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The clinical data of two children with refractory/relapsed acute B-lymphoblastic leukemia (ALL-B)treated with Blinatumomab in Department of Pediatrics, Peking University People′s Hospital from September 2019 to May 2021 were retrospectively analyzed.After 1 course of Blinatumomab infusion, both children achieved complete hematologic remission.During the infusion process, grade 2 cytokine release syndrome (CRS) was observed, and there were no fatal adverse reactions.One case underwent bridging hematopoietic stem cell transplantation after remission and achieves disease-free survival currently.The other case is still alive after subsequent consolidation chemotherapy.As a novel bispecific antibody, Blinatumomab has a good response rate to refractory/relapsed ALL-B and induces fewer adverse events, so it can be used as a candidate immunotherapy for patients with high tumor burden.
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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 6 th 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 3 th 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 ≥34.0×10 9/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 3 th 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 ≥34.0×10 9/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 ≥ 34.0×10 9/L and BCR/ ABL mRNA reduction less than 3 log from baseline (MMR) at the 3 th month of induction chemotherapy are independent risk factors for the long-term survival of pediatric Ph + ALL.
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Objective@#To evaluate the safety and efficacy of chimeric antigen receptors T cells (CAR-T) in childhood acute B lymphoblastic leukemia (B-ALL) to probe the prognosis-related factors.@*Methods@#Forty-eight children, 29 boys and 19 girls, aged 3-17years old (median age was 8 years old) , with recurrent or refractory CD19 positive B-ALL, were treated by the CD19 specific CAR-T cells. A total of 48 cases received 61 infusions. Flow cytometry or real-time quantitative polymerase chain reaction method were used to monitor micro residual disease (MRD) . The follow-up period was from 16 to 1 259 days with the median follow-up of 406 days. SPSS software was used to statistical analysis.@*Results@#No adverse reaction was observed during 61 infusions. The most common adverse reaction after CAR-T cell infusions was cytokine-release syndrome (CRS) . Only 2 cases experienced level 3 CRS performance, including continuous high fever, convulsions, delirium, serous cavity effusion, and decreasing of blood pressure. Tocilizumab was given to release CRS performance. No treatment-related death occurred. Thirty-seven patients showed response during 7 to 28 days after infusions. The early response rate was 77.1%, with MRD before infusion less than 5% group higher than the MRD more than 5% group (87.1% vs 58.8%, χ2=4.968, P=0.036) . For the 37 patients who showed response to CAR-T cell infusions, univariate analysis identified that age, disease status at the time of treatment, MRD before infusion affected 2-year OS rate (P<0.05) . Multivariate prognostic analysis for EFS disclosed that the MRD before infusion more than 5% (RR=3.433, 95% CI 1.333-8.844, P=0.011) and not bridge to HSCT (RR=4.996, 95% CI 1.852-13.474, P=0.001) were the independent risk factors.@*Conclusion@#The fourth generation CAR-T cells directed against CD19 could effectively and safely treat relapsed and refractory B-ALL, which implicated that CAR-T therapy as a novel therapeutic approach could be useful for patients with relapsed or refractory B-ALL who have failed all other treatment options. Reducing MRD as far as possible by effective pretreatment chemotherapy was in favor of increasing the response rate. Bridging HSCT after CAR-T cell treatment might be a better therapeutic strategy for the patient with refractory or molecular relapsed B-ALL.
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Objective@#To analyze the clinical outcome and the prognostic factor in pediatric patients with core binding factor-acute myeloid leukemia (CBF-AML).@*Methods@#A total of 121 newly diagnosed pediatric CBF-AML patients enrolled from Aug. 2005 to Sep. 2017 were retrospectively reviewed. Cumulative incidence of relapse (CIR), event-free survival (EFS) and overall survival (OS) rates were estimated by Kaplan-Meier method and prognostic factors were evaluated by Cox regression with SPSS.@*Results@#Of the 121 patients, 120 patients were assessed for bone marrow remission after induction chemotherapy. 100 cases (83.3%) achieved complete remission (CR) after the first course of chemotherapy. 119 cases (99.2%) achieved CR after the second course of chemotherapy. Of the 121 patients, 13 patients (10.7%) had recurrence with the median interval of recurrence as 13.8 months (3.7 to 58.8 months). 17 patients (14.0%) died. The CIR, EFS and OS at 3 years were 12.7%, 77.5% and 82.8%, respectively. The factors including age at diagnosis, sex, initial WBC count, presence of extramedullary leukemia, C-KIT expression, additional chromosomal abnormalities, and CR after the first course of chemotherapy were analyzed by multivariate regression analysis of Cox. Multivariate analysis identified that additional chromosomal abnormalities was the only independent risk factor affecting OS (HR=4.289, 95%CI 1.070-17.183, P=0.040).@*Conclusions@#Pediatric CBF-AML was a unique setting of prognostic subtypes. Chemotherapy produced good responses. Additional chromosomal abnormalities was the only independent risk factor for OS in pediatric CBF-AML.
