High-risk Essential Thrombocythemia Research Articles

Pegylated Interferon Alpha – 2a in Patients with Myeloproliferative Neoplasms (MPN): International Experience in 115 Cases

Abstract▪2818▪This icon denotes a clinically relevant abstract Background:Pegylated interferon alpha-2a (Peg INF2a) has been demonstrated to be active therapy for high-risk essential thrombocythemia (ET) and polycythemia vera (PV), as well as treatment for early myelofibrosis (MF). We retrospectively analyzed the outcomes of Peg INF2a therapy in MPN patients treated outside the constraints of a clinical trial in the USA and EU. Methods:Clinical records of MPN patients treated at the participating centers, receiving Peg INF2a outside of the context of a clinical trial, were analyzed for response (ET and PV by ELN criteria; MF by EUNMET and IWG-MRT criteria), toxicity, and duration of response. Results:Patients: 115 patients were identified (54 PV (47%), 44 ET (38%), 17 MF (15%)) with a median age at diagnosis (48) and gender distribution (59% females) typical for the disorders. The patients had been diagnosed with the MPN a median of 44 months (0.0–312 months) prior to initiation of the Peg IFN2a and 64% harbored the JAK2-V617F mutation. The majority of patients (81%) had received at least one prior cytoreductive therapy for their disease (73 hydroxyurea, 39 anagrelide, 37 aspirin, 21 prior interferon (non pegylated), 3 phlebotomy alone).Therapy: Median starting dose of Peg INF2a was 45 micrograms/week (range: 22.5–180) with peak starting doses ranging from 30 to 300 micrograms/week. A total of 84 patients (73%) remain on Peg IFN2a with median duration of treatment of 17 months (range: 1.0–92). Toxicity: Overall the Peg INF2a was well tolerated. Hematological toxicity was Gr 3 or lower. There were 6 cases with anemia (5%), 10 with thrombocytopenia (9%) and 8 had leukopenia (7%). Most common non-hematologic toxicities were Gr 1–3 fatigue in 27 (23%), Gr 1 LFT elevation in 6 (5%), Gr 2–3 skin/allergic reaction in 6 (5%), Gr 1–2 nausea in 5 (4%), and Gr 2 mood disorder in 5 (4%) patients. Twenty patients (17%) discontinued therapy secondary to toxicity. Response: ET-PV: By ELN criteria, 30 PV patients achieved CR (55%), 17 achieved PR (31%), 4 achieved NR (7%), and 3 patients (5%) were lost to follow up or were too early to evaluate for response. In ET, the responses were CR in 27 (61%), PR in 7 (16%), NR in 4 (9%), and 6 patients (14%) were lost to follow up or were too early to evaluate for response. MF: The responses by IWG criteria were 1 CR (6%), 2 PR (12%), 2 CI (12%) and 9 SD (53%). By EUNMET, there were 2 CR (12%), 4 major responses (24%), 4 moderate responses (24%), 1 minor response (6%), 2 no response (12%), and 3 patients (17%) were lost to follow up or were too early to evaluate for response. Conclusions:Peg INF2a used at doses consistent with published clinical trials is active and well-tolerated when administered in a clinical setting outside of the support of a clinical trial. Given the majority of patients had previously failed cytoreductive therapy these results substantiate prior reports of efficacy of Peg INF2a in MPNs. Upcoming randomized clinical trials through the Myeloproliferative Disorders Research Consortium will help further define the role of Peg INF2a as first line therapy in high-risk MPNs. Disclosures:Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding.

Annual Clinical Updates in Hematological Malignancies: A Continuing Medical Education Series: Polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk‐stratification, and management

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms primarily characterized by erythrocytosis and thrombocytosis, respectively. Other disease features include leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus, and a small risk of disease progression into acute leukemia or myelofibrosis. Diagnosis is based on JAK2 mutation status (PV and ET), serum erythropoietin (Epo) level (PV), and bone marrow histopathology (ET). The presence of a JAK2 mutation and subnormal serum Epo level confirm a diagnosis of PV. Differential diagnosis in ET should include chronic myelogenous leukemia and prefibrotic myelofibrosis. Current risk stratification in PV and ET is designed to estimate the likelihood of thrombotic complications: high-risk-age > 60 years or presence of thrombosis history; low-risk-absence of both of these two risk factors. Presence of extreme thrombocytosis (platelet count > 1,000 x 10⁹/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk factors for shortened survival in both PV and ET include age > 60 years, leukocytosis, history of thrombosis, and anemia. Survival is near-normal in ET and reasonably long in PV. The 10-year risk of leukemic/fibrotic transformation is < 1%/1% in ET and < 5%/10% in PV. In contrast, the risk of thrombosis exceeds 20%. The main goal of therapy is therefore to prevent thrombohemorrhagic complications and this is effectively and safely accomplished by the use of low-dose aspirin (PV and ET), phlebotomy (PV), and hydroxyurea (high risk PV and ET). Treatment with busulfan or interferon-a is usually effective in hydroxyurea failures.

