Abstract
OBJECTIVE:To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib.METHODS:Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing.RESULTS:We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months.CONCLUSIONS:Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome for these patients is poor, the development of new therapies for resistant chronic myeloid leukemia patients is necessary.
Highlights
Five patients were treated with dasatinib (28%), and 13 patients were treated with nilotinib (72%)
Our data show that only 22% of patients in the chronic phase (CP) stage showed long-term benefits from the administration of a 3rd tyrosine kinase inhibitors (TKIs) after imatinib and a 2nd TKI failure
We found that 89% of our patients in the CP stage achieved complete hematological response (CHR), 13% achieved complete cytogenetic response (CCyR), and 24% achieved Major molecular response (MMR); 50% of those patients lost CHR within a median of 23 months
Summary
Approximately 50% of chronic phase (CP) patients achieve a complete cytogenetic response (CCyR) when treated with second-generation TKIs [1,2]. Approximately 52% of patients must discontinue secondline TKI therapy, most often due to resistance or intolerance [3]. Allogeneic transplantation is the treatment of choice for patients who fail to respond to at least one second-generation TKI (2nd TKI). Transplantation is not feasible for many older patients, for patients with poor performance status and for patients who do not have an available donor
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