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OBJECTIVE： To provide reference for reasonable selection of tyrosine kinase inhibitors （TKI） in chronic myeloid leukemia （CML） patients with BCR-ABL35INS mutation. METHODS： Using “BCR-ABL insertional mutation” “ABL1 35ins mutation” “BCR-ABL c.1423_1424ins35” “ABL1 p.C475Tyrfs*11” as keywords， retrieved from CNKI， Wanfang database， Medline and COSMIC database， BCR-ABL35INS mutation CML patients were summarized and analyzed in respects of general information and treatment （treatment plan， patient compliance and drug withdrawal）， therapeutic effect （molecular biological mitigation and disease progress） and safety data （ADR） during 2007-2018. RESULTS： Totally 9 related literatures were included， involving 70 patients with BCR-ABL35INS mutation， all of them were foreign cases. Among them， 39 cases were male and 31 cases were female， with a median age of 49.2 years. The median time from the diagnosis of CML to the detection of BCR-ABL35INS mutation was 19 months. After detecting gene mutation， 39 cases were treated with imatinib （initial dose of 400 mg， po， once a day）， and molecular biological remission was achieved in 5 patients （12.9％）； 15 cases （38.5％） had molecular biological response but had disease progression； 8 patients （20.5％） had no response. Seventeen patients were treated with dasatinib （100 mg， po， once a day or 2 divided dose）， and 8 cases （47.1％） achieved molecular biological response. Twenty-one patients were treated with nilotinib （400 mg， po， 2 divided dose）， and 3 patients （14.3％） achieved molecular biological response； 2 patients achieved molecular biological response， but the disease progressed. Seven， three and seven of these patients stopped taking drugs due to adverse reactions， accounting for 17.9％， 17.6％ and 33.3％ respectively. All the ADRs were classified as grade 3-4 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events， and most of them were hematological toxicity. CONCLUSIONS： CML patients with BCR-ABL35INS mutation are less likely to achieve molecular response on imatinib therapy but are more sensitive to dashatinib. In the course of treatment， we should strengthen the monitoring of blood system and other related indicators to ensure the safety and effectiveness of drug use.
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Objective@#To explore the clinical features and prognostic factors of Ph-positive and/or BCR-ABL positive acute lymphoblastic leukemia (Ph+ ALL) in children.@*Methods@#The clinical data of 68 Ph+ ALL children who were treated at Peking University People's Hospital from December 2006 to December 2016 was retrospectively reviewed. Survival analysis were estimated by Kaplan-Meier method. Univariate analysis was estimated by Log-rank test and Chi-square, and multivariate analysis was estimated by Cox proportional hazards regression model.@*Results@#In the 68 cases, the proportion of male to female was 2.1∶1, with a median age of 8 (1-16) years, and the median overall survival (OS) and disease free survival (DFS) were 16.8 months and 13.5 months, respectively. The early response rate to treatment was 43.9%, with myeloid-antigens-expression group lower than the non-expression group (29.6% vs 61.3%, χ2=5.814, P=0.020); The complete remission (CR) rate after one-course induction therapy was 86.2% (56/65), with good-response group higher than the poor-response group (100.0% vs 74.2%, χ2=6.680, P=0.003);The CR rate after induction in patients receiving imatinib plus chemotherapy was higher than the patients receiving chemotherapy only (94.9% vs 73.1%, χ2=5.185, P=0.024). The 2-and 5-year OS were (61.4±7.0)% and (50.8±8.1)%, respectively. The 2-and 5-year DFS were (54.6±6.8)% and (48.6±7.3)%, respectively. Univariate analysis showed that the initial WBC, LDH, spleen size, liver size, with-myeloid-antigens-expression, early response to treatment, MRD (BCR-ABL) after one-course induction, application of imatinib and different treatment options affected 2-year OS rate (all P<0.05). LDH, spleen size, liver size, with-myeloid-antigens-expression, early response to treatment, MRD (BCR-ABL) after one-course induction, application of imatinib and different treatment options affected 2-year DFS rate (all P<0.05). Multivariate prognostic analysis for OS (RR=45.7, 95% CI 1.4-1 528.2, P=0.033) and DFS (RR=52.3, 95% CI 1.6-1 725.9, P=0.026) showed that the spleen ≥ 3 cm was the independent risk factor.@*Conclusions@#Pediatric Ph+ ALL is a special condition with unique clinical and biological features. The early response to treatment was poor in patients with myeloid-antigens-expression, which resulted in a low CR rate after one-course induction and the administration of imatinib can remarkably improve the CR rate. Initial spleen ≥ 3 cm is an independent prognostic factor. The efficacy of chemotherapy alone is poor, and imatinib combined with chemotherapy is applauded in the aim of improving outcomes.