High Rates of Molecular Response After Long-Term Follow-up of Patients with Advanced Essential Thrombocythemia (ET) or Polycythemia Vera (PV) Treated with Pegylated Interferon-ALFA-2A (PEG-IFN-α-2A; PEGASYS)

AbstractAbstract 461 Background:The use of IFN-α in polycythemia vera (PV) and essential thrombocythemia (ET) has been hampered by poor tolerance and inconvenient dosing schedules. The covalent attachment of polyethylene glycol to IFN-α renders a molecule with prolonged serum half-life, which can be administered weekly. Objectives:We conducted a phase II study of subcutaneous PEG-IFN-α-2a (Pegasys) in 84 patients (pts) with high-risk PV (n=44) or ET (n=40). We performed high throughput mutational analysis of JAK2, MPL, TET2, and ASXL1 in all pts. Patients and Therapy:Median age was 51 years (range, 18–79), time from diagnosis to PEG-IFN-α-2a 51 months (range, 0–355), and number of prior therapies was 1 (range, 0–6), including hydroxyurea (HU; n=47), anagrelide (AG; n=26), IFN-α (n=12: 5 oral and 7 sc), imatinib (n=7), and dasatinib (n=1). PEG-IFN-α-2a was initial therapy in 16 (19%) pts (7 PV) that refused HU. JAK2V617F was detected in 19/40 (48%) ET and in 42/44 (95%) PV pts. Nine (11%) pts had abnormal cytogenetics. Initial PEG-IFN-α-2a starting dose was 450 mcg/wk, but that was modified to the current starting dose of 90 mcg/wk. Results:After a median follow-up of 40 months (range, 8–62), 66/83 (80%) assessable pts have responded. Median time to response was 4 weeks (range, 0.5–26). Complete response (CR) was achieved by 62 (75%) pts (for ET: platelets <440×109/L, in the absence of thromboembolic events; for PV: Hb <15 g/dL, no phlebotomy, disappearance of splenomegaly) whereas 4 (5%) pts (2 PV, 2 ET) had a partial response ([PR]; no phlebotomy, off HU and AG, still palpable spleen). Of 5 pts with abnormal karyotype at study entry who were evaluable for response, 2 reverted to diploid cytogenetics.JAK2V617F to total JAK2 ratio was determined by quantitative pyrosequencing assay in all 84 pts prior to PEG-IFN-α-2a. Sixty-one (73%) pts carried the JAK2V617F mutation, which was quantitated at least once on therapy in 54 (64%). Overall, 29 (54%) had >20% reduction in JAK2V617F allele burden, including 10 (19%) in whom the mutation became undetectable (complete molecular response [CMR]) and 15 (28%) who had a >50% reduction (partial molecular response). Molecular responses have not yet reached a plateau among pts with PV.We also analyzed pts for mutations in exon 12 of JAK2, MPL, and the tumor suppressors TET2 and ASXL1 to determine their impact on response to PEG-IFN-α-2a. No pts carried JAK2 exon 12 mutations. One JAK2V617F−negative pt with ET had a MPLW515L mutation, achieved CHR but did not achieve a molecular response. Full length resequencing of all exons of TET2 and ASXL1 genes identified somatic TET2 mutations in 9/71 (13%) and somatic ASXL1 mutations in 3/71 (4%) pts; we identified TET2 (3 JAK2V617F− ET, 2 JAK2V617F+ ET, 3 JAK2V617F+ PV, 1 JAK2V617F− PV) and ASXL1 (1 pt with ET JAK2V617F+, ET JAK2V617F−, and PV JAK2V617F+) mutations in PV and ET pts who were JAK2V617F–positive and negative. TET2 or ASXL1 mutational status did not impact the likelihood of achievement of JAK2 molecular responses, and there was no difference in JAK2V617F allele burden with PEG-IFN-α-2a according to TET2 or ASXL1 mutational status. One pt with baseline mutations in JAK2, TET2, and ASXL1 became JAK2V617F–negative on PEG-IFN-α-2a.Most pts had grade 1–2 toxicities but at doses ≤90 mcg/wk, grade 3–4 toxicity was infrequent. Twenty-five (30%) patients were taken off study after a median of 9 months (range, 3–36) but only 13 (15%) of them due to therapy-related toxicity: g3 neutropenia, anorexia, depression (n=3), ischemic retinopathy, g2 fatigue (n=5), dyspnea, g2 neuropathy. The remaining 59 pts are currently receiving 450 mcg/wk (n=1), 360 mcg/wk (n=1), 240 mcg/wk (n=1), 180 mcg/wk (n=2), 135 mcg/wk (n=3), 90 mcg every 1 (n=8), 2 (n=12), 3 (n=2), or 4 wks (n=1), 45 mcg every 1 (n=9), 2 (n=5), 3 (n=6), or 4 wks (n=8). Conclusion:PEG-IFN-α-2a is remarkably active and acceptably safe in advanced, previously treated PV and ET. Clinical responses are frequently accompanied by significant reduction of JAK2V617F allele burden, which becomes undetectable in a proportion of them suggesting selective targeting of the JAK2V617F clones. Quantitative analysis of ASXL1 and TET2 mutational allele burden during PEG-IFN-α-2a therapy to determine clonal evolution, and methylcellulose-based clonogenic assays in pts who achieved CMR to assess for the presence of erythropoietin independent colony formation are ongoing and will be presented. Disclosures:No relevant conflicts of interest to declare.

