BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

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 investigate the clinical characteristics and prognostic of venetoclax (VEN) combined targeted therapy in acute leukemia (AL) patients with PICALM∷MLLT10 fusion gene positivity. METHODS: A retrospective analysis was conducted on 16 PICALM∷MLLT10-positive AL patients treated at the First Affiliated Hospital of Soochow University from January 2021 to August 2024. These patients were diagnosed by targeted RNA sequencing (RNA-seq) or reverse transcription multiplex PCR, including newly diagnosed and relapsed/refractory (R/R) cases. The immunophenotypes, genetic features, gene mutations, and the efficacy of VEN combination targeted therapy of patients were evaluated. RESULTS: Among the 16 cases, 3 were confirmed by reverse transcription multiplex PCR, and 13 were detected through targeted RNA-seq among 528 AL patients, with a detection rate of 2.46%. The averge age of patients was (28.0±8.58) years. Patients exhibited diverse immunophenotypes, including 7 cases of acute myeloid leukemia, 5 of acute T-lymphoblastic leukemia, 1 of acute B-lymphoblastic leukemia, 1 of acute undifferentiated leukemia, and 2 of mixed-phenotype acute leukemia. Among them, 11 had extramedullary disease (EMD), 14 expressed CD7, and 12 expressed CD33. Major co-occurring mutations included PHF6 (6 cases), NOTCH1 (5 cases), and 7 cases with complex karyotypes. Of the 12 patients who received standard induction therapy, 7 did not achieve remission (PR+NR). All 4 patients treated with VEN combination therapy achieved complete remission (CR). Among the 7 induction failure cases, 4 achieved CR upon re-induction with VEN, while the remaining 3 re-induced with standard therapy, did not achieve CR. Thirteen patients received allogeneic hematopoietic stem cell transplantation, including 6 who received maintenance therapy with hypomethylating agents (HMA) alone or in combination with VEN, and seven were followed up. Survival analysis showed that the overall survival was better in the maintenance therapy group (P =0.044). CONCLUSION PICALM∷MLLT10-positive AL involves multiple lineages and demonstrates poor response to conventional chemotherapy. VEN combination therapy shows promising efficacy in both newly diagnosed and R/R patients. Post-transplant maintenance therapy with HMA alone or combined with VEN may extend survival; however, further clinical validation is required.
Humans ; Sulfonamides/therapeutic use* ; Retrospective Studies ; Prognosis ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Adult ; Male ; Female ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Oncogene Proteins, Fusion/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*

