Copy number alteration (CNA) is a significant genetic change in pediatric B-cell acute lymphoblastic leukemia (B-ALL), with CDKN2A/B deletions, PAX5 deletions, and IKZF1 deletions being the most common. Recent studies have increasingly highlighted the potential prognostic significance of these gene deletions and multiple co-deletions in pediatric B-ALL. This paper reviews the main detection methods for CNA, as well as the prognostic characteristics and treatment approaches for common CNA in pediatric B-ALL.
Humans ; DNA Copy Number Variations ; Child ; PAX5 Transcription Factor/genetics* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Cyclin-Dependent Kinase Inhibitor p15/genetics* ; Ikaros Transcription Factor/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Gene Deletion ; Cyclin-Dependent Kinase Inhibitor p16/genetics* ; Prognosis

OBJECTIVE: To retrospectively analyze the clinical characteristics of 15 children with B-cell acute lymphoblastic leukemia (B-ALL) treated with blinatumomab, and summarize the efficacy and safety of blinatumomab in the treatment of pediatric B-ALL. METHODS: Fifteen children who received treatment with blinatumomab from February 2022 to January 2023 were enrolled in this study. One course (28 days) of blinatumomab concurrent with intrathecal chemotherapy was given according to the standard regimen, except for 2 cases who had shortened course of treatment due to hematopoietic stem cell transplantation (HSCT) and did not receive combined intrathecal chemotherapy, and 1 case had a shortened course of treatment due to economic problems. The efficacy and safety of the treatment were evaluated. RESULTS: In terms of efficacy, for the children who had achieved complete molecular remission (CMR) before treatment, blinatumomab treatment could effectively maintain CMR status; For the children who did not achieve CMR, the CMR rate after one standard course of treatment with blinatumomab reached 66.7%(4/6); For the children with relapsed/refractory ALL (R/R ALL) who had minimal residual disease (MRD), the MRD clearance rate reached 75.0%(3/4). The statistical results of the incidence of adverse events showed that 13.3%(2/15) of the children did not experience any adverse events. The most common adverse events were cytokine release syndrome (CRS) (73.3%, 11/15) and transaminase elevation (26.7%, 4/15); 33.3%(5/15) of the children experienced grade 3 or higher adverse events. All the adverse events were resolved after symptomatic treatment.The level of IgG decreased significantly after 4-7 weeks of treatment with blinatumomab, and gradually recovered after 8 weeks of treatment. CONCLUSION Blinatumomab can be used as a safe and effective treatment for inducing deep remission in pediatric R/R-ALL patients and as a bridge therapy for the pediatric ALL patients who are intolerant to chemotherapy.
Humans ; Antibodies, Bispecific/therapeutic use* ; Child ; Retrospective Studies ; Female ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Remission Induction ; Treatment Outcome ; Child, Preschool ; Adolescent ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*

OBJECTIVE: To analyze clinical characteristics and prognosis of B-cell acute lymphoblastic leukemia (B-ALL) patients with IKZF1 deletion. METHODS: 72 patients with B-ALL admitted to our hospital from April 2020 to January 2023 were selected, IKZF1 deletion were detected, and clinical characteristics and prognosis were analyzed. RESULTS: Among the 72 patients, a total of 32 patients (44.4%) were identified with IKZF1 deletions (IKZF1 ⁺ ). There was no statistically significant difference in basic clinical data between patients with normal IKZF1 (IKZF1 ^-) and those with IKZF1 ⁺ (P >0.05). The proportion of patients with IKZF1 ⁺ in Ph⁺ group was significantly higher than that in Ph^- group (P < 0.05). The main types of IKZF1 ⁺ were exon 1-8 deletion (34.4%) and exon 4-7 deletion (31.2%). The median OS and PFS of IKZF1 ^- patients were significantly longer than those of IKZF1 ⁺ patients (OS: 26.0 months vs 16.0 months, χ ²=23.094, P < 0.05; PFS: 26.0 months vs 16.0 months, χ ²=11.150, P < 0.05). Among IKZF1 ⁺ patients, the median OS of patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) was significantly longer than that of patients who did not receive allo-HSCT (no reached vs 15.0 months, χ ²=5.685, P < 0.05). CONCLUSION IKZF1 deletion is a risk factor affecting the prognosis of B-ALL patients.
Humans ; Ikaros Transcription Factor/genetics* ; Prognosis ; Gene Deletion ; Female ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Adult ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Adolescent ; Young Adult ; Middle Aged

