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1
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Yang C, Hu Y, Gao L, Li Z, Zhang Y, Zhuo R, Du Y, Liu H, Ji Q, Liu M, Pan J, Lu J, Xiao P, Tian Y, He S, Ling J, Hu S. Anagrelide and idarubicin combination induces GSDME-mediated pyroptosis as a potential therapy for high-PDE3A acute myeloid leukemia. Leukemia 2025; 39:98-111. [PMID: 39406931 DOI: 10.1038/s41375-024-02437-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 09/09/2024] [Accepted: 10/07/2024] [Indexed: 10/18/2024]
Abstract
Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy requiring novel treatment strategies. In this study, we identified phosphodiesterase 3 A (PDE3A) as a potential new target for drug repositioning in AML. PDE3A was preferentially overexpressed in AML cells than in normal cells, and high expression of PDE3A was correlated with lower event-free survival (EFS) in de novo AML patients. The PDE3A inhibitor anagrelide (ANA) profoundly suppresses the proliferation of high PDE3A-expressing AML cells while exhibiting minimal impact on those with low PDE3A expression. Moreover, synergistic effect of ANA with other chemotherapeutic drugs in high PDE3A expression AML cells was observed. The ANA-idarubicin (IDA) combination showed the most remarkable synergistic effect among all ANA-chemotherapeutic drugs commonly used in AML cell line models. Mechanistically, the synergy between ANA and IDA inhibited the survival of PDE3Ahigh AML cell lines through pyroptosis. This mechanism was initiated by GSDME cleavage triggered by caspase-3 activation. In vivo combination treatment of leukemic animals with high PDE3A expression significantly reduced leukemia burden and prolonged survival time compared with single-drug and vehicle control treatments. Our findings suggest that combined ANA and IDA treatment is an innovative and promising therapeutic strategy for AML patients with high PDE3A expression.
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MESH Headings
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/metabolism
- Humans
- Animals
- Mice
- Pyroptosis/drug effects
- Idarubicin/pharmacology
- Idarubicin/administration & dosage
- Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism
- Cyclic Nucleotide Phosphodiesterases, Type 3/genetics
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Xenograft Model Antitumor Assays
- Cell Proliferation/drug effects
- Drug Synergism
- Female
- Cell Line, Tumor
- Tumor Cells, Cultured
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Affiliation(s)
- Chenwei Yang
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Yixin Hu
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Li Gao
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Zhiheng Li
- Institution of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Yongping Zhang
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Ran Zhuo
- Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Yayun Du
- State Key Laboratory of Common Mechanism Research for Major Diseases and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China
| | - Hu Liu
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Qi Ji
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Minyuan Liu
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Jian Pan
- Institution of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Jun Lu
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Peifang Xiao
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China
| | - Yuanyuan Tian
- Institution of Pediatric Research, Children's Hospital of Soochow University, Suzhou, 215000, China.
| | - Sudan He
- State Key Laboratory of Common Mechanism Research for Major Diseases and Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China.
| | - Jing Ling
- Department of Transfusion Medicine, Children's Hospital of Soochow University, Suzhou, 215000, China.
| | - Shaoyan Hu
- Department of Pediatric Hematology and Oncology, Children's Hospital of Soochow University, Suzhou, 215000, China.
- Jiangsu Pediatric Hematology & Oncology Center, Jiangsu, China.
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2
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Papadopoulos KP, McKean M, Goldoni S, Genvresse I, Garrido MF, Li R, Wilkinson G, Kneip C, Yap TA. First-in-Human Dose-Escalation Study of the First-in-Class PDE3A-SLFN12 Complex Inducer BAY 2666605 in Patients with Advanced Solid Tumors Coexpressing SLFN12 and PDE3A. Clin Cancer Res 2024; 30:5568-5576. [PMID: 39437010 DOI: 10.1158/1078-0432.ccr-24-2713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 10/17/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
PURPOSE The study aims to evaluate the safety, tolerability, and pharmacokinetics of BAY 2666605, a velcrin that induces complex formation between the phosphodiesterase PDE3A and the protein Schlafen 12 (SLFN12), leading to a cytotoxic response in cancer cells. PATIENTS AND METHODS This was a first-in-human phase I study of BAY 2666605 (NCT04809805), an oral, potent first-in-class PDE3A-SLFN12 complex inducer, with reduced PDE3A inhibition. Adults with advanced solid tumors that coexpress SLFN12 and PDE3A received BAY 2666605 at escalating doses starting at 5 mg once daily in 28-day cycles. Forty-seven patients were prescreened for SLFN12 and PDE3A overexpression, and five biomarker-positive patients received ≥1 BAY 2666605 dose. RESULTS The most common adverse event was grade 3 to 4 thrombocytopenia in three of the five patients treated. The long half-life (>360 hours) and associated accumulation of BAY 2666605 led to the selection of an alternative schedule consisting of a loading dose with a once-daily maintenance dose. The maximum tolerated dose was not established as the highest doses of both schedules were intolerable. No objective responses were observed. Due to the high expression of PDE3A in platelets compared with tumor tissues, the ex vivo dose-dependent inhibitory effect of BAY 2666605 on megakaryocytes, and the pharmacokinetic profile of the compound, alternative schedules were not predicted to ameliorate the mechanism-based thrombocytopenia. CONCLUSIONS Despite the decreased PDE3A enzymatic inhibition profile of BAY 2666605, the occurrence of thrombocytopenia in treated patients, an on-target effect of the compound, precluded the achievement of a therapeutic window, consequently leading to trial termination.
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Affiliation(s)
| | | | - Silvia Goldoni
- Research and Early Development Oncology, Bayer Pharma, Cambridge, Massachusetts
| | | | | | - Rui Li
- Clinical Statistics, Bayer HealthCare Pharmaceuticals, Inc., Whippany, New Jersey
| | | | | | - Timothy A Yap
- Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
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3
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Ishitsuka K, Nishikii H, Kimura T, Sugiyama-Finnis A, Yamazaki S. Purging myeloma cell contaminants and simultaneous expansion of peripheral blood-mobilized stem cells. Exp Hematol 2024; 131:104138. [PMID: 38151170 DOI: 10.1016/j.exphem.2023.104138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/03/2023] [Accepted: 12/07/2023] [Indexed: 12/29/2023]
Abstract
Human hematopoietic stem cells (HSCs) are widely used as a cellular source for hematopoietic stem cell transplantation (HSCT) in the clinical treatment of hematological malignancies. After transplantation therapy, delays in hematopoietic recovery due to insufficient donor-derived HSCs can lead to increased risks of life-threatening infections and bleeding. Our previous studies developed an efficient ex vivo expansion culture medium (3a medium) for umbilical cord blood-derived HSCs (CBSCs), offering a potential solution to this problem. Nevertheless, the broader applicability of our culture method to alternative cell sources and, of greater significance, its efficacy in eliminating potentially disease-associated contaminated tumor cells, especially in autologous transplantation, raise critical clinical questions. In this study, we modified the 3a medium by incorporating UM729 to replace UM171, adding FMS-like tyrosine kinase 3 (Flt3) ligand, and adjusting the concentrations of butyzamide, 740Y-P, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG, Soluplus) to create the modified-3a medium. This sophistication allowed the efficient expansion of not only CBSCs but also peripheral blood-mobilized HSCs (PBSCs). Additionally, we successfully removed contaminated myeloma cells by adding bortezomib and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) at appropriate concentrations, although we maintained HSCs through the addition of lenalidomide. Our research findings present the potential for widespread clinical application of the modified-3a medium and suggest a safe ex vivo culture technique for expanding human HSCs within peripheral blood-derived donor grafts used for autologous HSCT.
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Affiliation(s)
- Kantaro Ishitsuka
- Laboratory for Stem Cell Therapy, Faculty of Medicine, Tsukuba University, Ibaraki, Japan
| | - Hidekazu Nishikii
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takaharu Kimura
- Laboratory for Stem Cell Therapy, Faculty of Medicine, Tsukuba University, Ibaraki, Japan
| | - Ayano Sugiyama-Finnis
- Division of Cell Regulation, Center of Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Yamazaki
- Laboratory for Stem Cell Therapy, Faculty of Medicine, Tsukuba University, Ibaraki, Japan; Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan; Division of Stem Cell Biology, Center for Stem Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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4
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Tremblay D. Cytoreduction for ET and PV: who, what, when, and how? HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2023; 2023:660-666. [PMID: 38066871 PMCID: PMC10727012 DOI: 10.1182/hematology.2023000451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Thrombotic complications are the primary contributor to morbidity and mortality in essential thrombocythemia (ET) and polycythemia vera (PV). Cytoreductive therapy is the main tool for primary or tertiary thrombosis prevention in these diseases. In general, high-thrombotic-risk patients and those with symptoms that may be ameliorated from cytoreductive therapy are candidates for this treatment, although the decision is highly individualized. Approved options for cytoreduction in ET and PV include hydroxyurea, long-acting interferons, anagrelide in ET, and ruxolitinib in PV. Selecting the ideal agent requires careful consideration of the toxicity profiles and individual treatment goals. In this review the existing literature on cytoreductive decisions in ET and PV is summarized, with an emphasis on risk-stratification, highlighting the need for personalized care in order to maximize the benefit of these therapies while minimizing toxicities.
