Management of side effects of BCR/ABL-negative chronic myeloproliferative neoplasm therapies. Focus on anagrelide

References

• Hasselbalch HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood 2012;119:3219-25
   PubMed Web of Science ®Google Scholar
• Bittencourt RI, Vassallo J, Chauffaille Mde L, et al. Philadelphia-negative chronic myeloproliferative neoplasms. Rev Bras Hematol Hemoter 2012;34:140-9
   Google Scholar
• Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379-90
   PubMed Web of Science ®Google Scholar
• Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22
   PubMed Web of Science ®Google Scholar
• Wolf D, Rudzki J, Gastl G. Current treatment concepts of Philadelphia-negative MPN. Curr Cancer Drug Targets 2011;11:44-55
   PubMed Web of Science ®Google Scholar
• Moulard O, Mehta J, Fryzek J, et al. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol 2014;92:289-97
   PubMed Web of Science ®Google Scholar
• Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 2014;55:595-600
   PubMed Web of Science ®Google Scholar
• de Lacerda JF, Oliveira SN, Ferro JM. Chronic myeloproliferative diseases. Handb Clin Neurol 2014;120:1073-81
   PubMedGoogle Scholar
• Landolfi R, Gennaro L. Prevention of thrombosis in polycythemia vera and essential thrombocythemia. Haematologica 2008;93:331-5
   PubMed Web of Science ®Google Scholar
• Falanga A, Marchetti M. Thrombosis in myeloproliferative neoplasms. Semin Thromb Hemost 2014;40:348-58
   PubMed Web of Science ®Google Scholar
• Barbui T, Finazzi G. Therapy for polycythemia vera and essential thrombocythemia is driven by the cardiovascular risk. Semin Thromb Hemost 2007;33:321-9
   PubMed Web of Science ®Google Scholar
• Crisà E, Venturino E, Passera R, et al. A retrospective study on 226 polycythemia vera patients: impact of median hematocrit value on clinical outcomes and survival improvement with anti-thrombotic prophylaxis and nonalkylating drugs. Ann Hematol 2010;89:691-9
   PubMed Web of Science ®Google Scholar
• Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011;29:761-70
   PubMed Web of Science ®Google Scholar
• Hernández-Boluda JC, Gomez M. Target hematologic values in the management of essential thrombocythemia and polycythemia vera. Eur J Haematol 2015;94:4-11
   PubMed Web of Science ®Google Scholar
• Marchioli R, Finazzi G, Specchia G, et al. CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013;368:22-33
   PubMed Web of Science ®Google Scholar
• Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 2004;350:114-24
   PubMed Web of Science ®Google Scholar
• Squizzato A, Romualdi E, Passamonti F, Middeldorp S. Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev 2013;4:CD006503
   PubMed Web of Science ®Google Scholar
• Barosi G, Birgegard G, Finazzi G, et al. Response criteria for essential thrombocythemia and polycythemia vera: result of a European LeukemiaNet consensus conference. Blood 2009;113:4829-33
   PubMed Web of Science ®Google Scholar
• Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015;90:162-73
   PubMed Web of Science ®Google Scholar
• Finazzi G, Caruso V, Marchioli R, et al. ECLAP Investigators. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 2005;105:2664-70
   PubMed Web of Science ®Google Scholar
• Björkholm M, Derolf AR, Hultcrantz M, et al. Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms. J Clin Oncol 2011;29:2410-15
   PubMed Web of Science ®Google Scholar
• Sever M, Newberry KJ, Verstovsek S. Therapeutic options for patients with polycythemia vera and essential thrombocythemia refractory/resistant to hydroxyurea. Leuk Lymphoma 2014;55:2685-90
   PubMed Web of Science ®Google Scholar
• Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015;372:426-35
   PubMed Web of Science ®Google Scholar
• Alvarez-Larrán A, Martínez-Avilés L, Hernández-Boluda JC, et al. Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea. Ann Hematol 2014;93:2037-43
