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Objective: To investigate the genomic signatures and prognosis of advanced-stage T cell lymphoblastic lymphoma (T-LBL) and to examine the relationship between T-LBL and T cell acute lymphoblastic leukemia (T-ALL). Methods: 35 Chinese T-LBL children with stage III or IV disease were recruited for this study. They were treated with combination chemotherapy and whole exome sequencing. The relationship of the clinical features, prognosis and specific gene mutations was researched. Gene chips of T-LBL and T-ALL were downloaded from a database, and differential gene expression was analyzed. Results: Germline causal gene mutations (CARS or MAP2K2) were detected in 2 patients; 3.06 ± 2.21 somatic causal gene mutations were identified in the 35 patients, and somatic mutations were observed in the NOTCH1, FBXW7, PHF6 and JAK3 genes. NOTCH1 mutations were signiï¬cantly associated with FBXW7 mutations, and the age at diagnosis of patients with NOTCH1-FBXW7 mutations was less than that of patients without such mutations (P < 0.05). 32 patients achieved complete remission (CR), and 14 and 18 patients were classified into the intermediate risk (IR) group and high risk (HR) group. During a median follow-up of 44 months, 3 patients relapsed. Three-year prospective event free survival (pEFS) was 82.286%, and no significant differences of pEFS were found for different sexes, ages, or statuses of NOTCH1-FBXW7 mutations, (P > 0.05); however, the mean survival time of the IR group was longer than that of the HR group (P < 0.05). Differential expression of genes in the T-LBL and/or T-ALL datasets was analyzed using the R package limma, and 1/3 of the differentially expressed genes were found in both the T-ALL and T-LBL datasets. High expression of PI3K-Akt signal pathway genes and the USP34 gene was found in the T-LBL dataset. Conclusion: Although T-ALL and T-LBL both originate from precursor T-cells and are considered different manifestations of the same disease and the outcome of T-LBL is favorable when using T-ALL-based chemotherapy, there are differences in the gene distribution between T-LBL and T-ALL. It seems that the PI3K-Akt signaling pathway and the USP34 gene play important roles in T-LBL, but medicines targeting the USP34 gene or the PI3K-Akt pathway may be invalid.
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Background: Exploring sensitive prognostic methods for patients with relapsed or refractory neuroblastoma (NB) is critical. The five NB genes (NB5) share a common trait: they are highly expressed in NB. Previous studies have identified their expression levels as markers for guiding micrometastasis. This study aimed to explore whether an improved NB5 detection method is superior to flow cytometry for predicting NB metastasis, measurable residual disease (MRD), and prognosis, and whether this result could serve as an independent factor to influence progression-free survival (PFS). Methods: We utilized reverse transcriptase polymerase chain reaction (RT-PCR) to assess the expression of NB5 (CHGA, DCX, DDC, PHOX2B, and TH) in bone marrow (BM), peripheral blood (PB), or cerebrospinal fluid (CSF) samples collected from 71 patients. The correlation between gene expression changes and clinical characteristics, as well as survival rates, based on 113 detections were analyzed. The NB5 detection results' sensitivity and specificity in all 71 patients collected from six research centers with a median follow-up of 14 months were assessed. Results: PB specimens showed 100% concordance with the BM specimens in terms of positive results. Furthermore, the BM specimens exhibited an additional 45.455% (5/11) positive results compared to the 34.091% (30/88) of PB specimens. The BM specimens were positive for NB5 assay, which was significantly higher than the positive results of flow cytometric MRD (15/88, 17.045%). NB5 was mainly expressed in newly diagnosed patients (P=0.043) and positive patients with flow cytometric MRD (P<0.001) or BM morphology (P<0.001). Positive rates of droplet digital PCR (ddPCR) were consistent with those of quantitative RT-PCR (qRT-PCR) in BM (13/18, 72.222%). However, in PB, the positive rate of ddPCR (2/5, 40.000%) was higher than that of qRT-PCR. A total of 38 specimens (BM, PB, CSF) were detected as positive under qRT-PCR. Among the positive results, the analysis revealed a significant difference between the CHGA and TH in pairwise comparisons (P=0.005). PFS analysis showed that among MRD-negative patients, the survival time of the NB5-positive group was significantly lower than that of NB5-negative group (27.408±10.791 vs. 35.961±3.084 months; P=0.034), and in the Cox regression model, risk stratification based on NB5 expression level was an independent prognostic factor for relapsed or refractory disease [95% confidence interval (CI):1.020 to 9.099, hazard ratio (HR) =3.046, P=0.046]. Combining the follow-up results, we found that the sensitivity and specificity of NB5 detection were both 100%. Conclusions: In our study, the improved NB5 detection method showed significantly higher sensitivity in assessing tumor relapse or residual disease compared to flow cytometric MRD. Moreover, it provided a more accurate assessment of treatment efficacy and prognosis. These findings support NB5 detection as an effective method for further stratification and monitoring of patients with relapsed or refractory NB.