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Objective To explore the prognostic value of quantitative monitoring of RUNX1-RUNX1T1 fusion gene in pediatric t(8;21)/RUNX1-RUNX1T1 positive acute myeloid leukemia(AML).Methods A total of 81 new-ly diagnosed AML children with t(8;21)/RUNX1-RUNX1T1 positive were enrolled in the People′s Hospital,Peking University,between August 2005 and January 2016.RUNX1-RUNX1T1 gene copy number of all the patients was analyzed by real-time quantitative PCR(qPCR)technology at diagnosis and after therapy in all patients.Cumulative incidence of relapse rate(CIR),event-free survival(EFS)rate and overall survival(OS)rate were estimated by Ka-plan-Meier method and prognostic factors were evaluated by COX regression. Results The level of RUNX1-RUNX1T1 gene on diagnosis was used as the baseline to determine whether the level of gene after treatment had a more than 3 logarithmic(3 log)reduction.After 2 courses of induction therapy,the patients with a more than 3 log reduction of RUNX1-RUNX1T1 transcript levels(≥3 log)had better EFS rate(82.4% vs.57.6%,χ2=7.454,P<0.01),and better OS(93.6% vs.59.3%,χ2=9.703,P<0.01),compared to the patients with a less than 3 log reduction(<3 log).Multivariate analysis showed that 3 log reduction in RUNX1-RUNX1T1 transcript levels after 2 courses of in-duction therapy was an independent prognostic factor for EFS rate[hazard ratio(HR)=4.223,95% confidence interval (CI):1.507-11.836,P<0.01]and OS rate(HR=5.002,95%CI:1.282-19.516,P<0.05).When periodically monitoring the RUNX1-RUNX1T1 gene,63 out of the 81 children patients were monitored for more than 6 times.The patients who had a more than 3 log reduction of gene before,but then those whose gene transcript level rose more than 1 log level were divided into group A,and the remaining patients were divided group B,and the difference of CIR was statistically significant between group A and group B(46. 7% vs. 4. 7%,P <0. 01). Conclusions RUNX1-RUNX1T1 gene copy number was detected with qPCR method in pediatric t(8;21)/RUNX1-RUNX1T1 positive AML,which can determine the treatment effect,predict the recurrence of patients and assess long-term prognosis.Thus it has great clinical application value.
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<p><b>OBJECTIVE</b>To evaluate the safety and efficacy of chimeric antigen receptors T cells (CAR-T) in childhood acute B lymphoblastic leukemia (B-ALL).</p><p><b>METHODS</b>A relapsed B-ALL child after allogeneic hematopoietic stem cell transplantation (allo-HSCT) was treated with CAR-T, and the related literatures were reviewed.</p><p><b>RESULT</b>An 11-year-old girl with TEL-AML1 fusion gene positive BALL who suffered a bone marrow relapse 28 months after remission from conventional chemotherapy. During the second remission, the patient received haploidentical allo-HSCT. She relapsed with detectable TEL-AML1 fusion gene even after chemotherapy and donor leukocyte infusions. She received an experimental donor-derived fourth generation CD19 CAR-T therapy. After infusion of 1 × 10(6)/kg CAR-T cells, she experienced only mild or moderate cytokine-release syndrome and the minimal residual disease turned negative. Then three maintenance of CAR-T cell infusions [(0.83-1.65)×10(6)/kg] was administered, and the disease-free survival had lasted for 10 months. However, the TEL-AML1 copies in her blood still increased and she died with leukemia relapse after additional CAR-T cell infusion.</p><p><b>CONCLUSION</b>Treatment of relapsed B-ALL with the fourth generation CAR-T cells directed against CD19 was effective and safe. CAR-T therapy is a novel therapeutic approach that could be useful for patients with relapsed and refractory B-ALL who have failed all other treatment options.</p>
Subject(s)
Child , Female , Humans , Bone Marrow , Core Binding Factor Alpha 2 Subunit , Genetics , Disease-Free Survival , Hematopoietic Stem Cell Transplantation , Neoplasm, Residual , Oncogene Proteins, Fusion , Genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Genetics , Therapeutics , Receptors, Antigen, T-Cell , Genetics , Recurrence , Remission Induction , T-Lymphocytes , Cell Biology , Transplantation, HomologousABSTRACT
Objectives To compare the efficacy and adverse effects of combining all-trans retinoic acid and arsenic triox-ide with or without anthracyclines on the treatment of childhood acute promyelocytic leukemia (APL) patients. Methods The retrospective study included 46 children as newly diagnosed APL from January 1st, 2001 to December 31st , 2012. Efficacy and adverse effects for different induction therapies and in high and low white blood cell (WBC) count subgroups were studied. Results In the non antharcycline containing group, 2 patients died during remission induction, and in the antharcycline containing group none of the patients died. No statistical difference was observed between the antharcycline containing group and the non antharcycline containing group in complete remission, the length of time to achieve molecular complete remission and minimal residual disease quantitative analysis at the end of the induction. The mean duration of high WBC count subgroup in the anthar-cycline containing group was shortened than that of the non antharcycline containing group (P<0.05). The recovery time of the abnormal coagulation was found similar between these two groups. Conclusions The use of antharcycline in induction therapy could shorten the duration of high WBC count and reduced the WBC count peak , thus reduces the risk of early death.
