Anagrelide and Mutational Status in Essential Thrombocythemia

• Published in: BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy biopharmaceuticals, and gene therapy, 2016-06, Vol.30 (3), p.219-223
• Main Authors: Iurlo, Alessandra, Cattaneo, Daniele, Orofino, Nicola, Bucelli, Cristina, Fabris, Sonia, Cortelezzi, Agostino
• Format: Article
• Language: English
• Subjects: Adult; Antibodies; Biomedical and Life Sciences; Biomedicine; Bone marrow; Calreticulin - genetics; Cancer Research; Conflicts of interest; Ethics; Female; Funding; Hematology; Humans; Janus Kinase 2 - genetics; Laboratories; Male; Middle Aged; Molecular Medicine; Mutation; Pharmacotherapy; Platelet Aggregation Inhibitors - therapeutic use; Quinazolines - therapeutic use; Receptors, Thrombopoietin - genetics; Response rates; Retrospective Studies; Short Communication; Thrombocythemia, Essential - drug therapy; Thrombocythemia, Essential - genetics; Treatment Outcome
• ISSN: 1173-8804; 1179-190X
• DOI: 10.1007/s40259-016-0170-9

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 JAK2 V617F 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.