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OBJECTIVE: To explore the molecular genetic characteristics of children with B-cell acute lymphoblastic leukemia (B-ALL) and the application value of RNA-sequencing (RNA-seq). METHODS: The clinical and laboratory examination data of newly diagnosed B-ALL children who were given treatment in the Department of Hematology, Children's Hospital of Chongqing Medical University from May 2015 to April 2020 were collected and analyzed. All children were confirmed by bone marrow morphology, histochemical staining and flow cytometry, and the karyotype analysis, FISH, RT-PCR and RNA-seq detection were conducted. RESULTS: There were 71 males and 58 females with a median age of 50(8-190) months in 129 newly diagnosed children with B-ALL. The fusion gene was positive in 99 children (76.7%). A total of 86 leukemia related or possibly related gene mutations were detected, with a positive rate of 66.7%. There was no significant difference in the detection rates of ETV6-RUNX1, BCR-ABL1, TCF3-PBX1 and KMT2A rearrangements among FISH, RT-PCR and RNA-seq. Rare fusion genes were detected by RNA-seq, including 1 case of KMT2A-USP2, 4 cases of Ph-like related fusion genes, 5 cases of MEF2D rearrangement, 5 cases of PAX5 rearrangement, 3 cases of ZNF384 rearrangement, as well as several fusion genes whose significance were not clear or had not been reported in children with leukemia. Besides, children with ETV6-RUNX1 fusion gene had good response to induction of remission, while children with BCR-ABL1 and ZNF384 rearrangement had poor response, the remission rate of minimal residual disease was statistically significant compared with other types (P<0.05). CONCLUSION: RNA-seq can not only detect known fusion genes, but also discover new or rare fusion genes and gene mutations. The application of RNA-seq has important guiding significance for risk classification and precise targeted therapy of pediatric B-ALL.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , RNARESUMO
Background and Aims: Hepatitis B vaccine is the most effective preventive measure against hepatitis B virus (HBV) infection. However, the risk of HBV breakthrough infection in fully immunized children (neonatal hepatitis B immunization) who receive immunosuppressive therapy and transfusion of blood components is not well characterized. In this real-world study, we aimed to investigate the immune protection conferred by neonatal hepatitis B vaccine in children with acute lymphoblastic leukemia (ALL) who were treated with immunosuppressive therapy and blood component transfusions. Methods: Children with ALL who had received all three doses of neonatal hepatitis B vaccine were included in this study. HBV seromarkers were detected before and after the initiation of immunosuppressive therapy. Results: A total of 1,011 children with ALL who were fully vaccinated against hepatitis B in infancy before the initiation of immunosuppressive therapy were eligible for inclusion. HBV infection was detected in four of 410 children (0.98%) with an HBsAg test after the initiation of immunosuppressive therapy. The median interval from treatment initiation was 19 months. Conclusions: Three doses of neonatal hepatitis B vaccine conferred adequate protection. In endemic regions, there is a low risk of HBV breakthrough infection in fully immunized children with immunosuppressive therapy.