Objective: To summarize the clinical data and prognosis of children with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) common genes. Methods: This was a retrospective cohort study.Clinical data of 56 children with Ph-like ALL common gene cases (Ph-like ALL positive group) treated from January 2017 to January 2022 in the First Affiliated Hospital of Zhengzhou University, Henan Children's Hospital, Henan Cancer's Hospital and Henan Provincial People's Hospital were collected, 69 children with other high-risk B cell acute lymphoblastic leukemia (B-ALL) at the same time and the same age were selected as the negative group. The clinical characteristics and prognosis of two groups were analyzed retrospectively. Comparisons between groups were performed using Mann-Whitney U test and χ² test. Kaplan-Meier method was used for survival curve, Log-Rank test was used for univariate analysis, and the Cox regression model was used for multivariate prognosis analysis. Results: Among 56 Ph-like ALL positive patients, there were 30 males and 26 females, and 15 cases were over 10 years old. There were 69 patients in Ph-like ALL negative group. Compared with the negative group, the children in positive group were older (6.4 (4.2, 11.2) vs. 4.7 (2.8, 8.4) years), and hyperleukocytosis (≥50×10⁹/L) was more common (25% (14/56) vs. 9% (6/69)), the differences were statistically significant (both P<0.05). In the Ph-like ALL positive group, 32 cases were positive for IK6 (1 case was co-expressed with IK6 and EBF1-PDGFRB), 24 cases were IK6-negative, of which 9 cases were CRLF2 positive (including 2 cases with P2RY8-CRLF2, 7 cases with CRLF2 high expression), 5 cases were PDGFRB rearrangement, 4 cases were ABL1 rearrangement, 4 cases were JAK2 rearrangement, 1 case was ABL2 rearrangement and 1 case was EPOR rearrangement. The follow-up time of Ph-like ALL positive group was 22 (12, 40) months, and 32 (20, 45) months for negative group. The 3-year overall survival (OS) rate of positive group was significantly lower than the negative group ((72±7) % vs. (86±5) %, χ²=4.59, P<0.05). Compared with the 24 IK6-negative patients, the 3-year event free survival (EFS) rate of 32 IK6 positive patients was higher, the difference was statistically significant ((88±9) % vs. (65±14) %, χ²=5.37, P<0.05). Multivariate Cox regression analysis showed that the bone marrow minimal residual disease (MRD) not turning negative at the end of first induction (HR=4.12, 95%CI 1.13-15.03) independent prognostic risk factor for patient with Ph-like ALL common genes. Conclusions: Children with Ph-like ALL common genes were older than other high-risk B-ALL patients at diagnosis, with high white blood cells and lower survival rate. The bone marrow MRD not turning negative at the end of first induction were independent prognostic risk factor for children with Ph-like ALL common gene.
Male ; Female ; Humans ; Child ; Prognosis ; Philadelphia Chromosome ; Retrospective Studies ; Receptor, Platelet-Derived Growth Factor beta/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Neoplasm, Residual

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 explore the efficacy and safety of Venetoclax combined with multidrug chemotherapy in patients with relapsed or refractory early T-cell precursor acute lymphoblastic leukemia (R/R ETP-ALL) . Methods: This study retrospectively analyzed 15 patients with R/R ETP-ALL who received Venetoclax combined with multidrug chemotherapy from December 2018 to February 2022. Among them, eight cases were combined with demethylated drugs, four cases were combined with demethylated drugs and HAAG chemotherapy regimen, two cases were combined with demethylated drugs and CAG regimen, and one case was combined with Cladribine. Specific usage and dosage of Venetoclax: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3-28, orally; when combined with azole antifungal drugs, dosage was reduced to 100 mg/d. Results: Fifteen patients (10 males and 5 females) with R/R ETP-ALL were treated with Venetoclax and multidrug chemotherapy with a median age of 35 (12-42) years old. Of 4 refractory and 11 relapsed patients, the efficacy was evaluated on the 21th day following combined chemotherapy: the overall response rate, the complete response (CR) rate, and the CR with incomplete hematological recovery (CRi) rate were 67.7% (10/15), 60.0% (9/15), and 6.7% (1/15), respectively. For the overall study population, the 12-month overall survival (OS) rate was 60.0%, and the median OS was 17.7 months. The disease-free survival (DFS) rate of all CR patients at 12 months was 60.0%, and the median DFS did not reach. About 14 patients had Ⅲ-Ⅳ hematological toxicity, but these adverse reactions were all controllable. No adverse reaction in the nervous system and tumor lysis syndrome occurred in this study, and no adverse reaction of organs above grade Ⅲ occurred. Conclusion: Venetoclax combined with multidrug chemotherapy may be a safe and promising treatment option for patients with R/R ETP-ALL.
Male ; Female ; Humans ; Adult ; Retrospective Studies ; Treatment Outcome ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Precursor Cells, T-Lymphoid ; Leukemia, Myeloid, Acute/drug therapy*

Objective: 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: 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: 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: 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