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Affiliation(s)
- Douglas Tremblay
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
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5
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Meanwell NA. Anagrelide: A Clinically Effective cAMP Phosphodiesterase 3A Inhibitor with Molecular Glue Properties. ACS Med Chem Lett 2023; 14:350-361. [PMID: 37077378 PMCID: PMC10108399 DOI: 10.1021/acsmedchemlett.3c00092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023] Open
Abstract
The mode of action by which the orphan drug anagrelide (1), a potent cAMP phosphodiesterase 3A inhibitor, reduces blood platelet count in humans is not well understood. Recent studies indicate that 1 stabilizes a complex between PDE3A and Schlafen 12, protecting it from degradation while activating its RNase activity.
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Affiliation(s)
- Nicholas A. Meanwell
- The Baruch S. Blumberg Institute, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States
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6
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Al-Mashdali AF, Aldapt MB, Rahhal A, Hailan YM, Elhakeem I, Ali EA, Rozi W, Yassin MA. Pediatric Philadelphia-Negative Myeloproliferative Neoplasms in the Era of WHO Classification: A Systematic Review. Diagnostics (Basel) 2023; 13:diagnostics13030377. [PMID: 36766480 PMCID: PMC9914355 DOI: 10.3390/diagnostics13030377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Philadelphia-negative myeloproliferative neoplasms (MPN) are most prevalent in the older population (median age at the diagnosis is above 60 years) and rarely diagnosed in pediatrics. Thus, our knowledge about the clinical presentation, mutational status, and complications of MPNs in pediatrics is limited. METHODS The literature in English (PubMed, SCOPUS, and Google Scholar) was searched for studies, reviews, case series, and case reports of patients with Philadelphia-negative MPNs (including essential thrombocythemia, polycythemia vera, primary myelofibrosis, and profibrotic myelofibrosis) in the pediatrics age group (less than 18 years). Only studies that fulfilled WHO 2008 or 2016 criteria for MPNs were included. We aimed to describe the clinical characteristics, vascular and long-term complications, types of driver mutations, and treatment approaches in pediatric patients with MPNs. RESULTS We reviewed 33 articles of available published literature from 2008 to 2022 and collected data from a total of 196 patients of the pediatric population. Among the cohort of patients, 139 had essential thrombocythemia (ET), 20 had polycythemia vera (PV), and 37 had primary myelofibrosis (PMF). The median age at the time of diagnosis for each disease varied, with 8.8 years for ET, 10 years for PV, and 3.6 years for MF. There was a slight difference in gender prevalence between both gender groups and all three diseases. The presenting symptoms were not mentioned in more than 50% of studies. We found that JAK2 was the most prevalent among all mutations. Both bleeding and thrombosis were present equally in ET, with 9% of cases complicated by bleeding and 9% complicated by thrombosis. Hemorrhagic events did not occur in patients with PV; thrombosis in children with MF was also not found. The progression into AML occurred in two patients with PV and one with ET. CONCLUSION Given the rarity of MPNs in pediatrics and their different characteristics compared with adults, we believe there is a need for unique diagnostic criteria to match the different molecular statuses in pediatrics. Based on our review, the incidence of MPN complications in pediatrics, including thrombotic events, hemorrhage, and leukemic transformation, differs from that in adults.
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Affiliation(s)
- Abdulrahman F. Al-Mashdali
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
- Correspondence: or (A.F.A.-M.); (M.A.Y.)
| | - Mahmood B. Aldapt
- Department of Medicine, Unity Hospital, Rochester Regional Health, Rochester, NY 14626, USA
| | - Alaa Rahhal
- Pharmacy Department, Hamad Medical Corporation, Doha 3050, Qatar
| | - Yousef M. Hailan
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
| | - Israa Elhakeem
- Clinical Oncology, Hamad Medical Corporation, Doha 3050, Qatar
| | - Elrazi A. Ali
- One Brooklyn Health, Interfaith Medical Center, Internal Medicine Department, Brooklyn, NY 11213, USA
| | - Waail Rozi
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
| | - Mohamed A. Yassin
- National Center for Cancer Care and Research, Department of Oncology, Hematology and BMT Section, Hamad Medical Corporation, Doha 3050, Qatar
- Correspondence: or (A.F.A.-M.); (M.A.Y.)
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7
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Badar F, Azeez H, Abdulrahman Z, Ashraf A, Iftikhar A. Anagrelide-Induced Supraventricular Tachycardia: A Case Report. Cureus 2022; 14:e26119. [PMID: 35747119 PMCID: PMC9213328 DOI: 10.7759/cureus.26119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2022] [Indexed: 11/25/2022] Open
Abstract
Anagrelide is an inhibitor of the phosphodiesterase-3 (PDE-3) enzyme that suppresses megakaryocytes; hence it is used in the treatment of essential thrombocythemia. Anagrelide can cause positive inotropic and chronotropic effects on the cardiovascular system. Its cardiovascular side effects are rare and include palpitations, tachyarrhythmias, cardiomyopathy, angina, and heart failure. We report the case of a 71-year-old female who presented with sudden onset chest pain. Her only outpatient medications included anagrelide and aspirin. She was found to have supraventricular tachycardia (SVT) with aberrancy that responded to beta-blockers. The chest X-ray, computed tomography angiogram (CTA), and echocardiogram were unremarkable. Her arrhythmia may be attributed to the anagrelide in the absence of any cardiovascular findings.
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8
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Nathan DI, Feld J, El Jamal SM, Mascarenhas J, Tremblay D. Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: Ringing in a new future. Leuk Res 2022; 115:106820. [DOI: 10.1016/j.leukres.2022.106820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/02/2022] [Accepted: 03/04/2022] [Indexed: 01/19/2023]
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9
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Tremblay D, Kosiorek HE, Dueck AC, Hoffman R. Evaluation of Therapeutic Strategies to Reduce the Number of Thrombotic Events in Patients With Polycythemia Vera and Essential Thrombocythemia. Front Oncol 2021; 10:636675. [PMID: 33665170 PMCID: PMC7921696 DOI: 10.3389/fonc.2020.636675] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 12/30/2020] [Indexed: 12/13/2022] Open
Abstract
Thrombosis is the largest contributor to morbidity and mortality in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Our understanding of the risk factors and pathophysiology of thrombosis in PV and ET patients is developing, including recent insights into the role of aberrant platelet-neutrophil interactions, JAK2 mutated endothelial cells and the pro-thrombotic inflammatory milieu. To date, few available therapies have demonstrated the ability to reduce the thrombotic burden in patients with these diseases. Although numerous therapeutic agents have been investigated in both PV and ET patients, few studies are designed to assess their impact on thrombotic events. In this review, we first describe the burden of thrombosis in patients with these myeloproliferative neoplasms (MPNs) and briefly explore their pathophysiologic mechanisms. We then critically assess and summarize the evidence behind currently available therapies with attention toward thrombotic endpoints. Finally, we describe a path forward for clinical research in MPNs that involves surrogate endpoint validation, biomarker development, and clinical trial design strategies in order to accurately assess reduction of thrombotic events when evaluating novel therapies.
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Affiliation(s)
- Douglas Tremblay
- Hematology/Oncology Section, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Heidi E. Kosiorek
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, United States
| | - Amylou C. Dueck
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, United States
| | - Ronald Hoffman
- Hematology/Oncology Section, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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10
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Gotic M, Egyed M, Gercheva L, Warzocha K, Kvasnicka HM, Achenbach H, Wu J. Cardiovascular Safety of Anagrelide Hydrochloride versus Hydroxyurea in Essential Thrombocythaemia. Cardiovasc Toxicol 2020; 21:236-247. [PMID: 33123978 PMCID: PMC7847982 DOI: 10.1007/s12012-020-09615-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 10/16/2020] [Indexed: 11/30/2022]
Abstract
Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac safety, efficacy and tolerability of first-line treatment with anagrelide or hydroxyurea in high-risk ET patients for up to 3 years. Eligible patients aged ≥ 18 years with a diagnosis of high-risk ET confirmed by bone marrow biopsy within 6 months of randomisation received anagrelide (n = 75) or hydroxyurea (n = 74), administered twice daily. Treatment dose for either compound was titrated to the lowest dose needed to achieve a response. Planned primary outcome measures were change in left ventricular ejection fraction from baseline over time and platelet count at Month 6. Planned secondary outcome measures were platelet count change from baseline at Months 3 and 36; percentage of patients with complete or partial response; time to complete or partial response; number of patients with thrombohaemorrhagic events; and changes in white blood cell count or red blood cell count over time. Neither treatment altered cardiac function. There were no significant differences in adverse events between treatment groups, and no reports of malignant transformation. The incidence of disease-related thrombotic or haemorrhagic events was numerically higher in anagrelide-treated patients. Both treatments controlled platelet counts at 6 months, with the majority of patients experiencing complete or partial responses. In conclusion, these results suggest that long-term treatment with anagrelide is not associated with adverse effects on cardiac function. This is one of the few studies using left ventricular ejection fraction assessment and central biopsy reading to confirm the diagnosis of ET. Trial registration number: Clinicaltrials.gov NCT00202644
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Affiliation(s)
- Mirjana Gotic
- Clinic for Hematology Clinical Centre of Serbia Belgrade, Medical Faculty, University of Belgrade, Koste Todorovica 2, 11000, Belgrade, Serbia.