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BACKGROUND: The KMT2A gene, formerly named the MLL gene, is rearranged (KMT2Ar) in 70-75% of infants, 5-6% of children and 10-15% of adult patients with B cell acute lymphoblastic leukemia (B-ALL). The outcome after chemotherapy of pediatric cases remains poor, and only a few studies have investigated the clinical and laboratory features, treatment response and prognosis in Chinese populations. METHODS: A total of 48 B-ALL children with KMT2Ar were enrolled in the study, and clinical and laboratory data were collected and analyzed by age group. The relationship between prognosis and traditional risk factors and treatment response was investigated for these patients who received chemotherapy. RESULTS: The 48 enrolled patients included 28 males and 20 females; 18 (37.50%) or 30 (62.50%) patients were an age of < 12 m (infant B-ALL) or of > 12 m at onset. An initial WBC count of 300 × 109/L was detected in 7 (14.58%) patients; testicular leukemia (TL) or central nervous system involvement was found in 5 (10.41%) or 3 (6.25%) patients, respectively. Statistical differences were not found in the age groups of sex or initial WBC count, whereas TL was more common in the infant group (P < 0.05). 11q23 was detected in 18 patients; KMT2Ar was detected in 46 (95.83%) or 45 (93.75%) patients by FISH or multiplex RT-PCR technology, respectively; RNA-seq data were obtained for 18 patients, and 3 patients with uncommon KMT2Ar were identified. KMT2A-AFF1, KMT2A-MLLT3 and KMT2A-MLLT1 were the most common transcripts. Statistical differences were not found in treatment response by age groups, including dexamethasone induction, bone marrow (BM) smear status and minimal residual disease (MRD) level at different time points (TP), treatment-related mortality (TRM), or complete remission (CR) rate (P > 0.05); MRD levels monitored by FCM or PCR were unequal at the same TP. Four patients died of treatment, and TRM was 8.33%; 40 patients achieved CR, and the CR rate for the cohort was 83.33%. Seven patients quit, 15 patients relapsed, and the 5 yr cumulative relapse rate was 59.16 ± 9.16%; the 5 yr prospective EFS (pEFS) for patients who were included or excluded from the TRM group was 36.86 ± 8.48% or 40.84 ± 9.16%, respectively. Multivariate analysis for prognosis and hazard ratio was performed for 37 patients without TRM and revealed that an initial WBC count of > 300 × 109/L and a positive level of FCM-MRD were strongly related to a poor outcome for B-ALL patients with KMT2Ar (P < 0.05).
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Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Feminino , Humanos , Masculino , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Estudos Prospectivos , Indução de RemissãoRESUMO
Specific fusion genes play important roles as risk factors for strategic treatment in pediatric B-cell acute lymphoblastic leukemia (B-ALL), and the risk factors in patients without common fusion genes have not been well demonstrated. We collected and analyzed clinical and laboratory findings, treatment responses and outcomes in B-ALL patients without specific fusion genes. Whole-exome sequencing (WES) and/or RNA sequencing (RNAseq) data from bone marrow relapsed patients were also analyzed. 283 patients were enrolled in the study. Traditional elements and treatment responses at different time points (TPs) were evaluated to classify risk groups and adjust the treatment strategy. Treatment-related mortality was found in 11 (3.89%) patients, 49 (17.31%) patients relapsed, and the ten-year prospective event-free survival (pEFS) was 78.2±2.5%. Univariate analysis revealed that significant differences were not found in the pEFS of traditional risk factors, including sex, age, WBC count or chromosome status; good responses of BM smears at TP1 and minimal residual disease (MRD) levels at TP2 and TP3 were strongly associated with prolonged pEFS. Compared with the IR or the HR group, patients in the SR group presented with longer pEFS and a lower relapse rate. Multivariable analysis of outcomes and hazard ratios revealed that a positive MRD level was a key risk factor. WES or RNAseq was performed for BM relapse patients, and adverse and unreported genetic abnormalities were discovered. Favorable outcomes were acquired in the cohort. The study results showed that traditional risk factors and poor prednisone response were overcome by modified chemotherapy, and a positive MRD level was a key risk factor in these patients. NGS is needed to discover more risk-related molecular abnormalities.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Células Precursoras de Linfócitos B , Criança , China/epidemiologia , Intervalo Livre de Doença , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Prognóstico , Estudos Prospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
T cell lymphoblastic lymphoma (T-LBL) is regarded as the leukemic phase of T cell acute lymphoblastic leukemia (T-ALL). The early T cell precursors ALL/LBL (ETP-LBL/ALL) are derived from thymic cells at the ETP differentiation stage and recognized as a high-risk subgroup of T-ALL/LBL. Most of these cases presented with ALL at the disease onset, but the ETP-LBL phase is uncommon. Here, we report a patient who presented with ETP-LBL at the disease onset. In this case, ALL developed even despite receiving chemotherapy, but the patient achieved a complete remission with intensive chemotherapy.