Cardiac surgery in a patient with essential thrombocythemia: a case report.

Patients with essential thrombocythemia (ET) are at increased risk of developing arterial thrombosis. We report a case of a 36-year-man with unstable angina in the presence of occlusion of two coronary arteries with insufficient collateral perfusion. We also found essential thrombocythemia in this patient. The patient underwent coronary artery bypass grafting (CABG). Ten days before surgery, the aspirin was replaced by a prophylactic dose of low-molecular-weight heparin. Postoperative follow-up was complicated by pulmonary embolisms and a cardiac tamponade. We conclude that ET is a risk factor for coronary heart disease that should be treated with aspirin. If a patient needs CABG, aspirin should be continued because of the high risk of thromboembolic events in the high-risk ET patients. (Neth Heart J 2010;18:378-80.).

Myelofibrotic transformation in essential thrombocythemia

The exact incidence of myelofibrotic transformation in essential thrombocythemia (ET) is still a critical issue1,2 and is certainly influenced by risk status and diagnostic criteria. In a recently published study by Passamonti and co-workers in this journal,3 a cohort of 605 patients with ET is described recruited during a lengthy period (1975 to 2008) from one center. Unfortunately, as explicitly stated, diagnosis of ET was performed using criteria at the time of the first observation, implicating that a large fraction, probably the majority of patients, were diagnosed by following the cited criteria of the Polycythemia Vera Study Group (PVSG),4 contrasting the more recently entered fraction to whom the WHO classification was applied.5 Consequently, the diagnostic guidelines are inconsistent regarding a strict differentiation of ET from early stages of primary myelofibrosis (PMF) with associated thrombocytosis. It has been demonstrated by different groups that significant differences exist between the PVSG versus the WHO classification schemes for ET: depending on risk factors and selection of patients only about 20–40% of ET cases diagnosed according to the PVSG4 are validated by the WHO criteria.6–8 The diagnosis of post-ET myelofibrosis was made by the authors using the criteria of the International Working Group on Myelofibrosis (IWG-MRT).9 However, these criteria do explicitly include as first major requirement the documentation of a previous diagnosis of WHO-defined essential thrombocythemia . This postulate can not be fulfilled by the obviously predominant PVSG-diagnosed series of patients incorporated into this investigation. Moreover, following the IWG-MRT criteria, bone marrow fibrosis grade 2–3 consistent with the cited European Consensus Grading System10 is the second major requirement. This important feature implicates the evaluation of sequential bone marrow biopsy specimens - has this been performed in all patients under study? Concerning the frequency of post-ET myelofibrosis, the transformation rate was 2.8% at a median follow-up of 9.1 years (or a 10-year risk of 3.9% and a 15-year risk of 6%).3 This relatively low incidence may possibly be created by including an unknown number of WHO-diagnosed ET cases into this study. When strictly following the diagnostic criteria of the PVSG4 applied in the UK-PT1 Study for high risk ET,11 in our retrospective evaluation of 539 patients under standard therapy, after three years overall incidence of myelofibrosis proved to be significantly different depending on diagnostic criteria (Table 1). Table 1. Risk of myelofibrotic transformation (post-essential thrombocythemia myelofibrosis) within 36 months in 539 high-risk patients with essential thrombocythemia strictly diagnosed according to the UK-PT1 Study criteria11 receiving standard therapy regimens. ... This difference was generated by discrimination of the total cohort according to the WHO classification5 into (true) ET and PMF with accompanying thrombocytosis mimicking this condition. On the other hand, when maintaining the PVSG guidelines,4 a comparable rate (2.8% vs. 2.6%)11 of progression into myelofibrosis was revealed during an observation time of about three years. Regarding leukemic transformation, although no systemic study has yet been published, similar discrepancies associated with applied classification schemes may be encountered. In conclusion, a thorough re-evaluation of this series of 605 patients with distinction into those diagnosed as ET cases according to PVSG criteria4 versus those in whom diagnosis was based on the WHO classification seems to be warranted, including a repeatedly performed calculation of progression rates into myelofibrosis and leukemia. As criteria for myelofibrotic transformation, the corresponding guidelines of the UK-PT1 Study11 should be used for the presumably prevalent ET group diagnosed after PVSG, and for the WHO classified series the IWG-MRT parameters can be applied. As has been reviewed for myelofibrosis in chronic myeloproliferative neoplasms,12 a significant difference between both groups of patients can be predicted consistent with the diagnostic criteria applied.

