The CEBPE rs2239633 genetic polymorphism on susceptibility to childhood acute lymphoblastic leukemia: an updated meta-analysis

OBJECTIVES@#We performed an updated meta-analysis to clarify the relationship between the CEBPE rs2239633 polymorphism and the childhood acute lymphoblastic leukemia (CALL) susceptibility.@*METHODS@#All the case-control studies were updated on October 5, 2020, through Web of Science, PubMed, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) electronic database. The heterogeneity in the study was tested by the Q test and I@*RESULTS@#A total of 20 case-control studies were selected, including 7014 patients and 16,428 controls. There was no association of CEBPE rs2239633 polymorphism with CALL (CC vs CT + TT: OR = 1.08, 95% CI = 0.94-1.26; CC + CT vs TT: OR = 1.10, 95% CI = 0.94-1.30; C vs T: OR = 1.02, 95% CI = 0.92-1.13). In the subgroup analysis by ethnicity, there is no significant association of this polymorphism and CALL risks among Asian and Caucasian populations in the three genetic models (CC vs CT + TT, CC + CT vs TT, and C vs T).@*CONCLUSION@#This meta-analysis found no significant association between the CEBPE rs2239633 polymorphism and susceptibility to CALL.

Retrospective evaluation and prediction of clearance and toxicity of high dose methotrexate in childhood acute lymphoblastic leukemia patients

To find the predictors of High Dose Methotrexate toxicities in childhood Acute Lymphoblastic Leukemia Patients. This study included 198 Childhood Acute Lymphoblastic Leukemia patients (303 infusions) who were treated with High Dose Methotrexate. Methotrexate levels at different time point were measured by modified enzyme multiplied immunoassay technique assay. The correlation between Methotrexate levels and toxicity was evaluated by Receiver Operating Characteristic curve. When the Methotrexate level at 42 h was lower than 0.76 µmol/L, the sensitivity for predicting thorough clearance at 66 h was 90.78%. When the Methotrexate level at 42 h was higher than1.5 µmol/L, the sensitivity for predicting delayed clearance was 82.17%. When the Methotrexate level at 66 h was higher than 0.5 µmol/L, the sensitivity for predicting Methotrexate toxicity was 89.09%. When the Methotrexate level at 66 h was lower than 0.1 µmol/L, the sensitivity for predicting Methotrexate nontoxicity was 92.73%. The Methotrexate level at 42 h could be predictor for delayed clearance. The Methotrexate level at 66 h could be predictor for toxicity.

Survival of Filipino children with acute lymphoblastic leukemia diagnosed in a tertiary referral center for childhood cancer: A retrospective cohort study

BACKGROUND@#Acute lymphoblastic leukemia (ALL) represents the largest group of pediatric malignancies. The high cure rate of childhood ALL represents one of the most remarkable success stories in the war against cancer. In a lower middle income country (LMIC) like the Philippines, we reviewed the 5-year survival in a tertiary referral center.@*OBJECTIVES@#This study aims to determine the 5-year survival of childhood ALL at a tertiary referral center for childhood cancer.@*METHODOLOGY@#Medical charts of newly diagnosed ALL ages 1 to 18 years old from January 2012 to December 2016 were reviewed.@*OUTCOME@#A total of 435 subjects were included in the study. The 5-year overall survival (OS) and event free survival (EFS) were 65.3% and 62.8%, respectively. The 5-year OS for standard risk ALL was 68.8% and for high risk ALL was 50%. The 5-year OS for the remission group was 83.7% and for the relapse was 21.1%. Univariate and multivariate analysis showed that WBC count at diagnosis, risk classification, immunophenotyping, and relapse showed significant prognostic impact for mortality.@*CONCLUSION@#The 5-year OS and EFS were lower compared to developed countries but are comparable with other LMICs. The prognostic factors for relapse and mortality were compatible with the literature. Overall, the adopted treatment protocols for childhood ALL in this institution showed acceptable results.

Comparison of Survival by Risk-stratified Therapy in Children and Adolescents with Acute Lymphoblastic Leukemia in a Single Institute / 임상소아혈액종양