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Fanconi anemia (FA) is the most common inherited bone marrow failure disorder, with a predisposition to neoplasia. While Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are the most common hematologic malignancies seen in patients with FA, cases of acute lymphoblastic leukemia (ALL) have also been described in the literature but it is uncommon. In our case report, a 12 years 5 months old boy, who was detected with heterozygote mutation of FANCC gene and nonsynonymous single nucleotide variability (SNV) mutation of AKAP9 gene, presented with precursor T cell ALL (T-ALL) at onset, myelodysplasia or myeloid biomarkers were not found at initial diagnosis. He received chemotherapy and achieved complete remission (CR) after a course of remission induction, but severe cytopenia was presented, sepsis and Invasive fungal infection also arose. With following-up and continue chemotherapy, secondary AML arose 17 months later, the patient died of sepsis related to chemotherapy at AML status. FA patients usually presented with homozygous or bilateral heterozygosity mutation in literature reports, whereas heterozygosity gene mutation of FANCC and AKAP9 has not reported yet. AKAP9 protein which was encoded by AKAP9 gene is widely distributed in many kinds of cells, thus ensuring the specificity and accuracy of signal transduction. We speculate that AKAP9 protein may interfere with the normal signal transduction of heterozygous mutation expression of FANCC gene and result in the inactivation of FANCC gene function. Unfortunately, the patient died of sepsis and we don't have enough blood samples to explore the role of AKAP9 gene mutation in patients with heterozygosity FANCC gene mutation.
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BACKGROUND: Mature B cell acute lymphoblastic leukaemia (BAL) is characterised by French-American-British (FAB)-L3 morphology and the presence of surface immunoglobulin (sIgM) light chain restriction. BAL is also considered as the leukaemic phase of Burkitt lymphoma (BL), in which t (8; 14) (q24; q32) or its variants are related to the myelocytomatosis oncogene (MYC) rearrangement (MYCr) is usually present. However, BAL with lysine methyltransferase 2A (KMT2A, previously called Mixed lineage leukaemia, MLL) gene rearrangement (KMT2Ar, previously called MLLr) is rare. RESULTS: Three BAL patients with KMT2Ar were enrolled between January 2017 and November 2019, accounting for 1.37% of the B-ALL population in our hospital. We also reviewed 24 previously reported cases of BAL and KMT2Ar and analysed the features, treatment, and prognosis. Total 13 males and 14 females were enrolled in our research, and the average age at diagnosis was 19.5 ± 4.95 months old. In these 27 patients, renal, central nervous system (CNS) and skin involvement were existent in 6, 4 and 3 patients, respectively; 26 patients (26/27) showed non-ALL-L3 morphology, while one patient is ALL-L3; overexpression of CD19 was detected in most cases, negative or suspicious expression of CD20 was found in 64% of patients. KMT2Ar was reported, but MYCr was not observed. 25 patients (25/27) achieved complete remission after chemotherapy or Stem cell transplantation. The patients were sensitive to chemotherapy, prospective event-free survival (pEFS) of BAL patients with KMT2Ar who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) was higher than that in patients who received chemotherapy alone (83.33% vs 41.91%). CONCLUSION: BAL patients with KMT2Ar had unique manifestations, including younger age at diagnosis and overexpression of CD19; expression of CD20 was rare, and MYCr was undetectable. The pEFS was higher in patients undergoing allo-HSCT than in patients undergoing chemotherapy alone.
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Linfoma de Burkitt , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Linfócitos B , Criança , Pré-Escolar , Feminino , Rearranjo Gênico/genética , Humanos , Lactente , Masculino , Proteínas Nucleares , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudos ProspectivosRESUMO
Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour's metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT-mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology.
