Comparison of Clinical Data and Treatment Responses of Patients with Essential Thrombocythemia Using Anagrelide by JAK2 Gene Mutation Status

Abstract

Introduction: Essential Thrombocytemia (ET) is a clonal stem cell disease that manifests itself with proliferation in the megakaryocytic lineage in the bone marrow, with clinical presentations ranging from asymptomatic to bleeding and thrombosis spectrum. In medical treatment, aspirin and/or monitoring are recommended for low-risk patients, while cytoreductive therapy is recommended for high-risk patients. Cytoreductive therapy is often used in patients with a very high platelet count (>1,000,000). The first choice in cytoreductive treatment is Hydroxyurea, and Anagrelid treatment is preferred in the young patient group and patients with hydroxyurea resistance/intolerance. This study aimed to evaluate the effects of the JAK2 mutation, which is associated with high risk, in the patient group receiving anagrelide therapy. Method: The files of patients diagnosed with ET according to 2016 WHO criteria and followed up under Anagrelide therapy in our center between January 2002 and December 2021 were reviewed retrospectively. In addition to the demographic data of the patients, diagnostic tests, bone marrow evaluations, JAK2 mutation status, and laboratory data were noted. Patients were divided into two groups according to JAK2 mutation positivity and negativity. The obtained data were compared between the two groups. Results: Thirty-three patients (male/female: 20/13) treated with Anagrelide for the diagnosis of ET were included in the study. It was observed that 14 (42%) of the patients were positive for JAK2 mutation. There was no significant difference between the groups regarding age at diagnosis, gender, duration of anagrelide use, and bone marrow fibrosis degrees. When the laboratory tests were compared at the time of diagnosis, the WBC count was significantly higher in the JAK2 positive group; other series were similar. When the last control laboratory data of the patients were compared, WBC, neutrophil, and hemoglobin levels were observed to be significantly higher in JAK2 positive patients, while LDH levels were significantly lower. Conclusion: It was observed that JAK2 mutation positivity, which is associated with high risk in ET risk staging, did not negatively affect anagrelide treatment response. In ET patients, leukocytosis (>11,000/mm3) has been identified as a risk factor for the whole lifespan. It was observed that the WBC counts of the patients who were positive for JAK2 were significantly higher at the time of diagnosis and during the treatment process. Since the LDH level after treatment is higher in patients with positive JAK2 mutation, it has been evaluated that JAK2 mutation may play a role in resistance to cytoreductive therapy.

Keywords

• Anagrelide
• JAK2
• essential thrombocytemia

References

1. Cross NC. Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2011;2011:208-14. doi: 10.1182/ asheducation-2011.1.208.
2. Oh ST, Gotlib J. JAK2 V617F and beyond: role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms. Expert Rev Hematol. 2010 Jun;3(3):323-37. doi: 10.1586/ehm.10.28.
3. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, Futreal PA, Erber WN, McMullin MF, Harrison CN, Warren AJ, Gilliland DG, Lodish HF, Green AR. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med. 2007 Feb 1;356(5):459-68. doi: 10.1056/NEJMoa065202.
4. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391- 405. Blood. 2016 Jul 21;128(3):462-3. doi: 10.1182/ blood-2016-06-721662.
5. Guglielmelli P, Vannucchi AM. Current management strategies for polycythemia vera and essential thrombocythemia. Blood Rev. 2020 Jul;42:100714. doi: 10.1016/j.blre.2020.100714.
6. Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, Them NC, Berg T, Elena C, Casetti IC, Milanesi C, Sant’antonio E, Bellini M, Fugazza E, Renna MC, Boveri E, Astori C, Pascutto C, Kralovics R, Cazzola M; Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014 Mar 6;123(10):1544-51. doi: 10.1182/blood-2013-11-539098.
7. Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, Dupriez B, Levine RL, Passamonti F, Gotlib J, Reilly JT, Vannucchi AM, Hanson CA, Solberg LA, Orazi A, Tefferi A; International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008 Feb;22(2):437-8. doi: 10.1038/sj.leu.2404914.
8. Dusa A, Staerk J, Elliott J, Pecquet C, Poirel HA, Johnston JA, Constantinescu SN. Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2. J Biol Chem. 2008 May 9;283(19):12941-8. doi: 10.1074/jbc.M709302200.