OBJECTIVE: To analyze the gene mutation profile in children with acute lymphocyte leukemia (ALL) and to explore its prognostic significance. METHODS: Clinical data of 249 primary pediatric ALL patients diagnosed and treated in the Department of Hematological Oncology of Wuhan Children's Hospital from January 2018 to December 2021 were analyzed retrospectively. Next-generation sequencing (NGS) was used to obtain gene mutation data and analyze the correlation between it and the prognosis of children with ALL. RESULTS: 227 (91.2%) were B-ALL, 22 (8.8%) were T-ALL among the 249 cases, and 178 (71.5%) were found to have gene mutations, of which 85 (34.1%) had ≥3 gene mutations. NRAS(23.7%), KRAS (22.9%),FLT3(11.2%), PTPN11(8.8%), CREBBP (7.2%), NOTCH1(6.4%) were the most frequently mutated genes, the mutations of KRAS, FLT3, PTPN11, CREBBP were mainly found in B-ALL, the mutations of NOTCH1 and FBXW7 were mainly found in T-ALL. The gene mutation incidence of T-ALL was significantly higher than that of B-ALL (χ²= 5.573，P＜0.05) and were more likely to have co-mutations (P＜0.05). The predicted 4-year EFS rate (47.9% vs 88.5%, P＜0.001) and OS rate (53.8% vs 94.1%, P＜0.001) in children with tp53 mutations were significantly lower than those of patients without tp53 mutations. Patients with NOTCH1 mutations had higher initial white blood cell count （128.64×10⁹/L vs 8.23×10⁹/L，P＜0.001）, and children with NOTCH1 mutations had a lower 4-year EFS rate than those of without mutations (71.5% vs 87.2%, P＝0.037). CONCLUSION Genetic mutations are prevalent in childhood ALL and mutations in tp53 and NOTCH1 are strong predictors of adverse outcomes in childhood ALL, with NGS contributing to the discovery of genetic mutations and timely adjustment of treatment regimens.
Child ; Humans ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Cell Cycle Proteins/genetics* ; Proto-Oncogene Proteins p21(ras)/genetics* ; Retrospective Studies ; Ubiquitin-Protein Ligases/genetics* ; Prognosis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Mutation ; Lymphocytes

OBJECTIVE: To discover the relationship between matrix remodeling associated 7 (MXRA7) and acute B lymphoblastic leukemia (B-ALL), and explore the effect of MXRA7 on the biological functions of B-ALL cell line REH. METHODS: The expression of MXRA7 in blood diseases was searched and analyzed through BloodSpot database. Real-time qPCR was used to detect the expression level of MXRA7 in B-ALL cell line 697 and REH cells. Lentivirus-mediated shRNA interference technology was utilized to knock down the expression of MXRA7 in REH cells. The effects of MXRA7 on the biological functions of REH cells were studied by in vitro experiments. Cell proliferation was detected by CCK-8 assay, cell cycle was detected by PI staining, cell apoptosis was detected by Annexin V and 7-AAD staining, and the expression of apoptosis pathway related proteins was detected by Western blot. RESULTS: Database analysis showed that MXRA7 was highly expressed in B-ALL patients, and real-time qPCR results showed that MXRA7 was also highly expressed in cell lines 697 and REH cells. Knockdown of MXRA7 in REH cells inhibited the cell proliferation and increased the percentage of G₀/G₁ phase cells. After treatment with cytarabine, the apoptotic ratio was increased in MXRA7-impaired REH cells, and the activation of caspase-3 and caspase-9 were also increased. CONCLUSION Knockdown of MXRA7 can reduce the malignancy of REH cells by inhibiting the cell proliferation and increasing the sensitivity of REH cells to cytarabine. These results indicate MXRA7 may be as a novel target for the treatment of B-ALL, and the potential usefulness of MXRA7 in B-ALL deserves further investigation.
Humans ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Cytarabine ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism*

