JAK2突变克隆的共存可能导致慢性髓性白血病患者对酪氨酸激酶抑制剂的血液学抗性

Carmen Fava , Giovanna Rege Cambrin , Dario Ferrero , Stefano Ulisciani , Anna Serra
{"title":"JAK2突变克隆的共存可能导致慢性髓性白血病患者对酪氨酸激酶抑制剂的血液学抗性","authors":"Carmen Fava ,&nbsp;Giovanna Rege Cambrin ,&nbsp;Dario Ferrero ,&nbsp;Stefano Ulisciani ,&nbsp;Anna Serra","doi":"10.3816/CLM.2009.n.102","DOIUrl":null,"url":null,"abstract":"<div><p>Coexistence of JAK2 mutation and BCR-ABL has been rarely described. We report 3 cases with the presence of 2 different clones, 1 Philadelphia chromosome positive and the other JAK2 mutated, becoming prevalent after treatment with tyrosine kinase inhibitors (TKIs). The presence of a JAK2-positive clone may cause hematologic resistance to TKIs.</p></div><div><h3>Full Abstract</h3><p></p></div><div><h3>Introduction</h3><p>In myeloproliferative neoplasms, coexistence of the JAK2 mutation and BCR-ABL rearrangement has been rarely described in patients. We report 3 such cases.</p></div><div><h3>Case 1</h3><p>Patient 1 was diagnosed as chronic myeloid leukemia (CML) following the discovery of thrombocytosis. She took imatinib with no platelet control, and hydroxyurea (HU) was added. She started nilotinib for leukocytosis, thrombocytosis, and 100% Philadelphia chromosome (Ph) positivity. In 6 months she obtained a complete cytogenetic response (CCyR), but the hematologic improvement was transient. We thus researched the JAK2 mutation that was positive. Interestingly, the JAK2<sup>V617F</sup> was present since nilotinib start, but its expression achieved the maximum with CCyR.</p></div><div><h3>Case 2</h3><p>Patient 2 was diagnosed as primary myelofibrosis with leukocytosis, thrombocytopenia, splenomegaly, and fibrosis in the bone marrow (BM). Karyotype was normal. After 2 years with no treatment, BM showed 15% myeloblasts with 100% Ph positivity. The patient started imatinib. After an initial improvement, a new increase of leukocytes and platelets followed, with normal karyotype. HU was added, but hematologic control remained unsatisfactory and imatinib was stopped. The patient stayed on CCyR with insufficient hematologic response for more than one year, until he developed a Ph-negative myeloblast crisis with homozygosis for JAK2<sup>V617F</sup>. We found that before imatinib the patient had a 50% JAK2-mutated phenotype, and after 3 months of therapy, more than 70%.</p></div><div><h3>Case 3</h3><p>Patient 3 was diagnosed as having essential thrombocytopenia with a normal karyotype. Good control of the thrombocytosis was obtained with HU, which continued for 10 years, and then the patient refused therapy for the next 3 years of stable disease, until he developed bone pain, leukocytosis, and enlarged spleen. Conventional cytogenetics was normal, but fluorescence in situ hybridization disclosed a 47% Ph positivity. The patient started imatinib with a rapid decrease of leukocytes; however, the platelets increased, and HU was added. After 3 months, the BM showed 7.4% Ph-positive cells. JAK2 was found mutated from imatinib start. This report suggests the presence of 2 different clones, one Ph-positive and the other JAK2 mutated and the prevalence of the latter when the former was inhibited by a tyrosine kinase inhibitor (TKI). The presence of a JAK2-positive clone may be a rare cause of hematologic resistance to TKIs.