| Objective: To investigate the efficacy and adverse events of second-generation tyrosine kinase inhibitors(TKIs)(nilotinib and dasatinib) in the treatment of chronic myelogenous leukemia(CML).Methods: The clinical datas of 155 CML patients receiving second-generation TKIs in the Institute of Hematology, Fujian Medical University Union Hospital from January2006 to December 2014 were analyzed retrospectively. 105 patients received nilotinib300 mg twice daily or 400 mg twice daily, 50 patients received dasatinib 100 mg once daily for patients in chronic phase(CP) or 70 mg twice daily for patients in accelerated phase or blast phase(AP/BP). Among 105 patients of nilotinib group, 9 patients treated with nilotinib as first-line therapy, 96 patients treated with nilotinib as second-line therapy. Among 96 patients treated with nilotinib as second-line therapy, 93 patients treated with imatinib(IM). And 88 patients resistant to IM, 5 patients intolerant to IM, 3patients remaining treated without IM. Among 50 patients of dasatinib group, 6 patients treated with dasatinib as first-line therapy, 44 patients treated with dasatinib as second-line therapy. Among 44 patients treated with dasatinib as second-line therapy,34 patients treated with IM, and all of them resistant to IM, 10 patients remaining treated without IM. The hematologic, cytogenetic, molecular biology response, overall survival(OS) and adverse effects(AE) of two TKIs were assessed.Results: 1. 105 patients received nilotinib treatment, 82 patients in CP, 15 patients in AP, 8 patients in BP. The median treatment time of nilotinib were 12.0(3.0-89.0), 20.0(4.0-63.0) and 5.5(4.0-22.0) months, respectively. Among 82 patients in CP, 98.7%(75/76) achieved complete hematologic response(CHR), and 53.8%(28/52) patients achieved major molecular response(MMR), 19.2% achieved complete molecular response(CMR) after 3 months. Major cytogenetic response(MCy R),complete cytogenetic response(CCy R), MMR, CMR were achieved by 81.3%(13/16), 81.3%(13/16), 60.9%(28/46) and 21.7%(10/46) after 6 months, respectively. CCy R, MMR and CMR were achieved by 66.7%(8/12), 68.6%(24/35) and 42.3%(15/35) after 12 months, respectively. For 15 patients in AP, 93.3%(14/15) patients achieved CHR. The median time to achieving CHR was 3.0 months and none ot them achieved cytogenetic response(Cy R). 18.2(2/11) achieved MMR, and only one achieved CMR till to last follow-up. 20.0%(3/15) patients in AP progressed. For 8 patients in BP, only62.5%(5/8) patients achieved CHR and none of them achieved Cy R. Death or disease progression happened in 62.5%(5/8) patients in BP. The median OS for the BP patients were 10.0 months. 2-year OS of patients in CP, AP and BP were 90.2%, 66.7% and 0,respectively. 3-year OS of patients in CP, AP and BP were 80.5%, 60.0% and 0,respectively. The OS was higher in patients with AP/BP than in patients with CP. 105 patients of nilotinib group, 9 patients treated with nilotinib as first-line therapy, CHR,MMR and CMR were achieved by 100.0%(9/9), 100.0%(8/8) and 100.0%(8/8),respectively. 96 patients treated with nilotinib as second-line therapy, CHR, MMR and CMR were achieved by 92.7%(89/96), 56.8%(50/88) and 36.8%(32/87), respectively.The first-line therapy and the second-line therapy of nilotinib reported similar rates of CHR. The first-line therapy and the second-line therapy of nilotinib showed a significantly higher rates of MMR and CMR. 93 patients treated with imatinib(IM), 88 patients resistant to IM and 5 patients intolerant to IM showed similar rates of CHR,MMR and CMR. Hematologic AE related to nilotinib were unsevere. 105 patients of nilotinib, 9.5% patients experienced grade 1~2 hematologic AE, 20.0% patients experienced grade 3~4 hematologic AE, 8.6% patients experienced grade 3~4 of neutropenia, 7.9% patients had grade 3~4 anemia, and 16.2% patients experienced grade 3~4 of thrombocytopenia. The frequency of hematologic AE was higher in patients with AP/BP than in patients with CP. The hematologic AE could be managed by dose interruption or supportive care. Only one patient died because of serious bone marrow suppression, one patient stoped nilotinib because of grade 3 of neutropenia and grade 4 of thrombocytopenia. The common non-hematologic AE related to nilotinib were grade 1~2 abnormal liver function(11.2%-18.1%), weakness(17.1%), edema(6.7%), diarrhea(8.7%) and so on. And the frequency of non-hematologic AE was higher in patients with AP/BP than in patients with CP. 2. 50 patients received dasatinib treatment, 17 patients in CP, 6 patients in AP, 27 patients in BP. The median treatment time of dasatinib were 24.0(4.0-79.0), 16.5(3.0-36.0) and 3.0(1.0-28.0) months, respectively. 17 patients in CP, CHR were achieved by 88.2%(15/17) after 3 months,50.0%(3/6) patients achieved CCy R after 6 months. For 6 patients in AP, 83.3%(5/6)patients achieved CHR after 3 months and none of them achieved Cy R. 25.0%(1/4)achievde CMR. Only one patient in AP died. For 27 patients in BP, CHR was 37.0%(10/27), and 47.1%(8/17) achieved CHR in 3 months. 24 patients in BP died due to disease progress. The median OS for the patients were 3.0 months. 2-year OS of patients in CP, AP and BP were 52.9%, 33.3% and 3.7%, respectively. 3-year OS of patients in CP, AP and BP were 47.0%, 16.7% and 0, respectively. The OS was higher in patients with AP/BP than in patients with CP. 50 patients of dasatinib group, 6patients treated with dasatinib as first-line therapy, CHR, MMR and CMR were achieved by 100.0%(5/5), 100.0%(4/5) and 100.0%(4/5), respectively. 44 patients treated with dasatinib as second-line therapy, CHR, MMR and CMR were achieved by54.5%(24/44), 22.2%(8/36) and 16.7%(6/36), respectively. The first-line therapy and the second-line therapy of dasatinib showed similar rates of CHR. The first-line therapy and the second-line therapy of dasatinib showed a significantly higher rates of MMR and CMR. Hematologic AE related to dasatinib were unsevere. Among 50 patients of dasatinib group, 8.0% experienced grade 1~2 of hematologic AE. 16.0% experienced grade 3~4 of hematologic AE. 18.5%, 14.8% and 18.5% of patients in BP experienced grade 3~4 of neutropenia, anemia, and thrombocytopenia, respectively. But these AEs were manageable by dose interruption or supportive care, only 2 patients stoped dasatinib because of thrombocytopenia related to dasatinib. The common non-hematologic AE related to dasatinib were grade 1-2 edema(18.0%), pleural effusion(3.0%), weakness(17.1%), rash(6.0%), diarrhea(8.6%), abnormal liver function(2.0%-14.0%) and so on. And the frequency of non-hematologic AE was higher in patients with AP/BP than in patients with CP.Conclusion: Second-generation TKIs(nilotinib and dasatinib) can be used in CML, and patients can achieve relatively sustained hematologic, cytogenetic and even molecular biology response, expecially for patients in CP, safe and well tolerated. |
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