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Aminoidrolases/genética , Antígeno B7-H1/genética , Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Enzimas Multifuncionais/genética , Neoplasias Pancreáticas/genética , Processamento de Proteína Pós-Traducional , Linfócitos T Citotóxicos/imunologia , Aminoidrolases/antagonistas & inibidores , Aminoidrolases/imunologia , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinogênese/imunologia , Carcinogênese/patologia , Linhagem Celular Tumoral , Embrião de Mamíferos , Fibroblastos/imunologia , Fibroblastos/patologia , Ácido Fólico/imunologia , Ácido Fólico/metabolismo , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/imunologia , Metilenotetra-Hidrofolato Desidrogenase (NADP)/antagonistas & inibidores , Metilenotetra-Hidrofolato Desidrogenase (NADP)/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Enzimas Multifuncionais/antagonistas & inibidores , Enzimas Multifuncionais/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Transdução de Sinais , Linfócitos T Citotóxicos/patologia , Carga Tumoral , Evasão Tumoral , Uridina Difosfato N-Acetilglicosamina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To study the occurrence of serious adverse events (SAEs) related to chemotherapy with CCCG-ALL-2015 regimen in children with acute lymphoblastic leukemia (ALL) and the risk factors for death after the SAEs. METHODS: A retrospective analysis was performed on the medical data of 734 children with ALL. They were treated with CCCG-ALL-2015 regimen from January 2015 to June 2019. The occurrence of SAEs during the treatment was investigated. The children with SAEs were divided into a death group with 25 children and a survival group with 31 children. A multivariate logistic regression analysis was used to analyze the risk factors for death after the SAEs. RESULTS: Among the 734 children with ALL, 56 (7.6%) experienced SAEs (66 cases) after chemotherapy, among which 41 cases occurred in the stage of remission induction therapy. Of all 66 cases of SAEs, 46 (70%) were infection-related SAEs, including 25 cases of septic shock (38%), 20 cases of severe pneumonia (30%), and 1 case of severe chickenpox (2%), and 87% of the children with infection-related SAEs had neutrophil deficiency. The most common infection sites were blood and the lungs. The most common pathogens were Gram-negative bacteria, viruses, fungi, and Gram-positive bacteria. There were 16 cases (24%) of hemorrhage-related SAEs, with 11 cases of gastrointestinal bleeding (17%), 4 cases of pulmonary bleeding (6%), and 1 case of intracranial bleeding (2%). Of all 734 children with ALL, 66 (9.0%) died, among whom 25 died due to SAEs. The treatment-related mortality rate was 3.4%, and infection (72%) and bleeding (24%) were the main causes of death. Severe pneumonia was an independent risk factor for treatment-related death in ALL children (OR=4.087, 95%CI: 1.161-14.384, P=0.028). CONCLUSIONS: SAEs often occur in the stage of remission induction therapy, and infection-related SAEs are more common in ALL children accepting chemotherapy with CCCG-ALL-2015 regimen. The development of severe pneumonia suggests an increased risk for death in these children.
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Antineoplásicos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Bactérias Gram-Negativas , Humanos , Neutrófilos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos , Fatores de RiscoRESUMO
PURPOSE: Hemophilia care in China is characterized by widespread use of on-demand regimens and low-dose prophylaxis. With a limited number of approved recombinant factor VIII (FVIII) products, the incidence of arthropathy and disability in hemophilia patients remains high in China. The purpose of this trial was to evaluate the safety and efficacy of turoctocog alfa for prophylaxis and treatment of bleeding episodes in patients from China with severe hemophilia A across all age groups. PATIENTS AND METHODS: In this Phase 3, open-label trial, previously treated males of all ages with severe hemophilia A from China received turoctocog alfa for prophylaxis or on-demand treatment of bleeds. The primary endpoint was hemostatic effect for the treatment of bleeds during the main phase of the trial. Secondary endpoints included annualized bleeding rate during prophylaxis and the frequency of FVIII inhibitor development. RESULTS: Overall, 42 pediatric patients (age <12 years) and 26 adolescent/adult patients (≥12 years) were dosed with turoctocog alfa; 51 patients initiated treatment with prophylaxis, while 17 patients initiated on-demand treatment. During the main phase of the trial (6 months), hemostatic success was 95.1%. During the full trial (up to 24 months), hemostatic success was 95.4%; the overall median ABR was 1.18 bleeds/patient/year for prophylaxis patients; and 25 (51.0%) of 49 patients with target joints at baseline had all target joints resolved. No FVIII inhibitors (≥0.6 BU) were reported. CONCLUSION: Turoctocog alfa was safe and effective for prophylaxis and treatment of bleeding episodes and for surgery in patients from China with severe hemophilia A across all ages.
