier method. The authors thank Jonathan Berkowitz for help with statistical analysis and our colleagues in the division of Hematology at St. Paul's Hospital and Vancouver General Hospital for their support. Erica A. Peterson*, Leslie Zypchen*, Vivian H. Y. Lee , Janet Nitta*, Lynda M. Foltz [email protected] , * Division of Hematology, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada, Department of Medicine, University of British Columbia, Vancouver, BC, Canada, Division of Hematology, St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.