| PART I CLINICAL CHARACTERISTICS AND RISK FACTORS OF CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIAObjective:To study the clinical characteristics and risk factors of childhood acute lymphoblastic leukemia(ALL),and to lay a foundation for further treatment optimization for reducing relapse and increasing longterm survival rate.Methods:A retrospective study was conducted to investigate the clinical features,therapeutic effects,outcome and prognosis of children with acute lymphoblastic leukemia treated with CCLG-ALL-2008 protocol.Results:Among 438 newly diagnosed children with ALL,376 patients(85.84%)suffered from B-cell precursor acute lymphoblastic leukemia(BCP-ALL)and 62 patients(14.16%)were with acute Tlymphoblastic leukemia(T-ALL).The gender ratio of male and female in BCP-ALL was 2.55:1,and that of T-ALL was 4.17:1(P=0.001).The median age of children with BCP-ALL was 49 months,including 1 case under 1 year old,328 cases between 1~10 years old and 47 cases over 10 years old;the median age of children with T-ALL was 101.5 months,including 43 cases between 1~10 years old(69.35%)and 19 cases over 10 years old(30.65%).There was significant difference in age distribution between the two groups(P=0.000).Twenty-three children with BCP-ALL(6.12%)had peripheral white blood cell count(WBC)>100 × 109/L at diagnosis,and 27 children with T-ALL(43.55%)had WBC>100 × 109/L at diagnosis,with significant difference(P=0.000)between patients with different diseases.Among the 398 patients received karyotype detection,46% BCP-ALL and 25% T-ALL patients had abnormal karyotypes(P = 0.002).Four fusion genes(ETV6/RUNX1,E2A/PBX1,BCR/ABL and MLL rearrangement)were detected in 345 children with BCP-ALL and 61 children with T-ALL;one of the four fusion genes was found in 93 children with BCP-ALL and all T-ALL cases were negative(P=0.002).Chest radiographic examination was performed in 98 children with BCP-ALL and 60 T-ALL children,and mediastinal mass were found in 40 T-ALL children and no BCP-ALL children(P = 0.000).Prednisone sensitive was achieved in 349 children(92.82%)with BCP-ALL and in 39 children(62.90%)with T-ALL(P = 0.000).In all 286 children with BCP-ALL and 50 children with T-ALL that received MRD detection on the day 33,8(2.80%)BCP-ALL and 10(20.0%)T-ALL patients were found positive,with a significant difference(P = 0.044)between two type of diseases.Follow-up until August 2017,29 children(8.01%)with BCP-ALL and 21 children(36.21%)with T-ALL relapsed after complete remission,with mean EFS and OS of 75.94±2.61 months and 94.25 ±1.93 months in BCPALL and,53.50 ± 6.62 months and 54.93 ±6.58 months in T-ALL,respectively,which showed significant differences between the two groups(P=0.000).Three hundred twenty eight BCP-ALL children aged 1~10 years old and 48 children aged < 1 year or over 10 years old were with EFS 77.63 ± 2.74 months and 57.55 ± 6.76 months,(P = 0.021)and OS 95.52 ± 1.97 months and 73.77 ± 6.13 months(P = 0.035),respectively.The children with WBC < 100 × 109/L and WBC > 100 × 109/L in BCP-ALL were with EFS 76.90 ± 2.66 months and 43.02 ± 7.63 months(P = 0.025)and OS 95.10 ± 1.93 months and 54.53 ± 7.40 months(P = 0.021),respectively.Among 345 BCP-ALL patients received four fusion genes detection,93 were found with one of the four fusion genes,38 were with TEL-AML1,27 were with BCR-ABL,18 were with E2A-PBX1 fusion gene,10 were with MLL rearrangement.The EFS of patients with four fusion genes and without fusion genes were 90.50 ± 7.87 months,47.62 ± 9.56 months,42.41 ± 7.94 months,18.78 ± 6.34 months and 74.29 ± 2.88 months(P = 0.000),respectively.All the children with positive TELAML1 fusion gene survived,and the OS of the other groups were 61.11 ± 10.33,58.23 ± 6.10,26.65 ±6.33,and 92.76 ± 2.04 months(P = 0.000),respectively.In 376 cases of BCP-ALL,362 cases achieved complete remission(CR)and 14 cases did not achieve complete remission(NCR)on the 33 rd day of induction remission.Between the patients achieved CR and NCR,the average EFS was 76.82 ± 2.61 months and 9.75 ± 2.82 months(P = 0.001),respectively,and the average OS was 95.19 ± 1.89 months and 10.25 ± 2.53 months(P = 0.000),respectively.In 286 BCP-ALL children received MRD detection at day 33,278 children with MRD negative and 8 children with MRD positive were with EFS 65.98 ± 1.93 months and 22.00 ± 6.81 months(P = 0.001),and OS 76.56 ± 1.40 months and 33.06 ± 8.74 months(P = 0.002),respectively.In T-ALL,40 children with mediastinal mass and in 20 children without mediastinal mass were with EFS 41.12 ± 7.48 months and 71.07 ± 11.38 months(P = 0.039)and OS 42.52 ± 7.48 months and 73.61 ± 11.13 months(P = 0.047),respectively.Among 62 children with T-ALL,39 children prednisone sensitive and 23 children prednisone insensitive were with EFS 69.20 ± 8.25 months and 22.47 ± 6.05 months(P = 0.001),and OS 71.96 ± 8.12 months and 22.68 ± 5.69 months(P = 0.000),respectively.Among 50 T-ALL patients underwent MRD detection at the day 33 of induced remission.40 children with MRD positive and 10 children with negative were with EFS 44.48 ± 5.99 months and 17.20 ± 8.14 months(P = 0.007),and OS 46.59 ± 5.93 and 20.11 ± 8.74 months(P = 