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: To identify the differentially expressed gene (DEG) core genes in early T-cell precursor acute lymphoblastic leukemia (ETP ALL) and to analyze their interactions with upstream miRNAs, lncRNAs and involved pathways; to clarify the regulatory mechanism of ETP ALL development; and to explore the molecular targets for clinical diagnosis and treatment. METHODS: The DEG of ETP ALL were screened based on the intersection of GEO database and TCGA database. The functional enrichment analysis and interaction analysis were carried out for DEG. Next, MCODE algorithm was used to screen core genes of DEG, and the mirDIP online tool and starBase online tool were utilized to predict upstream miRNA and lncRNA of the core genes. RESULTS: A total of 424 DEG with a high credibility were identified, which were mainly enriched in the biological activity, such as transcriptional regulation, signaling pathway and protein function activation according to GO function, and the KEGG pathway was enriched in hematopoiesis, anoxic stress response, transcriptional misregulation, immunity and other functions, which interrelated each other 7 core genes were identified. Subsequently, 7 miRNAs and 19 lncRNAs were predicted to meet screening criteria. Finally, a lncRNA-miRNA-mRNA-pathway regulatory network was constructed. CONCLUSION The DEG in ETP ALL has been identified based on data mining methods; the core genes have been gained by co-expression analysis, and their upstream miRNA and lncRNA can be predicted for the early diagnosis of ETP ALL, thus providing a theoretical basis for the early diagnosis and reasonable treatment of ETP ALL, and helping to look for new tumor biomarkers of ETP ALL different from classical T-ALL.
Humans ; MicroRNAs ; Precursor Cells, T-Lymphoid ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; RNA, Long Noncoding ; RNA, Messenger

Objective: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently recognized high-risk T lymphoblastic leukemia subgroup. The optimal therapeutic approaches to adult patients with ETP-ALL are poorly characterized. In this study, we explore the efficacy and outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for ETP-ALL. Methods: The clinical data of 23 patients with ETP-ALL receiving allo-HSCT from 2010 to 2018 were retrospectively analyzed. Patients with ETP-ALL were diagnosed based on the characteristic immunophenotypes. Second-generation sequencing was done in all patients. As to the donors, 12 patients had haploidentical donors (Haplo-HSCT) , 7 HLA-matched sibling donors (Sib-HSCT) and 4 HLA-matched unrelated donors (URD-HSCT) . Before transplantation, 19 patients achieved complete remission (CR) and 4 patients without. Results: The main clinical features of ETP-ALL included high white blood cell counts in 5 patients, splenomegaly in 14, lymphadenopathy in 19, and thymus masses in 5. According to cytogenetic and molecular characteristics, 11 patients had gene mutations related to myeloid tumors, and 7 with high risk Karyotype. After first induction regimen, 14/23 patients achieved CR. 5 patients reached CR after more than 2 cycles of chemotherapy, while another 4 patients did not reach CR. After allo-HSCT, 22 patients were successfully implanted. The median time of granulocyte and platelet reconstitution was +12 and +19 days. One patient died of transplant-related infection at +14 days. The estimated 18-month overall survival (OS) and relapse-free survival (RFS) rates were (55.0±14.4) % and (48.1±14.7) % respectively. Transplant-related mortality was 4.3%. The median OS in patients achieving CR before transplantation was 20 months, however, that in patients without CR was only 13 months. OS and RFS between haplo-HSCT and sib-HSCT were comparable (P=0.460 and 0.420 respectively) . Conclusions: Allo-HSCT is an effective therapy in some patients with ETP-ALL. Salvage HSCT cannot overcome the poor outcome. Haplo-HSCT and sib-HSCT in ETP-ALL patients have the similar clinical outcome.
Adult ; Hematopoietic Stem Cell Transplantation ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Precursor Cells, T-Lymphoid ; Remission Induction ; Retrospective Studies