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Chronic myeloid leukemia (CML) is relatively rare in childhood and few studies have reported the clinical use of imatinib (IM) in pediatric CML. In this study, we evaluated the efficacy and tolerability of IM in children and adolescents with CML.We investigated 21 patients under 18 years of age with newly diagnosed CML and treated with IM in Children's Hospital of Chongqing Medical University between May 2014 and February 2018. The disease was staged according to the European LeukemiaNet criteria and the IM dose was determined based on the disease stage. Cumulative responses and survival probabilities were estimated according to the Kaplan-Meier method.The estimated complete hematologic response rate of chronic phase-chronic myeloid leukemia (CML-CP) was 89.5% at 3 months. The complete cytogenetic response rates increased with time, reaching 47.4%, 73.7%, and 80.3% at 6, 12, and 24 months, respectively. The cumulative major molecular response rates were 42.1% and 76.3% at 12 and 24 months, respectively. With a median follow-up time of 33.8 months (range, 3.2-61.7 months), the estimated 2-year overall survival (OS) rate for CML was 95.2% (95% confidence interval [CI], 70.7%-99.3%). None of the CML-CP patients progressed to the accelerated phase or had a blast crisis. The 2-year OS and progression-free survival rates for the CML-CP cohort were both 100%, while the estimated 2-year event-free survival rate was 68% (95% CI, 42.1%-84.2%). None of the patients in this group had treatment-related deaths or IM discontinuation due to drug toxicities, and only 1 patient had a grade III-IV nonhematologic adverse event. Overall, anemia was the most common adverse effect and 42.9% of patients had a decrease in bone mineral density.IM was effective and the adverse effects were well-tolerated throughout the follow-up period in Chinese CML patients under 18 years of age.
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Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adolescente , Criança , China/epidemiologia , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Dasatinib, a second-line tyrosine kinase inhibitor (TKI), has been widely used in chronic myeloid leukemia (CML) and Philadelphia-positive B-cell acute lymphoblastic leukemia (Ph + B-ALL). Although dasatinib has been well tolerated, side effects including hemorrhage are not rare. Cases of bleeding disorders ultimately result in thrombocytopenia, but platelet aggregation dysfunction induced by dasatinib has also been demonstrated in Ph + B-ALL and CML patients. We report three Chinese children with Ph + B-ALL who received a combination treatment of chemotherapy and dasatinib and developed gastrointestinal bleeding several months later. The platelet count and clotting tests were normal, and these patients presented with dasatinib-induced platelet dysfunction. These findings reveal that physicians should be aware of and carefully monitor for side effects, including bleeding disorders.
