Efficacy Of Switching To Nilotinib Among Patients Failed To Achieve A BCR-ABL Transcript Level ≤10% After 6 Months After Imatinib Initiation

Objective:Treatment with tyrosine kinase inhibitors(TKIs) is the standard of care for patients with chronic myelogenous leukemia(CML) in chronic phase(CP).Imatinib was the first tyrosine kinase inhibitors approved for first-line therapy based on improved cytogenetic and molecular response rates compared with patients treated with interferon.However,approximately 30% of CML-CP patients do not achieve a complete cytogenetic response(CCy R) after 12 months of imatinib therapy.Nilotinib and dasatinib are second-generation TKIs that have been shown to be beneficial for CML-CP patients who are resistant or intolerant to imatinib.Clinical trial data have shown the benefits of switching to a second generation TKI(nilotinib or dasatinib) after imatinib resistance,greater CCy R rates were achieved at 12 months among patients who switched to a second-generation TKI compared with patients who received an increased dose of imatinib.The prognostic role of an early molecular response(EMR) defined as ≤10% of the BCR-ABL transcript level at 3 months following imatinib or dasatinib therapy for chronic myeloid leukemia(CML) has been well established.An EMR was demonstrated to have a strong correlation with long-term outcomes including progression free(PFS) and overall survival(OS) not only following Imatinib therapy but also after 2nd generation tyrosine kinase inhibitor therapy for Imatinib failure.Furthermore,the 6 month BCR-ABL transcript level was reported to have a strong association with survival.A BCR-ABL transcript level at 6 months >1%(89%) was found to be associated with inferior 5 year OS survival compared to a level ≤1%(97%).The recently published new ELN recommendations for the management of CML have incorporated the concept of EMR into the clinical decision making process.The milestones of a BCR-ABL transcript level ≤10% at 3 months as well as ≤1% at 6 months were included.The ELN recommendations do not consider a single measurement of the BCR-ABL transcript level at 3 months as sufficient to define〝failure〞necessitating a change of treatment and therefore recommend a repeat level at 6 months.Levels >10% at 3 months were defined as 〝 warning 〞 and not〝failure〞.Levels >10% at 6 months were defined as〝failure〞while those between 1-10% at 6 months were also defined as〝warning〞.Levels<1% at 6 months were defined as an〝optimal〞response.Thus molecular testing is recommended every 3 months to detect the achievement of a major molecular response which defined as BCR-ABL transcript level ≤0.1% using quantitative polymerase chain reaction(q PCR) and the international scale(IS).The achievement of a MMR has been shown to be an important end point associated with prolonged overall survival.Recently studies are warranted to investigate the effect of switching based on molecular testing.The European Leukemia Network(ELN) guidelines recommend changing TKI therapy for patients with CML-CP who fail to achieve a BCR-ABL transcript level ≤10% after 6 months after primary TKI initiation.Therefore,the objective of this study was to estimate the clinical effect of switching to nilotinib among patients taking first-line imatinib therapy and who failed to achieve a BCR-ABL transcript level ≤10% after 6 months after imatinib initiation.Patients and Methods:We retrospectively analyzed 81 CML-CP patients from January,2007 and January,2015 in The Second Hospital of Hebei Medical University who initiated imatinib as first-line therapy and failed to achieve a BCR-ABL transcript level ≤10% after 6 months.All the patients met the following criteria:(1) diagnosed with Ph(+) and/or BCR-ABL fusion gene CML-CP;(2) at least 18 years of age as of their first CML diagnosis;(3) initiated imatinib as first-line therapy between January,2007 and January,2015;(4) maintained an imatinib dose of at least 300 mg/d for at least 6 consecutive months without any treatment interruption of more than 30 consecutive days;(5) tested for molecular response by 3 months after its initiation,and results of a BCR-ABL transcript level >10% after 6 months as a treatment failure and need to switch a secondgeneration TKI therapy.Selected patients were classified into 2 parts.Patients who switched to a second generation TKI after failure to achieve a BCR-ABL transcript level ≤10% after 6 months were defined as switchers,and those who continued taking imatinib for at least 3 months after failure to achieve a BCR-ABL transcript level ≤10% after 6 months were defined as nonswitchers.The switchers include 22 patients,the median age was 37.5(18-67) yeas,the median duration was 34.5(12-53) months,the median duration of imatinib therapy was 12.5(6-36) months and the median duration of nilotinib therapy was 17.5(8-36) months.The nonswitchers include 59 patients,the median age was 40(24-62) yeas,the median duration was 48(15-72) months,the median duration of imatinib therapy was 43(15-72) months.After Comparisons of the proportion of patients achieving MMR by 3,6,9,12 months were performed using χ2 tests,Timely switchers had statistically significantly greater likelihood of achieving MMR compared with nonswitchers after failure to achieve a BCR-ABL transcript level ≤10% after 6 months.During the treatment,blood routine examination,blood biochemistry,bone marrow,genetic testing of BAR-ABL were taken regularly to evaluate the efficacy.Results:During the treatment,compared with the nonswitchers,most of patients of the switchers achieved MMR.The switchers(n=17,77.3%),the nonswitchers(n=25,42.4%),P=0.005.In addition,in each period,the switchers achieved MMR greater than the nonswitchers.Among them,in 3 months,the switchers(n=8,36.4%),the nonswitchers(5,8.5%),P=0.007;in 6 months,the switchers(13,59.1%),the nonswitchers(16,27.1%),P=0.008;in 9 months,the switchers(15,68.2%),the nonswitchers(19,32.2%),P=0.004;in 12 months,the switchers(17,77.3%),the nonswitchers(25,42.4%),P=0.005.The results show that the switchers achieved MMR earlier than the nonswitchers,and the switchers had statistically significantly greater likelihood of achieving MMR compared with nonswitchers.After compared the two groups of patients with drug adverse reaction,nilotinib has less adverse reaction and better tolerance.Conclusion:CML-CP patients who switching from imatinib to a second generation TKI nilotinib after failuring to achieve a BCR-ABL transcript level ≤10% after 6 months was associated with an ealier and greater likelihood of achieving MMR compared with not switching to a second-generation TKI.Nilotinib,compared with imatinib,has less adverse reaction and better tolerance.