| Objective: To analyze the incidence, factors associated with mutations and prognostic significance of ABL kinase mutations in patients with chronic myelogenous leukemia(CML) treated with tyrosine kinase inhibitor(TKI).Methods: The clinical data of 137 CML patients who were treated with TKI and assessed for ABL kinase domain mutations in Fujian Medical University Union Hospital from January 2008 to September 2015 were collected. All cases were divided into imatinib, nilotinib and dasatinib arms depending on the different TKIs. Comparing the frequencies of mutations among 3 study arms, factors associated with mutations and prognostic significance of mutations were involved in the analysis.Results: Among the 137 CML patients, 126 patients received imatinib(IM), 117 in the chronic phase(CP), 8 in the accelerated phase(AP) and 1 in the blast phase(BP), 22 cases discontinued treatment(off-treatment). 45 patients received nilotinib, 38 in the CP, 5 in the AP and 2 in the BP. 8 patients were treated with nilotinib as first-line therapy, and 37 as second-line.30 patients received dasatinib, 23 in the CP, 2 in the AP and 5 in the BP. 3 patients were treated with dasatinib as first-line therapy, and 27 as second-line.Of the 137 TKI-treated patients, 136 had achieved complete hematological response(CHR) with a median time of 2 months and 89 had achieved major molecular response(MMR) in a median follow-up of 12 months. Forty(29.20%) mutations in 27 amino acids were identified in 137 patients after a median follow up of 32 months. Phosphatebinding loop(P-loop) mutations were the most frequent(20 [50%] of 40), followed by imatinib-binding region(9 [22.50%] of 40). Among the 126 imatinib-treated patients, 28(22.22%) mutations were identified in 126 patients, and the most common mutants were G250 E, E255K/V, Y253 H, H396 R and T315 I. 12 mutations were identified in 45(28.89%) nilotinib-treated patients. In these 13 patients, the most common mutants were Y253H/F, T315 I, F359 V, M244 V and E255 V. Of the 30 dasatinib-treated patients, 8(26.67%) mutations were identified, and the most common mutants were T315 I, E255V/K, F317 L and E459 K. Frequencies of mutations were similar in imatinib, nilotinib and dasatinib study arms,(22.22%, 26.67%, 26.67%, respectively, P>0.05). The rate of a complete hematological response at mutation assessed time was significantly lower in patients with mutations than patients without mutant(37.5%, 15 of 40; 67.01%, 65 of 97; respectively, P<0.05). The rate of maintaining a major molecular response in patients with mutations(7.50%, 3 of 40) was significantly lower compared with those without mutant(21.65%, 21 of 97, P<0.05). The rate of disease progression was significantly higher in patients with mutations than patients without mutant(57.5%, 23 of 40; 14.43%, 14 of 97; respectively; P<0.05). Frequencies of mutations were lower in patients achievement of CHR within 3 month than achieved a CHR after 3 months, whereas there was no significant difference(25.68%, 28 of 109; 40.70%, 11 of 27; respectively; P=0.097). Lack of a MMR was also associated with a higher likelihood of detecting a mutation; 21(43.75%) of 48 patients without an MMR had mutations compared with 19(27.14%) of 89 with an MMR,(P<0.05). Of the 126 imatinib-treated patients, imatinib-resistant patients had a higher mutation rate(50%, 24 of 48) than non-resistant patients(20.51%, 16 of 78; P<0.05). Frequencies of mutations were significantly higher in imatinib-on-treatment patients(40.91%, 9 of 22) than imatinib-off-treatment patients(18.27%, 19 of 104; P<0.05). Patients who commenced TKI more than 3 months from diagnosis had a significantly higher incidence of mutations(10 [47.62%] of 21) compared with those treated within 3 months(30 [25.86%] of 116, P<0.05). 23(57.50%, 23 of 40) patients had disease progression in mutations patients(median follow-up of 29 months), while 14 patients(14.43%, 14 of 97) had progression in patients without mutant, after a median follow-up of 41.5 months. 5-year PFS rates in patients with mutations and without mutant were 57.20% and 91.50%, respectively, the difference was significant(P<0.001). The development of mutations was associated with a significantly shorter survival.Conclusion: Among the CML patients treated with TKI, the most common ABL kinase mutations were located at P-Loop and imatinib-binding region. Mutations were associated with increased rate of progression and poorer prognosis. Achievement of CHR within 3 months, lack of MMR, off-treatement, imatinib-resistance, duration from diagnosis to treatment were associated with development of mutations. |
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