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It has been reported that overexpression of the CRLF2 gene is associated with poor outcomes in pediatric B cell acute lymphoblastic leukemia (B-ALL), but the incidence rates, clinical characteristics and outcomes of CRLF2 gene overexpression in pediatric T cell ALL (T-ALL) have not been systematically analyzed. In this study, CRLF2 mRNA expression levels and clinical and laboratory parameters in 63 pediatric T-ALL patients were detected at the Children's Hospital of Chongqing Medical University and Children's Hospital of Xianyang between February 2015 and June 2018. The patients were treated according to the modified St. Jude TXV ALL protocol, and early treatment responses (bone marrow smear and MRD level) and prognoses in the enrolled patients were assessed. CRLF2 overexpression was detected in 21/63 (33.33%) patients. Statistical differences were not found for clinical or laboratory parameters (including sex, age, initial WBC count, incidence mediastinal involvement, abnormal karyotype and fusion genes) between patients with high CRLF2 expression and patients with low expression of CRLF2 (P>0.05). One patient died of tumor lysis syndrome and renal failure, and the treatment response was monitored on day 19 (TP1) of remission in 62 patients. One patient quit treatment because of family decisions, and 61 patients underwent treatment response evaluation on day 46 (TP2) of remission. Significant differences were not found between patients with high CRLF2 expression and patients with low CRLF2 expression in terms of the treatment responses at TP1 or TP2 (P>0.05). Following October 2018, 12 patients among the 61 evaluable patients relapsed (relapse rate: 19.67%), 3 patients died from chemotherapy, and the treatment-related mortality (TRM) rate was 4.92%. Secondary tumors occurred in 1 patient. The 3-year prospective EFS rate was 54.1±11.2% and 77.7±6.6% for the 61 evaluable patients and 58 patients without TRM. Patients with low CRLF2 expression had longer EFS durations than patients with high CRLF2 expression (61 evaluable patients: 35.91± 2.38 months vs 23.43± 2.57 months; 58 patients without TRM: 37.86± 2.08 months vs 24.55±2.43 months, P<0.05). CRLF2 expression levels were also monitored in 13 patients at TP1 and TP2, and the MRD level did not vary with the CRLF2 expression level. Our data suggest that clinical features, laboratory findings and treatment responses in the pediatric T-ALL population do not vary based on the overexpression of CRLF2 but that CRLF2 overexpression can contribute to a high risk of relapse in pediatric T-ALL. Thus, CRLF2 expression levels should not be used as biomarkers for monitoring MRD.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Recidiva Local de Neoplasia/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptores de Citocinas/metabolismo , Adolescente , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Prognóstico , Estudos Prospectivos , Receptores de Citocinas/genéticaRESUMO
INTRODUCTION: To investigate the correlation of long noncoding RNA-SOX6-1 (lnc-SOX6-1) with clinicopathological features and treatment outcomes in pediatric acute myeloid leukemia (AML) patients, and further explore its function in AML cell proliferation and apoptosis. METHODS: A total of 146 de novo pediatric AML patients and 73 nonhematologic malignancy patients/donors were recruited. Bone marrow samples were obtained, followed by measurement of lnc-SOX6-1 expression by qPCR. Besides, lnc-SOX6-1 expression in various AML cells and control cells was detected. Blank overexpression (NC (+)), lnc-SOX6-1 overexpression (Lnc RNA (+)), blank shRNA (NC (-)), and lnc-SOX6-1 shRNA plasmids (Lnc RNA (-)) were transferred into KG-1 cells and THP-1 cells. Cell proliferation rate and cell apoptosis rate were detected by CCK-8 assay and AV/PI assay, respectively. RESULTS: Lnc-SOX6-1 expression was upregulated in pediatric AML patients compared to controls, and its high expression correlated with the presence of monosomal karyotype, severer risk stratification, lower possibility of complete response achievement, shorter event-free survival, and poor overall survival. Furthermore, lnc-SOX6-1 expression was elevated in various AML cells compared to normal cells. In KG-1 cells and THP-1 cells, cell proliferation rate was elevated in Lnc RNA (+) group but reduced in Lnc RNA (-) group at 48 and 72 hours, and cell apoptosis rate was decreased in Lnc RNA (+) group but increased in Lnc RNA (-) group at 72 hours compared to the corresponding control groups. CONCLUSION: Lnc-SOX6-1 is highly expressed and correlates with worse risk stratification and poor treatment outcomes, and promotes cell proliferation while represses apoptosis in pediatric AML.