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Objective To explore the prognostic significance of bone marrow examination at different time points by using different methods during induction therapy.Methods From Feb.2004 to Jan.2013,268 newly diagnosed (B acute lymphoblastic leukemia,B-ALL) pediatric patients in Peking University People's Hospital,were enrolled for the study.In this study,the overall survival (OS) ratio and event-free survival(EFS) ratio of patients with different bone marrow morphology on day 8 and day 15 were analyzed.Based on different cut off value of minimal residual disease (MRD) on day 15 and end-of-induction,the OS ratio and EFS ratio of the higher patients and the lower patients were compared.Results Patients with M1,M2 or M3 marrows on day 8 had no significant difference in OS ratio (P =0.372) or EFS ratio (P =0.393).When it came to day 15,patients with M1,M2 or M3 marrows had no significant difference in OS ratio (P =0.050) or EFS ratio (P =0.324).Patients with MRD ＞ 10.00％ on day 15 had lower OS ratio than those with MRD ≤ 10.00％,and it had significant difference(P =0.022).But there was no significant difference in EFS ratio (P =0.191).As for MRD on the end-of-induction,when using the MRD level of 0.0l ％,0.10％,1.00％ as cut-off values,the lower group of end-of-induction MRD was significantly associated with a higher probability of OS ratio and it had significant differences(P =0.018,0.006,0.002),and it showed the same results at EFS ratio (P =0.002,0.000,0.000).Conclusions The bone marrow morphology on day 8 and day 15 during induction therapy had no prognostic significance.The MRD of day 15 had prognostic significance when using 10.00％ as the cut off value.The critical value of MRD on the end-of-induction MRD should be 0.01％ for the prognosis.
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Objectives To investigate the inlfuence of polymorphisms of SLC19A1 80G>A, MDR1 exon26C>T and MDR1 exon21G>T/A on curative effect and adverse reaction of high-dose methotrexate in patients with acute lymphoblastic leukemia. Methods MALDI-TOF-MS technique was used to detect the polymorphisms of SLC19A1 80G>A, MDR1 exon 26C>T and MDR1 exon21G>T/A in 108 patients with acute lymphoblastic leukemia (ALL). The relationship of genetic polymorphism, survival rate and toxicity was analyzed. Results The 36-month event-free survival was not related to any polymorphisms of MDR1 and SLC19A1. Patients with mutant types of MDR1 exon26C>T and MDR1 exon21G>T/A showed a much higher MTX plasma levels at 24 hours and higher incidence of hepatic injury (PT, MDR1 exon21G>T/A has a large inlfuence on hepatic toxicity and plasma concentra-tions of MTX.
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Objective To detect specific IgM of Lyme disease indirect ELISA using recombinant outer surface protein C(OpsC)of Borrelia burgdorferi in vitro was established. Methods Coated concentration of recombinant OspC and dilution multiple of serum anol concentration of enzyme secondary antibody were determined by block,and degree of percision.specificity interference and interruption test were performed. Results Best concentration of OspC was 150 μg/L.within-run CV was 6.3% between-run CV was 11.8%.Confimred 33 Lyme patients in clinic and 57 controls were examined meanwhile by this method and import ELISA kit,coincidena rate was 97.8%.Conclusion This ELISA using recombinant OspC was a good method for early diagnostic of Lyme disease.