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Anagrelide

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Carlos Besses – One of the best experts on this subject based on the ideXlab platform.

  • treatment of essential thrombocythemia in europe a prospective long term observational study of 3649 high risk patients in the evaluation of Anagrelide efficacy and long term safety study
    Haematologica, 2018
    Co-Authors: Gunnar Birgegård, Carlos Besses, Martin Griesshammer, Luigi Gugliotta, Claire N Harrison, Mohamed Hamdani, Jingyang Wu, Heinrich Achenbach, Jeanjacques Kiladjian

    Abstract:

    Evaluation of Anagrelide (Xagrid®) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: Anagrelide (Xagrid®) (n=804), other cytoreductive therapy (n=2666), or Anagrelide + other cytoreductive therapy (n=141). The median age was 56 vs. 70 years for Anagrelide vs. other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 vs. 2.06 for total thrombosis and 0.15 vs. 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 vs. 0.43), especially with anti-aggregatory therapy (1.35 vs. 0.33) and myelofibrosis (1.04 vs. 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 vs. 0.07) and other malignancies (1.29 vs. 0.44). Post hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for Anagrelide were found. Live births occurred in 41/54 pregnancies (76%). clinicaltrials.gov Identifier: 00567502.

  • combination therapy of hydroxycarbamide with Anagrelide in patients with essential thrombocythemia in the evaluation of xagrid r efficacy and long term safety study
    Haematologica, 2014
    Co-Authors: Luigi Gugliotta, Jeanjacques Kiladjian, Jonathan Smith, Carlos Besses, Ruth Coll, Brihad Abhyankar, Martin Griesshammer, Claire N Harrison, Gunnar Birgegård

    Abstract:

    Available information is limited regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid® Efficacy and Long-term Safety study. Of 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + Anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167, 54.9%) and Anagrelide (n=123, 40.5%). Median weekly doses of hydroxycarbamide and Anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581×109/L and 411×109/L before and after starting hydroxycarbamide + Anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts less than 400×109/L increased from 33 (21.6%) to 74 (48.4%; P <0.0001), and with platelet counts less than 600×109/L, from 82 (53.6%) to 132 (86.3%; P <0.0001). Hydroxycarbamide + Anagrelide was discontinued in 158 patients: 76 (48.1%) stopped hydroxycarbamide, 59 (37.3%) stopped Anagrelide, 19 (12.0%) stopped both and 4 (2.5%) had another therapy added. The most frequent reasons for discontinuation were intolerance/side-effects, lack of efficacy, and therapeutic strategy. Combination therapy, usually hydroxycarbamide + Anagrelide, is used in approximately 10% of all high-risk patients with essential thrombocythemia and may be a useful approach in treating patients for whom monotherapy is unsatisfactory. ( [Clinicaltrials.gov][1] identifier:[NCT00567502][2] )

    [1]: http://Clinicaltrials.gov
    [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00567502&atom=%2Fhaematol%2F99%2F4%2F679.atom

  • comparison of pharmacokinetic parameters of Anagrelide in healthy japanese and caucasian volunteers
    Blood, 2012
    Co-Authors: Shinichiro Okamoto, Jonathan Smith, Yuzuru Kanakura, Ian Hodgson, Steven Troy, Brihad Abhyankar, Carlos Besses

    Abstract:

