国产甲磺酸伊马替尼治疗儿童慢性髓系白血病慢性期的早期疗效和安全性分析
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摘要
目的评价国产甲磺酸伊马替尼(商品名昕维)治疗新诊断儿童慢性髓系白血病慢性期(chronic phase of chronic myeloid leukemia,CP-CML)的早期血液学、细胞遗传学、分子学反应和安全性。方法收集35例从2014年1月至2018年1月在首都医科大学附属北京儿童医院初次确诊CP-CML的患儿,给予甲磺酸伊马替尼260～340 mg/m2,1次/d治疗,根据药物种类分为国产仿制药(昕维)组和进口原研药(格列卫)两组,国产仿制药(昕维)治疗组20例,原研药(格列卫)治疗组15例,随访至2018年5月。对比进口原研药,评价国产仿制药治疗CML患者3、6、12个月时的血液学、细胞遗传学和分子学反应及安全性。结果 35例初诊CP-CML患儿中位年龄10岁(1～16岁),其中男性18名,女性17名。治疗3个月时,国产仿制药组患儿完全血液学反应(complete hematologic responses,CHR)率为75%(15/20); 80%(16/20)获得主要细胞遗传学反应(minor cytogenetic response,MCyR),45%(9/20) BCR-ABL转录本水平≤10%。治疗6个月时,CHR率为94%(15/16);完全细胞遗传学反应(complete cytogenetic response,CCyR)为62. 5%(10/16); 43. 8%(7/16) BCR-ABL≤1%。治疗12个月时,CCyR为92. 3%(12/13); 77%(10/13) BCR-ABL≤0. 1%,对比进口原研药,差异无统计学意义(P> 0. 05)。15%(3/20)不良反应为血液学不良反应,无严重Ⅳ级不良反应;非血液学不良反应依次为疼痛35%(7/20),消化道症状25%(5/20),水肿15%(3/20),不明原因发热10%(2/20),乏力5%(1/20),皮疹5%(1/20)。治疗3个月,国产仿制药CCyR略低于原研药(P=0. 021),差异无统计学意义(P> 0. 05)。不良反应易控制,无药物毒性相关性死亡。结论国产甲磺酸伊马替尼初始治疗新诊断儿童CP-CML的早期血液学、细胞遗传学和分子学反应良好,安全可靠,本研究尚未发现国产仿制药与原研药在疗效和安全性上有明显差别。
Objective To evaluate the hematological,cytogenetic,molecular responses and safety of generic imatinib( Xinwei) in newly diagnosed patients with children of chronic phase of chronic myeloid leukemia( CP-CML). Methods Thirty-five CP-CML children patients diagnosed in Beijing Children's Hospital,Capital Medical University received oral imatinib 260-340 mg/m2,with domestic generic imatinib( Xinwei) and imported original imatinib( Gleevec),who were collected from Jan 2014 to Jan 2018 and followed up to May 2018.Compared with imported original imatinib( Gleevec) among which 20 cases were treacted with the domestic genenc imatinib( Xinwei) and15 cases were treated with the imported original imatinib( Gleevec),hematological responses,cytogenetic examinations,BCR-ABL transcript levels,and the safety with domestic generic imatinib treatment were monitored after 3,6,and 12 month treatment. Results A total of 35 children CP-CML patients( 18 males and 17 females with a median age of 10 years) were collected among which 20 cases were treated with the domestic generic imatinib( Xinwei),and 15 cases were treated with the imported original imatinib( Gleevec). At 3-month,the domestic generic imatinib group 75 %( 15/20) patients achieved the complete hematologic responses( CHR),and patients with minor cytogenetic response( MCyR) or BCR-ABL ≤10% were 80%( 16/20) and 45%( 9/20),respectively. At 6-month,94%( 15/16) patients achieved CHR,patients with complete cytogenetic response( CCyR) and BCR-ABL ≤1 % was 62. 5%( 10/16) and 43. 8%( 7/16). At 12-month,92. 3%( 12/13) CCyR and 77%( 10/13) BCR-ABL ≤0. 1 %. There was no significant difference between two group at all stages( P> 0. 05). The hematologic toxicity occurred in 15%( 3/20),with no grade Ⅲ hematologic toxicity. The non-hematologic toxicities included pain 35%( 7/20),gastrointestinal reaction 25%( 5/20),edema 15%( 3/20),fever 10%( 2/20),fatigue 5%( 1/20),and rash 5%( 1/20). Compared with imported original imatinib,CCyR was lower in generic imatinib group at 3-month( P = 0. 021). There was no other significant difference( P > 0. 05). The adverse reactions were easy to control and there were no drug-related deaths. Conclusion Generic imatinib has a good efficacy in the hematological,cytogenetic molecular reponses with CP-CMP patients in newly diagnosed,without serious adverse reactions. There is no significant difference in efficacy and safety between generic and imported original imatinib in our study.