   PubMed Web of Science ®Google Scholar
• Cervantes F. Management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program 2011;2011:215-21
   PubMed Web of Science ®Google Scholar
• Passamonti F, Rumi E, Arcaini L, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica 2008;93:1645-51
   PubMed Web of Science ®Google Scholar
• Montanaro M, Latagliata R, Cedrone M, et al. Thrombosis and survival in essential thrombocythemia: a regional study of 1,144 patients. Am J Hematol 2014;89:542-6
   PubMed Web of Science ®Google Scholar
• Prieto R, Martĺnez-Sellés M, Fernández-Avilés F. Essential thrombocytemia and acute coronary syndrome: clinical profile and association with other thromboembolic events. Acute Card Care 2008;10:116-20
   PubMedGoogle Scholar
• Michiels JJ. Acquired von Willebrand disease due to increasing platelet count can readily explain the paradox of thrombosis and bleeding in thrombocythemia. Clin Appl Thromb Hemost 1999;5:147-51
   PubMed Web of Science ®Google Scholar
• Alvarez-Larrán A, Cervantes F, Besses C. Treatment of essential thrombocythemia. Med Clin (Barc) 2013;141:260-4
   PubMed Web of Science ®Google Scholar
• Ramirez G, García-Sanchez R, Plaza S. Management of patients with essential thrombocythemia. Med Clin (Barc) 2013;140:278-82
   PubMed Web of Science ®Google Scholar
• Tefferi A, Barbui T. Personalized management of essential thrombocythemia-application of recent evidence to clinical practice. Leukemia 2013;27:1617-20
   PubMed Web of Science ®Google Scholar
• Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132-6
   PubMed Web of Science ®Google Scholar
• Birgegàrd G. Long-term management of thrombocytosis in essential thrombocythaemia. Ann Hematol 2009;88:1-10
   PubMed Web of Science ®Google Scholar
• Hernández-Boluda JC, Alvarez-Larrán A, Gómez M, et al. Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia. Br J Haematol 2011;152:81-8
   PubMed Web of Science ®Google Scholar
• European Medicines Agency (EMA). Xagrid®, “Summary of Product Characteristics” Updated 18-February-2014. Available from: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000480/WC500056557.pdf
   Google Scholar
• Lengfelder E, Griesshammer M, Hehlmann R. Interferon-alpha in the treatment of essential thrombocythemia. Leuk Lymphoma 1996;22(Suppl 1):135-42
   PubMed Web of Science ®Google Scholar
• Barbui T, Finazzi G. Myeloproliferative disease in pregnancy and other management issues. Hematol Am Soc Hematol Educ Program 2006;246:52
   Google Scholar
• Emadi A, Spivak JL. Anagrelide: 20 years later. Expert Rev Anticancer Ther 2009;9:37-50
   PubMed Web of Science ®Google Scholar
• Griesshammer M. Role of platelet counts in the management of essential thrombocythemia: experience with anagrelide. Expert Rev Hematol 2009;2:227-36
   PubMed Web of Science ®Google Scholar
• Ahluwalia M, Donovan H, Singh N, et al. Anagrelide represses GATA-1 and FOG-1 expression without interfering with thrombopoietin receptor signal transduction. J Thromb Haemost 2010;8:2252-61
   PubMed Web of Science ®Google Scholar
• Besses C, Zeller W, Alvarez-Larrán A, et al. Pharmacokinetics and tolerability of anagrelide hydrochloride in young (18 - 50 years) and elderly (≥ 65 years) patients with essential thrombocythemia. Int J Clin Pharmacol Ther 2012;50:787-96
   PubMed Web of Science ®Google Scholar
• Okamoto S, Miyakawa Y, Smith J, et al. Open-label, dose-titration and continuation study to assess efficacy, safety, and pharmacokinetics of anagrelide in treatment-naïve Japanese patients with essential thrombocythemia. Int J Hematol 2013;97:360-8
   PubMed Web of Science ®Google Scholar
• Harrison CN, Campbell PJ, Buck G, et al. United Kingdom Medical Research Council Primary Thrombocythemia 1 Study. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med 2005;353:33-45
   PubMed Web of Science ®Google Scholar
• Steurer M, Gastl G, Jedrzejczak WW, et al. Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile. Cancer 2004;101:2239-46
