Comparison of the Efficacy of the First and Second-Generation Tyrosine Kinase Inhibitors in the First-Line Treatment of Ph-Positive Acute Lymphoblastic Leukemia

It is reported that compared with the the good efficacy of imatinib as the first-line treatment of Ph-positive acute lymphoblastic leukemia (Ph⁺ ALL),, 2^nd-generation tyrosine kinase inhibitor (TKI) cannot get higher rate of complete remision (CR) and overall survival (OS). It is also reported that the patients treated with dasatinib have higher incidence of pleural effusions and hemorrhage and BCR-ABL mutant of T315I. Whether 2^nd-generation TKI can be the first-line treatment of Ph⁺ ALL needs more clinical research. Aim of this retrospective study is to compare the efficacy and safety of 1^st and 2^nd-generation TKI in the first line treatment of Ph⁺ALL.

50 patients with newly diagnosed Ph⁺ ALL and first-line treated by TKI combined with chemotherapy and / or allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Nanfang hospital between January, 2010 and May, 2014 were enrolled and their clinical data were retrospectively analyzed in this study. Among these patients, 33 cases were treated with 1^st-generation TKI, 17 with 2^nd-generation TKIs, all of which started from the diagnosis and lasted to the time of allo-HSCT or the end of follow-up. Besides TKIs, VILP / VCDLP were the routine induction regimens, and hyper-CVAD-A ± L-asp/B were the consolidation regimens, furthermore 36/50 cases received allo-HSCT. Quantitative detection of BCR-ABL level as minimal residual disease (MRD) monitoring in bone marrow after every cycle of chemotherapy with RTQ-PCR methold.

Compared with the group treated with 1^st-generation TKI, there were more male patients (P=0.017), older median age of onset (P=0.041), higher incidence of additional karyotype (P=0.022) and BCR-ABL(P210) transcript (P=0.001) and ABL1 gene mutations (P=0.022) in the group treated with 2^nd -generation TKIs, while no significant differrnce in white blood cell count, incidence of central nervous system leukemia, EGIL classification, IGH gene rearrangement and P16 gene deletion. With respect to early response, no statistical difference was observed between the two groups, such as the first and second-cycle cumulative rate of CR and >3-log reduction in MRD level (19/33 vs 7/17, P=0.272.; 28/33 vs 12/17, P= 0.232; 12/33 vs 4/17, P=0.357; 21/33 vs 7/17, P=0.130, respectively）,  totle CR rate (29/33 vs 16/17, P=0.486), median time to achieve CR [40(15-113) vs 30(12-80) days, P=0.364], MRD negative rate (27/33 vs 11/17, P=0.180) and median time to achieve MRD negative [78(28-189) vs 88(29-155) days, P=0.316]. Median age of onset ≥35y, BCR-ABL(P210) transcript and ABL1 gene mutations were analyzed to be the risk factors for early molecular response. With median follow-up of 403(30-1880) days, both OS and disease-free survival (DFS) were not significantly different between the two groups, either in all patients or in those received allo-HSCT. No statistical difference in pleural effusion and hemorrhage except BCR-ABL mutant of T315I (0/10 vs 3/5) in was observed between the two groups.

To sum up, in the first-line treatment of Ph⁺ ALL, 2^nd-generation TKI is equivalent to 1^st-generation TKI, but might take therapeutic advantage in the patients with older age, BCR-ABL(P210) transcript and ABL1 gene mutation, and BCR-ABL mutant of T315I in failed cases treated with 2^nd-generation TKI needs more attention.