Final Results of the ANAHYDRET-Study: Non-Inferiority of Anagrelide Compared to Hydroxyurea in Newly Diagnosed WHO-Essential Thrombocythemia Patients

Background: Both anagrelide and hydroxyurea effectively lower platelet counts in essential thrombocythemia (ET) and other thrombocythemic myeloproliferative neoplasms. Anagrelide has a selective inhibitory effect on megakaryopoiesis and platelet production in contrast to hydroxyurea, which is a nonspecific, myelosuppressive compound inhibiting megakaryopoiesis as well as granulopoieses and erythropiesis. Based on the superiority of hydroxyurea+aspirin over anagrelide+aspirin in ET patients in the PT1-trial, guidelines for cytoreductive therapy favor hydroxyurea as first line therapy for ET. However, the diagnosis of ET in the PT1-trial was made according to the PVSG cassification and it remains questionable if these recommendations can be applied to ET patients diagnosed according to the WHO classification.Patients and methods: In this prospective randomized single blind international multicenter phase III study efficacy and tolerability of anagrelide and hydroxyurea monotherapies were compared in high risk ET patients diagnosed according to the WHO classification. The study was designed as a non-inferiority trial as the limited number of treatment naïve ET patients available and the expected low number of ET related events following treatment with a cytoreductive therapy would not have allowed the conduct of a conventional superiority trial. After informed consent 258 treatment naïve, high risk patients with ET were randomized to receive either anagrelide (n=122) or hydroxyurea (136). The patients characteristics were equally distributed within both arms with a median age of 58,1 years, range 19–90 years; 46 male, 76 female in the anagrelide arm vs. a median age of 56,4 years, range 22– 83 years, 47 male, 89 female in the hydroxyurea arm. Anagrelide (Thromboreductin) was started with a dose of 1mg/day and hydroxyurea was initiated using a dose of 1500mg/day.Results: A central blinded pathologic review of 236 bone marrow biopsies revealed a high reproducibility of the ET diagnosis by applying the WHO classification: 194 (82.2%) of patients were classified as ET, 16 patients (6,8%) were reclassified as PMF-0 and 16 patients (6,8%) were considered to be early PVs with an ET-like clinical phenotype. Confirmatory proof of non-inferiority was achieved after a mean observation time of 2,1 years (comprising 539 patient years) based on predefined equivalence criteria for platelet counts, course of hemoglobin levels and white cell count during therapy, and for the rate of ET related events. In the anagrelide arm 75,4% of the patients received a complete response of platelet counts (<450×109/l) compared to 81,7% in the hydroxyurea arm. Neutrophile counts remained unchanged in the anagrelide arm but were significantly reduced by hydroxyurea. No significant differences were observed for the rates of major and minor clinical complications in the anagrelide group (4,29%, and 16,8%, resp.) compared to hydroxyurea (4,25%, and 12,8%, resp.). During the whole study period 11 major ET related complications occurred in the anagrelide group (5 arterial events, 2 venous thrombotic complications and 4 bleedings) and 12 major events were seen in the hydroxyurea arm (5 arterial events, 5 venous thrombositic events and 2 bleedings). 43 minor ET related events occurred in the anagrelide arm as compared to 36 such events in the hydroxyurea arm. Adverse drug reactions or poor response were reasons for discontinuations of the study drug in 19 patients treated with anagrelide and in 10 patients treated with hydroxyurea. Transformations to myelofibrosis were not reported during the whole study period. The JAK2 mutation status was evaluated in 189 patients with 101 JAK2 positive (53,4%) and 88 (46,6%) JAK2 negative patients. The impact of this mutation on thrombotic events in both arms will be presented at the meeting.Conclusion: The final analysis of the study provides evidence for non-inferiority of anagrelide compared to hydroxyurea in the treatment of ET diagnosed according to the WHO classification. Therefore it can be speculated that in these cases a thromboreductive therapy represented by anagrelide may be sufficient in order to prevent thrombotic complications whereas in other thrombocythemic MPN patients a cytoreductive treatment (e.g. with hydroxyurea) may be necessary.

Similar Rate of Thrombosis in Essential Thrombocythemia and Polycythemia Vera Patients after Stratification for JAK2 V617F Allele Burden.