   PubMed Web of Science ®Google Scholar
• Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013;121:1720-8
   PubMed Web of Science ®Google Scholar
• Silver RT. Anagrelide is effective in treating patients with hydroxyurea-resistant thrombocytosis in patients with chronic myeloid leukemia. Leukemia 2005;19:39-43
   PubMed Web of Science ®Google Scholar
• Giralt M, Navas V, Hernández-Nieto L, et al. en representación del Grupo de Estudio de Enfermedades Mieloproliferativas Filadelfia Negativas (GEMFIN). Retrospective analysis of the efficacy and tolerability of anagrelide in patients with essential thrombocytemia: Spanish registry of essential thrombocytemia. Med Clin (Barc) 2009;133:86-90
   PubMed Web of Science ®Google Scholar
• Schmitz S, Stauch M, Schlag R. Anagrelide for the treatment of thrombocythaemia in daily clinical practice: a post-marketing observational survey on efficacy and safety performed in Germany. Onkologie 2010;33:39-44
   PubMed Web of Science ®Google Scholar
• Hernández-Boluda JC, Pereira A, Cervantes F, et al. Grupo Español de Enfermedades Mieloproliferativas Filadelfia Negativas (GEMFIN). Clinical evaluation of the European LeukemiaNet response criteria in patients with essential thrombocythemia treated with anagrelide. Ann Hematol 2013;92:771-5
   PubMed Web of Science ®Google Scholar
• Penka M, Schwarz J, Ovesná P, et al. kolektiv Ceske pracovni skupiny pro myeloproliferativni choroby (CZEMP). The effectiveness of anagrelide treatment in patients with Ph-negative myeloproliferative diseases: influence on the incidence of thrombosis in the data from the Registry of patients with essential thrombocythemia and thrombocythemia associated with other myeloproliferative diseases treated with Thromboreductin® to the end of 2012. Vnitr Lek 2013;59:516-31
   PubMedGoogle Scholar
• Kiladjian JJ, Besses C, Griesshammer M, et al. Efficacy and safety of cytoreductive therapies in patients with essential thrombocythaemia aged >80 years: an interim analysis of the EXELS study. Clin Drug Investig 2013;33:55-63
   PubMed Web of Science ®Google Scholar
• Rey J, Viallard JF, Keddad K, FOX study investigators. Characterization of different regimens for initiating anagrelide in patients with essential thrombocythemia who are intolerant or refractory to their current cytoreductive therapy: results from the multicenter FOX study of 177 patients in France. Eur J Haematol 2014;92:127-36
   PubMed Web of Science ®Google Scholar
• Kanakura Y, Miyakawa Y, Wilde P, et al. Phase III, single-arm study investigating the efficacy, safety, and tolerability of anagrelide as a second-line treatment in high-risk Japanese patients with essential thrombocythemia. Int J Hematol 2014;100:353-60
   PubMed Web of Science ®Google Scholar
• D’adda M, Micheletti M, Drera M, et al. The combined use of hydroxyurea and anagrelide allows satisfactory hematologic control in patients with chronic myeloproliferative disorders and thrombocytosis: a report on 13 patients with poor tolerance to hydroxyurea monotherapy. Leuk Lymphoma 2008;49:2216-18
   PubMed Web of Science ®Google Scholar
• Christoforidou A, Pantelidou D, Anastasiadis A, et al. Hydroxyurea and anagrelide combination therapy in patients with chronic myeloproliferative diseases resistant or intolerant to monotherapy. Acta Haematol 2008;120:195-8
   PubMed Web of Science ®Google Scholar
• Ahn IE, Natelson E, Rice L. Successful long-term treatment of Philadelphia chromosome-negative myeloproliferative neoplasms with combination of hydroxyurea and anagrelide. Clin Lymphoma Myeloma Leuk 2013;13(Suppl 2):S300-4
   PubMedGoogle Scholar
• Gugliotta L, Besses C, Griesshammer M, et al. Combination therapy of hydroxycarbamide with anagrelide in patients with essential thrombocythemia in the evaluation of Xagrid(R) efficacy and long-term safety study. Haematologica 2014;99:679-87
   PubMed Web of Science ®Google Scholar