    Abstract 5066 Aim: Currently, it is not fully elucidated how ethnicity influences the pharmacokinetic (PK) profile of Anagrelide. The aim of this retrospective analysis was to compare the PK profile of Anagrelide in healthy Japanese and Caucasian volunteers. Methods: Retrospective analyses were conducted on two phase I studies with Anagrelide: a study of healthy Japanese volunteers (study A) and healthy Caucasian volunteers (study B). In study A, healthy males received Anagrelide (0. 5, 1. 0 or 2. 0 mg) or placebo under fasted or fed conditions. In study B, healthy volunteers received a single 1. 0 mg dose under fasted conditions. PK analysis of Anagrelide was conducted as part of these original studies. The calculated PK parameters were maximum plasma concentration (Cmax), time for Cmax (tmax), area under plasma concentration from time zero to time infinity (AUC0-inf) and terminal-phase disposition half-life (t1/2). Results: PK data for healthy Japanese males (n=6) aged 20–35 years, with a body weight of 50–80 kg and receiving 1. 0 mg Anagrelide in study A were compared with PK data for healthy Caucasian volunteers (n=10, 8 male and 2 female) aged 40–69 years, with a body weight of 56–100 kg and receiving 1. 0 mg Anagrelide in study B. Single-dose PK parameters under fasted conditions across both studies are shown in the Table for Anagrelide and its metabolite 2-amino-5, 6-dichloro-3, 4-dihydroquinazilone (RL603). Compared with Caucasian volunteers, healthy Japanese volunteers exhibited similar Cmax, and slightly higher AUC0-inf for Anagrelide. In contrast, Cmax and AUC0-inf for the inactive metabolite RL603 were considerably higher in Japanese volunteers. Five adverse events (AEs) were reported in 3 volunteers in study A and 9 AEs in 3 volunteers in study B: 5 and 3 AEs, respectively, were considered possibly related to treatment. The most commonly reported AEs were headache and nausea. No serious AEs were observed during either study. Discussion: The PK analyses conducted on volunteers receiving a single 1 mg dose showed that under fasted conditions Anagrelide was rapidly absorbed with similar Cmax and tmax between Japanese and Caucasian volunteers. The slightly higher AUC0-inf of Anagrelide in Japanese volunteers may be an artefact of the high inter-subject variability, which is common with drugs such as Anagrelide that exhibit extensive pre-systemic metabolism. It remains unclear as to why Japanese volunteers had higher RL603 Cmax and AUC0-inf values than Caucasian individuals. Analyses of PK data from studies of patients with essential thrombocythaemia (ET) (Okamoto et al, manuscript in preparation; Besses et al, Int J Clin Pharmacol Ther, 2012, manuscript in press) noted that compared with non-Japanese patients, Japanese patients also had slightly higher Cmax (2. 81±0. 99 vs 5. 88±4. 58 ng/mL) and AUC (6. 8±2. 4 vs 16. 3±6. 5 ng·h/mL) for Anagrelide. Overall, across both ethnic groups, patients with ET had higher Anagrelide exposures than healthy volunteers. However, within the Japanese population, Cmax and AUC0-inf values were only slightly higher in patients with ET than in volunteers, which may suggest that the PK exposures of Anagrelide did not differ substantially between these Japanese cohorts. Conclusion: Anagrelide exhibits high inter- and intra-subject variability, which makes it difficult to compare PK exposures in studies with small populations. The PK data across all these studies indicate that the first-pass metabolism of Anagrelide may be marginally lower in the Japanese population than in Caucasian individuals; however these differences do not translate to different clinical outcomes with respect to the observed treatment-related AEs associated with Anagrelide therapy. Despite the small differences observed in metabolism of Anagrelide, it is well tolerated in Japanese populations and ethnicity-specific dosing regimens are not required. Disclosures: Kanakura:Shire: Consultancy. Hodgson:Shire Pharmaceutical Development Ltd: Employment. Troy:Shire Development, LLC: Employment. Abhyankar:Shire Pharmaceuticals: Employment. Smith:Shire Pharmaceuticals: Employment. Besses:Shire: Honoraria; Novartis: Honoraria.

Ayalew Tefferi – One of the best experts on this subject based on the ideXlab platform.

  • decreased survival and increased rate of fibrotic progression in essential thrombocythemia chronicled after the fda approval date of Anagrelide
    American Journal of Hematology, 2019
    Co-Authors: Ayalew Tefferi, Natasha Szuber, Rangit Vallapureddy, Kebede H Begna, Mrinal M Patnaik, Michelle A Elliott, Christopher C Hook, Alexandra P Wolanskyj, Curtis A Hanson, Rhett P Ketterling

    Abstract:

    : First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and Anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of Anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for Anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of Anagrelide. Whether or not Anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.

  • Decreased survival and increased rate of fibrotic progression in essential thrombocythemia chronicled after the FDA approval date of Anagrelide.
    American Journal of Hematology, 2018
    Co-Authors: Ayalew Tefferi, Natasha Szuber, Rangit Vallapureddy, Kebede H Begna, Mrinal M Patnaik, Michelle A Elliott, Christopher C Hook, Alexandra P Wolanskyj, Curtis A Hanson, Rhett P Ketterling

    Abstract:

    : First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and Anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of Anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for Anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P 

  • Anagrelide associated cardiomyopathy in polycythemia vera and essential thrombocythemia
    Blood, 2004
    Co-Authors: Donald J Jurgens, Alvaro Morenoaspitia, Ayalew Tefferi

    Abstract:

    Introduction: Anecdotal reports of “idiopathic” cardiomyopathy (ICM) in patients receiving Anagrelide therapy have surfaced but not formally studied. We undertook a tertiary-center comprehensive study of ICM that was diagnosed in the setting of either polycythemia vera (PV) or essential thrombocythemia (ET). Methods: Standard criteria were used for the diagnosis of both ET and PV. A diagnosis of ICM required echocardiogram documentation of a reduced left ventricular systolic ejection fraction (EF Results: Initial data inquiry yielded a total of 434 patients whose medical histories were thoroughly reviewed for the presence of an echocardiogram-documented ICM that post-dated a diagnosis of either ET or PV. Nine such patients (7 females; age range 46–78 years) were identified. Anagrelide therapy, at standard doses (median 2 mg/day), was temporally associated with ICM in 4 of the 9 patients while treatment in the remaining 5 patients consisted of either phlebotomy alone (3 patients) or other cytoreductive agents (2 patients). A similar database inquiry at Mayo Clinic Jacksonville identified 2 more patients with ICM that was temporally associated with Anagrelide treatment. A normal echocardiogram was documented in 3 of the 6 patients with Anagrelide-associated ICM at 2, 15, and 39 months prior to treatment (table 1). Anagrelide therapy was immediately discontinued when ICM was diagnosed in 5 of the 6 patients and after further worsening of EF on continued Anagrelide therapy in the sixth patient (first patient in table 1). All 6 patients with Anagrelide-associated ICM experienced symptomatic improvement after drug discontinuation but the corresponding improvement in EF, after a period of 0.2–16 months, was often suboptimal (table 1). In contrast, ICM not associated with Anagrelide therapy remained unchanged both in terms of symptoms and EF in all 5 cases. Conclusion: Anagrelide-induced cardiomyopathy might occur in some patients with either PV or ET. Prompt recognition and drug discontinuation has the potential to adequately reverse the situation in some but not all patients.