| | - Miklos Egyed
- Somogy Megyei Kaposi Mór Oktató Kórház, Kaposvár, 7400, Hungary
| | - Liana Gercheva
- Clinic of Hematology, University Hospital St. Marina, 9010, Varna, Bulgaria
| | - Krzysztof Warzocha
- Institute of Hematology and Transfusion Medicine, Department of Haematology, 00-791, Warsaw, Poland
| | - Hans Michael Kvasnicka
- Institute of Pathology, University Clinic Wuppertal, University of Witten / Herdecke, Wuppertal, Germany
| | - Heinrich Achenbach
- Research & Development, Shire International GmbH (a Member of the Takeda Group of Companies), 6300, Zug, Switzerland
| | - Jingyang Wu
- Research & Development, Shire (a Member of the Takeda Group of Companies), Lexington, MA, 02421, USA
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11
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Takaishi K, Takeuchi M, Tsukamoto S, Takayama N, Oshima M, Kimura K, Isshiki Y, Kayamori K, Hino Y, Oshima-Hasegawa N, Mitsukawa S, Takeda Y, Mimura N, Ohwada C, Iseki T, Nakamura S, Eto K, Iwama A, Yokote K, Nakaseko C, Sakaida E. Suppressive effects of anagrelide on cell cycle progression and the maturation of megakaryocyte progenitor cell lines in human induced pluripotent stem cells. Haematologica 2019; 105:e216-e220. [PMID: 31488559 DOI: 10.3324/haematol.2018.214841] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Koji Takaishi
- Department of Hematology, Chiba University Hospital, Chiba
| | | | | | - Naoya Takayama
- Department of Regenerative Medicine, Chiba University Graduate School of Medicine, Chiba
| | - Motohiko Oshima
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo
| | - Kenji Kimura
- Department of Hematology, Chiba University Hospital, Chiba
| | - Yusuke Isshiki
- Department of Hematology, Chiba University Hospital, Chiba
| | | | - Yutaro Hino
- Department of Hematology, Chiba University Hospital, Chiba
| | | | - Shio Mitsukawa
- Department of Hematology, Chiba University Hospital, Chiba.,Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba
| | - Yusuke Takeda
- Department of Hematology, Chiba University Hospital, Chiba
| | - Naoya Mimura
- Department of Hematology, Chiba University Hospital, Chiba.,Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba
| | - Chikako Ohwada
- Department of Hematology, Chiba University Hospital, Chiba
| | - Tohru Iseki
- Department of Hematology, Chiba University Hospital, Chiba.,Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba
| | - Sou Nakamura
- Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto
| | - Koji Eto
- Department of Regenerative Medicine, Chiba University Graduate School of Medicine, Chiba.,Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto
| | - Atsushi Iwama
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo
| | - Koutaro Yokote
- Department of Clinical Biology and Medicine, Chiba University Graduate School of Medicine, Chiba
| | | | - Emiko Sakaida
- Department of Hematology, Chiba University Hospital, Chiba
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12
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Stasik S, Middeke JM, Kramer M, Röllig C, Krämer A, Scholl S, Hochhaus A, Crysandt M, Brümmendorf TH, Naumann R, Steffen B, Kunzmann V, Einsele H, Schaich M, Burchert A, Neubauer A, Schäfer-Eckart K, Schliemann C, Krause S, Herbst R, Hänel M, Frickhofen N, Noppeney R, Kaiser U, Baldus CD, Kaufmann M, Rácil Z, Platzbecker U, Berdel WE, Mayer J, Serve H, Müller-Tidow C, Ehninger G, Bornhäuser M, Schetelig J, Thiede C. EZH2 mutations and impact on clinical outcome: an analysis in 1,604 patients with newly diagnosed acute myeloid leukemia. Haematologica 2019; 105:e228-e231. [PMID: 31413097 DOI: 10.3324/haematol.2019.222323] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Affiliation(s)
- Sebastian Stasik
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany
| | - Jan M Middeke
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany
| | - Michael Kramer
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany
| | - Christoph Röllig
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany
| | - Alwin Krämer
- Universitätsklinikum Heidelberg, Medizinische Klinik V, Heidelberg, Germany
| | - Sebastian Scholl
- Universitätsklinikum Jena, Klinik für Innere Medizin II, Jena, Germany
| | - Andreas Hochhaus
- Universitätsklinikum Jena, Klinik für Innere Medizin II, Jena, Germany
| | - Martina Crysandt
- Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostasiologie und Stammzelltransplantation, Aachen, Germany
| | - Tim H Brümmendorf
- Uniklinik RWTH Aachen, Klinik für Hämatologie, Onkologie, Hämostasiologie und Stammzelltransplantation, Aachen, Germany
| | - Ralph Naumann
- St. Marien-Krankenhaus Siegen, Medizinische Klinik III, Siegen, Germany
| | - Björn Steffen
- Universitätsklinikum Frankfurt, Medizinische Klinik II, Frankfurt am Main, Germany
| | - Volker Kunzmann
- Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany
| | - Hermann Einsele
- Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany
| | - Markus Schaich
- Rems-Murr-Klinikum Winnenden, Klinik für Hämatologie, Onkologie und Palliativmedizin, Winnenden, Germany
| | - Andreas Burchert
- Philipps Universität Marburg, Klinik für Hämatologie, Onkologie, Immunologie, Marburg, Germany
| | - Andreas Neubauer
- Philipps Universität Marburg, Klinik für Hämatologie, Onkologie, Immunologie, Marburg, Germany
| | | | | | - Stefan Krause
- Universitätsklinikum Erlangen, Medizinische Klinik V, Erlangen, Germany
| | - Regina Herbst
- Klinikum Chemnitz, Medizinische Klinik III, Chemnitz, Germany
| | - Mathias Hänel
- Klinikum Chemnitz, Medizinische Klinik III, Chemnitz, Germany
| | | | - Richard Noppeney
- Universitätsklinikum Essen, Klinik für Hämatologie, Essen, Germany
| | - Ulrich Kaiser
- St. Bernward Krankenhaus, Medizinische Klinik II, Hildesheim, Germany
| | - Claudia D Baldus
- Charité-Universitätsmedizin Berlin, Hämatologie und Onkologie, Berlin, Germany
| | - Martin Kaufmann
- Robert-Bosch-Krankenhaus, Abteilung für Hämatologie, Onkologie und Palliativmedizin, Stuttgart, Germany
| | - Zdenek Rácil
- Masaryk University and University Hospital, Department of Internal Medicine, Hematology and Oncology, Brno, Czech Republic
| | - Uwe Platzbecker
- Universitätsklinikum Leipzig, Medizinische Klinik und Poliklinik I, Hämatologie und Zelltherapie, Leipzig, Germany
| | - Wolfgang E Berdel
- Universitätsklinikum Münster, Medizinische Klinik A, Münster, Germany
| | - Jiri Mayer
- Masaryk University and University Hospital, Department of Internal Medicine, Hematology and Oncology, Brno, Czech Republic
| | - Hubert Serve
- Universitätsklinikum Frankfurt, Medizinische Klinik II, Frankfurt am Main, Germany
| | | | - Gerhard Ehninger
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany
| | - Martin Bornhäuser
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany
| | - Johannes Schetelig
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany.,DKMS Clinical Trials Unit, Dresden, Germany
| | - Christian Thiede
- Universitätsklinikum Carl Gustav Carus, Medizinische Klinik und Poliklinik I, Dresden, Germany
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13
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Abstract
Introduction: Despite our recent progress in the understanding of essential thrombocythemia (ET) pathogenesis, the therapeutic management of this disease has remained largely unchanged in the past decades. Treatment has mostly focused on decreasing the risk of complications, especially prevention of thrombotic or hemorrhagic events. Areas covered: Over recent years, the treatment options of ET have been expanding with some novel agents on the horizon. The classes of agents described in this review include targeted and immunomodulatory agents, such as JAK1/2 inhibitors, interferon-α, histone deacetylase inhibitors, telomerase inhibitors and human double minute 2 inhibitors. These compounds entered various stages of development, albeit the only portion of them is currently actively undergoing evaluation in clinical trials. In this review, we look at the current therapies and discuss novel agents available in the management of ET. Expert opinion: The drug development in ET possesses several challenges stemming from its relatively benign and prolonged disease course. Therapy focused on reducing the risk of thrombotic and hemorrhagic complications and symptom management needs to be chosen wisely as a vast majority of these patients have a near-normal life expectancy. To date, no therapy has shown effective and definitive alteration of the disease behavior. Although novel agents are in development and hopefully some of them will extend treatment armamentarium of ET, their exact role remains to be determined.
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Affiliation(s)
- Lucia Masarova
- a MD Anderson Cancer Center , The University of Texas , Houston , TX , USA
| | - Srdan Verstovsek
- a MD Anderson Cancer Center , The University of Texas , Houston , TX , USA
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14
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Tefferi A, Szuber N, Vallapureddy RR, Begna KH, Patnaik MM, Elliott MA, Christopher Hook C, Wolanskyj AP, Hanson CA, Ketterling RP, Pardanani A, Gangat N. Decreased survival and increased rate of fibrotic progression in essential thrombocythemia chronicled after the FDA approval date of anagrelide. Am J Hematol 2019; 94:5-9. [PMID: 30252953 DOI: 10.1002/ajh.25294] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 09/19/2018] [Indexed: 01/01/2023]
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.