• Birgegard G, Besses C, Griesshammer M, et al. Treatment of Essential Thrombocythemia in Europe: An Observational Study of 3649 High-Risk Patients in Exels. 56th American Society of Hematology (ASH) Annual Meeting and Exposition. 6 – 9 December 2014. San Francisco, CA, Blood 2014. 124(21):A1846
   Google Scholar
• Vaidya R, Siragusa S, Huang J, et al. Mature survival data for 176 patients younger than 60 years with primary myelofibrosis diagnosed between 1976 and 2005: Evidence for survival gains in recent years. Mayo Clin Proc 2009;84:1114-19
   PubMed Web of Science ®Google Scholar
• Wolanskyj AP, Schwager SM, McClure RF, et al. Essential thrombocythemia beyond the first decade: Life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc 2006;81:159-66
   PubMed Web of Science ®Google Scholar
• Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009;113:2895-901
   PubMed Web of Science ®Google Scholar
• Tefferi A, Siragusa S, Hussein K, et al. Transfusion-dependency at presentation and its acquisition in the first year of diagnosis are both equally detrimental for survival in primary myelofibrosis: Prognostic relevance is independent of IPSS or karyotype. Am J Hematol 2010;85:14-17
   PubMed Web of Science ®Google Scholar
• Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010;115:1703-8
   PubMed Web of Science ®Google Scholar
• Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011;29:392-7
   PubMed Web of Science ®Google Scholar
• Guglielmelli P, Barosi G, Specchia G, et al. Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele. Blood 2009;114:1477-83
   PubMed Web of Science ®Google Scholar
• Tefferi A, Guglielmelli P, Larson DR, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood 2014;124:2507-13
   PubMed Web of Science ®Google Scholar
• Cervantes F, Barosi G, Demory JL, et al. Myelofibrosis with myeloid metaplasia in young individuals: disease characteristics, prognostic factors and identification of risk groups. Br J Haematol 1998;102:684-90
   PubMed Web of Science ®Google Scholar
• Verstovsek S, Mesa RA, Gotlib J, et al. Three-year efficacy, overall survival, and safety of ruxolitinib therapy in patients with myelofibrosis from the COMFORT-I study. Haematologica 2015. [Epub ahead of print]
   Google Scholar
• Martínez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: Results in 40 patients. Ann Hematol 2010;89:1233-7
   PubMed Web of Science ®Google Scholar
• Palandri F, Catani L, Testoni N, et al. Long-term follow-up of 386 consecutive patients with essential thrombocythemia: safety of cytoreductive therapy. Am J Hematol 2009;84:215-20
   PubMed Web of Science ®Google Scholar
• Barosi G, Besses C, Birgegard G, et al. A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia 2007;21:277-80
   PubMed Web of Science ®Google Scholar
• Spivak JL, Hasselbalch H. Hydroxycarbamide: a user’s guide for chronic myeloproliferative disorders. Expert Rev Anticancer Ther 2011;11:403-14
   PubMed Web of Science ®Google Scholar
• Finazzi G, Barbui T. Efficacy and safety of hydroxyurea in patients with essential thrombocythemia. Pathol Biol (Paris) 2001;49:167-9
   PubMed Web of Science ®Google Scholar
• Zaccaria E, Cozzani E, Parodi A. Secondary cutaneous effects of hydroxyurea: possible pathogenetic mechanisms. J Dermatol Treat 2006;17:176-8
   PubMed Web of Science ®Google Scholar
• Boonyawat K, Wongwaisayawan S, Nitiyanant P, Atichartakarn V. Hydroxyurea and colonic ulcers: a case report. BMC Gastroenterol 2014;14:134
   PubMed Web of Science ®Google Scholar
• Birgegård G, Björkholm M, Kutti J, et al.Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica 2004;89:520-7
   PubMed Web of Science ®Google Scholar
• Storen EC, Tefferi A. Long-term use of anagrelide in young patients with essential thrombocythemia. Blood 2001;97:863-6
   PubMed Web of Science ®Google Scholar
• Proietti R, Rognoni A, Ardizzone F, et al. Atypical Takotsubo syndrome during anagrelide therapy. J Cardiovasc Med (Hagerstown) 2009;10:546-9
