Long-Term Safety of Dasatinib in Chinese Chronic Phase Chronic Myeloid Leukemia Patients with Imatinib-Resistance or -Intolerance: Results from a 6-Year Follow-up of a Multicenter Phase II Study
Authors: Huang Xiaojun , Jiang Qian , Hu Jianda , Li Jianyong , Jin Jie , Meng Fanyi , Shen Zhixiang , Liu Ting , Wu Depei , Wang Jianmin , Wang Jianxiang 
Published: October 2019

Abstract
Background:The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) has turned chronic myeloid leukemia (CML) from a fatal disease into a controllable chronic condition. Most CML patients, especially those who were in chronic phase (CP), now may require life-long TKIs therapy. Thus, the long-term safety of TKIs is of great importance. Dasatinib is a second-generation TKI that has been approved in China in 2011 as a treatment for imatinib-resistant or -intolerant CML. Previously we have reported safety findings from the Chinese dasatinib registration study after 4 years of follow-up. The results showed that dasatinib was well tolerated, with a low rate of discontinuation and a safety profile that supported previous data from large Phase 3 clinical trials (CA180-034)[1]. Here we present the safety results from the 6-year follow-up of 59 CML-CP patients in this pivotal Chinese study
Aims:To evaluate the long-term safety of dasatinib in Chinese CML-CP patients who were resistant to or intolerant of imatinib after 6 years of follow-up. Important endpoints included the incidence and severity of adverse events (AEs) and treatment discontinuation due to drug-related AEs.
Methods:This was an open-label, single-arm phase 2 clinical study conducted at 10 centers in China. Adult, Chinese CML patients with imatinib-resistant or -intolerant were recruited. CML-CP patients received oral dasatinib of 100mg/d, until disease progression or intolerable toxicity. Follow-up visits were scheduled at least every 4 weeks until all study-related toxicities returned to baseline or ≤ National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0 Grade 1, stabilized or were irreversible.
Results:A total of 140 patients were enrolled, 59 of whom had CML-CP. After 6 years of follow-up, 61% (36/59) of patients with CML-CP remained on treatment. Between the 4- and 6-year follow-up, there were no further deaths on the study and no more patients with CML-CP discontinued treatment due to drug-related AEs.
Overall, drug-related AEs of any grade were experienced by 74.6% (44/59) of patients with CML-CP, of which 3 patients experienced drug-related AEs after 4-year follow-up (Table). 20.3% (12/59) of patients with CML-CP experienced drug-related, Grade 3-4 AEs and 16.9% (10/59) experienced drug-related serious AEs (Table). 16.9% (10/59) of patients experienced haematological AEs (Grade 3-4, 11.9%, 7/59) and none of the 10 cases happened after 4-year follow-up. The most frequently reported drug-related AEs for CML-CP patients remained pleural effusion (25.4%, 15/59; Grade 3-4, 3.4%, 2/59) and 1.7% (1/59) of the patients discontinued dasatinib treatment due to pleural effusion. Only 1 new case of pleural effusion occurred between 4-year and 6-year follow-up and no more Grade 3-4 pleural effusion has been observed after 4-year follow-up. Pulmonary hypertension were experienced by 8.5% (5/59) patients. Only 1 new case of pulmonary hypertension happened between 4-year and 6-year follow-up and no more Grade 3-4 pulmonary hypertension occurred after 4-year follow-up. Between 4-year and 6-year follow-up, 1 patient (1.7%) experienced Grade 1-2 pulmonary arterial hypertension and this was the only case of pulmonary arterial hypertension observed in the study. Deep vein thrombosis (1.7%, 1/59) occurred to 1 patient in 4-year follow-up and no more cases of deep vein thrombosis occurred between 4-year and 6-year follow-up.
Conclusion:The safety profile of dasatinib after 6-year follow-up was consistent with the results from 4-year follow-up, which confirmed the long-term safety of dasatinib in the treatment for Chinese CML-CP patients with imatinib-resistance or -intolerance. Pleural effusion remained the most common adverse event during long-term follow up. As TKI-associated vascular AEs (VAEs) is drawing more and more attention in recent years, we have evaluated their incidence in our study and the results showed that the risk of VAEs remained low with long-term dasatinib treatment.
Acknowledgment: BMS funded this research and medical writing support.
Reference
[1] Huang XJ, Hu JD, Li JY, et al. Four-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukaemia receiving dasatinib: efficacy and safety. Poster (#54229) presented at the 19th European Haematology Association Annual Congress; 12-15 June 2014; Milan, Italy

Disclosures
No relevant conflicts of interest to declare.