Abstract
Background
Anagrelide is an orally active, quinazolone-derived, platelet-lowering agent that acts by blocking megakaryocyte maturation and polyploidization as well as proplatelet formation, and is currently indicated for second-line treatment of high-risk patients with essential thrombocythemia (ET) in Europe. In recent years various clinical trials have confirmed the safety and efficacy of this drug in ET, with some also considering Janus kinase 2 (JAK2) mutational status, but have not confirmed the impact that the other driver mutations, i.e., calreticulin (CALR) and myeloproliferative leukemia virus (MPL), may have on the response to this therapy.
Objective
To assess the impact of JAK2, MPL, CALR gene mutational status on response to anagrelide therapy in patients with ET treated at the Oncohematology Division, IRCCS Ca’ Granda–Maggiore Policlinico Hospital Foundation, Milan between 2004 and 2015.
Methods
Among 213 ET patients who were diagnosed between January 1983 to November 2014, 21 consecutive cases who were started on anagrelide as a second-line therapy and received at least 1-year of treatment were included. Inclusion criteria were the availability of demographic, clinical, histological, and hematologic data at diagnosis, and at least one granulocyte DNA sample to assess the mutational status of the JAK2, MPL, and CALR genes.
Results
The JAK2V617F mutation was detected in seven patients (33.3 %), CALR mutations were identified in another seven cases, and the remaining seven patients were defined as “triple-negative” (i.e., no JAK2, CALR, or MPL mutation). After a median anagrelide treatment duration of 4.6 years, 16 of 21 patients (76.2 %) achieved at least a partial platelet response: in particular, the hematological response rate was substantially comparable between JAK2-positive and “triple-negative” patients, whereas the five patients who did not achieve any platelet response all had CALR mutations.
Conclusion
Although it needs to be confirmed with a larger number of ET patients treated with anagrelide, we suggest that mutational status should be considered carefully when deciding on the most appropriate therapy for each patient, mainly because anagrelide alone was not able to achieve an appropriate hematological response in CALR-mutated ET cases.
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References
Silverstein MN, Petitt RM, Solberg LA Jr, Fleming JS, Knight RC, Schacter LP. Anagrelide: a new drug for treating thrombocytosis. N Engl J Med. 1988;318:1292–4.
Mazur EM, Rosmarin AG, Sohl PA, Newton JL, Narendran A. Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans. Blood. 1992;79:1931–7.
Espasandin YR, Glembotsky AC, Grodzielski M, Lev PR, Goette NP, Molinas FC, et al. 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.
Barbui T, Barosi G, Grossi A, Gugliotta L, Liberato LN, Marchetti M, et al. Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation. Haematologica. 2004;89:215–32.
Gisslinger H, Gotic M, Holowiecki J, Penka M, Thiele J, Kvasnicka HM, ANAHYDRET Study Group, et al. Anagrelide compared to hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET study, a randomized controlled trial. Blood. 2013;121:1720–8.
Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, United Kingdom Medical Research Council Primary Thrombocythemia 1 Study, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353:33–45.
Mela Osorio MJ, Ferrari L, Goette NP, Gutierrez MI, Glembotsky AC, Maldonado AC, et al. Long-term follow-up of essential thrombocythemia patients treated with anagrelide: subgroup analysis according to JAK2/CALR/MPL mutational status. Eur J Haematol. 2015;. doi:10.1111/ejh.12614 (Epub 2015 Jun 27).
Cascavilla N, De Stefano V, Pane F, Pancrazzi A, Iurlo A, Gobbi M, et al. Impact of JAK2(V617F) mutation status on treatment response to anagrelide in essential thrombocythemia: an observational, hypothesis-generating study. Drug Des Devel Ther. 2015;9:2687–94.
Shire. Exploratory multi-centre trial in patients with ET treated with XAGRID® (EMIX) [ClinicalTrials.gov identifier NCT01352585]. US National Institutes of Health, ClinicalTrials.gov. https://www.clinicaltrials.gov. Accessed 16 Mar 2016.
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779–90.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–97.
Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med. 2006;3:e270.
Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1,182 patients. Blood. 2006;108:3472–6.
Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90.
Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405.
Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, Lengfelder E, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013;121:4778–81.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Cancer Genome Project, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054–61.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. editors. WHO classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2008. p. 48–50.
Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood. 2014;124:3529–37.
Besses C, Kiladjian JJ, Griesshammer M, Gugliotta L, Harrison C, Coll R, et al. Cytoreductive treatment patterns for essential thrombocythemia in Europe. Analysis of 3643 patients in the EXELS study. Leuk Res. 2013;37:162–8.
Tomer A. Effects of anagrelide on in vivo megakaryocyte proliferation and maturation in essential thrombocythemia. Blood. 2002;99:1602–9.
Di Buduo CA, Moccia F, Battiston M, De Marco L, Mazzucato M, Moratti R, et al. The importance of calcium in the regulation of megakaryocyte function. Haematologica. 2014;99:769–78.
Shivarov V, Ivanova M, Tiu RV. Mutated calreticulin retains structurally disordered C terminus that cannot bind Ca(2+): some mechanistic and therapeutic implications. Blood Cancer J. 2014;4:e185.
Author contributions
AI was responsible for the integrity of the work as a whole. AI and DC interpreted the data and wrote the manuscript. SF carried out molecular analyses. AI, DC, NO, and CB collected the data. AC reviewed the data and approved the manuscript.
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AI received speaker funding from Shire. DC, NO, CB, SF, and AC declare no conflicts of interest.
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Iurlo, A., Cattaneo, D., Orofino, N. et al. Anagrelide and Mutational Status in Essential Thrombocythemia. BioDrugs 30, 219–223 (2016). https://doi.org/10.1007/s40259-016-0170-9
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DOI: https://doi.org/10.1007/s40259-016-0170-9