   PubMed Web of Science ®Google Scholar
• Martínez-Sellés M, Datino T, Figueiras-Graillet L, et al. Cardiovascular safety of anagrelide in healthy subjects: effects of caffeine and food intake on pharmacokinetics and adverse reactions. Clin Drug Investig 2013;33:45-54
   PubMed Web of Science ®Google Scholar
• Lim YH, Lee YY, Kim JH, et al. Development of acute myocardial infarction in a young female patient with essential thrombocythemia treated with anagrelide: a case report. Korean J Hematol 2010;45:136-8
   PubMedGoogle Scholar
• Schaaf M, Sibellas F. Acute myocardial infarction and anagrelide. Int J Cardiol 2013;168:e50-2
   PubMed Web of Science ®Google Scholar
• Dziewierz A, Olszanecka A, Wiliński J, et al. Inverted takotsubo cardiomyopathy in a patient with essential thrombocythemia exposed to anagrelide and phentermine. Int J Cardiol 2012;160:e31-2
   PubMed Web of Science ®Google Scholar
• Lee SH, Kim YS. Reversible dilated cardiomyopathy associated with long-term anagrelide therapy in a patient with chronic myeloproliferative disease: A serial 2-dimensional speckle tracking echocardiographic study. Int J Cardiol 2014;173:e45-6
   PubMed Web of Science ®Google Scholar
• Gugliotta L, Tieghi A, Tortorella G, et al. Low impact of cardiovascular adverse events on anagrelide treatment discontinuation in a cohort of 232 patients with essential thrombocythemia. Leuk Res 2011;35:1557-63
   PubMed Web of Science ®Google Scholar
• Troy S, Parks V, Purkayastha J, et al. Effect of anagrelide on cardiac repolarization in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled, thorough QT study. Pharma Res Per 2014;2:e00080
   Google Scholar
• Besses C, Martínez-Sellés M. Anagrelide and cardiovascular events. Much ado about nothing? Leuk Res 2011;35:1543-4
   PubMed Web of Science ®Google Scholar
• Fruchtman SM, Petitt RM, Gilbert HS, Anagrelide Study Group. Anagrelide: analysis of long-term efficacy, safety and leukemogenic potential in myeloproliferative disorders. Leuk Res 2005;29:481-91
   PubMed Web of Science ®Google Scholar
• Hong Y, Wang G, Del Arroyo AG, et al. Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation: selectivity of anagrelide for the megakaryocytic lineage. Leukemia 2006;20:1117-22
   PubMed Web of Science ®Google Scholar
• Hasselbalch HC. A new era for IFN-α in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Expert Rev Hematol 2011;4:637-55
   PubMed Web of Science ®Google Scholar
• Cassinat B, Verger E, Kiladjian JJ. Interferon alfa therapy in CALR-mutated essential thrombocythemia. N Engl J Med 2014;371:188-9
   PubMed Web of Science ®Google Scholar
• Hasselbalch HC, Kiladjian JJ, Silver RT. Interferon alfa in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. J Clin Oncol 2011;29:e564-5
   PubMed Web of Science ®Google Scholar
• European Medicines Agency (EMA). IntronA®, “Summary of Product Characteristics”. Updated 20-January-2014. Available from: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000281/WC500034679.pdf
   Google Scholar
• Berlin NI. Treatment of the myeloproliferative disorders with 32P. Eur J Haematol 2000;65:1-7
   PubMed Web of Science ®Google Scholar
• Tennvall J, Brans B. EANM procedure guideline for 32P phosphate treatment of myeloproliferative diseases. Eur J Nucl Med Mol Imaging 2007;34:1324-7
   PubMed Web of Science ®Google Scholar
• Besses C, Kiladjian JJ, Griesshammer M, et al. Cytoreductive treatment patterns for essential thrombocythemia in Europe. Analysis of 3643 patients in the EXELS study. Leuk Res 2013;37:162-8
   PubMed Web of Science ®Google Scholar
• Rosenthal A, Mesa RA. Janus kinase inhibitors for the treatment of myeloproliferative neoplasms. Expert Opin Pharmacother 2014;15:1265-76
   PubMed Web of Science ®Google Scholar
• Tibes R, Mesa RA. Emerging drugs for polycythemia vera. Expert Opin Emerg Drugs 2013;18:393-404
   PubMed Web of Science ®Google Scholar