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Affiliation(s)
- Ayalew Tefferi
- Divisions of Hematology; Mayo Clinic; Rochester Minnesota
| | - Natasha Szuber
- Divisions of Hematology; Mayo Clinic; Rochester Minnesota
| | | | | | | | | | | | | | | | - Rhett P. Ketterling
- Departments of Internal and Laboratory Medicine, Laboratory Genetics and Genomics; Mayo Clinic; Rochester Minnesota
| | | | - Naseema Gangat
- Divisions of Hematology; Mayo Clinic; Rochester Minnesota
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15
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Kanakura Y, Shirasugi Y, Yamaguchi H, Koike M, Chou T, Okamoto S, Achenbach H, Wu J, Nakaseko C. A phase 3b, multicenter, open-label extension study of the long-term safety of anagrelide in Japanese adults with essential thrombocythemia. Int J Hematol 2018; 108:491-498. [PMID: 30121892 DOI: 10.1007/s12185-018-2510-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 07/25/2018] [Accepted: 07/30/2018] [Indexed: 12/25/2022]
Abstract
Cytoreductive therapy is used in high-risk essential thrombocythemia (ET) to reduce risk of thrombohemorrhagic complications. Anagrelide is an orally active, quinazolone-derived platelet-lowering agent approved for first-line treatment of high-risk ET in Japan. Long-term safety and efficacy data were collected from 53 Japanese high-risk ET patients (Study 308); 41 patients who completed Study 308 entered this phase 3b, open-label extension (Study 309; NCT01467661). Reductions in mean platelet counts occurred throughout the study, from 1021.6 × 109/L (at Study 308 baseline) to 675.4 × 109/L at final assessment. At month 48 (since Study 308 enrollment), mean platelet count was 444.5 × 109/L in the 10 patients who completed 4 years of therapy. Overall, platelet counts decreased from 1088.3 × 109/L at Study 308 baseline (n = 33) to 473.5 × 109/L at final assessment (n = 31). Long-term platelet count reductions were maintained without marked changes in mean anagrelide dose. Anagrelide was generally well tolerated, with anemia (54.7%) and headache (49.1%) as the most frequent adverse events. These findings indicate that anagrelide effectively reduces platelet counts in high-risk Japanese ET patients, with titration resulting in a well-tolerated, effective and sustainable dose. In conclusion, these results support anagrelide administration to high-risk Japanese ET patients using individualized dosing strategies defined in instructions previously approved in Europe and the USA.
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Affiliation(s)
- Yuzuru Kanakura
- Graduate School of Medicine, Osaka University, Osaka University Hospital, C9, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.
| | | | | | | | | | | | | | - Jingyang Wu
- Global Biometrics, Shire Pharmaceuticals, Lexington, MA, USA
| | - Chiaki Nakaseko
- Chiba University Hospital, Chiba, Japan.,International University of Health and Welfare School of Medicine, Narita, Japan
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16
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Ruxolitinib for the Treatment of Essential Thrombocythemia. Hemasphere 2018; 2:e56. [PMID: 31723782 PMCID: PMC6746005 DOI: 10.1097/hs9.0000000000000056] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 05/13/2018] [Accepted: 05/14/2018] [Indexed: 12/21/2022] Open
Abstract
Deregulated Janus Kinase 2 (JAK2) activation is central to the pathogenesis of most myeloproliferative neoplasms (MPNs), of which essential thrombocythemia (ET) is the most common entity. Patients with ET are risk-stratified according to their risk of thrombo-hemorrhagic complications. High-risk patients are offered treatments to reduce their platelet count using cytoreductive therapy. The disease course is often long and therapy intolerance is not infrequent. Ruxolitinib, a Janus Kinase (JAK) 1/JAK2 inhibitor, has demonstrated efficacy in patients with both myelofibrosis (MF) and polycythemia vera and is well tolerated. Side effects include predictable cytopenias and an augmented risk of infections. Ruxolitinib has been investigated in a small group of ET patients who were refractory/intolerant to hydroxycarbamide (HC) and demonstrated improvements in both symptoms and splenomegaly. Of note, a proportion of treated patients (13.2%) also had a significant reduction in platelet counts. However, these results require further validation in comparison with conventional therapy. Recently, a randomized-controlled phase 2 study (MAJIC-ET) assessed the role of Ruxolitinib in patients refractory or intolerant to HC. This study revealed that Ruxolitinib demonstrated some clinical efficacy but was only superior in terms of symptom control. In clinical practice, some individuals with ET do exhaust all potential treatment options and there may well be a role for Ruxolitinib in such patients or those with a significant symptom burden. However, in the wider context the goal of therapy with the use of JAK inhibitor therapy in ET needs to be defined carefully and we explore this within this timely review article.
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17
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Petrides PE, Schoergenhofer C, Widmann R, Jilma B, Klade CS. Pharmacokinetics of a Novel Anagrelide Extended-Release Formulation in Healthy Subjects: Food Intake and Comparison With a Reference Product. Clin Pharmacol Drug Dev 2018; 7:123-131. [PMID: 28301098 PMCID: PMC5811889 DOI: 10.1002/cpdd.340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 01/18/2017] [Indexed: 11/10/2022]
Abstract
Anagrelide is an established therapy for essential thrombocythemia. Common adverse effects have been linked to peak plasma concentrations of anagrelide and its 3OH metabolite. Our study was performed to investigate the pharmacokinetics (PK) of a novel anagrelide extended-release (AER) formulation and its active metabolites. Thirty healthy volunteers were randomized to receive either 2 mg AER (under fasting and fed conditions) or 2 mg commercially available reference product (CARP) in an open-label, 3-way crossover trial with washout periods of 6 days. Plasma concentrations of anagrelide and its active metabolites were assessed by tandem mass spectrometry. The PK differed significantly between all treatment periods. Bioavailability of AER was 55% of the CARP under fasting conditions and 60% under fed conditions. Cmax , AUCt, and AUC∞ were significantly higher and Tmax and T1/2 were significantly shorter after the CARP compared with AER. Food had a significant impact on the PK of AER, increasing the Cmax and AUCt while reducing the T1/2 , plateau, and mean residence time. Both formulations were well tolerated, with a trend toward more frequently occurring adverse events after the CARP. The PK of AER and the CARP differed significantly in all parameters. Food enhanced the bioavailability of AER.
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Affiliation(s)
- Petro E. Petrides
- Hematology Oncology Center and Ludwig Maximilians University of Munich Medical SchoolMunichGermany
| | | | | | - Bernd Jilma
- Department of Clinical PharmacologyMedical University of ViennaViennaAustria
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18
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Khanna D, Denton CP, Lin CJF, van Laar JM, Frech TM, Anderson ME, Baron M, Chung L, Fierlbeck G, Lakshminarayanan S, Allanore Y, Pope JE, Riemekasten G, Steen V, Müller-Ladner U, Spotswood H, Burke L, Siegel J, Jahreis A, Furst DE. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann Rheum Dis 2018; 77:212-220. [PMID: 29066464 PMCID: PMC5867414 DOI: 10.1136/annrheumdis-2017-211682] [Citation(s) in RCA: 186] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 09/15/2017] [Accepted: 09/19/2017] [Indexed: 01/16/2023]
Abstract
OBJECTIVES Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study. METHODS Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96. RESULTS Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was -3.1 (6.3 (-5.4 to -0.9)) for placebo and -5.6 (9.1 (-8.9 to-2.4)) for tocilizumab at week 48 and -9.4 (5.6 (-8.9 to -2.4)) for placebo-tocilizumab and -9.1 (8.7 (-12.5 to -5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period. CONCLUSIONS Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab. TRIAL REGISTRATION NUMBER NCT01532869; Results.
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Affiliation(s)
- Dinesh Khanna
- University of Michigan Scleroderma Program, Ann Arbor, Michigan, USA
| | | | | | | | - Tracy M Frech
- University of Utah, Veterans Affairs Medical Center, Salt Lake City, Utah, USA
| | - Marina E Anderson
- University of Liverpool and Aintree University Hospital, Liverpool, UK
| | | | - Lorinda Chung
- Stanford University School of Medicine and Palo Alto VA Health Care System, Palo Alto, California, USA
| | | | | | | | - Janet E Pope
- Schulich School of Medicine and Dentistry, University of Western Ontario, St Joseph’s Health Care, London, Canada
| | | | | | - Ulf Müller-Ladner
- Justus-Liebig University Giessen, Kerckhoff Clinic, Bad Nauheim, Germany
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19
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Prinzmetal Angina in a Young Patient with Essential Thrombocythemia, After Anagrelide Initiation - Case Report and Literature Review. ARS MEDICA TOMITANA 2018. [DOI: 10.2478/arsm-2018-0009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
We report a case of Prinzmetal angina as inaugural manifestation of coronary disease, in a young adult male patient, recently started on anagrelide for essential thrombocythemia. Moderate proximal left anterior descendent coronary artery stenosis was documented by angiography, and interventional or surgical revascularization has been discussed. Patient’s option was for medical therapy alone. Anagrelide was temporarily withdrawn and rechallenged uneventfully after a couple of months and clinical evolution is good at four years follow-up. The mechanism by which anagrelide could induce coronary spasm and ischemia remains to be clarified.
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20
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Giaretta A, Rocca B, Di Camillo B, Toffolo GM, Patrono C. In Silico Modeling of the Antiplatelet Pharmacodynamics of Low-dose Aspirin in Health and Disease. Clin Pharmacol Ther 2017; 102:823-831. [PMID: 28378909 DOI: 10.1002/cpt.694] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/06/2017] [Accepted: 03/11/2017] [Indexed: 01/25/2023]
Abstract
The influence of platelet turnover on cyclooxygenase (COX-1) inhibition by low-dose aspirin remains largely uncharacterized due to limited feasibility of studying aspirin pharmacodynamics in bone marrow precursors. We developed an in silico compartmental model describing the aspirin effects on COX-1 activity in a population of megakaryocytes (MK) and in peripheral platelets. Model parameters were inferred from the literature and calibrated using measurements of serum thromboxane B2 (sTXB2 ), as proxy of COX-1 activity in peripheral platelets, in 17 healthy subjects and 24 patients with essential thrombocythemia (ET). The model reproduced well the average time-course of sTXB2 inhibition in healthy (accuracy = 10.4%), the reduced inhibition of sTXB2 observed in ET, and the effect of different dosing regimens. In conclusion, the in silico model accurately describes COX-1 inactivation by low-dose aspirin in MK and platelets in different clinical settings, and might help personalize aspirin regimens in conditions of altered megakaryopoiesis.