0.013),respectively.COX multivariate regression analysis showed that risk stratification was an independent prognostic risk factor for EFS and OS in children with BCP-ALL.The presence of mediastinal mass and the level of MRD on day 33 were independent prognostic factors for EFS and OS in children with T-ALL.Conclusion:Compared with the children with BCP-ALL admitted at the same time,T-ALL children were with increased ratio of male,elderly,high white blood cell count,and mediastinal involvement and decreased abnormal chromosomal karyotype and fusion genes.Prednisone responses,MRD,EFS and OS of T-ALL were significantly inferior to BCP-ALL children.Age,peripheral leukocyte count at diagnosis,specific fusion genes,bone marrow cytology and MRD at the day 33 of remission induction significantly influenced the EFS and OS in children with BCPALL;risk group was an independent prognostic risk factor for EFS and OS in children with BCP-ALL.Mediastinal involvement,prednisone response,and MRD at the day 33 of remission induction affected the EFS and OS in children with T-ALL;mediastinal involvement was associated and MRD at the day 33 of remission induction were independent prognostic risk factors of EFS and OS in children with T-ALL.PART II CLINICAL STUDY OF UPPER GASTROINTESTINAL MUCOSAL LESIONS IN CHILDREN WITH NEWLY DIAGNOSED ACUTE LYMPHOBLASTIC LEUKEMIAObjective : To study the pathological characteristics of upper gastrointestinal mucosal lesions in children with newly diagnosed acute lymphoblastic leukemia(ALL)by painless gastroscopy,to study the influencing factors of the onset and progression of upper gastrointestinal mucosal lesions in children with ALL,and to analyze the protective effect of preventive and therapeutic drugs on upper gastrointestinal mucosal lesions in children with ALL during chemotherapy.Methods:Clinical and laboratory data of 129 newly diagnosed children with ALL were collected and analyzed.Painless gastroscopy was performed before chemotherapy.Drug regimens were randomly selected to prevent or treat upper gastrointestinal mucosal lesions according to the results of the examination.After VDLDex induced remission chemotherapy,painless gastroscopy was re-examined to evaluate the changes and curative effect of upper gastrointestinal mucosal lesions.Results : Among 129 children with ALL diagnosed by painless gastroscopy,107(82.94%)had upper gastrointestinal mucosal lesions before chemotherapy,101 had gastric mucosal lesions,11 had esophageal mucosal lesions,and 51 had duodenal bulb mucosal lesions.Among 22 children without upper gastrointestinal mucosal injury before chemotherapy,6 received cimetidine or omeprazole to prevent gastrointestinal mucosal injury during induction and remission chemotherapy.After induction and remission chemotherapy,painless gastroscopy was reexamined.The results showed that 3 patients had new gastrointestinal mucosal injury and 3 patients had new gastrointestinal mucosal injury.Sixteen children who refused prophylactic treatment received painless gastroscopy after induction and remission chemotherapy,15 had new gastrointestinal mucosal lesions,and only one patient remained in a disease-free state.There were significant differences in the incidence of gastrointestinal lesions between the two groups(P=0.046).For ALL patients with upper gastrointestinal mucosal injury before chemotherapy,the overall outcome of upper gastrointestinal mucosal injury in ALL patients treated with cimetidine or omeprazole combined with or without Kangfuxin Liquid was significantly improved after induced remission chemotherapy(P = 0.002).The rate of increase(P = 0.003)and the rate of progress decreased(P =0.001).There was no significant effect of Kangfuxin Liquid on the overall efficacy of different drugs and the improvement rate of disease(P > 0.05),but Kangfuxin Liquid could significantly reduce the progression rate of disease(P = 0.049)and the risk of disease progression(OR = 0.737,95% CI: 0.552-0.983).For the children treated by cimetidine combined with or without Kangfuxin Liquid,there was no significant change in the overall efficacy,improvement rate and progress rate(P > 0.05).For the children treated by omeprazole,combined use of Kangfuxin Liquid could effectively improve the overall efficacy(P = 0.013)and the improvement rate(P = 0.011,OR=2.398,95% CI: 1.229-4.695)and significantly reduce the progression rate(P=0.044,OR=0.500,95%CI: 0.284-0.880).Conclusion:Most children with ALL have upper gastrointestinal mucosal injury before chemotherapy.Chemotherapy can aggravate the injury.It is suggested that cimetidine or omeprazole should be given routinely for prevention and treatment,and painless gastroscopy should be given before chemotherapy if necessary.Omeprazole or cimetidine can effectively treat upper gastrointestinal mucosal lesions and reduce the progression of lesions caused by chemotherapy in newly diagnosed ALL patients with upper gastrointestinal mucosal lesions before chemotherapy.Kangfuxin solution can significantly reduce the progression rate of mucosal lesions and has a good synergistic effect on omeprazole. |
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