Impact of Second-Generation Tyrosine Kinase Inhibitors As Second Line Treatment for Patients with Chronic Myeloid Leukemia,

Imatinib has shown an outstanding improvement in the prognosis of chronic myeloid leukemia (CML) patients. Nevertheless, some of them have proven to be resistant or intolerant to imatinib. For these patients, second-generation tyrosine kinase inhibitors (TKIs) are available. These drugs may be indicated in different circumstances as primary or second resistance, suboptimal responses or intolerance.The real benefits of second-generation TKIs as salvage treatment are surely in dependence with the indication in each case and are, therefore, difficult to evaluate. Second-generation TKIs are being evaluated as first line treatment compared to imatinib with quite favourable outcomes so long, but have not yet been compared with a strategy combining imatinib followed by second-generation TKIs for patients with previous unfavourable responses. Aims: Evaluate the real benefit of second-generation TKIs in second line treatment for CML patients regardless of the indication for its use. Study groups and methods: We have studied 98 patients treated with imatinib as first tyrosin kinase inhibitor (TKI) in our centre. These patients have been classified according whether second-generation TKIs were available or not. Group 1 includes 60 patients treated since 2001 to 2005, when the only salvage treatment was an increased imatinib dose, chemotherapy or allogenic stem cell transplantation. Group 2 includes 38 patients treated since 2005 until today. In the second group second-generation TKIs (dasatinib or nilotinib) were used according to the indications mentioned above. Follow up period was 39 months and 32 months for group 1 and 2 respectively. Sokal risk index was high in 14% and 16%; intermediate 42 % and 40%; and low in 44% and 44 % for group 1 and 2 respectively. Results: The use of second-generation TKIs as second line resulted in significant benefit to patients in terms of responses. Complete cytogenetic responses (CCR) at any time were achieved in 73% and 86% for patients in group 1 and 2 (p=.09). Probability of the achievement of mayor molecular responses (MMR) was 42% vs 71% for group 1 and 2 respectively [p=.009; ratio=0.3 (0.1–0.7)]. Response rates at the last follow up for group 1 and 2 were: MMR: 33% vs 62%; CCR: 68% vs 94% and failure 32% vs 6% (p=.008). Progression free survival (including all the patients who started treatment) was 88% vs 94% for group 1 and 2 respectively. We found no correlation among responses and some prognostic factors (Sokal index, mutations at the TK domain or imatinib plasma levels). Imatinib doses were increased in 21 patients (35%) in group 1 (reasons for increasing doses were failure in 14 patients and suboptimal responses in 7 patients). 10 patients (26%) in group 2 received second-line TKIs as second line treatment (4 because imatinib failure, 3 by suboptimal responses and 3 due to intolerance). Conclussions: The use of second-generation TKIs as salvage has improved the responses of CML patients treated with TKIs. Once the second-generation TKIs has shown benefit compared to imatinib in first line treatment, this therapeutic strategy should be compared vs the use of imatinib followed of second-line TKIs for patients without optimal responses to imatinib.

Montalban:Red Temática de Investigación Cooperativa en Cancer (RETICC): Research Funding; Asociación Española contra el Cancer: Research Funding.