</p></div>","PeriodicalId":100272,"journal":{"name":"Clinical Lymphoma and Myeloma","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2009-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3816/CLM.2009.n.102","citationCount":"3","resultStr":"{\"title\":\"Coexistence of a JAK2 Mutated Clone May Cause Hematologic Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia\",\"authors\":\"Carmen Fava ,&nbsp;Giovanna Rege Cambrin ,&nbsp;Dario Ferrero ,&nbsp;Stefano Ulisciani ,&nbsp;Anna Serra\",\"doi\":\"10.3816/CLM.2009.n.102\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Coexistence of JAK2 mutation and BCR-ABL has been rarely described. We report 3 cases with the presence of 2 different clones, 1 Philadelphia chromosome positive and the other JAK2 mutated, becoming prevalent after treatment with tyrosine kinase inhibitors (TKIs). The presence of a JAK2-positive clone may cause hematologic resistance to TKIs.</p></div><div><h3>Full Abstract</h3><p></p></div><div><h3>Introduction</h3><p>In myeloproliferative neoplasms, coexistence of the JAK2 mutation and BCR-ABL rearrangement has been rarely described in patients. We report 3 such cases.</p></div><div><h3>Case 1</h3><p>Patient 1 was diagnosed as chronic myeloid leukemia (CML) following the discovery of thrombocytosis. She took imatinib with no platelet control, and hydroxyurea (HU) was added. She started nilotinib for leukocytosis, thrombocytosis, and 100% Philadelphia chromosome (Ph) positivity. In 6 months she obtained a complete cytogenetic response (CCyR), but the hematologic improvement was transient. We thus researched the JAK2 mutation that was positive. Interestingly, the JAK2<sup>V617F</sup> was present since nilotinib start, but its expression achieved the maximum with CCyR.</p></div><div><h3>Case 2</h3><p>Patient 2 was diagnosed as primary myelofibrosis with leukocytosis, thrombocytopenia, splenomegaly, and fibrosis in the bone marrow (BM). Karyotype was normal. After 2 years with no treatment, BM showed 15% myeloblasts with 100% Ph positivity. The patient started imatinib. After an initial improvement, a new increase of leukocytes and platelets followed, with normal karyotype. HU was added, but hematologic control remained unsatisfactory and imatinib was stopped. The patient stayed on CCyR with insufficient hematologic response for more than one year, until he developed a Ph-negative myeloblast crisis with homozygosis for JAK2<sup>V617F</sup>. We found that before imatinib the patient had a 50% JAK2-mutated phenotype, and after 3 months of therapy, more than 70%.</p></div><div><h3>Case 3</h3><p>Patient 3 was diagnosed as having essential thrombocytopenia with a normal karyotype. Good control of the thrombocytosis was obtained with HU, which continued for 10 years, and then the patient refused therapy for the next 3 years of stable disease, until he developed bone pain, leukocytosis, and enlarged spleen. Conventional cytogenetics was normal, but fluorescence in situ hybridization disclosed a 47% Ph positivity. The patient started imatinib with a rapid decrease of leukocytes; however, the platelets increased, and HU was added. After 3 months, the BM showed 7.4% Ph-positive cells. JAK2 was found mutated from imatinib start. This report suggests the presence of 2 different clones, one Ph-positive and the other JAK2 mutated and the prevalence of the latter when the former was inhibited by a tyrosine kinase inhibitor (TKI). The presence of a JAK2-positive clone may be a rare cause of hematologic resistance to TKIs.</p></div>\",\"PeriodicalId\":100272,\"journal\":{\"name\":\"Clinical Lymphoma and Myeloma\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2009-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.3816/CLM.2009.n.102\",\"citationCount\":\"3\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Lymphoma and Myeloma\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1557919011700531\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Lymphoma and Myeloma","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1557919011700531","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 3