Objective To evaluate the hematological,cytogenetic,molecular responses and safety of generic imatinib( Xinwei) in newly diagnosed patients with children of chronic phase of chronic myeloid leukemia( CP-CML). Methods Thirty-five CP-CML children patients diagnosed in Beijing Children's Hospital,Capital Medical University received oral imatinib 260-340 mg/m2,with domestic generic imatinib( Xinwei) and imported original imatinib( Gleevec),who were collected from Jan 2014 to Jan 2018 and followed up to May 2018.Compared with imported original imatinib( Gleevec) among which 20 cases were treacted with the domestic genenc imatinib( Xinwei) and15 cases were treated with the imported original imatinib( Gleevec),hematological responses,cytogenetic examinations,BCR-ABL transcript levels,and the safety with domestic generic imatinib treatment were monitored after 3,6,and 12 month treatment. Results A total of 35 children CP-CML patients( 18 males and 17 females with a median age of 10 years) were collected among which 20 cases were treated with the domestic generic imatinib( Xinwei),and 15 cases were treated with the imported original imatinib( Gleevec). At 3-month,the domestic generic imatinib group 75 %( 15/20) patients achieved the complete hematologic responses( CHR),and patients with minor cytogenetic response( MCyR) or BCR-ABL ≤10% were 80%( 16/20) and 45%( 9/20),respectively. At 6-month,94%( 15/16) patients achieved CHR,patients with complete cytogenetic response( CCyR) and BCR-ABL ≤1 % was 62. 5%( 10/16) and 43. 8%( 7/16). At 12-month,92. 3%( 12/13) CCyR and 77%( 10/13) BCR-ABL ≤0. 1 %. There was no significant difference between two group at all stages( P> 0. 05). The hematologic toxicity occurred in 15%( 3/20),with no grade Ⅲ hematologic toxicity. The non-hematologic toxicities included pain 35%( 7/20),gastrointestinal reaction 25%( 5/20),edema 15%( 3/20),fever 10%( 2/20),fatigue 5%( 1/20),and rash 5%( 1/20). Compared with imported original imatinib,CCyR was lower in generic imatinib group at 3-month( P = 0. 021). There was no other significant difference( P > 0. 05). The adverse reactions were easy to control and there were no drug-related deaths. Conclusion Generic imatinib has a good efficacy in the hematological,cytogenetic molecular reponses with CP-CMP patients in newly diagnosed,without serious adverse reactions. There is no significant difference in efficacy and safety between generic and imported original imatinib in our study.
引文
[1]中华医学会血液学分会.中国慢性髓性白血病诊断与治疗指南(2016年版)[J].中华血液学杂志,2016,37(8):633-639.
[2] Baccarani M,Deininger M W,Rosti G,et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia[J]. Blood,2013,122(6):872-884.
[3] Pallera A,Altman J K,Berman E,et al. NCCN guidelines insights:chronic myeloid leukemia,version 1. 2017[J]. J Natl Compr Canc Netw,2016,14(12):1505-1512.
[4] Mauro M J. Goals for chronic myeloid leukemia TK inhibitor treatment:how little disease is too much?[J]. Hematology Am Soc Hematol Educ Program,2014(1):234-249.
[5] Kalmanti L,Saussele S,Lauseker M,et al. Safety and efficacy of imatinib in CM L over a period of 10 years:data from the randomized CM L-study IV[J]. Leukemia,2015,29(5):1123-1132.
[6] NCI,NIH,DHHS. Cancer Therapy Evaluation Program,Common Terminology Criteria for Adverse Events[EB/OL].(2006-08-31)[2018-10-01]http://ctep.cancer. gov.
[7] Saikia T. The cure of chronic myeloid leukemia:are we there yet?[J]. Curr Oncol Rep,2018,20(2):12.
[8] Horibe K,Tsukimoto I,Ohno R. Clinicopathologic characteristics of leukemia in Japanese children and young adults[J]. Leukemia,2001,15(8):1256-1261.
[9] Chen Y,Wang H,Kantarjian H,et al. Trends in chronic myeloid leukemia incidence and survival in the united states from 1975 to 2009[J]. Leuk Lymphoma,2013,54(7):1411-1417.
[10] Millot F,Baruchel A,Guilhot J,et al. Imatinib is effective inchildren w ith previously untreated chronic myelogenous leukemiain early chronic phase:Results of the French national phase IV trial[J]. J Clin Oncol,2011,29(20):2827-2832.
[11] Suttorp M,Schulze P,Glauche I,et al. Front-line imatinib treatment in children and adolescents w ith chronic myeloid leukemia:results from a phaseⅢtrial[J]. Leukemia,2018,32(7):1657-1669.
