Upfront treatment with the first and second-generation tyrosine kinase inhibitors in Ph-positive acute lymphoblastic leukemia.

Guopan Yu,Dan Xu,Qifa Liu,Li Xuan,Qianli Jiang,Jing Sun,Xiaoli Liu,Changxin Yin,Zhiping Fan,Fang Chen,Qiang Wang

doi:10.18632/oncotarget.22206

Guopan Yu, Dan Xu + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.22206

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Journal: Oncotarget	Publication Date: Oct 31, 2017
Citations: 10	License type: cc-by

Affiliation: Nanfang Hospital

Abstract

The treatment of Ph-positive acute lymphoblastic leukemia (Ph+ ALL) has entranced tyrosine kinase inhibitors (TKIs) era. Currently both imatinib and dasatinib are registered as the front-line treatment for Ph+ ALL, and the other 2nd-generation TKIs are suggested as an alternative for those who failed the first-line treatment. However, it remains unclear who could benefit from the 2nd-generation TKIs as the first-line treatment for Ph+ ALL. In this study we compared the efficacy and safety of the 1st and 2nd-generation TKIs in the front-line treatment of Ph+ ALL and found a trend toward better disease-free survival (DFS) in the 2nd-generation TKIs group, though no significant difference in early response and long-term survival between the two groups. Furthermore, subgroup analysis showed that if allogeneic hematopoietic stem cell transplantation (allo-HSCT) was incorporated as consolidation, the 2nd-generation TKIs benefited patients with better DFS and overall survival (OS). The two generation TKIs were well tolerated. Higher incidence of acquiring T315I mutation was observed in the patients relapsed on the 2nd-generation TKIs. These findings suggested front-line treatment of Ph+ ALL with the 2nd-generation TKIs might benefit patients with better survival when allo-HSCT was incorporated as consolidation therapy; meanwhile, the higher incidence of T315I mutation in patients relapsed on the 2nd-generation TKIs deserved further attention.

Highlights

The Philadelphia chromosome (Ph), resulting from fusion of BCR-ABL gene, is the most common cytogenetic abnormality in adult patients with acute lymphoblastic leukemia (ALL), occurring in about 20% to 30% of all cases [1,2]
tyrosine kinase inhibitors (TKI) combined with multiagent chemotherapy has been well accepted as the front-line treatment of Ph+ ALL, and the patients under 65 are recommended to receive allo-hematopoietic stem cell transplantation (HSCT) if a matched donor is available [20, 24]
We confirmed the survival advantage of consolidation with allo-HSCT in Ph+ ALL patients, even though TKIs had been continuously used through induction and consolidation

Summary

Introduction

The Philadelphia chromosome (Ph), resulting from fusion of BCR-ABL gene, is the most common cytogenetic abnormality in adult patients with acute lymphoblastic leukemia (ALL), occurring in about 20% to 30% of all cases [1,2]. Ranging from 40%–65%, compared to the 20%–40% in pre-imatinib era. It has become the standard of care. The second (2nd)-generation TKIs, for example dasatinib, is 300-fold more active than imatinib in vitro [11,12], and has shown marked efficacy in relapsed patients or those refractory to imatinib [13,14,15], especially in those with imatinib-resistant BCR-ABL mutations. The 2nd-generation TKIs have been used as first-line treatment with promising results [16,17,18,19]. Up until now, to our knowledge, there were no randomized trials directly comparing the 1st and 2nd -generation TKIs in treating newly diagnosed Ph+ ALL [20]. Literature review of prospective studies of each TKIs www.impactjournals.com/oncotarget

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