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Affiliation(s)
- A Giaretta
- Department of Information Engineering, University of Padova, Padova, Italy
| | - B Rocca
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
| | - B Di Camillo
- Department of Information Engineering, University of Padova, Padova, Italy
| | - G M Toffolo
- Department of Information Engineering, University of Padova, Padova, Italy
| | - C Patrono
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
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21
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Sakurai K, Fujiwara T, Hasegawa S, Okitsu Y, Fukuhara N, Onishi Y, Yamada-Fujiwara M, Ichinohasama R, Harigae H. Inhibition of human primary megakaryocyte differentiation by anagrelide: a gene expression profiling analysis. Int J Hematol 2016; 104:190-9. [DOI: 10.1007/s12185-016-2006-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 04/05/2016] [Accepted: 04/05/2016] [Indexed: 11/29/2022]
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23
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Espasandin YR, Glembotsky AC, Grodzielski M, Lev PR, Goette NP, Molinas FC, Marta RF, Heller PG. Anagrelide platelet-lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: insight into potential mechanisms. J Thromb Haemost 2015; 13:631-42. [PMID: 25604267 DOI: 10.1111/jth.12850] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 01/04/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND OBJECTIVES Anagrelide represents a treatment option for essential thrombocythemia patients. It lowers platelet counts through inhibition of megakaryocyte maturation and polyploidization, although the basis for this effect remains unclear. Based on its rapid onset of action, we assessed whether, besides blocking megakaryopoiesis, anagrelide represses proplatelet formation (PPF) and aimed to clarify the underlying mechanisms. METHODS AND RESULTS Exposure of cord blood-derived megakaryocytes to anagrelide during late stages of culture led to a dose- and time-dependent inhibition of PPF and reduced proplatelet complexity, which were independent of the anagrelide-induced effect on megakaryocyte maturation. Whereas anagrelide was shown to phosphorylate cAMP-substrate VASP, two pharmacologic inhibitors of the cAMP pathway were completely unable to revert anagrelide-induced repression in megakaryopoiesis and PPF, suggesting these effects are unrelated to its ability to inhibit phosphodiesterase (PDE) 3. The reduction in thrombopoiesis was not the result of down-regulation of transcription factors which coordinate PPF, while the myosin pathway was identified as a candidate target, as anagrelide was shown to phosphorylate the myosin light chain and the PPF phenotype was partially rescued after inhibition of myosin activity with blebbistatin. CONCLUSIONS The platelet-lowering effect of anagrelide results from impaired megakaryocyte maturation and reduced PPF, both of which are deregulated in essential thrombocythemia. These effects seem unrelated to PDE3 inhibition, which is responsible for anagrelide's cardiovascular side-effects and antiplatelet activity. Further work in this field may lead to the potential development of drugs to treat thrombocytosis in myeloproliferative disorders with an improved pharmacologic profile.
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Affiliation(s)
- Y R Espasandin
- Departamento de Hematología Investigación, Instituto de Investigaciones Médicas Alfredo Lanari, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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24
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Cappelli S, Bellando-Randone S, Guiducci S, Matucci-Cerinic M. Is immunosuppressive therapy the anchor treatment to achieve remission in systemic sclerosis? Rheumatology (Oxford) 2014; 53:975-87. [PMID: 24185765 DOI: 10.1093/rheumatology/ket312] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Since activation of the immune system and a perivascular infiltrate of inflammatory cells are key features of SSc, immunosuppression has long been considered to be an anchor treatment. Non-selective immunosuppression remains central to the treatment of interstitial lung disease (ILD) and skin involvement, with CYC most widely used to obtain remission. The use of MTX as a first-line agent may be considered in the presence of skin involvement without ILD. More recently, MMF has shown encouraging results in observational studies, but still needs more formal evaluation to verify if it can be considered an alternative drug to CYC or a maintenance agent such as AZA. Rituximab has provided promising results in small open-label studies and other novel therapies targeting specific molecular and cellular targets are under evaluation. Patients with rapidly progressing diffuse cutaneous SSc should be evaluated for haematopoietic stem cell transplantation.
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25
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Dingli D, Tefferi A. Anagrelide: an update on its mechanisms of action and therapeutic potential. Expert Rev Anticancer Ther 2014; 4:533-41. [PMID: 15270658 DOI: 10.1586/14737140.4.4.533] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Thrombocytosis is an increasingly recognized clinical problem due to the widespread availability of automated cell counters. While reactive thrombocytosis does not require any therapeutic intervention, clonal thrombocytosis may require therapy to prevent thrombohemorrhagic complications. The clinician has a number of therapeutic options available when confronted with a patient having clonal thrombocytosis. One of these agents is anagrelide (Agrylin, Bristol-Myers Squibb). In this drug profile, a synopsis of the available data on this agent and its role in the control of thrombocytosis will be provided. The main side effects of the medication are discussed, as well as the potential future developments in the field.
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Affiliation(s)
- David Dingli
- Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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27
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Besses C. Anagrelide hydrochloride for essential thrombocythemia. Expert Opin Orphan Drugs 2013. [DOI: 10.1517/21678707.2013.858030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Michiels JJ, Ten Kate FWJ, Koudstaal PJ, Van Genderen PJJ. Aspirin responsive platelet thrombophilia in essential thrombocythemia and polycythemia vera. World J Hematol 2013; 2:20-43. [DOI: 10.5315/wjh.v2.i2.20] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 01/06/2013] [Indexed: 02/05/2023] Open
Abstract
Essential thrombocythemia (ET) and polycythemia vera (PV) frequently present with erythromelalgia and acrocyanotic complications, migraine-like microvascular cerebral and ocular transient ischemic attacks (MIAs) and/or acute coronary disease. The spectrum of MIAs in ET range from poorly localized symptoms of transient unsteadiness, dysarthria and scintillating scotoma to focal symptoms of transient monocular blindness, transient mono- or hemiparesis or both. The attacks all have a sudden onset, occur sequentially rather than simultaneously, last for a few seconds to several minutes and are usually associated with a dull, pulsatile or migraine-like headache. Increased hematocrit and blood viscosity in PV patients aggravate the microvascular ischemic syndrome of thrombocythemia to major arterial and venous thrombotic complications. Phlebotomy to correct hematocrit to normal in PV significantly reduces major arterial and venous thrombotic complications, but fails to prevent the platelet-mediated erythromelalgia and MIAs. Complete long-term relief of the erythromelalgic microvascular disturbances, MIAs and major thrombosis in ET and PV patients can be obtained with low dose aspirin and platelet reduction to normal, but not with anticoagulation. Skin punch biopsies from the erythromelalgic area show fibromuscular intimal proliferation of arterioles complicated by occlusive platelet-rich thrombi leading to acrocyanotic ischemia. Symptomatic ET patients with erythromelalgic microvascular disturbances have shortened platelet survival, increased platelet activation markers β-thromboglobulin (β-TG), platelet factor 4 (PF4) and thrombomoduline (TM), increased urinary thromboxane B2 (TXB2) excretion, and no activation of the coagulation markers thrombin fragments F1+2 and fibrin degradation products. Inhibition of platelet cyclooxygenase (COX1) by aspirin is followed by the disappearance and no recurrence of microvascular disturbances, increase in platelet number, correction of the shortened platelet survival times to normal, and reduction of increased plasma levels of β-TG, PF4, TM and urinary TXB2 excretion to normal. These results indicate that platelet-mediated fibromuscular intimal proliferation and platelet-rich thrombi in the peripheral, cerebral and coronary end-arterial microvasculature are responsible for the erythromelalgic ischemic complications, MIAs and splanchnic vein thrombosis. Baseline platelet P-selectin levels and arachidonic acid induced COX1 mediated platelet activation showed a highly significant increase of platelet P-selectin expression (not seen in ADP and collagen stimulated platelets), which was significantly higher in JAK2V617F mutated compared to JAK2 wild type ET.
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Deutsch VR, Tomer A. Advances in megakaryocytopoiesis and thrombopoiesis: from bench to bedside. Br J Haematol 2013; 161:778-93. [PMID: 23594368 DOI: 10.1111/bjh.12328] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Megakaryocytopoiesis involves the commitment of haematopoietic stem cells, proliferation and terminal differentiation of megakaryocytic progenitors (MK-p) and maturation of megakaryocytes (MKs) to produce functional platelets. This complex process occurs in specialized niches in the bone marrow where MKs align adjacent to vascular endothelial cells, form proplatelet projections and release platelets into the circulation. Thrombopoietin (THPO, TPO) is the primary growth factor for the MK lineage and necessary at all stages of development. THPO is constitutively produced in the liver, and binds to MPL (c-Mpl) receptor on platelets and MKs. This activates a cascade of signalling molecules, which induce transcription factors to drive MK development and thrombopoiesis. Decreased turnover rate and platelet number result in increased levels of free THPO, which induces a concentration-dependent compensatory response of marrow-MKs to enhance platelet production. Newly developed thrombopoietic agents operating via MPL receptor facilitate platelet production in thrombocytopenic states, primarily immune thrombocytopenia. Other drugs are available for attenuating malignant thrombocytosis. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease states, and the innovative drugs and therapeutic modalities to stimulate or decrease thrombopoiesis.