Patients with Essential Thrombocythemia (ET) can be categorized as either JAK2 V617F mutated (V617F+) or wild type (V617F−). Mutated patients display multiple features resembling Polycythemia Vera (PV), with significantly higher hemoglobin level and neutrophil counts, lower platelet count, more pronounced bone marrow erythropoiesis and granulopoiesis and higher tendency to transform in PV. Presence of the mutation and/or allele burden has been variably associated with the rate of vascular complications in ET and PV, but a direct comparison between the two disorders under this respect has not been performed. To tackle this issue, we compared the rate of major thrombosis in 867 ET patients (57% were JAK2 V617F+) with that in 415 PV patients (all V617F+). The median follow-up was 4.9 (0 – 39) and 3.8 (0 – 26) years in ET and PV, respectively. High risk ET patients (age ≥ 60 years and/or previous thrombosis) received Hydroxyurea whereas the vast majority of low-risk remained untreated. PV patients were treated according to the current risk-stratified recommendations. Thrombotic episodes were recorded over time and calculated as rates % per patient/year (pt/yr). After adjusting for age, the thrombosis-free survival curves of JAK2 V617F+ and V617F− ET patients were superimposable until 10 years after the diagnosis, then they diverged so that the actuarial probability of major thrombosis in mutated ET patients reached that of PV (48% vs 55%, test for trend p=0.05). We found that JAK2 V617F+ allele burden measured by real-time quantitative PCR influenced these rates in a comparable way in both ET and PV. Actually, in JAK2 wild type ET (n=376, 43%) the rate was 1.4% pt/yr. In ET patients with JAK2 V617F+ allele burden ranging from 1 to 25% (N=190; 49%) the rate was 1.9 % pt/yr compared to 1.2 in PV patients (N=64, 19%); in the group with 26–50% the rate was 2.0 % pt/yr in ET (N=177; 45%) and 3.0 in PV patients (N=118, 36%); in cases of V617F+ allele burden greater than 50% the rate was 3.8 % pt/yr in ET (N=23; 6%) and 2.9 in PV patients (N=147, 45%). In conclusion, from this retrospective analysis, we conclude that in patients with ET harboring JAK2 V617F mutation the rate of stroke, myocardial infarction and venous thromboembolic complications is similar to that of PV patients and increases in dependence of V617F allele burden, supporting the hypothesis that ET and PV may be viewed as a continuum also in terms of vascular complications

Pegylated Interferon-ALFA-2A (PEG-IFN-α-2A; PEGASYS) Therapy Renders High Clinical and Molecular Response Rates in Patients with Essential Thrombocythemia (ET) and Polycythemia VERA (PV)

Patients with high-risk essential thrombocythemia (ET) and polycythemia vera (PV) are typically managed with cytoreductive agents such as recombinant interferon-alpha (IFN-α), hydroxyurea (HU), and anagrelide (AG). Despite the significant activity of IFN-α in ET and PV, this agent is frequently hindered by poor tolerance and inconvenient dosing schedules. PEG-IFN-α is formulated by covalently attaching polymers of ethylene glycol to the native IFN-α molecule, resulting in decreased renal excretion and increased serum half-life that allows for weekly administration. On this basis, we are conducting a phase II study of subcutaneous PEG-IFN-α-2a (Pegasys) for patients with ET or PV. A total of 76 patients have been enrolled and treated thus far (36 ET, 40 PV). Median age is 53 years (range, 18–77), time from diagnosis to PEG-IFN-α-2a 49 months (range, 0–355), WBC count 8.7×109/L (range, 3.7–27.8), hemoglobin 13.5 g/dL (range, 8.9–18.8), and platelet count 554×109/L (range, 140–1641). Prior therapies (median 1; range 0–6) included HU (n=44), AG (n=29), IFN-α (n=11: 5 oral and 6 sc), imatinib (n=7), and dasatinib (n=1). PEG-IFN-α-2a was the initial therapy in 13 patients that refused therapy with HU. The JAK2 V617F mutation was detected in 20 (56%) of 36 ET and in 37 (92.5%) of 40 PV patients. Nine (12%) patients had abnormal cytogenetics. Initial starting dose of PEG-IFN-α-2a was 450 mcg/week, but that was modified to the current starting dose of 90 mcg/week. Dose modifications are allowed according to response or toxicity. Patients are currently receiving 450 mcg (n=1), 270 mcg (n=3), 180 mcg (n=14), 135 mcg (n=8), 90 mcg (n=27), and 45 mcg (n=7). After a median follow-up of 23 months (range, 2–38), 63 (85%) of 74 assessable patients have responded. The median time to response was 4 weeks (range, 0.5–26). Complete response (CR) was achieved by 60 (81%) patients (for ET: platelets <440×109/L, off HU and AG, in the absence of thromboembolic events; for PV: Hb <15 g/dL, off HU and AG, no phlebotomy, with disappearance of splenomegaly) whereas 3 (4%) patients (1 PV, 2 ET) had a partial response ([PR]; no phlebotomy, off HU and AG, but still palpable spleen). Of 5 assessable patients with abnormal karyotype at the start of the study, 2 reverted to diploid cytogenetics. The mutant JAK2 V617F to total JAK2 ratio was determined by quantitative pyrosequencing assay in all 76 patients prior to PEG-IFN-α-2a and was repeated at least once during therapy in 41 JAK2 V617F-positive patients. Overall, 23 (56%) had >10% reduction in JAK2 V617F expression, including 14 (34%) who had a >50% reduction. In 5 (11%) of the latter the mutant allele became undetectable. PEG-IFN-α-2a was well tolerated in most patients. Thirty-nine episodes of grade 3–4 toxicity were reported: neutropenia (n=15), elevated transaminases (n=5), infection (n=4), fatigue (n=3), pain (n=3), cardiac (n=2), and anemia, thrombocytopenia, depression, shortness of breath, pruritus, thrombosis, and dizziness in 1 case each. Sixteen (21%) patients were taken off study after a median of 8 months (range, 2–26) on PEG-IFN-α-2a but only 7 (9%) of them due to due to therapy-related toxicities: grade 3 neutropenia, anorexia, depression, ischemic retinopathy, dyspnea, confusion, and pruritic rash. In conclusion, PEG-IFN-α-2a therapy results in remarkable clinical activity with an acceptable toxicity profile in advanced, previously treated, patients with ET or PV. Clinical responses are frequently accompanied by significant reduction of JAK2 V617F allele burden, which becomes undetectable in a proportion of them, suggesting selective targeting of the malignant clone.