Assuntos
Apoptose , Proliferação de Células , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidade , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Regulação para Cima , Criança , Pré-Escolar , Feminino , Células HL-60 , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Estudos Prospectivos , Fatores de Risco , Células THP-1RESUMO
OBJECTIVE: To investigate the correlation between the expression level of PRPS1 and the clinical characteristics in children with acute leukemia(AL). METHODS: Real-time quantitative RT-PCR and Western blot were used to detect the level of PRPS1 mRNA and protein expression in bone marrow samples from 176 patients diagnosed as AL (126 cases were newly diagnosed and 50 cases in complete remission), and its relevance with clinical indicators was statistically analyzed. The bone marrow samples from 21 children with non-malignant hematological disease were used as controls. RESULTS: (1)In B-ALL group, the level of PRPS1 mRNA in newly diagnosed patients were significantly higher than that in control and than that in complete remission patients (both P<0.0001). In T-ALL and AML group, differences was only observed between newly diagnosed patients and complete remission patients(both P<0.0001); (2)In B-ALL group, the expression level of PRPS1 increase with along risk enhancement (P<0.01), while no significant difference was observed in T-ALL (P>0.05). In AML patients, expression difference was shown between low risk group and high risk group(P<0.05); (3)High PRPS1 mRNA expression level were associated with high WBC counts and MRD positive in B-ALL patients (P=0.020, P=0.026, respectively); (4)Expression of NT5C2, an essential gene for relapse and drug resistance, was found to be positively correlated with PRPS1 expression in AL samples(P<0.05). CONCLUSION: High expression of PRPS1 is relevant factor of unfavourable prognosis in B-ALL children, which suggest PRPS1 may be a new indicator for prognosis of pediatric B-ALL and an index to guide individualized chemotherapy.
Assuntos
Leucemia Mieloide Aguda/metabolismo , Ribose-Fosfato Pirofosfoquinase/metabolismo , Medula Óssea/metabolismo , Criança , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Prognóstico , Indução de RemissãoRESUMO
OBJECTIVE: To summarize the clinical characteristics, laboratory findings and prognosis of patients with Down syndrome-related acute leukemia (DS-AL). METHODS: The clinical data, laboratory findings, chemotherapy and prognosis of 21 children with DS-AL were analyzed. RESULTS: Most of the children had disease onset of leukemia at 1 to 5 years of age (85.7%), and acute myeloid leukemia accounted for 57.1% of these cases; 61.9% of the patients had increased lactate dehydrogenase level by 2 folds or more. Of the 13 cases undergoing echocardiaography, 10 (67.9%) showed abnormal findings, and complex congenital heart disease was common (38.5%). Six of the children received chemotherapy and complete remission was achieved in 4 cases; 2 patients died of infection, and the treatment-related mortality was 33.3%. The 2 patients receiving reduced intensive chemotherapy have so far had event-free survival for 21 and 43 months. CONCLUSION: Acute myeloid leukemia is the most common subtype of DS-AL. Patients with DS-AL are sensitive to chemotherapy and the prognosis was favorable with reduced intensive chemotherapy.
Assuntos
Síndrome de Down/complicações , Leucemia Mieloide Aguda/complicações , Protocolos de Quimioterapia Combinada Antineoplásica , Pré-Escolar , Intervalo Livre de Doença , Humanos , Lactente , Leucemia Mieloide Aguda/tratamento farmacológico , Prognóstico , Indução de RemissãoRESUMO
OBJECTIVE: To explore the clinical features, laboratory findings and treatment of infant leukemia. METHODS: A retrospective analysis of the clinical data was performed of the cases with the diagnosis of infant acute leukemia from August 1993 to October 2014 in our hospital. RESULTS: A total of 144 cases of infant leukemia were diagnosed in the defined period, including 83 cases of acute lymphoblastic leukemia, 55 myeloid leukemia, 1 hybrid acute leukaemia and 5 with incompatible cytological and immunophenotyping findings. The patients at the age of 9 to 12 months accounted for the largest proportion (38.2%), and 87.5% of the patients had hepatosplenomegaly; Six patients below 6 months old had skin infiltration. In about 1/3 of the patients, the white blood cells count was no greater than 100 × 109 /L. Ninety-five patients had chromosome examinations, which identified chromosome abnormalities in 67 patients, including 18 positive for t(4;11)or t(9;11)or t(11;19), and younger patients were more likely to have chromosome abnormalities. Thirty-seven patients underwent MLL gene detection and 11 of them had positive results; the positive patients had higher rate of chromosome 11 abnormalities than the negative patients. Most of the patients gave up treatments after diagnosis and only 6 patients older than 6 months completed regular chemotherapeutic treatments and were now in complete remission. CONCLUSION: Infant leukemia is a rare type of leukemia with different clinical features from other types of leukemia. The patients often present with hepatosplenomegaly, high white blood cell counts, MLL gene fusion, and chromosome 11 abnormalities. The prognosis of infant leukemia is not favorable, and the current treatment still relies on chemotherapy.