尼洛替尼治疗伊马替尼耐药的慢性髓系白血病临床分析

许家健; 杜新; 楼瑾; 蔡云; 黄瑞宏; 李明; 卓家才

尼洛替尼治疗伊马替尼耐药的慢性髓系白血病临床分析

- 深圳市第二人民医院深圳市血液病研究所(广东深圳, 518035)

详细信息

通讯作者: 杜新,E-mail:duxingz@medmail.com.cn

中图分类号: R733.72

收稿日期: 2012-09-29

Efficacy and safety of nilotinib on imatinib-resistant chronic myeloid leukemia

- Institute of Hematology, the Second People's Hospital of Shenzhen, Shenzhen, 518035, China

More Information

Corresponding author: DU Xin, E-mail: duxingz@medmail.com.cn

Received Date: 29 September 2012

摘要

摘要: 目的：探讨尼洛替尼治疗伊马替尼耐药的慢性髓系白血病（CML）的疗效及安全性。方法：收集伊马替尼治疗失败而接受尼洛替尼治疗的10例患者，其中慢性期7例，加速期2例，急变期1例。接受伊马替尼治疗的平均时间为36.7个月，停用原因为丧失疗效或未达主要分子学反应（MMR）7例、进展至加速期或急变期2例、原发性耐药1例。4例患者检测出5个点突变，其中1例慢性期患者检出2个突变点。10例患者接受尼洛替尼的剂量均为400 mg q12 h，每个月复查血常规，每3个月监测细胞遗传学及分子生物学缓解情况（FISH及RQ-PCR法），定期监测肝肾功能、胰酶、电解质及心电图等，并记录有无皮疹、头痛等不良反应。结果：10例患者接受尼洛替尼治疗的平均时间为12.5（3~30）个月。8例获得主要遗传学反应以上疗效，其中5例获得完全细胞遗传学反应，3例获得MMR。2例加速期患者中，1例恢复至慢性期并持续获得MMR，1例死亡。1例急单变患者（Ph⁺伴附加染色体异常）获部分细胞遗传学反应后丧失疗效，最终死亡。不良反应依次为轻度皮疹6例、胆红素升高3例、转氨酶升高2例、头痛1例、血糖升高1例及3/4级血液学不良反应1例。结论：尼洛替尼结合ABL激酶的效价更高，选择性更强，能抑制除T315I、Y253H、F359V/C及E255K/V以外的致伊马替尼耐药的点突变，且不良反应少，可用于伊马替尼耐药及不耐受的慢性期或加速期CML。
- 慢性髓系白血病 /
- 伊马替尼 /
- 耐药 /
- 尼洛替尼 /
- 疗效 /
- 安全性
Abstract: Objective: To evaluate the efficacy and safety of nilotinib on imatinib-resistant chronic myeloid leukemia (CML).Method: Ten CML patients resistant to imatinib changed to nilotinib therapy because of response lost or without MMR (7 cases),progressed to accelerated phase or blast phase (2 cases),primary resistance (1 case).Five BCR-ABL point mutations were detected in four patients.Two mutations were found in one patient with chronic phase.All of 10 patients were treated with nilotinib 400 mg q12 h.Regular physical examinations,analyses of blood,bone marrow or ECG were taken to observe the tolerance,the hematology,genetics and molecular responses.Result: After the follow-up of 12.5 months,8 cases achieved MCyR including 5 cases achieved CCyR and 3 cases achieved MMR.One of 2 CML-accelerated phase patients returned to the chronic phase and achieved MMR,while the other one died.The CML-blastic phase patient with ACAs lost PCyR and died.The adverse events included rash (6 cases),hyperbilirubinemia (3 cases),ALT elevation (2 cases),headache (1 case),hyperglycemia (1 case),and grade 3/4 hematologic adverse event (1 case).Conclusion: Nilotinib is effective and well tolerated for the CML patients who failed imatinib therapy.
- chronic myeloid leukemia /
- imatinib /
- resistance /
- nilotinib /
- efficacy /
- safety

HTML全文

参考文献(15)

[1]	HUGHES T P,HOCHHAUS A,BRANFORD S,et al.Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia:an analysis from the International Randomized Study of Interferon and STI571(IRIS)[J].Blood,2010,116:3758-3765.
[2]	RJIAN H,O'BRIEN S,TALPAZ M,et al.Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure[J].Cancer,2007,109:1556-1560.
[3]	KANTARJIAN H M,GILES F J,BHALLA K N,et al.Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance:24-month follow-up results[J].Blood,2011,117:1141-1145.
[4]	LE COUTRE P D,GILES F J,HOCHHAUS A,et al.Nilotinib in patients with Ph+ chronic myeloid leukemia in accelerated phase following imatinib resistance or intolerance:24-month follow-up results[J].Leukemia,2012,26:1189-1194.
[5]	GILES F J,KANTARJIAN H M,LE COUTRE P D,et al.Nilotinib is effective in imatinib-resistant or-intolerant patients with chronic myeloid leukemia in blastic phase[J].Leukemia,2012,26:959-962.
[6]	HUGHES T,SAGLIO G,BRANFORD S,et al.Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase[J].J Clin Oncol,2009,27:4204-410.
[7]	O'HARE T,EIDE C A,DEININGER M W.BCR-Abl kinase domain mutations,drug resistance,and the road to a cure for chronic myeloid leukemia[J].Blood,2007,110:2242-2249.
[8]	REDAELLI S,PIAZZA R,ROSTAGNO R,et al.Activity of bosutinib,dasatinib,and nilotinib against 18 imatinib-resistant BCR/ABL mutants[J].J Clin Oncol,2009,27:469-471.
[9]	CORTES J,JABBOUR E,KANTARJIAN H,et al.Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors[J].Blood,2007,110:4005-4011.
[10]	JABBOUR E,KANTARJIAN H,JONES D,et al.Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy[J].Blood,2008,112:53-55.
[11]	BRANFORD S,MELO J V,HUGHES T P.Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure:does the BCR-ABL mutation status really matter[J]?Blood,2009,114:5426-5435.
[12]	KIM T D,TVRKMEN S,SCHWARZ M,et al.Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia[J].Haematologica,2010,95:582-588.
[13]	CORTES J E,HOCHHAUS A,LE COUTRE P D,et al.Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib[J].Blood,2011,117:5600-5606.
[14]	KOREN-MICHOWITZ M,LE COUTRE P,DUYSTER J,et al.Activity and tolerability of nilotinib:a retrospective multicenter analysis of chronic myeloid leukemia patients who are imatinib resistant or intolerant[J].Cancer,2010,116:4564-4572.
[15]	NICOLINI F E,TURKINA A,SHEN Z X,et al.Expanding Nilotinib Access in Clinical Trials (ENACT):an open-label,multicenter study of oral nilotinib in adult patients with imatinib-resistant or imatinib-intolerant Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase[J].Cancer,2012,118:118-126.