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Affiliation(s)
- Varda R Deutsch
- The Haematology Institute, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
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Begonja AJ, Gambaryan S, Schulze H, Patel-Hett S, Italiano JE, Hartwig JH, Walter U. Differential roles of cAMP and cGMP in megakaryocyte maturation and platelet biogenesis. Exp Hematol 2012; 41:91-101.e4. [PMID: 22981933 DOI: 10.1016/j.exphem.2012.09.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Revised: 08/24/2012] [Accepted: 09/03/2012] [Indexed: 10/27/2022]
Abstract
The cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) regulate the activity of protein kinase A (PKA) and protein kinase G (PKG), respectively. This process helps maintain circulating platelets in a resting state. Here we studied the role of cAMP and cGMP in the regulation of megakaryocyte (MK) differentiation and platelet formation. Cultured, platelet-producing MKs were differentiated from fetal livers harvested from 13.5 days postcoital mouse embryos. MK development was accompanied by a dramatic increase in cAMP production and expression of soluble guanylate cyclase, PKG, and PKA as well as their downstream targets vasodilator-stimulated phosphoprotein (VASP) and MENA. Stimulation of prostaglandin E(1) receptor/adenylyl cyclase or soluble guanylate cyclase/PKG in cultured MKs increased VASP phosphorylation, indicating that these components share a common signaling pathway. To dissect out the role of cyclic nucleotides in MK differentiation, cAMP/PKA and cGMP/PKG signaling were alternately blocked in cultured MKs. Down-regulation of cAMP pathway effectors decreased MK numbers and ploidy. Notably, cGMP levels increased at the beginning of MK development and returned to basal levels in parallel with MK maturation. However, inhibition of cGMP pathway effectors had no effect on MK development. In addition, platelet release from mature MKs was enhanced by cGMP and inhibited by cAMP. Our data suggest that cAMP plays an important role in MK differentiation, while cAMP and cGMP have opposite effects on platelet production. Identifying the signaling pathways that underpin MK development and proplatelet formation will provide greater insights into thrombopoiesis and may potentially yield useful therapeutic targets.
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Affiliation(s)
- Antonija Jurak Begonja
- Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany.
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Moinzadeh P, Khan K, Ong VH, Denton CP. Sustained improvement of diffuse systemic sclerosis following human cytomegalovirus infection offers insight into pathogenesis and therapy. Rheumatology (Oxford) 2012; 51:2296-8. [PMID: 22718869 DOI: 10.1093/rheumatology/kes137] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Arellano-Rodrigo E, Alvarez-Larrán A, Reverter JC, Villamor N, Jou JM, Cervantes F. Automated assessment of the neutrophil and platelet activation status in patients with essential thrombocythemia. Platelets 2011; 23:336-43. [DOI: 10.3109/09537104.2011.630112] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Thrombocytosis: diagnostic evaluation, thrombotic risk stratification, and risk-based management strategies. THROMBOSIS 2011; 2011:536062. [PMID: 22084665 PMCID: PMC3200282 DOI: 10.1155/2011/536062] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 03/17/2011] [Indexed: 12/11/2022]
Abstract
Thrombocytosis is a commonly encountered clinical scenario, with a large proportion of cases discovered incidentally. The differential diagnosis for thrombocytosis is broad and the diagnostic process can be challenging. Thrombocytosis can be spurious, attributed to a reactive process or due to clonal disorder. This distinction is important as it carries implications for evaluation, prognosis, and treatment. Clonal thrombocytosis associated with the myeloproliferative neoplasms, especially essential thrombocythemia and polycythemia vera, carries a unique prognostic profile, with a markedly increased risk of thrombosis. This risk is the driving factor behind treatment strategies in these disorders. Clinical trials utilizing targeted therapies in thrombocytosis are ongoing with new therapeutic targets waiting to be explored. This paper will outline the mechanisms underlying thrombocytosis, the diagnostic evaluation of thrombocytosis, complications of thrombocytosis with a special focus on thrombotic risk as well as treatment options for clonal processes leading to thrombocytosis, including essential thrombocythemia and polycythemia vera.
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Bontscho J, Schreiber A, Manz RA, Schneider W, Luft FC, Kettritz R. Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis. J Am Soc Nephrol 2011; 22:336-48. [PMID: 21233415 DOI: 10.1681/asn.2010010034] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Anti-neutrophil cytoplasmic autoantibodies (ANCA) cause vasculitis and necrotizing crescentic glomerulonephritis (NCGN). Steroids and cytotoxic drugs reduce mortality but can cause significant adverse events. The proteasome inhibitor bortezomib (BTZ) prevents glomerulonephritis in mouse models of lupus but its efficacy in ANCA-associated glomerulonephritis is unknown. We induced anti-MPO IgG-mediated NCGN by transplanting wild-type bone marrow (BM) into irradiated MPO-deficient mice immunized with MPO. Four weeks after BM transplantation, we treated mice with steroid/cyclophosphamide (S/CYC) or BTZ. Compared with untreated control mice, both S/CYC and BTZ significantly reduced urine abnormalities, NCGN, and infiltration of neutrophils and macrophages. Response to BTZ depended on timing of administration: BTZ abrogated NCGN if begun 3 weeks, but not 5 weeks, after BM transplantation. BTZ treatment significantly reduced total and MPO-specific plasma cells in both the spleen and bone marrow, resulting in significantly reduced anti-MPO titers. Furthermore, BTZ affected neither B cells nor total CD4 and CD8 T cells, including their naive and effector subsets. In contrast, S/CYC reduced the total number of cells in the spleen, including total and MPO-specific plasma cells and B cells. In contrast to BTZ, S/CYC did not affect total and MPO-specific plasma cells in the bone marrow. Three of 23 BTZ-treated mice died within 36 hours after BTZ administration. In summary, BTZ depletes MPO-specific plasma cells, reduces anti-MPO titers, and prevents NCGN in mice.
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Affiliation(s)
- Julia Bontscho
- Experimental and Clinical Research Center at the Charité and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany
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Tsukamoto H, Nagafuji K, Horiuchi T, Mitoma H, Niiro H, Arinobu Y, Inoue Y, To K, Miyamoto T, Iwasaki H, Teshima T, Harada M, Akashi K. Analysis of immune reconstitution after autologous CD34+ stem/progenitor cell transplantation for systemic sclerosis: predominant reconstitution of Th1 CD4+ T cells. Rheumatology (Oxford) 2010; 50:944-52. [DOI: 10.1093/rheumatology/keq414] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Dingli D, Tefferi A. A critical review of anagrelide therapy in essential thrombocythemia and related disorders. Leuk Lymphoma 2009; 46:641-50. [PMID: 16019501 DOI: 10.1080/10428190400029817] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Thrombocytosis is a common clinical problem and it represents either a primary myeloid disorder (a clonal process) or a reactive phenomenon. While reactive thrombocytosis is often inconsequential, clonal thrombocytosis may require cytoreductive therapy to prevent thrombohemorrhagic complications. In this regard, a controlled clinical trial has previously demonstrated the efficacy of hydroxyurea in reducing the risk of thrombosis in high-risk patients with essential thrombocythemia (ET). Despite the absence of similar evidence for clinical benefit, the platelet-lowering agent anagrelide has been widely used in both ET and polycythemia vera (PV) and recent reports of serious side-effects suggest that such practice might be detrimental to patients. In the current review we provide basic drug information as well as a critical assessment of anagrelide treatment in ET and related disorders.
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Affiliation(s)
- David Dingli
- Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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Holmberg LA, Furst DE, McSweeney PA, Nash RA. Thymoglobulin and cyclophosphamide as treatment for diffuse cutaneous systemic sclerosis. J Rheumatol 2009; 36:1839. [PMID: 19671826 DOI: 10.3899/jrheum.081268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
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BOHGAKI TOSHIYUKI, ATSUMI TATSUYA, BOHGAKI MIYUKI, FURUSAKI AKIRA, KONDO MAKOTO, SATO-MATSUMURA KAZUKOC, ABE RIICHIRO, KATAOKA HIROSHI, HORITA TETSUYA, YASUDA SHINSUKE, AMASAKI YOSHIHARU, NISHIO MITSUFUMI, SAWADA KENICHI, SHIMIZU HIROSHI, KOIKE TAKAO. Immunological Reconstitution after Autologous Hematopoietic Stem Cell Transplantation in Patients with Systemic Sclerosis: Relationship Between Clinical Benefits and Intensity of Immunosuppression. J Rheumatol 2009; 36:1240-8. [DOI: 10.3899/jrheum.081025] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Objective.To analyze the relationship between clinical benefits and immunological changes in patients with systemic sclerosis (SSc) treated with autologous hematopoietic stem cell transplantation (HSCT).Methods.Ten patients with SSc were treated with high-dose cyclophosphamide followed by highly purified CD34+ cells (n = 5) or unpurified grafts (n = 5). Two groups of patients were retrospectively constituted based on their clinical response (good responders, n = 7; and poor responders, n = 3). As well as clinical findings, immunological reconstitution through autologous HSCT was assessed by fluorescence-activated cell sorter analysis, quantification of signal joint T cell receptor rearrangement excision circles (sjTREC), reflecting the thymic function, andfoxp3, a key gene of regulatory T cells, mRNA levels.Results.Patients’ clinical and immunological findings were similar between good and poor responders, or CD34-purified and unpurified groups at inclusion. The sjTREC values were significantly suppressed at 3 months after autologous HSCT in good responders compared with poor responders (p = 0.0152). Reconstitution of CD4+CD45RO− naive T cells was delayed in good responders compared with poor responders. The phenotype of other lymphocytes, cytokine production in T cells, andfoxp3gene expression levels after autologous HSCT did not correlate with clinical response in good or poor responders. Clinical and immunological findings after autologous HSCT were similar between CD34-purified and unpurified groups.Conclusion.Our results suggest that immunosuppression intensity, sufficient to induce transient suppression of thymic function, is attributable to the feasible clinical response in patients with SSc treated with autologous HSCT. Appropriate monitoring of sjTREC values may predict clinical benefits in transplanted SSc patients after autologous HSCT.