Objective: To evaluate the clinical characteristics of T-cell acute leukemia/lymphoma (T-ALL) and explore the prognosis significance of early T-cell precursor leukemia/lymphoma. Methods: A cohort of 126 patients diagnosed with T-ALL from 2008 to 2014 in West China Hospital, Sichuan University were enrolled in this study. They were further categorized by immunophenotype according to the expression of T-cell lineage markers CD1a, CD8, CD5 and one or more stem cell or myeloid markers. The laboratory indicators and prognosis factors were also statistically analyzed. Results: Of all patients, the ratio of male to female was 2.5∶1, with the median age of 25 years old (range 14 to 77) . The percentage of ETP-ALL was up to 47.6%. T-ALL patients showed higher ratio in first clinical remission rate (CR(1)) than T-LBL ones (64.4% vs 30.8%, P=0.032) . Group with WBC count higher than 50×10(9)/L at presentation showed higher ration of achieving CR(1) than those lower than 50×10(9)/L (78.4% vs 50.9%, P=0.010) . In comparison with the non-ETP-ALL, ETP-ALL patients had older age of onset (P<0.001) , lower WBC count (P<0.001) , lower risk of CNS involvement (10.0% vs 30.2%, P=0.009) and slightly inferior overall survival (P=0.073) . T-cell lineage markers CD1a(-), CD8(-) and CD4(-) positive patients had higher CR(1) than their corresponding negative ones (P=0.002, P=0.000, P=0.001) , while CD33(-) and CD56(-) positive patients had lower ratio of achieving CR(1) than their negative ones, respectively (P=0.035, P=0.035) . Conclusion: Flow cytometry and associated markers for immunophenotyping was of significance in the diagnosis and prognosis monitoring of T-ALL/LBL. The percentage of ETP-ALL/LBL subtype was high in Chinese adolescent and adult T-ALL patients. ETP-ALL/LBL was a high risk subtype, which needs more precise standard for diagnosis and advanced therapies for better outcome.
Adolescent ; Adult ; Aged ; China ; Female ; Humans ; Immunophenotyping ; Male ; Middle Aged ; Precursor Cells, T-Lymphoid/cytology* ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis* ; Prognosis ; Young Adult

Objective: To analyze the clinical, laboratory characteristics and prognosis of adult early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Methods: The clinical data of 13 adult ETP-ALL patients from January 2009 to March 2017 were retrospectively analyzed and compared with non-ETP ALL patients. Results: 13 ETP-ALL patients (17.3%) were identified in 75 adult T-ALL patients, the median age of the patients was 35 years old (15 to 49 years) and 10 patients were male (76.9%). ETP-ALL patients had lower WBC count, LDH level, blasts in peripheral blood, lower incidence of thymic mass and higher PLT count compared to non-ETP ALL patients. The CR rate after one course induction chemotherapy for ETP-ALL and non-ETP ALL patients was 33.3% and 90.1%, respectively (χ(2)=26.521, P<0.001). The median overall survival(OS) was 11.33 (95%CI 0-28.46) and 25.69 (95%CI 11.98-39.41) months, respectively. The 3-year OS was 41.7% and 40.7%, respectively (P=0.699). The median event free survival (EFS) was 1.51 (95%CI 1.23-1.79) and 21.36 (95%CI 4.67-38.04) months, respectively. The 3-year EFS was 16.7% and 39.5%, respectively (P=0.002). The 3-year relapse free survival (RFS) was 53.0% and 52.0%, respectively (P=0.797). Multivariate analysis revealed that CNSL and allo-HSCT were independent risk factors affecting OS of T-ALL and ETP-ALL didn't affect the prognosis of T-ALL. Conclusion: To our knowledge, this study is the first report on characteristics and prognosis of adult ETP-ALL patients in China. At total of 13 T-ALL patients (17.3%) were classified as having ETP-ALL. These patients had a lower leukemia burden and lower CR rate after one course induction compared to non-ETP ALL patients. Allo-HSCT can improve the prognosis of ETP-ALL.
Adolescent ; Adult ; China ; Disease-Free Survival ; Female ; Humans ; Male ; Middle Aged ; Precursor Cells, T-Lymphoid ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; Remission Induction ; Retrospective Studies ; Young Adult

