| ObjectivesThe principal aims of this study were to understand the clinical characteristics of childhood acute lymphoblastic leukemia(ALL),to evaluate early treatment response and late effects of the CCCG-ALL-2015 protocol,and to explore the prognostic factors that influence the outcomes of childhood ALL.We also aimed to assess the prognostic effects of toxicities associated with high-dose methotrexate(HD-MTX)therapy as well as 6-mercaptopurine(6-MP)intolerance during maintenance therapy,and to explore the roles of pharmacogenetic polymorphisms during HD-MTX and 6-MP treatment.MethodsWe retrospectively analyzed the clinical data of 253 children with newly diagnosed ALL from January 2015 to June 2020.The ratio of male to female was 1.6:1,with a median age of 4.9 years,and the median follow-up time was 52 months.All patients were treated with CCCG-ALL-2015 protocol.The peripheral blood blast cell count on day 5,and minimal residual disease(MRD)on day 19 and day 46 of induction treatment were used to evaluate the early treatment response.We also performed laboratory tests(including complete blood count,biochemical tests,and coagulation function),and imaging tests(including color ultrasound of the liver,gallbladder,spleen,and pancreas,cardiac color Doppler ultrasound,and electrocardiogram)with long-term follow-up.HD-MTX was given four times at 3 g/m~2and 5 g/m~2 among low-risk and intermediate-/high-risk patients,respectively;delayed MTX elimination was defined as a 44-hour serum MTX concentration>1μmol/L,and MTX associated toxicities included myelotoxicity,mucositis,hepatic impairment,and acute kidney injury.The planned oral 6-MP dose during maintenance therapy was 50 mg/m~2 daily,and 6-MP intolerance was defined as a tolerable dose of<25 mg/m~2 daily.The data of pharmacogenetic polymorphisms were also collected.ResultsPart 1.Clinical Characteristics,early treatment response and prognostic factors of childhood ALL1.1 Among all included 253 children with ALL,48(19.0%)were hyper-leukocytic ALL and15(5.9%)were KMT2A rearrangement-ALL(KMT2Ar-ALL).The rates of induced complete remission(CR)and MRD<0.01%on day 46 of induction were 98.4%and 88.5%,respectively.190 cases(75.1%)had completed chemotherapy during the study period,and we observed a few cases with abnormal parameters in laboratory and imaging tests at the end of treatment,and those with abnormal examinations returned to normal at 6 months after completing treatment.1.2 15 cases abandoned treatment after CR(5.9%),resulting in 9 relapses and 5 deaths after abandonment.Among 238 children with planned treatment,29 cases relapsed(12.2%)with a median time to relapse of 30 months;the mortality rate was 7.6%,the 5-year overall survival(OS)rate was(91.4±2.0)%,and the 5-year event-free survival(EFS)rate was(82.5±2.7)%.1.3 Multivariate Cox regression analysis showed that abandonment was one of independent risk factors for relapse and death(P<0.05).Hyper-leukocytic ALL(HR=2.57,95%CI:1.22-5.42,P=0.013),KMT2Ar-ALL(HR=4.67,95%CI:1.78-12.23,P=0.002),and MRD≥0.01%on day 46 of induction(HR=2.83,95%CI:1.03-7.76,P=0.043)were independent risk factors for EFS.After adjusting for the final risk group and MRD on day 19 and day 46 of induction,the peripheral blood blast cell count of≥5%on day 5 of induction was an independent risk factor for EFS(HR=3.35,95%CI:1.42-7.89,P=0.006).Part 2.HD-MTX associated toxicities and its impact on prognosis in childhood ALL2.1 This retrospective analysis reviewed the clinical data of 249 children with ALL who received a total of 990 courses of HD-MTX therapy.MTX elimination was delayed in 175of the 990 courses(17.7%);MTX dose of>3 g/m~2(OR=2.80,95%CI:1.34-5.83,P=0.006)and the first HD-MTX course(OR=2.04,95%CI:1.34-2.91,P<0.001)were