BACKGROUND: Impressive improvement of survival rate has been achieved in childhood acute lymphoblastic leukemia (ALL). In an effort to balance the risks and benefits of therapy, risk-stratified therapy has been adopted. The aim of this study was to evaluate treatment outcome of childhood ALL by risk stratification. METHODS: From 184 patients (age, <18 years) with ALL newly diagnosed at Chonnam National University Hospital and Chonnam National University Hwasun Hospital between 2000 and 2010, we retrospectively analyzed 157 patients. Patients with infant ALL, L3, Down syndrome, and those transferred to another hospital were excluded. Three risk groups were defined as standard risk (SR, n=88), high risk (HR, n=52) and very high risk (VHR, n=17). RESULTS: The 7-year overall survival and event-free survival (EFS) rates were 85.2+/-2.9% and 80.2+/-3.3%, respectively. The 7-year EFS rates were 86.5+/-3.9% for SR, 78.8+/-5.7% for HR and 52.9+/-12.1% for VHR (P<0.001). Relapse occurred in 17 patients, and the cumulative incidence of relapse at 7 years was not different according to risk groups (SR vs. HR vs. VHR=8.9% vs. 17.3% vs. 5.9%, P=0.171). Among relapsed patients, 11 underwent hematopoietic stem cell transplantation of whom 5 survive event-free with a median follow-up of 5.2 years. The cumulative incidence of non-relapse mortality was highest in VHR (SR vs. HR vs. VHR=4.6% vs. 3.8% vs. 47.2%, P<0.001). CONCLUSION: Although, the number of patients included in this study is relatively small, the survival rates of childhood ALL with current strategies are encouraging. Also, efforts should be focused to further improve survival in the VHR, especially to reduce non-relapse mortality.

Comparison of Survival by Risk-stratified Therapy in Children and Adolescents with Acute Lymphoblastic Leukemia in a Single Institute / 임상소아혈액종양

BACKGROUND: Impressive improvement of survival rate has been achieved in childhood acute lymphoblastic leukemia (ALL). In an effort to balance the risks and benefits of therapy, risk-stratified therapy has been adopted. The aim of this study was to evaluate treatment outcome of childhood ALL by risk stratification.METHODS: From 184 patients (age, <18 years) with ALL newly diagnosed at Chonnam National University Hospital and Chonnam National University Hwasun Hospital between 2000 and 2010, we retrospectively analyzed 157 patients. Patients with infant ALL, L3, Down syndrome, and those transferred to another hospital were excluded. Three risk groups were defined as standard risk (SR, n=88), high risk (HR, n=52) and very high risk (VHR, n=17).RESULTS: The 7-year overall survival and event-free survival (EFS) rates were 85.2+/-2.9% and 80.2+/-3.3%, respectively. The 7-year EFS rates were 86.5+/-3.9% for SR, 78.8+/-5.7% for HR and 52.9+/-12.1% for VHR (P<0.001). Relapse occurred in 17 patients, and the cumulative incidence of relapse at 7 years was not different according to risk groups (SR vs. HR vs. VHR=8.9% vs. 17.3% vs. 5.9%, P=0.171). Among relapsed patients, 11 underwent hematopoietic stem cell transplantation of whom 5 survive event-free with a median follow-up of 5.2 years. The cumulative incidence of non-relapse mortality was highest in VHR (SR vs. HR vs. VHR=4.6% vs. 3.8% vs. 47.2%, P<0.001).CONCLUSION: Although, the number of patients included in this study is relatively small, the survival rates of childhood ALL with current strategies are encouraging. Also, efforts should be focused to further improve survival in the VHR, especially to reduce non-relapse mortality.

Expression and significance of BAFF/APRIL in childhood acute lymphoblastic leu-kemia / 中国免疫学杂志

Objective:To investigate the expression and significance of B cell activating factor (BAFF) and a proliferation-inducing ligand ( APRIL) in children with acute lymphoblastic leukemia ( ALL).Methods:The mRNA and protein expressions in ALL.

Perfil de metilación de genes supresores de tumores APAF1, ASSP1, p73 y FHIT en pacientes con leucemia linfoblástica aguda infantil / Detection of hypermethylation in tumor suppressor genes APAF1, ASSP1, p73 and FHIT in childhood acute lymphoblastic leukemia