Pharmacotherapy of essential thrombocythemia

Background: The natural history of essential thrombocythemia is characterized by an increased incidence of thrombotic and hemorrhagic events and, in the long-term, a tendency for disease transformation to myelofibrosis or acute leukemia. Advanced age and a prior history of thrombosis are the major predictors of thrombotic complications. Objective: The aim of this study was to outline the current evidence and the authors' opinion regarding the clinical management of patients with essential thrombocythemia. Methods: The study reviewed the pertinent literature addressing the management options for essential thrombocythemia patients. Results/conclusions: Cytoreductive agents can reduce the rate of thrombotic events, but do not affect the overall survival or rate of disease transformation. Thus, a risk-adapted strategy is recommended for the management of patients with essential thrombocythemia. High-risk patients with essential thrombocythemia should be treated with cytoreductive therapy and low-dose aspirin. Hydroxycarbamide is the agent of choice in most patients: however, interferon-α is a reasonable alternative in young patients, pregnancy or those intolerant of hydroxycarbamide. Low-risk patients can be safely observed. The management of intermediate-risk patients needs to be individualized: however, low-dose aspirin can be used after excluding acquired von Willebrand's disease. In the future we await the role of molecularly targeted therapy with JAK2 inhibitors in high-risk essential thrombocythemia patients.

198 INVITED Acute lymphoblastic leukaemia

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a “high-risk” or “low-risk” category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100 mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.

200 INVITED What is known about HPV natural history? Current trends and variation in incidence, mortality and relation to screening programmes in Europe

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a “high-risk” or “low-risk” category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100 mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.

Effects of Anagrelide on Megakaryopoiesis and Platelet Production

Possible pathomechanisms regarding the thromboreductive effect of anagrelide (ANA) include decrease in the megakaryocyte cell mass or life span of platelets, interference with maturation, and stimulation of apoptosis and proliferation. Finally, a fibrogenic effect has been reported in patients with high-risk essential thrombocythemia (ET). Based on scrutinized evaluations, including immunohistochemistry and morphometry performed on representative bone marrow (BM) biopsies, ANA was found to exert a significant influence on the endoreduplicative activity of megakaryopoiesis, with an arrest of maturation at lower ploidy stages causing a predominance of precursors. This result confirms and greatly extends former investigations that also failed to document a decrease in quantity or enhancement of apoptosis. Moreover, a comparative study on the putative mutagenic capacity of hydroxyurea (HU) versus ANA treatment reveals that both agents generate a left-shifting of megakaryocytes. However, HU creates conspicuously expressed maturation defects consistent with dysplastic changes of megakaryopoiesis, and therefore supports concerns about the possible leukemogenic potential of this drug. On the other hand, in follow-up examinations of BM specimens, ANA failed to show a stimulation of myelofibrosis in ET, provided diagnosis was established according to the World Health Organization criteria.

The Impact of Clinicopathological Studies on Staging and Survival in Essential Thrombocythemia, Chronic Idiopathic Myelofibrosis, and Polycythemia Rubra Vera

In chronic myeloproliferative disorders (MPDs), varying results regarding staging of disease and assessment of outcome have been reported. Risk classification is mainly based on clinical data; however, in those disorders associated with an elevated platelet count, discrimination of (true) essential thrombocythemia (ET) may be difficult without the possibility to recognize characteristic histopathological bone marrow patterns according to the World Health Organization (WHO) guidelines. Patients with ET reveal no relevant reduction of life expectancy and the impact of disease is significantly higher in elderly patients, especially in chronic idiopathic myelofibrosis (IMF) and polycythemia rubra vera (PV). In high-risk ET, the overall incidence of myelofibrotic transformation after 36 months of follow-up is 2.8% when considering the Polycythemia Vera Study Group guidelines. In contrast, classification according to WHO fails to show a relevant transformation into myelofibrosis either by clinical or morphological standards in (true) ET. Early stages of IMF show a more favorable outcome, but in multivariate risk classification, signs of myeloid metaplasia have the most important impact on prognosis. In PV, the risk for thrombosis increases with age, and furthermore, signs of generalization are generally associated with a worsening of prognosis. It has been shown that examination of bone marrow specimens enhances the diagnostic reliability and also enables the recognition of evolving myelofibrotic transformation in MPDs.

