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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.
ABSTRACT
<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
Objective To establish a convenient and specific molecular method for cytomegalovirus(CMV) surveillance in recipients of allogeneic hematopoietic stem cell transplantation(allo-HSCT) and ana-lyze the correlation between cytomegalovirus genotypes and transplant-related complication to decrease CMV-related mortality through restricted endoenzyme digestion.Methods 135blood samples were regularly col-lected from79consecutive patients who received allo-HSCT between April2001and April2003.Of the79 patients observed,median age was32(range from11to60) and the ratio of male and female was1.63∶1.DNA extracted from whole blood was amplified with CMV sequence using Nested PCR and gB genotypes were identified through restriction enzyme analysis.Results Among the135clinical isolates from79pa-tients,42cases(66specimens) were Positive.The gB genotype from42cases(45samples) were identified as gB1,21(46.7%);gB2,14(31.1%);gB3,7(15.6%);gB4,3(6.7%),respectively,by restric-tion enzyme analysis.Among them,3patients were successively infected with CMV gB1and gB2.The inci-dence of GVHD in groups of CMV(+) and CMV(-) was81.0% and32.4%,respectively(P
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CMV related matrix protein pp65 antigenemia was screened in 100 Allo HSCT patients after transplantation. As control groups, samples from fourteen autologous HSCT patients, seventeen patients with various hematological malignant disorders, as well as twenty seven normal donors also were detected. CMV antigenemia was found in 91/100 Allo HSCT patients (91%) after transplantation. 56 % patients with antigenemia developed CMV disease. 54% patients developed acute GVHD. In 87 patients survived more than three months, 52 9% patients developed chronic GVHD. After follow up 18(4～36) months post transplantation, 21 patients died of CMV related diseases. Compared with autologous and non transplantation patients, CMV antigenemia and CMV diseases were particularly associated with Allo HSCT patients. It was obviously correlated with acute and chronic GVHD. CMV infection is a major factor affecting the clinical outcome of Allo HSCT patients.
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To investigate the significance of GATA-2 and immunoglobulin heavy chain germline gene C( micro ) (IgH germline gene C( micro )) expression and coexpression in various leukemia cells, GATA-2 and IgH germline gene C( micro ) mRNA in bone marrow and peripheral blood cells from 63 leukemia patients were detected by reverse transcription-polymerase chain reaction (RT-PCR). No GATA-2 or IgH germline gene C( micro ) mRNA were detected in normal bone marrow and peripheral blood. GATA-2 mRNA were be detected in 91.3% patients with acute myeloid leukemia (AML), 75% patients with acute lymphoblastic leukemia (ALL) as well as 83.3% patients with chronic myeloid leukemia (CML-CP); IgH germline gene C( micro ) mRNA were be identified in 47.8% AML, 41.6% ALL, as well as 5.6% CML-CP. All patients with CML-AP and CML-BC expressed GATA-2 mRNA and partly expressed IgH germline gene C( micro ) mRNA. 47.8% AML and 41.6% ALL patients coexpressed GATA-2 and IgH germline gene C( micro ) mRNA. GATA-2(+) IgH germline gene C( micro )(+) cells of AML and ALL were mainly HLA-DR positive. As aberration of the transcription factors, GATA-2 and germline IgH germline gene C( micro ) gene might been linked to leukemogenesis. Various expression of GATA-2 and germline IgH germline gene C( micro ) gene in leukemia might correlated with the heterogeneous differentiation level of leukemia cells. The fact that leukemia with GATA-2(+) IgH germline gene C( micro )(+) coexpression indicated multilineage impairment of hematopoietic cells.