independent risk factors for delayed MTX elimination.MTX associated toxicities were diagnosed in 362of the 990 courses(36.6%),and myelotoxicity(22.2%)was the most common type of toxicities;the first HD-MTX course(OR=1.93,95%CI:1.43-2.62,P<0.001)and delayed MTX elimination(OR=2.70,95%CI:1.91-3.83,P<0.001)were the main independent risk factors for toxicities.2.2 Delayed MTX elimination and subsequent reduction of MTX dose did not significantly affect the prognosis of children with ALL(P>0.05),but myelotoxicity was an independent risk factor for relapse in childhood ALL(HR=2.04,95%CI:1.04-4.00,P=0.038).2.3 86 cases genotyped polymorphisms,and clinical data analysis of their 339 courses of HD-MTX therapy revealed that ABCB1,MTHFR C677T and A1298C polymorphisms could not be used to predict delayed MTX elimination(P>0.05),but ABCB1polymorphisms could be used as a predictor of occurrence of mucositis(P=0.040),and MTHFR A1298C polymorphisms could be used as a predictor of occurrence of myelotoxicity(P=0.003).Part 3.Association of gene polymorphisms with 6-MP intolerance and its impact on prognosis in childhood ALL3.1 Among included 125 children with ALL,the minor allele frequencies(MAF)of TPMT,NUDT15,ITPA and ABCC4 were 2.0%,12.8%,16.4%and 17.2%,respectively.During maintenance chemotherapy,the tolerable 6-MP dose was 35.0(95%CI:32.8-37.3)mg/m~2/d,and the incidence of 6-MP intolerance was 24.8%.NUDT15 gene polymorphisms alone could be used as a predictor of 6-MP intolerance(P=0.001),while TPMT,ITPA,and ABCC4 gene polymorphisms could not be used alone to predict 6-MP intolerance(P>0.05).However,combination analysis of TPMT,NUDT15,ITPA,and ABCC4variants had a predictive value for 6-MP intolerance in children with ALL(P=0.001).3.2 6-MP intolerance during maintenance chemotherapy had no significant effect on the prognosis in childhood ALL(P>0.05).Combined wild-type genotype of TPMT,NUDT15,ITPA,and ABCC4 was an independent risk factor for relapse in childhood ALL(HR=3.80,95%CI:1.14-12.62,P=0.033).Conclusion1.Early treatment response of childhood ALL treated with CCCG-ALL-2015 protocol was favorable.The long-term OS rate and EFS rate had reached 91.4%and 82.5%,respectively.Late effects of chemotherapy were mild and controllable.The incidence of abandonment after CR was 5.9%,and abandonment was one of the important independent risk factors for relapse and death.Children with hyper-leukocytic ALL,KMT2Ar-ALL,and MRD≥0.01%on day 46 of induction had a poor EFS,and they should receive more intensive treatment.The peripheral blood blast cell count of≥5%on day 5 of induction therapy had a poor EFS and it could be used as a prognostic indicator.2.During HD-MTX chemotherapy,the first HD-MTX course and MTX dose of>3 g/m~2were independent risk factors for delayed MTX elimination.The first MTX course and delayed elimination were the main independent risk factors for MTX-associated toxicities.Delayed MTX elimination did not affect the prognosis of children with ALL,but myelotoxicity increased the risk of relapse in childhood ALL.ABCB1,MTHFR C677T and A1298C polymorphisms cannot be used to predict the risk of delayed MTX elimination,but have a certain predictive value for the risk of MTX-associated toxicities.3.Among children with ALL in this single center,TPMT variants are rare while NUDT15,ITPA and ABCC4 variants are relatively common,and poor tolerance limited the utility of6-MP.NUDT15 polymorphisms could be used alone as a predictor of 6-MP intolerance.6-MP intolerance during maintenance chemotherapy did not affect the prognosis of children with ALL,but the cases with combined wild-type genotype of TPMT,NUDT15,ITPA,and ABCC4 had a higher risk of relapse. |
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