Long-Term Incidence of Hematological Evolution in Three French Prospective Studies of Hydroxyurea and Pipobroman in Polycythemia Vera and Essential Thrombocythemia

Despite recent discoveries made in myeloproliferative disorders other than chronic myelogenous leukemia, which it is hoped will result in earlier diagnosis, and better evaluation and management of patients, hematological evolution to myelofibrosis, acute leukemia, and myelodysplastic syndromes (AL/MDS) remain major causes of long-term mortality in polycythemia vera (PV) and essential thrombocythemia (ET) patients. Evaluation of long-term leukemogenic risk of currently available drugs, therefore, is crucial. We report updated results of three French prospective trials of hydroxyurea and pipobroman in PV and ET patients with a median follow-up longer than 10 years. The results show that the incidence of AL/MDS is higher than previously reported with no evidence of a plateau (with approximately 40% of AL/MDS cases occurring after the 12th year of follow-up). Although hydroxyurea currently remains the first choice in the treatment of high-risk PV and ET patients, the use of nonleukemogenic drugs, such as interferon alpha (IFN-alpha) or anagrelide, should be assessed more widely in randomized trials using accurate diagnostic criteria and taking into account the presence of the JAK2 mutation, given that they may have an impact on disease evolution.

Hydroxyurea Compared with Anagrelide in High-Risk Essential Thrombocythemia

We conducted a randomized comparison of hydroxyurea with anagrelide in the treatment of essential thrombocythemia. A total of 809 patients with essential thrombocythemia who were at high risk for vascular events received low-dose aspirin plus either anagrelide or hydroxyurea. The composite primary end point was the actuarial risk of arterial thrombosis (myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, or peripheral arterial thrombosis), venous thrombosis (deep-vein thrombosis, splanchnic-vein thrombosis, or pulmonary embolism), serious hemorrhage, or death from thrombotic or hemorrhagic causes. After a median follow-up of 39 months, patients in the anagrelide group were significantly more likely than those in the hydroxyurea group to have reached the primary end point (odds ratio, 1.57; 95 percent confidence interval, 1.04 to 2.37; P=0.03). As compared with hydroxyurea plus aspirin, anagrelide plus aspirin was associated with increased rates of arterial thrombosis (P=0.004), serious hemorrhage (P=0.008), and transformation to myelofibrosis (P=0.01) but with a decreased rate of venous thromboembolism (P=0.006). Patients receiving anagrelide were more likely to withdraw from their assigned treatment (P<0.001). Equivalent long-term control of the platelet count was achieved in both groups. Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for vascular events.

Treatment with Pegylated Interferon α (PegIntron) for High-Risk Essential Thrombocythemia: Results of a Phase II Study.

In high risk Essential Thrombocythemia (ET) there is a indication for cytoreductive therapy. However, especially in younger patients long-term use of alkylating agents or hydroxyurea is a matter of concern. Modification of the pharmacokinetic profile of interferon α, a non-leukemogenic agent, through addition of a polyethylenglicol (pegylation) has resulted in slower absorption and lower elimination rate, thus enabling a weekly application with potentially increased compliance compared to conventional interferon α.In this phase II study we evaluate the safety, tolerability and efficacy of pegylated Interferon α (PegIntron, Essex Pharma) in high risk essential thrombocythemia. PegIntron is administered subcutaneously at a starting dose of 50 μg weekly. In patients not achieving a platelet count < 500 G/l after 8–12 weeks, the dosages can be increased by 25 μg/week up to 150 μg/week. Between 12/01 and 09/03 a total of 36 high risk ET patients (either platelet > 1500 G/l, or age> 60 years, or previous ET related complications) were enrolled by a total of 16 centers (16 male and 20 female patients, median platelet count at diagnosis 900 G/l, median age at diagnosis 54 years [range: 24–72 years]). Treatment was indicated because of at least one of the following reasons: Age > 60 years (38%), platelet count > 1500 G/l (36%) or previous ET related complications (50%). 10 patients (28%) were previously treated (hydroxyurea: 8 patients, anagrelide: 2 patients).In this analysis there are 35 of 36 patients evaluable, 1 patient was lost to follow-up. Of these 35 patients, 24 (69%) are still on therapy with PegIntron after a median observation time of 18 months. The individual dosages of PegIntron are shown in table 1. A platelet count < 500 G/l was achieved in 57% of the patients after 3 months and in 75% and 89% after 6 and 12 months, respectively.In 9 patients (26%) therapy was stopped because of drug related side effects (alopecia: 2 patients, arthralgia: 2 patients, flu-like symptoms: 2 patients, psoriasis: 1 patient, depression: 1 patient, diarrhea: 1 patient). In one patient an alternative cytoreductive therapy was initiated because of an insufficient platelet control. One patient suffered from a cerebral stroke and subsequently was taken off PegIntron application. After a median observation time of 18 months, we observed one potentially ET related complication (stroke) during PegIntron therapy so far.These preliminary data indicate the efficacy of PegIntron in the treatment of high risk ET at relatively low doses and reasonable toxicity and safety compared to conventional interferon α. [Display omitted]