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Palmblad J, Björkholm M, Kutti J, Lärfars G, Löfvenberg E, Markevärn B, Merup M, Mauritzson N, Westin J, Samuelsson J, Birgegård G. TPO, but not soluble-IL-6 receptor, levels increase after anagrelide treatment of thrombocythemia in chronic myeloproliferative disorders. Int J Med Sci 2008; 5:87-91. [PMID: 18414650 PMCID: PMC2293642 DOI: 10.7150/ijms.5.87] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2008] [Accepted: 04/13/2008] [Indexed: 11/05/2022] Open
Abstract
Anagrelide is often used in the treatment of thrombocythemia in myeloproliferative disease (MPD), but information concerning effects of treatment on cytokines involved in regulation of blood platelet levels is limited. Here, we investigated serum levels of thrombopoietin (TPO) and soluble IL-6 receptor (sIL-6R) in relation to response to treatment with and plasma concentrations of anagrelide. Samples from 45 patients with thrombocythemia due to MPD (ET=31, PV=14), being treated with anagrelide for 6 months, were analyzed for TPO, sIL-6R and anagrelide levels. The mean baseline platelet count was 983x10(9)/L. A reduction of platelets to <600 in asymptomatic or <400 x 10(9)/L in symptomatic patients was defined as a complete remission (CR), a reduction with >50% of baseline as partial remission, and <50% reduction as failure. At 6 months, 35 patients were in CR, 1 had a partial remission and 9 were treatment failures. For all patients, there was an increase in TPO of 44% from baseline; this change was more pronounced for patients with partial remission and failure. sIL-6R levels did not change significantly. There was no correlation between levels of anagrelide and cytokine levels at 6 months, and changes of cytokine levels did not relate to changes of platelet counts. Thus, a pronounced increase of TPO levels after 6 months of anagrelide treatment indicated that this treatment affected a major regulatory mechanism for megakaryocyte and platelet formation in MPD.
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Affiliation(s)
- Jan Palmblad
- Hematology Center, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Abstract
Megakaryocytes and platelets express the Gs-coupled VPAC1 receptor, for which the pituitary adenylyl cyclase-activating peptide (PACAP) and the vasointestinal peptide (VIP) are agonists. We here demonstrate a regulatory role for VPAC1 signaling during megakaryopoiesis. A total of 2 patients with trisomy 18p with PACAP overexpression and transgenic mice overexpressing PACAP in megakaryocytes have thrombopathy, a mild thrombocytopenia, and a reduced number of mature megakaryocytes in their bone marrow. In vitro differentiation of hematopoietic stem cells from the patient and transgenic mice shows a reduced number of megakaryocyte colonies compared with controls. The addition of PACAP, VIP, or the adenylyl cyclase activator forskolin to CD34(+) cells inhibits megakaryocyte differentiation. In contrast, neutralizing monoclonal anti-PACAP (PP1A4) or anti-VPAC1 (23A11) antibodies inhibit cAMP formation and stimulate megakaryopoiesis in a thrombopoietin-independent manner. Moreover, wild-type mice obtain an increased platelet count after subcutaneous injection of PP1A4 or 23A11. These antibodies also elevate platelet numbers in animal models of myelosuppressive therapy and in GATA1-deficient mice with congenital thrombocytopenia. Furthermore, 23A11 stimulates the in vitro megakaryocyte differentiation of both normal and GATA1-deficient human CD34(+) cells. Together, our data strongly suggest that VPAC1 signaling tempers normal megakaryopoiesis, and that inhibition of this pathway stimulates megakaryocyte differentiation, enhancing platelet recovery after myelosuppressive therapy and in GATA1 deficiency.
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Abstract
Megakaryocytopoiesis involves the commitment of haematopoietic stem cells, and the proliferation, maturation and terminal differentiation of the megakaryocytic progenitors. Circulating levels of thrombopoietin (TPO), the primary growth-factor for the megakaryocyte (MK) lineage, induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signalling induction. Decreased platelet turnover rates results in increased concentration of free TPO, enabling the compensatory response of marrow MKs to increased platelet production. C-Mpl activity is orchestrated by a complex cascade of signalling molecules that induces the action of specific transcription factors to drive MK proliferation and maturation. Mature MKs form proplatelet projections that are fragmented into circulating particles. Newly developed thrombopoietic agents operating via c-Mpl receptor may prove useful in supporting platelet production in thrombocytopenic state. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease state, and the new approaches to thrombopoietic therapy.
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Affiliation(s)
- Varda R Deutsch
- The Haematology Institute, Tel Aviv Sourasky Medical Centre, Tel Aviv, Israel.
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Thiele J, Kvasnicka HM, Vardiman J. Bone marrow histopathology in the diagnosis of chronic myeloproliferative disorders: A forgotten pearl. Best Pract Res Clin Haematol 2006; 19:413-37. [PMID: 16781481 DOI: 10.1016/j.beha.2005.07.015] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Histopathology of bone marrow (BM) biopsies plays a crucial role in the interdisciplinary approach to diagnosis and classification of chronic myeloproliferative disorders (CMPDs). Based on careful clinicopathologic studies, BM features are critical determinants that help to predict overall prognosis, to detect complications such as progression to myelofibrosis and blast crisis, and to assess therapy-related changes. A systematic evaluation of BM histopathology allows an objective identification of cases of (true) essential thrombocythemia (ET) and their separation from (false) ET, which often is the prodromal stage of chronic idiopathic myelofibrosis (CIMF). By follow-up examinations that include BM biopsies, the progression of the disease process is unveiled, which is especially important for patients with initial (early) polycythemia vera and prefibrotic CIMF that may require a different therapeutic approach than the full-blown stages. In conclusion, BM biopsy should be considered as major diagnostic tool for evaluation and follow-up of patients enrolled in prospective studies.
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Affiliation(s)
- J Thiele
- Institute of Pathology, University of Cologne, Joseph-Stelzmann-Str.9, D-50924 Cologne, Germany.
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43
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Schafer AI. Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia. Blood 2006; 107:4214-22. [PMID: 16484586 DOI: 10.1182/blood-2005-08-3526] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
AbstractRecent insights into the molecular mechanisms of polycythemia vera (PV) and essential thrombocythemia (ET) are challenging the traditional diagnostic classification of these myeloproliferative disorders (MPDs). Clonality analysis using X-chromosome inactivation patterns has revealed apparent heterogeneity among the MPDs. The recently discovered single somatic activating point mutation in the JAK2 gene (JAK2-V617F) is found in the great majority of patients with PV, but also in many patients with phenotypically classified ET and other MPDs. In contrast to the acquired MPDs, mutations of the erythropoietin receptor and thrombopoietin receptor have been identified in familial forms of nonclonal erythrocytosis and thrombocytosis, respectively. The mechanisms of major clinical complications of PV and ET remain poorly understood. Quantitative or qualitative abnormalities of red cells and platelets do not provide clear explanations for the thrombotic and bleeding tendency in these MPDs, suggesting the need for entirely new lines of research in this area. Recently reported randomized clinical trials have demonstrated the efficacy and safety of low-dose aspirin in PV, and an excess rate of arterial thrombosis, major bleeding, and myelofibrotic transformation, but decreased venous thrombosis, in patients with ET treated with anagrelide plus aspirin compared to hydroxyurea plus aspirin.
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Affiliation(s)
- Andrew I Schafer
- Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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Wang G, Franklin R, Hong Y, Erusalimsky JD. Comparison of the biological activities of anagrelide and its major metabolites in haematopoietic cell cultures. Br J Pharmacol 2006; 146:324-32. [PMID: 16041400 PMCID: PMC1576287 DOI: 10.1038/sj.bjp.0706341] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The platelet-lowering drug anagrelide inhibits bone marrow megakaryocytopoiesis by an unknown mechanism. Recently, it was found that anagrelide is bio-transformed in humans into two major metabolites (6,7-dichloro-3-hydroxy-1,5 dihydro-imidazo[2,1-b]quinazolin-2-one (BCH24426) and 2-amino-5,6-dichloro-3,4,-dihydroquinazoline (RL603). Whether these metabolites have biological activities that may underlie the mode of action of the parent drug is presently unclear. To clarify this question here we have compared the activities of anagrelide, BCH24426 and RL603 on the growth and differentiation of CD34(+) haematopoietic progenitor cells in liquid culture and on the migration of differentiated megakaryocytes. Incubation with either anagrelide, BCH24426 or RL603 did not affect the early expansion of CD34(+) cells stimulated by thrombopoietin. In contrast, both anagrelide and BCH24426 potently inhibited the development of megakaryocytes (IC(50) +/- s.e.m. = 26 +/- 4 and 44 +/- 6 nM, respectively), whereas RL603 showed no significant effect. Anagrelide and BCH24426 did not affect erythroid or myelomonocytic differentiation stimulated by erythropoietin or granulocyte-macrophage colony-stimulating factor, demonstrating the selectivity of these compounds against the megakaryocytic lineage. Neither anagrelide nor its metabolites showed a significant effect on the migratory response of megakaryocytes towards stromal cell-derived factor-1alpha. Although BCH24426 was shown to be considerably more potent than anagrelide as an inhibitor of phosphodiesterase type III (PDEIII) (IC(50) = 0.9 vs 36 nM) this activity did not correlate with the potency of inhibition of megakaryocyte development. Furthermore, other PDEIII inhibitors of widely differing potency were shown to have negligible effects on megakaryocytopoiesis. Taken together our results demonstrate that anagrelide and BCH24426 target a cellular event involved specifically in the megakaryocyte differentiation programme, which is independent of PDEIII inhibition.