[12]江倩,赵东陆,金洁,等.国产甲磺酸伊马替尼治疗慢性髓性白血病慢性期早期疗效和安全性的前瞻性、多中心临床研究[J].中华血液学杂志,2015,36(8):651-655.
[13] Millot F,Baruehel A,Guilhot J,et al. Imatinibis effective inchildren w ith reviously untreated chronic myelogenous leukemia in early chronic phase:results of the French National Phase IV Trial[J]. J Clin Oncol,2011,29(20):2827-2832.
[14] Jaeger B A,Tauer J T,Ulmer A,et al. Changes in bone metabolic parameters in children w ith chronic myeloid leukemia on imatinib treatment[J]. M ed Sci M onit,2012,18(12):CR721-8.
[15] Millot F,Guilhot J,Baruchel A,et al. Growth deceleration inchildren treated w ith imatinib for chronic myeloid leukaemia[J]. Eur J Cancer,2014,50(18):3206-3211.
[16] Narayanan K R,Bansal D,Walia R,et al. Growth failure in children w ith chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis[J]. Pediatr Blood Cancer,2013,60(7):1148-1153.
[17] Choeyprasert W,Yansomdet W,Natesirinilkul T,et al.Adverse effects of imatinib in children with chronic myelogenous leukemia[J]. Pediatr Int,2017,59(3):286-292.
[2] Baccarani M,Deininger M W,Rosti G,et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia[J]. Blood,2013,122(6):872-884.
[3] Pallera A,Altman J K,Berman E,et al. NCCN guidelines insights:chronic myeloid leukemia,version 1. 2017[J]. J Natl Compr Canc Netw,2016,14(12):1505-1512.
[4] Mauro M J. Goals for chronic myeloid leukemia TK inhibitor treatment:how little disease is too much?[J]. Hematology Am Soc Hematol Educ Program,2014(1):234-249.
[5] Kalmanti L,Saussele S,Lauseker M,et al. Safety and efficacy of imatinib in CM L over a period of 10 years:data from the randomized CM L-study IV[J]. Leukemia,2015,29(5):1123-1132.
[6] NCI,NIH,DHHS. Cancer Therapy Evaluation Program,Common Terminology Criteria for Adverse Events[EB/OL].(2006-08-31)[2018-10-01]http://ctep.cancer. gov.
[7] Saikia T. The cure of chronic myeloid leukemia:are we there yet?[J]. Curr Oncol Rep,2018,20(2):12.
[8] Horibe K,Tsukimoto I,Ohno R. Clinicopathologic characteristics of leukemia in Japanese children and young adults[J]. Leukemia,2001,15(8):1256-1261.
[9] Chen Y,Wang H,Kantarjian H,et al. Trends in chronic myeloid leukemia incidence and survival in the united states from 1975 to 2009[J]. Leuk Lymphoma,2013,54(7):1411-1417.
[10] Millot F,Baruchel A,Guilhot J,et al. Imatinib is effective inchildren w ith previously untreated chronic myelogenous leukemiain early chronic phase:Results of the French national phase IV trial[J]. J Clin Oncol,2011,29(20):2827-2832.
[11] Suttorp M,Schulze P,Glauche I,et al. Front-line imatinib treatment in children and adolescents w ith chronic myeloid leukemia:results from a phaseⅢtrial[J]. Leukemia,2018,32(7):1657-1669.
[12]江倩,赵东陆,金洁,等.国产甲磺酸伊马替尼治疗慢性髓性白血病慢性期早期疗效和安全性的前瞻性、多中心临床研究[J].中华血液学杂志,2015,36(8):651-655.
[13] Millot F,Baruehel A,Guilhot J,et al. Imatinibis effective inchildren w ith reviously untreated chronic myelogenous leukemia in early chronic phase:results of the French National Phase IV Trial[J]. J Clin Oncol,2011,29(20):2827-2832.
[14] Jaeger B A,Tauer J T,Ulmer A,et al. Changes in bone metabolic parameters in children w ith chronic myeloid leukemia on imatinib treatment[J]. M ed Sci M onit,2012,18(12):CR721-8.
[15] Millot F,Guilhot J,Baruchel A,et al. Growth deceleration inchildren treated w ith imatinib for chronic myeloid leukaemia[J]. Eur J Cancer,2014,50(18):3206-3211.
[16] Narayanan K R,Bansal D,Walia R,et al. Growth failure in children w ith chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis[J]. Pediatr Blood Cancer,2013,60(7):1148-1153.
[17] Choeyprasert W,Yansomdet W,Natesirinilkul T,et al.Adverse effects of imatinib in children with chronic myelogenous leukemia[J]. Pediatr Int,2017,59(3):286-292.