Pharmacotherapy of essential thrombocythaemia: economic considerations

The clinical course of essential thrombocythaemia (ET) is mainly outlined by a predisposition to both thromboembolic, and more rarely, haemorrhagic complications. The individual clinical course is, however, variable, ranging from an event-free course to life-threatening thromboembolic episodes. In order to treat ET patients economically, it is necessary, above all, to consider if cytoreductive therapy is really indicated. Risk stratification according to clinical criteria such as age, previous ET-related events and platelet count may help to define patients at risk. In low-risk ET patients, a watch-and-wait strategy seems to be feasible. There is a clear indication for cytoreductive therapy in high risk ET patients as demonstrated in a Phase III clinical trial. Because of the lack of Phase III trials, it is not clear which of the cytoreductive drugs – hydroxyurea, pipobroman, IFN-α, pegylated-IFNs or anagrelide – is the best therapeutic option. Factors that influence the choice out of the available drugs are efficacy, safety and cost. The efficacy and safety data of the available drugs for ET are derived from Phase II studies or observational studies. IFN-α is the most expensive drug. Newer drugs like anagrelide or pegylated-IFNs are still expensive, but may have a better cost-benefit effect in patients < 60 years of age. Two cost-effectiveness analyses revealed a result in favour of anagrelide, however, in these cost-effectiveness models, assumptions were based on non-randomised trials. For patients > 60 years of age, hydroxyurea may be the best therapeutic option with regard to both the efficacy and cost-effectiveness.

Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis.

Essential thrombocythaemia (ET) is a disease associated with an elevated risk of thrombosis. This study evaluated the efficacy and safety of pipobroman (PB) in the long-term control of ET patients who had, at diagnosis, one or more of the following currently known risk factors for thrombosis or haemorrhage (high-risk patients): age > 60 years, history of thrombosis or haemorrhage, platelets >1000 x 10(9)/l. From 1978 to 2000, with a median follow-up of 10 years, 118 previously untreated high-risk ET patients (median age 62 years, range 25-82), were treated with PB at the starting dose of 0.8-1 mg/kg/d. All patients reached a platelet count <600 x 10(9)/l and 91% achieved a platelet count <400 x 10(9)/l. During follow-up, 13 patients had thrombosis, with a 10-year cumulative risk of 14%. Acute myeloid leukaemia, myelofibrosis and solid tumours occurred in three, two and seven patients with a 10-year cumulative risk of 3%, 2% and 7% respectively. Actuarial survival at 20 years was 64% and the standardized mortality ratio was 1.1 (95% CI: 0.7-1.7), not statistically different from the general population (P = 0.54). Age was associated with a higher risk of death (P = 0.00009) and thrombosis (P = 0.003). The duration of PB treatment did not correlate with the occurrence of second malignancies. This study, with a median follow-up of 10 years, demonstrates that pipobroman is effective and well tolerated. The low cumulative 10-year risk of thrombosis, leukaemia and solid tumours indicates that pipobroman is an adequate treatment for patients with high risk ET.

Aspirin and platelet-lowering agents for the prevention of vascular complications in essential thrombocythemia.

Low-risk essential thrombocythemia patients include patients aged 18 to < 80 years with no vascular risk factor or previous thrombosis, no associated disease, a normal life expectancy, and a platelet count between 400 and 1,000 x 10(9)/L up to 1,500 x 10(9)/L. Asymptomatic essential thrombocythemia patients may be at risk for microvascular circulation disturbances. The indication for low-dose aspirin in asymptomatic essential thrombocythemia patients is uncertain, therefore randomization for aspirin 50 mg versus placebo is recommended. Symptomatic essential thrombocythemia patients with erythromelalgia and its ischemic complications, atypical transient ischemic attacks, minor stroke, visual disturbances and "superficial thrombophlebitis" in the absence of bleeding, vascular risk factors, or vascular disease have a clear indication for aspirin in a regular dose. To determine whether 50 mg/day is as effective as 100 mg/day for the prophylaxis of microvascular circulation disturbances in essential thrombocythemia, a randomized trial comparing low-dose aspirin 50 mg versus 100 mg at platelet counts between 400 and 1,000 up to 1,500 x 10(9)/L is recommended. To address the question whether reduction of the platelet count to normal (< 350 x 10(9)/L) is as effective as low-dose aspirin for the long-term relief of microvascular circulation disturbances, a randomized study comparing low-dose aspirin with the correction of platelet count to normal by anagrelide is recommended. High-risk essential thrombocythemia patients have a clear indication for platelet reductive therapy, including: (a) platelets > 1,500 x 10(9)/L, history of major thrombosis (myocardial infarction, stroke, peripheral occlusive vascular disease), or presence of vascular disease (e.g., arteriosclerosis); (b) history or presence of spontaneous or major bleedings, bleedings elicited by low-dose aspirin for the secondary prevention of vascular complications in essential thrombocythemia at platelet counts < 1500 x 10(9)/L, and side effects of long-term aspirin treatment such as gastritis; and progression from low- to high-risk essential thrombocythemia patients during follow-up or progressive myeloproliferative disease such as significant splenomegaly, myelofibrosis, leukocytosis, etc. To address the question of optimal treatment of high-risk essential thrombocythemia patients, randomization for anagrelide versus interferon at < 65 years of age and anagrelide versus hydroxyurea at an age > 65 years is recommended.