摘要

JAK2突变与BCR-ABL共存的报道很少。我们报告了3例存在2个不同克隆的病例,1个费城染色体阳性,另一个JAK2突变,在使用酪氨酸激酶抑制剂(TKIs)治疗后变得普遍。jak2阳性克隆的存在可能导致对TKIs的血液学抗性。摘要在骨髓增殖性肿瘤中,JAK2突变和BCR-ABL重排的共存在患者中很少被描述。我们报告了3个这样的案例。病例1患者1在发现血小板增多后被诊断为慢性髓性白血病(CML)。患者在不控制血小板的情况下服用伊马替尼,并添加羟基脲(HU)。她开始服用尼罗替尼治疗白细胞增多、血小板增多和100%费城染色体(Ph)阳性。6个月后,她获得了完全的细胞遗传学缓解(CCyR),但血液学改善是短暂的。因此,我们研究了阳性的JAK2突变。有趣的是,JAK2V617F在尼罗替尼开始时就存在,但其表达在CCyR时达到最大值。病例2患者2被诊断为原发性骨髓纤维化伴白细胞增多、血小板减少、脾肿大和骨髓纤维化(BM)。核型正常。未经治疗2年后,BM显示成髓细胞15%,Ph值100%阳性。病人开始服用伊马替尼。在最初的改善之后,白细胞和血小板又增加了,核型正常。加入HU,但血液学控制仍不理想,停用伊马替尼。患者在血液学反应不足的情况下接受CCyR治疗超过一年,直到出现ph阴性的成髓细胞危像,伴有JAK2V617F纯合子。我们发现,在伊马替尼治疗前,患者有50%的jak2突变表型,治疗3个月后,超过70%。病例3患者3被诊断为原发性血小板减少症,核型正常。使用HU治疗后,血小板增多得到了很好的控制,这种情况持续了10年,随后患者拒绝治疗3年,病情稳定,直到出现骨痛、白细胞增多和脾脏肿大。常规细胞遗传学正常,但荧光原位杂交显示47%的Ph阳性。患者开始使用伊马替尼时白细胞迅速减少;然而,血小板增加,HU增加。3个月后,BM的ph值为7.4%。JAK2从伊马替尼开始发生突变。该报告表明存在2个不同的克隆,一个ph阳性,另一个JAK2突变,当前者被酪氨酸激酶抑制剂(TKI)抑制时,后者的患病率。jak2阳性克隆的存在可能是TKIs血液学耐药的罕见原因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Coexistence of a JAK2 Mutated Clone May Cause Hematologic Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Coexistence of JAK2 mutation and BCR-ABL has been rarely described. We report 3 cases with the presence of 2 different clones, 1 Philadelphia chromosome positive and the other JAK2 mutated, becoming prevalent after treatment with tyrosine kinase inhibitors (TKIs). The presence of a JAK2-positive clone may cause hematologic resistance to TKIs.

Full Abstract

Introduction

In myeloproliferative neoplasms, coexistence of the JAK2 mutation and BCR-ABL rearrangement has been rarely described in patients. We report 3 such cases.

Case 1

Patient 1 was diagnosed as chronic myeloid leukemia (CML) following the discovery of thrombocytosis. She took imatinib with no platelet control, and hydroxyurea (HU) was added. She started nilotinib for leukocytosis, thrombocytosis, and 100% Philadelphia chromosome (Ph) positivity. In 6 months she obtained a complete cytogenetic response (CCyR), but the hematologic improvement was transient. We thus researched the JAK2 mutation that was positive. Interestingly, the JAK2V617F was present since nilotinib start, but its expression achieved the maximum with CCyR.

Case 2

Patient 2 was diagnosed as primary myelofibrosis with leukocytosis, thrombocytopenia, splenomegaly, and fibrosis in the bone marrow (BM). Karyotype was normal. After 2 years with no treatment, BM showed 15% myeloblasts with 100% Ph positivity. The patient started imatinib. After an initial improvement, a new increase of leukocytes and platelets followed, with normal karyotype. HU was added, but hematologic control remained unsatisfactory and imatinib was stopped. The patient stayed on CCyR with insufficient hematologic response for more than one year, until he developed a Ph-negative myeloblast crisis with homozygosis for JAK2V617F. We found that before imatinib the patient had a 50% JAK2-mutated phenotype, and after 3 months of therapy, more than 70%.

Case 3

Patient 3 was diagnosed as having essential thrombocytopenia with a normal karyotype. Good control of the thrombocytosis was obtained with HU, which continued for 10 years, and then the patient refused therapy for the next 3 years of stable disease, until he developed bone pain, leukocytosis, and enlarged spleen. Conventional cytogenetics was normal, but fluorescence in situ hybridization disclosed a 47% Ph positivity. The patient started imatinib with a rapid decrease of leukocytes; however, the platelets increased, and HU was added. After 3 months, the BM showed 7.4% Ph-positive cells. JAK2 was found mutated from imatinib start. This report suggests the presence of 2 different clones, one Ph-positive and the other JAK2 mutated and the prevalence of the latter when the former was inhibited by a tyrosine kinase inhibitor (TKI). The presence of a JAK2-positive clone may be a rare cause of hematologic resistance to TKIs.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信