This article reports two cases of children with B-cell acute lymphoblastic leukemia (B-ALL) complicated by invasive fungal disease (IFD) who received bridging treatment using blinatumomab. Case 1 was a 4-month-old female infant who experienced recurrent high fever and limb weakness during chemotherapy. Blood culture was negative, and next-generation sequencing (NGS) of peripheral blood, bronchoalveolar lavage fluid, and cerebrospinal fluid were all negative. Chest CT and cranial MRI revealed obvious infection foci. Case 2 was a 2-year-old male patient who experienced recurrent high fever with multiple inflammatory masses during chemotherapy. Candida tropicalis was detected in peripheral blood and abscess fluid using NGS, while blood culture and imaging examinations showed no obvious abnormalities. After antifungal and blinatumomab therapy, both cases showed significant improvement in symptoms, signs, and imaging, and B-ALL remained in continuous remission. The report indicates that bridging treatment with blinatumomab in children with B-ALL complicated by IFD can rebuild the immune system and control the underlying disease in the presence of immunosuppression and severe fungal infection.
Child, Preschool ; Female ; Humans ; Infant ; Male ; Antibodies, Bispecific/therapeutic use* ; Invasive Fungal Infections/drug therapy* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Remission Induction

OBJECTIVE: To explore the consistency of flow cytometry (FCM) method and polymerase chain reaction (PCR) technique in the detection of minimal residual disease (MRD) at different treatment stages in pediatric patients with TCF3/PBX1⁺ B-cell acute lymphoblastic leukemia (B-ALL) and the correlations between the detection results and prognosis. METHODS: The clinical data of 64 newly diagnosed pediatric patients with TCF3/PBX1⁺ B-ALL admitted to the Department of Pediatrics of Peking University People's Hospital from January 2005 to December 2017 were retrospectively analyzed. FCM and PCR methods were used to monitor the MRD level in bone marrow samples from 64 children during the same period of treatment on d33 and d90 respectively, and the detection results were analyzed. RESULTS: There were 37 males and 27 females in the 64 patients, with a median age of 8 years(range 0.8 to 16 years). The complete remission (CR) rate after the first cycle of induction chemotherapy was 98.4% (62/63), with overall CR rate of 100%. 12 patients experienced recurrence, with a median recurrence time of 16.9 (5.3-46.3) months. The median follow-up time of the 64 patients was 77.2 (1.0-184.8) months , and the 5-year overall survival (OS) rate and event-free survival (EFS) rate were 82.8%±4.7% and 75.0%±5.4%, respectively. On d90, the concordance rate of the MRD results from the two methods was 98.4%, and the related kappa value was 0.792 (P < 0.001), which were significantly higher than those on d33. After induction chemotherapy (d33), the 5-year EFS rate of MRD-FCM^- group (79.3%±5.3%) was significantly better than that of MRD-FCM⁺ group (40.0%±21.9%) (P =0.028), there were no significant differences in the 5-year OS rate and EFS rate between MRD-PCR⁺ group and MRD-PCR^- group, and the 5-year EFS rate of MRD-FCM^-/PCR^- group (85.4%±5.5%) was significantly better than that of MRD-FCM⁺/PCR⁺ group (40.0 %±21.9%) (P =0.026). CONCLUSION In children with TCF3/PBX1⁺ B-ALL, the MRD results detected by FCM and PCR methods show good consistency, especially in consolidation therapy period (d90). The MRD level at the end of induction therapy (d33) is an important factor affecting the long-term prognosis, especially the MRD results detected by FCM method, which is significantly associated with prognosis.
Male ; Female ; Child ; Humans ; Infant ; Child, Preschool ; Adolescent ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Neoplasm, Residual/diagnosis* ; Clinical Relevance ; Retrospective Studies ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Burkitt Lymphoma ; Basic Helix-Loop-Helix Transcription Factors/therapeutic use*