BACKGROUND: Precursor T-cell acute lymphoblastic leukemia (T-ALL) has worse prognosis than B-cell ALL. We aimed to evaluate prognostic variables in pediatric T-ALL. METHODS: Medical records of 36 T-ALL patients (27 males and 9 females; median age at diagnosis, 10.6 years) diagnosed and treated at Asan Medical Center from 2001 to 2017 were reviewed. Six patients (16.7%) had early T-cell precursor ALL (ETP-ALL). Most patients received the Children's Cancer Group-1882 (CCG1882) or Korean multicenter high risk ALL (ALL0601) protocols and prophylactic cranial irradiation. Clinical features at presentation, response to therapy, and treatment outcomes were analyzed. RESULTS: The six patients with ETP-ALL and 17 of 30 with non-ETP-ALL received CCG1882 or ALL0601 chemotherapy. Three patients, including two with ETP-ALL, did not achieve complete remission after induction. Rapid early response during induction was achieved by 26 patients. Five year overall survival (OS) and event free survival (EFS) rates were 71.4% and 70.2%, respectively. ETP-ALL and slow early response during induction were significant adverse prognostic factors, while hyperleukocytosis at diagnosis was not. CCG1882/ALL0601 chemotherapy resulted in superior survival (OS: 78.9%, EFS: 73.3%) compared with CCG1901 chemotherapy (OS: 64.3%, EFS: 64.3%), and patients undergoing prophylactic cranial irradiation had superior EFS to non-radiated patients. CONCLUSION: A high risk ALL protocol with intensified post-remission therapy, including prophylactic cranial irradiation, conferred T-ALL survival outcomes comparable with those of Western studies. Further treatment intensification should be considered for patients with ETP-ALL and slow induction responders. Additionally, CNS-directed treatment intensification, without prophylactic cranial irradiation, is needed.
B-Lymphocytes ; Chungcheongnam-do ; Cranial Irradiation ; Diagnosis ; Disease-Free Survival ; Drug Therapy ; Female ; Humans ; Male ; Medical Records ; Precursor Cell Lymphoblastic Leukemia-Lymphoma* ; Precursor Cells, T-Lymphoid ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; Prognosis ; T-Lymphocytes*

Operational tolerance (OT), defined as maintaining stable graft function without immunosuppression after transplant surgery, is an ideal goal for kidney transplant recipients (KTRs). Recent investigations have demonstrated the distinctive features of B cells, T cells, and dendritic cell-related gene signatures and the distributions of circulating lymphocytes in these patients; nonetheless, substantial heterogeneities exist across studies. This study was conducted to determine whether previously reported candidate gene biomarkers and the profiles of lymphocyte subsets of OT could be applied in Korean KTRs. Peripheral blood samples were collected from 153 patients, including 7 operationally tolerant patients. Quantitative real-time PCR and flow cytometry were performed to evaluate gene expression and lymphocyte subsets, respectively. Patients with OT showed significantly higher levels of B cell-related gene signatures (IGKV1D-13 and IGKV4-1), while T cell-related genes (TOAG-1) and dendritic cell-related genes (BNC2, KLF6, and CYP1B1) were not differentially expressed across groups. Lymphocyte subset analyses also revealed a higher proportion of immature B cells in this group. In contrast, the distributions of CD4⁺ T cells, CD8⁺ T cells, mature B cells, and memory B cells showed no differences across diagnostic groups. An OT signature, generated by the integration of IGKV1D-13, IGKV4-1, and immature B cells, effectively discriminated patients with OT from those in other diagnostic groups. Finally, the OT signature was observed among 5.6% of patients who had stable graft function for more than 10 years while on immunosuppression. In conclusion, we validated an association of B cells and their related signature with OT in Korean KTRs.
B-Lymphocytes ; Biomarkers ; Flow Cytometry ; Gene Expression ; Humans ; Immunosuppression ; Kidney Transplantation ; Kidney* ; Lymphocyte Subsets ; Lymphocytes ; Memory ; Precursor Cells, B-Lymphoid ; Real-Time Polymerase Chain Reaction ; RNA, Messenger ; T-Lymphocytes ; Transplant Recipients* ; Transplants

