Molecular response and prognosis of pediatric patients with Ph-positive acute lymphoblastic leukemia treated by tyrosine kinase inhibitors with chemotherapy

Objective To explore the molecular response and prognostic factors of pediatric patients with Ph-positive acute lymphoblastic leukemia (Ph+ ALL) treated by tyrosine kinase inhibitors (TKI) with chemotherapy in TKI era. Methods The clinical data of children newly diagnosed with Ph+ ALL admitted at Department of Pediatrics, Peking University People′s Hospital from August 2006 to February 2017 were retrospectively reviewed.The molecular biological characteristics and survival prognosis of the 30 patients who received continuous TKI with chemotherapy from early induction combined and no subsequent transplantation were analyzed. Results The 30 patients with Ph+ ALL had 19 males and 11 females with a median age of 8-year-old (ranging from 2 to 16 years). The complete remission (CR) rate after the first cycle of induction chemotherapy was 96.7% (29/30 cases), with overall CR rate of 100.0%; Before treatment, the mean level of BCR/ABL mRNA in the 30 patients was 73.2% (0.12%-160.60%) and the level declined significantly with the progression of chemotherapy courses, reaching the plateau stage at the 6th month of chemotherapy (Z=-1.922, P>0.05); nine patients had recurrence, with a median recurrence time of 7 months (3.7-58.8 months). Univariate analysis showed that age (P<0.05), the lever of minimal residual disease (MRD) after induction chemotherapy (P<0.01) and the MRD level at the 3th month of induction chemotherapy (P<0.01) affected the recurrence rate.The median follow-up time of 30 patients was 42.6 months (6.4-96.5 months), and the 3-year overall survival (OS) rate and event-free survival (EFS) rate were (78.6±7.8)% and (72.4±8.4)%, respectively; Cox multivariate analysis showed that the initial white blood cell count ≥34.0×109/L (OR=11.955, 95% CI: 1.075-132.899, P<0.05) and BCR/ABL mRNA reduction less than 3 log from baseline [major molecular response (MMR)] at the 3th month of induction chemotherapy (OR=8.563, 95% CI: 1.254-58.478, P<0.05) were independent risk factors affecting the 3-year EFS rate.In addition, the initial white blood cell count ≥34.0×109/L (OR=14.327, 95% CI: 1.843-243.592, P<0.05) was also an independent risk factor affecting the 3-year OS rate. Conclusions The application of TKI can significantly deepen the molecular response of Ph+ ALL in children.In the TKI era, the initial white blood cell count ≥ 34.0×109/L and BCR/ABL mRNA reduction less than 3 log from baseline (MMR) at the 3th month of induction chemotherapy are independent risk factors for the long-term survival of pediatric Ph+ ALL. Key words: Philadelphia chromosome; Acute lymphoblastic leukemia; Child; Tyrosine kinase inhibitor; Mole-cular response