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Affiliation(s)
- Guosu Wang
- The Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6BT
| | - Richard Franklin
- Shire Pharmaceutical Development, Hampshire International Business Park, Chineham, Basingstoke, Hampshire RG24 8EP
| | - Ying Hong
- The Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6BT
| | - Jorge D Erusalimsky
- The Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Gower Street, London WC1E 6BT
- Author for correspondence:
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Abstract
Anagrelide (Agrylin, Xagrid) is an oral imidazoquinazoline agent which is indicated in Europe for the reduction of elevated platelet counts in at-risk patients with essential thrombocythaemia who are intolerant of or refractory to their current therapy, and in the US for the reduction of elevated platelet counts and the amelioration of thrombohaemorrhagic events in patients with thrombocythaemia associated with myeloproliferative disorders. Anagrelide is well established as an effective platelet-lowering agent in most patients with essential thrombocythaemia, including both treatment-naive patients and those refractory to other cytoreductive therapy. Results of the only randomised trial to date (the Primary Thrombocythaemia 1 [PT1] study) indicated that the composite primary endpoint (arterial or venous thrombosis, serious haemorrhage or death from vascular causes) occurred more often in recipients of anagrelide plus aspirin than in those receiving hydroxycarbamide (hydroxyurea) plus aspirin. This trial also indicated that the incidence of the secondary endpoints transient ischaemic attack and gastrointestinal bleeding favoured hydroxycarbamide plus aspirin, while the incidence of venous thrombosis favoured anagrelide plus aspirin. There were no differences between the groups in the incidence of secondary endpoints myocardial infarction, stroke, unstable angina, pulmonary embolism, hepatic-vein thrombosis, other serious haemorrhage or related deaths. The design of the PT1 study has been queried with respect to the heterogeneous nature of the study population (possible inclusion of patients with early myelofibrotic disease) and the concomitant use of aspirin (interaction with anagrelide causing increased bleeding events). Further data are therefore required before the role of anagrelide in essential thrombocythaemia can be finalized. In the meantime, when considering treatment options for patients with this disorder, anagrelide's positive effects on platelet function, lack of mutagenicity and lack of association with leukaemia or angiogenesis must be balanced against its comparative expense and positive inotropic effects. Thus, the role of anagrelide in the management of high-risk patients with essential thrombocythaemia will ultimately depend on individual patient assessment and future clarification of the potential leukaemogenicity of hydroxycarbamide.
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McCarty JM, Melone PD, Simanis JP, Kanamori D, Dessypris EN, Warshamana-Greene GS. A preliminary investigation into the action of anagrelide: Thrombopoietin–c-Mpl receptor interactions. Exp Hematol 2006; 34:87-96. [PMID: 16413395 DOI: 10.1016/j.exphem.2005.09.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2005] [Revised: 08/04/2005] [Accepted: 09/14/2005] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Many studies have validated the clinical efficacy of anagrelide to reduce platelet counts in thrombocythemic conditions. With the ability to support human megakaryopoiesis in vitro using thrombopoietin (TPO), specific investigation of changes in platelet levels can be carried out in human systems. Using CD34(+) stem cells and murine BaF3 cells transfected with the human or murine TPO receptor, c-Mpl (BaF3mpl), the effect of anagrelide on cell differentiation, proliferation, and signaling was examined in the presence of TPO. METHODS Inhibition of TPO-mediated cell differentiation by anagrelide was evaluated by fluorescein-activated cell sorting analysis. Cell proliferation was monitored by 3-(4,5-dimethylthiazol-2-yl)-5-3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays. Effect of anagrelide on TPO-mediated phosphotyrosine (pTyr) activity was examined by Western analysis of whole cell lysates. RESULTS In the presence of TPO, anagrelide reduced the number of CD41(+) cells without a reduction in the total mononuclear cell number in a dose-dependent manner. Growth inhibition was also observed in BaF3 cells transfected with human c-Mpl. Anagrelide also reduced TPO-specific pTyr activity in a species-specific manner. No inhibitory effect could be demonstrated with interleukin-3 stimulation. CONCLUSION Parallel dose-response effects were found in both CD41(+) number and TPO-specific pTyr activity. These results suggest that anagrelide reduces TPO-mediated megakaryocyte proliferation of CD34(+) cells through a mechanism that leads to inhibition of intracellular signaling events. Furthermore, data also suggest that it is a species-specific effect, with no inhibitory activity against the murine receptor. Because there is a less than 10% difference in DNA sequence homology between human and murine receptors, the difference in sequence-specific activity must reside in these amino acid differences.
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Affiliation(s)
- John M McCarty
- Department of Hematology/Oncology and Bone Marrow Transplantation Program, Massey Cancer Center, VCU Health Systems/MCV Hospitals at Virginia Commonwealth University, Richmond, 23298, USA.
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Abstract
Myeloproliferative disorders are characterized by overproduction of one or more blood lineages. The clinical course of the Philadelphia-negative myeloproliferative disorders, particularly essential thrombocythemia and polycythemia vera, are characterized by vascular symptoms and in the long-term, transformation to myelofibrosis and leukemia may occur. Control of myeloproliferation has traditionally been achieved using cytotoxic agents but many of these have a documented ability to increase the risk of leukemia. Anagrelide, initially developed as an antiaggregant, is an attractive alternative to these agents as it appears to be relatively selective in reducing the platelet count and is unlikely to be leukemogenic. This article reviews clinical studies in these patients and discusses the future scope for anagrelide.
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Affiliation(s)
- Claire N Harrison
- Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, Lambeth Palace Road, London, UK.
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Zhu Z, Gonthier R, Neirinck L. High-performance liquid chromatography–mass spectrometry method for determination of anagrelide in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2005; 822:238-43. [PMID: 16005692 DOI: 10.1016/j.jchromb.2005.06.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2005] [Revised: 05/25/2005] [Accepted: 06/04/2005] [Indexed: 11/15/2022]
Abstract
This paper describes a simple, fast and sensitive liquid chromatography-mass spectrometry method for quantification of an anti-thrombocythemic agent, anagrelide in human plasma. The samples were subjected to a liquid-liquid extraction after addition of a buffer and an internal standard. Chromatography was performed on an Inertsil ODS2 column and the extract was injected onto a HPLC system coupled with mass spectrometric detection. Linear responses for standards were observed from 50 to 7500 pg/ml. The accuracy of intra-assay and inter-assay were in the ranges 4.3-4.4% and 4.8-5.6%, respectively. The method is simple and reproducible with a run time of less than 2 min.
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Affiliation(s)
- Z Zhu
- Pharmascience, 6111 Royalmount Ave. Suite 100, Montreal, Que., Canada.
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Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, Wilkins BS, van der Walt JD, Reilly JT, Grigg AP, Revell P, Woodcock BE, Green AR. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005; 353:33-45. [PMID: 16000354 DOI: 10.1056/nejmoa043800] [Citation(s) in RCA: 615] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND We conducted a randomized comparison of hydroxyurea with anagrelide in the treatment of essential thrombocythemia. METHODS 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. RESULTS 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. CONCLUSIONS Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for vascular events.
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Affiliation(s)
- Claire N Harrison
- Department of Haematology, University of Cambridge, and Addenbrooke's National Health Service Trust, Cambridge, United Kingdom
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Petrides PE. Anagrelide: a decade of clinical experience with its use for the treatment of primary thrombocythaemia. Expert Opin Pharmacother 2005; 5:1781-98. [PMID: 15264993 DOI: 10.1517/14656566.5.8.1781] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Primary thrombocythaemia (PT) is the most frequent among the rare chronic myeloproliferative disorders. Life expectancy is determined by thromboembolic and haemorrhagic complications, which can be prevented by cytoreductive therapy. For a long time, hydroxyurea has been considered as the therapeutic gold standard. However, hydroxyurea treatment is not lineage-specific, may not be tolerated because of adverse effects (skin, gastrointestinal tract) and is leukaemogenic when sequentially used with other DNA-targeting drugs. Hence, anagrelide was welcomed in 1988 when it was first described as being efficient at normalising elevated platelet counts, specific for megakaryocytes and non-mutagenic. Since then, anagrelide has been approved in the US and Canada (Agrylin), Shire Pharmaceuticals) as well as in Austria and other countries of the EU (Thromboreductin), AOP Orphan Pharmaceuticals). Clinical Phase III trials (PT1 and ANAHYDRET) are underway to directly compare the efficacy and safety of anagrelide and hydroxyurea.
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Affiliation(s)
- Petro E Petrides
- Hematology Oncology Center, Zweibruckenstr. 2, 80331 Munich, Germany.
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