BACKGROUND: Precursor B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common neoplasm in children and is characterized by genetic and epigenetic aberrations in hematopoietic transcription factor (TF) genes. This study evaluated promoter DNA methylation and aberrant expression levels of early- and late-acting hematopoietic TF genes homeobox A4 and A5 (HOXA4 and HOXA5), Meis homeobox 1 (MEIS1), T-cell acute lymphocytic leukemia 1 (TAL1), and interferon regulatory factors 4 and 8 (IRF4 and IRF8) in pediatric B-cell ALL. METHODS: Blood samples of 38 ALL patients and 20 controls were obtained. DNA was treated with sodium bisulfite and DNA methylation level of HOXA4, HOXA5, MEIS1, TAL1, IRF4, and IRF8 was assessed using quantitative methylation-specific polymerase chain reaction (PCR). Relative gene expression was measured using quantitative reverse transcription-PCR. RESULTS: Aberrant methylation of TAL1, IRF8, MEIS1, and IRF4 was observed in 26.3%, 7.9%, 5.3%, and 2.6% patients, respectively, but not in controls. HOXA4 and HOXA5 were methylated in some controls and hypermethylated in 16% and 5% patients, respectively. IRF8, MEIS1, and TAL1 expression was lower in patients than in controls. MEIS1 expression was inversely correlated with white blood cell (WBC) count. HOXA4 expression was down-regulated in patients with high risk according to the National Cancer Institute (NCI) classification. TAL1 methylation was slightly elevated in patients aged >9 years and in patients showing relapse, suggesting its potential prognostic value. CONCLUSION: Aberrant methylation and expression of the selected hematopoietic genes were correlated with demographic/clinical prognostic factors of pediatric ALL, such as age, WBC count, and NCI risk classification.
B-Lymphocytes* ; Child ; Classification ; DNA ; DNA Methylation ; Epigenomics ; Gene Expression ; Genes, Homeobox ; Humans ; Interferon Regulatory Factors ; Leukocytes ; Methylation* ; National Cancer Institute (U.S.) ; Polymerase Chain Reaction ; Precursor Cell Lymphoblastic Leukemia-Lymphoma* ; Precursor Cells, B-Lymphoid ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; Recurrence ; Sodium ; Transcription Factors

No abstract available.
Leukemia* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma* ; Precursor Cells, T-Lymphoid*

We examined the immunogenicity of H-2 class I-restricted and HLA-A2-restricted epitopes through peptide immunization of HLA-A2-transgenic mice that also express mouse H-2 class I molecules. All four of the tested epitopes restricted by H-2 class I robustly elicited T-cell responses, but four of seven epitopes restricted by HLA-A2 did not induce T-cell responses, showing that HLA-A2-restricted peptide epitopes tend to be poorly immunogenic in HLA-A2-transgenic mice. This finding was confirmed in HLA-A2-transgenic mice infected with a recombinant vaccinia virus expressing hepatitis C virus proteins. We examined the precursor frequency of epitope-specific naive CD8+ T cells in HLA-A2-transgenic and conventional C57BL/6 mice and found that the poor immunogenicity of HLA-A2-restricted peptide epitopes is related to the paucity of naive CD8+ T-cell precursors in HLA-A2-transgenic mice. These results provide direction for the improvement of mouse models to study epitope repertoires and the immunodominance of human T-cell responses.
Animals ; Epitopes* ; Epitopes, T-Lymphocyte ; Hepacivirus ; HLA-A2 Antigen ; Humans ; Immunization ; Mice* ; Precursor Cells, T-Lymphoid* ; T-Lymphocytes ; Vaccinia virus