Gunnar Birgegård – One of the best experts on this subject based on the ideXlab platform.

  • No effect of Anagrelide on bone marrow fibrosis in patients with chronic myeloproliferative disorders, estimated with hyaluronan and reticulin staining
    , 2020
    Co-Authors: Magnus Hultdin, Gunnel Sundstrom, Anders Wahlin, Berith Lundström, Jörgen Samuelsson, Gunnar Birgegård, Anna Engström-laurent

    Abstract:

    No effect of Anagrelide on bone marrow fibrosis in patients with chronic myeloproliferative disorders, estimated with hyaluronan and reticulin staining

  • treatment of essential thrombocythemia in europe a prospective long term observational study of 3649 high risk patients in the evaluation of Anagrelide efficacy and long term safety study
    Haematologica, 2018
    Co-Authors: Gunnar Birgegård, Carlos Besses, Martin Griesshammer, Luigi Gugliotta, Claire N Harrison, Mohamed Hamdani, Jingyang Wu, Heinrich Achenbach, Jeanjacques Kiladjian

    Abstract:

    Evaluation of Anagrelide (Xagrid®) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: Anagrelide (Xagrid®) (n=804), other cytoreductive therapy (n=2666), or Anagrelide + other cytoreductive therapy (n=141). The median age was 56 vs. 70 years for Anagrelide vs. other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 vs. 2.06 for total thrombosis and 0.15 vs. 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 vs. 0.43), especially with anti-aggregatory therapy (1.35 vs. 0.33) and myelofibrosis (1.04 vs. 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 vs. 0.07) and other malignancies (1.29 vs. 0.44). Post hoc multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for Anagrelide were found. Live births occurred in 41/54 pregnancies (76%). clinicaltrials.gov Identifier: 00567502.

  • combination therapy of hydroxycarbamide with Anagrelide in patients with essential thrombocythemia in the evaluation of xagrid r efficacy and long term safety study
    Haematologica, 2014
    Co-Authors: Luigi Gugliotta, Jeanjacques Kiladjian, Jonathan Smith, Carlos Besses, Ruth Coll, Brihad Abhyankar, Martin Griesshammer, Claire N Harrison, Gunnar Birgegård

    Abstract:

    Available information is limited regarding the use of cytoreductive combination therapy in high-risk patients with essential thrombocythemia. This analysis aims to evaluate the clinical relevance and patterns of cytoreductive combination treatment in European high-risk patients with essential thrombocythemia in the Evaluation of Xagrid® Efficacy and Long-term Safety study. Of 3643 patients, 347 (9.5%) received combination therapy. Data were recorded at each 6-month update. Of 347 patients who received combination therapy, 304 (87.6%) received hydroxycarbamide + Anagrelide. Monotherapies received before this combination were hydroxycarbamide (n=167, 54.9%) and Anagrelide (n=123, 40.5%). Median weekly doses of hydroxycarbamide and Anagrelide were: 7000 and 10.5 mg when used as prior monotherapy; 3500 and 7.0 mg when used as add-on treatment. Overall, median platelet counts were 581×109/L and 411×109/L before and after starting hydroxycarbamide + Anagrelide, respectively. In patients with paired data (n=153), the number of patients with platelet counts less than 400×109/L increased from 33 (21.6%) to 74 (48.4%; P <0.0001), and with platelet counts less than 600×109/L, from 82 (53.6%) to 132 (86.3%; P <0.0001). Hydroxycarbamide + Anagrelide was discontinued in 158 patients: 76 (48.1%) stopped hydroxycarbamide, 59 (37.3%) stopped Anagrelide, 19 (12.0%) stopped both and 4 (2.5%) had another therapy added. The most frequent reasons for discontinuation were intolerance/side-effects, lack of efficacy, and therapeutic strategy. Combination therapy, usually hydroxycarbamide + Anagrelide, is used in approximately 10% of all high-risk patients with essential thrombocythemia and may be a useful approach in treating patients for whom monotherapy is unsatisfactory. ( [Clinicaltrials.gov][1] identifier:[NCT00567502][2] )

    [1]: http://Clinicaltrials.gov
    [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00567502&atom=%2Fhaematol%2F99%2F4%2F679.atom