Abstract
Tyrosine kinase inhibitors (TKI) resistance is a predominant cause of therapy failure of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The mutation in the BCR-ABL kinase domain, as the indicator of drug resistance, suggested recurrence and poor prognosis. Our data aimed to evaluate the factors having significant roles in the prognostic value of the acquired BCR-ABL mutations. Three hundred and thirteen Ph+ ALL patients (64 patients with BCR-ABL mutations and 171 patients without BCR-ABL mutations) were enrolled in this study. Univariate and multivariable logistic regression analysis was used to evaluate the relationship between clinical features and BCR-ABL KD mutation. Univariate analysis showed that the patients with higher WBC (P=0.005), MMR after first induced chemotherapy (P=0.053), and Age≥45 years (P=0.072) were more likely to occur BCR-ABL mutations during the treatments. Finally, multivariable logistic regression indicated that higher WBC (≥22×109/L) was an independent risk of resistance to TKI and raise the possibility of KD mutations in Ph+ ALL patients. The happen of BCR-ABL mutations mean poor prognosis with shorter OS (P=0.000) and allogeneic hematopoietic stem-cell transplantation (allo-HSCT) would improve the long-term survival (OS: P=0.000). Conversely, for the defined low-risk populations, no significant difference was found between the transplant group and the non-transplant group in subgroup analysis, providing a rationale to potentially avoid allo-HSCT in this subgroup of patients.
Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome–positive acute lymphoblastic leukemia