OBJECTIVE: To investigate the expression, clinical significance and prognosis of vitamin D receptor (VDR) gene and NF-κB pathway in children with acute lymphoblastic leukemia (ALL). METHODS: Thirty children with definitive diagnoses of ALL from December 2018 to December 2021 were selected as ALL group, and 30 healthy children under physical examination were selected as control group. Peripheral blood of all study subjects was collected. The VDR and NF-κB mRNA and protein expressions were detected by real-time quantitative PCR and Western blot, respectively. The relationship between mRNA expression of the above genes and clinical characteristics of children was retrospectively analyzed. RESULTS: The relative expression of VDR mRNA in peripheral blood of children with ALL was significantly lower than that in the control group (P < 0.05), while NF-κB mRNA was higher (P < 0.001). The expression of NF-κB mRNA in ALL children with peripheral blood white blood cell count (WBC) < 50×10⁹/L at initial diagnosis was significantly higher than those with WBC≥50×10⁹/L (P < 0.01). The expression of NF-κB mRNA in ALL children with infection was significantly higher than that those without infection (P < 0.05). There were no significant differences in NF-κB mRNA expression between children with different sex, age, hemoglobin at initial diagnosis, platelet, immunologic typing, risk and induced response (P >0.05). CONCLUSION The expression of NF-κB is of value to diagnosis and prognosis of ALL in children.
Child ; Humans ; NF-kappa B ; Receptors, Calcitriol/genetics* ; Retrospective Studies ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; RNA, Messenger/genetics*

Humans ; Receptors, Chimeric Antigen/therapeutic use* ; DNA-Binding Proteins/genetics* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Proto-Oncogene Proteins c-bcl-2/genetics* ; Cell- and Tissue-Based Therapy ; Oncogene Proteins, Fusion/genetics* ; Translocation, Genetic

Objective:b> Murine CD19 chimeric antigen receptor T-cell (CAR-T) products have been approved for the treatment of refractory/relapsed (R/R) B-cell acute lymphocytic leukemia (B-ALL) ; moreover, humanized products are also undergoing clinical trials. This study aimed to explore the differences in safety and short- and long-term follow-up efficacy between humanized and murine CD19 CAR-T-cells for treating relapsed and refractory B-ALL. Methods:b> Clinical data of 80 patients with R/R B-ALL treated with CD19-targeted CAR-T-cells at the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology between May 2016 and March 2023 were analyzed, which included 31 patients with murine CAR-T and 49 with humanized products. Results:b> The proportion of patients with cytokine-release syndrome (CRS) in the murine and humanized groups was 63.1% and 65.3%, respectively. Moreover, a higher proportion of patients suffered from severe CRS in the murine group than in the humanized CAR-T group (19.4% vs 8.2%, P=0.174). Furthermore, one patient per group died of grade 5 CRS. The incidence of grade 1-2 immune effector cell-associated neurotoxicity syndrome (ICANS) was 12.9% and 6.1%, respectively; severe ICANS were not observed. Among patients receiving murine CAR-T-cells, an overall response (OR) was observed in 74.2%. Conversely, the OR rate of patients receiving humanized CAR-T-cells was 87.8%. During the median follow-up time of 10.5 months, the median recurrence-free survival (RFS) of patients with murine CAR-T-cells was 12 months, which was as long as that of patients with humanized CAR-T-cells. The median overall survival (OS) were not reached in both groups. Of the 45 patients with a bone marrow burden over 20% at baseline, humanized CAR-T therapy was associated with a significantly improved RFS (43.25% vs 33.33%, P=0.027). Bridging transplantation was an independent factor in prolonging OS (χ(2)=8.017, P=0.005) and PFS (χ(2)=6.584, P=0.010). Common risk factors, such as age, high proportion of bone marrow blasts, and BCR-ABL fusion gene expression, had no significant effect on patients' long-term follow-up outcomes. Three patients reached complete remission after reinfusion of humanized CAR-T-cells. However, one patient relapsed one month after his second infusion of murine CAR-T-cells. Conclusions:b> The results indicate that humanized CAR-T therapy showed durable efficacy in patients with a higher tumor burden in the bone marrow without any influence on safety. Moreover, it could overcome immunogenicity-induced CAR-T resistance, providing treatment options for patients who were not treated successfully with CAR-T therapies.
Animals ; Humans ; Mice ; Antigens, CD19 ; Burkitt Lymphoma/drug therapy* ; Cell- and Tissue-Based Therapy ; Follow-Up Studies ; Immunotherapy, Adoptive ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy* ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Receptors, Chimeric Antigen