Objective: To observe the treatment response of a two-dose regimen of inotuzumab ozogamicin (inotuzumab), a monoclonal antibody targeting CD22, for patients with heavily treated relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), including those failed or relapsed after chimeric antigen receptor (CAR) -T-cell therapy. Methods: Pediatric and adult patients who received two doses of inotuzumab and who were evaluated after inotuzumab treatment were included. Antibody infusions were performed between March 2020 and September 2022. All patients expressed CD22 antigen as detected by flow cytometry (>80% leukemic cells displaying CD22) before treatment. For adults, the maximum dosage per administration was 1 mg (with a total of two administrations). For children, the maximum dosage per administration was 0.85 mg/m(2) (no more than 1 mg/dose; total of two administrations). The total dosage administered to each patient was less than the standard dosage of 1.8 mg/m(2). Results: Twenty-one patients with R/R B-ALL were included, including five children (<18 years old) and sixteen adults. Seventeen patients presented with 5.0% -99.0% leukemic blasts in the bone marrow/peripheral blood or with extramedullary disease, and four patients were minimal residual disease (MRD) -positive. Fourteen patients underwent both CD19 and CD22 CAR-T-cell therapy, four underwent CD19 CAR-T-cell therapy, and three underwent blinatumomab therapy. Eleven patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). After inotuzumab treatment, 14 of 21 patients (66.7% ) achieved a complete response (CR, one was MRD-positive CR), and all four MRD-positive patients turned MRD-negative. Four of six patients who failed recent CD22 CAR-T-cell therapy achieved a CR after subsequent inotuzumab treatment. Seven patients (33.3% ) demonstrated no response. Grade 1-3 hepatotoxicity occurred in five patients (23.8% ), one child with no response experienced hepatic veno-occlusive disease (HVOD) during salvage transplantation and recovered completely. Conclusion: For patients with heavily treated R/R B-ALL, including those who had undergone allo-HSCT and CD19/CD22 CAR-T-cell therapy, the two-dose regimen of inotuzumab resulted in a CR rate of 66.7%, and the frequency of hepatotoxicity and HVOD was low.
Adult ; Humans ; Child ; Adolescent ; Inotuzumab Ozogamicin ; Receptors, Chimeric Antigen ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy* ; Antibodies, Monoclonal ; Adaptor Proteins, Signal Transducing ; Antigens, CD19 ; Chemical and Drug Induced Liver Injury

OBJECTIVE: To investigate the diagnostic efficacy of seven glomerular filtration rate (GFR) evaluation formulas Schwartz2009, Schwartz1976, Counahan-Barratt, Filler, CKD-EPI_scysc, Cockrofi-Gault, CKD-EPI_ScysC-Scr in high concentration of methotrexate (HDMTX) chemotherapy dose adjusted cut-off point (GFR ≤85 ml/min) in children with acute lymphoblastic leukemia (ALL). METHODS: One hundred and twenty-four children with ALL were included in the study. GFR determined by renal dynamic imaging (sGFR) was used as the standard to evaluate the accuracy, consistency of eGFR calculated by seven formulas and sGFR, and the diagnostic efficacy of each formula when the sGFR ≤85 ml/min boundary. RESULTS: All of the accuracy of eGFR estimated by Schwartz2009 were greater than 70% in the 0-3, >4 and ≤6, >6 and ≤9, >9 and ≤16 years old group and male group, and the consistency exceeded the professional threshold. When the sensitivity of the ROC curve sGFR ≤85 ml/min was 100% of CKD-EPI_scysc in the 0-3, >3 and ≤4 years old group, Filler in the >3 and ≤4 years old group, and Cockrofi-Gault in the >6 and ≤9 years old group, the specificity was 73.02%, 78.95%, 78.95%, 69.32%, respectively, and the AUC under the ROC curve was the largest (P<0.05). CONCLUSION Schwartz2009 formula predicts the highest accuracy of eGFR in the 7 glomerular filtration rate. CKD-EPI_scysc, Filler, and Cockrofi-Gault formulas have more guiding signi-ficance for the adjustment of HDMTX chemotherapy in pre-adolescence in children with ALL when sGFR ≤85 ml/min.
Adolescent ; Humans ; Male ; Child ; Child, Preschool ; Glomerular Filtration Rate ; Methotrexate ; Creatinine ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Renal Insufficiency, Chronic/diagnosis*