La leucemia linfoblástica aguda (LLA), es la neoplasia mas frecuente en la población infantil. Se manifiesta por una perdida de diferenciación de progenitores linfoides produciendo un aumento de células inmaduras. La hipermetilación en la región promotora de genes supresores de tumores (GST) puede producir un silenciamiento génico que le proporciona a la célula leucémica una ventaja proliferativa o la previene de la apoptosis. Se estudia el estado de hipermetilación de 4 GST involucrados en la apoptosis: APAF1, ASPP1, p73 y FHIT y su asociación con la sobrevida de pacientes menores de 15 años con diagnóstico de LLA. Se analizaron 38 muestras de médula ósea mediante modificación con bisulfito del ADN y reacción en cadena de la polimerasa especifica de metilación (MSP). El rango de edad al diagnóstico fue de 10 meses a 13,8 años. La sobrevida global fue de 69 por ciento a los 5 años. El 81,5 por ciento de los pacientes tuvo al menos un gen hipermetilado. La frecuencia de metilación observada fue: APAF1 68,4 por ciento, FHIT 56,4 por ciento, p73 42 por ciento y ASPP1 18,4 por ciento. La asociación entre hipermetilación y grupo <5 años y 5 años fue: Global p=0,20, APAF1 p=0,03, FHIT p=0,51, p73 p=0,51 y ASPP1 p=0.67. Las curvas de sobrevida se calcularon según frecuencia de hipermetilación de cada gen: APAF1 p=0,05, FHIT p=0,31, p73 p=0,98 y ASPP1 p=0,82. La alta frecuencia de hipermetilación obtenida reafirma la participación de la metilación en la región promotora de GST en la patogénesis de la LLA. La hipermetilación del gen APAF1 fue muy frecuente y se asoció significativamente a la sobrevida del grupo de estudio, mostrando a este gen como un factor predictivo de mal pronostico en pacientes con LLA.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. It is manifested by a loss of differentiation of lymphoid progenitors, producing an increase of immature cells. Hypermethylation in promoter region of tumor suppressor genes (GST) may produce a gene silencing that provides a leukemic cell a proliferative advantage or prevent apoptosis. We studied the hypermethylation status of 4 GST involved in apoptosis: APAF1, ASPP1, p73 and FHIT and its association with survival of patients <15 years diagnosed with ALL. We analyzed 38 samples of bone marrow by DNA bisulfite modification and chain reaction methylation-specific polymerase (MSP). The mean age at diagnosis was 10 months to 13.8 years. Overall survival was 69 percent at 5 years. 81.5 percent of patients had at least one hypermethylated gene. The frequency observed was: APAF1 68.4 percent, 56.4 percent FHIT, p73 ASPP1 42 percent and 18.4 percent. The association between hypermethylation and group <5 years and 5 years was: Global p = 0.20, APAF1 p = 0.03, FHIT p = 0.51, p73 p = 0.51, ASPP1 p = 0.67. Survival curves were calculated by frequency of hypermethylation of each gene: APAF1 p = 0.05, p = 0.31 FHIT, p73 p = 0.98 and ASPP1 p = 0.82. The high frequency of hypermethylation obtained confirms enrollment of methylation in the promoter region of GST in the pathogenesis of ALL. APAF1 gene hypermethylation was very frequent and was significantly associated with survival in the study group, showing this gene as a predictor of poor prognosis in patients with ALL.

Apoyo de organizaciones no gubernamentales a pacientes pediátricos con leucemia linfoblástica aguda afiliados al Seguro Popular en México / Support from nongovernmental organizations to pediatric patients with acute lymphoblastic leukemia affiliated with the Seguro Popular insurance program in Mexico

Introducción. El cáncer es la segunda causa de mortalidad infantil. La leucemia linfoblástica aguda es el tipo de cáncer más frecuente en niños. En México, las familias afiliadas al Seguro Popular tienen acceso a los servicios médico-quirúrgicos, farmacéuticos y hospitalarios que satisfacen sus necesidades de salud. El objetivo de este trabajo fue conocer el impacto del apoyo de las organizaciones no gubernamentales en la mortalidad de pacientes con leucemia linfoblástica aguda afiliados al Seguro Popular. Métodos. Se aplicaron 182 entrevistas a familiares de pacientes con leucemia linfoblástica aguda, vivos y fallecidos, en nueve instituciones afiliadas al Seguro Popular. Las preguntas se enfocaron en conocer los gastos durante el tratamiento, si recibían apoyo de alguna organización no gubernamental y en qué consistía este apoyo. Se realizó un análisis bivariado para conocer el peso estadístico del apoyo de las organizaciones no gubernamentales sobre la mortalidad cruda. Resultados. Los familiares de pacientes con leucemia linfoblástica aguda afiliados al Seguro Popular realizaron gastos complementarios durante el tratamiento. El apoyo de las organizaciones no gubernamentales fue estadísticamente significativo como protector de la mortalidad (OR = 0.25; IC 95% 0.11-0.54), y se efectuó en rubros como alimentos, medicamentos, antibióticos y catéteres. Conclusiones. Las organizaciones no gubernamentales son de gran apoyo para los pacientes con leucemia linfoblástica aguda y, aunque no suplen el apoyo del Seguro Popular, facilitan el tratamiento integral y parecen tener un efecto positivo en la reducción de la mortalidad.

Background. Cancer is the second leading cause of pediatric mortality. Acute lymphoblastic leukemia (ALL) is the most common type of cancer. In Mexico, families affiliated with the Seguro Popular insurance program have access to medical, pharmaceutical and hospital services that meet their health needs. The objective of the study was to determine the impact of nongovernmental organization (NGO) support on mortality in ALL patients affiliated with the Seguro Popular program. Methods. We conducted 182 interviews with families with living and deceased patients with ALL in nine institutions affiliated with the Seguro Popular program. We inquired about the expenses necessary during ALL treatment and whether they received support from NGO and the type of support received. We performed bivariate analysis to determine the statistical weight of the support of NGO on crude mortality. Results. Families of patients with ALL affiliated with the Seguro Popular insurance program incurred additional expenses during treatment. NGO support was statistically significant in protection from mortality (OR = 0.25; 95% CI 0.11-0.54). Significant items were support with food, medicines, antibiotics and catheters. Conclusions. NGO offer a high level of support for ALL patients and although they are not a substitute for the support of the Popular Insurance Scheme, they provide a holistic type of support and demonstrate a positive effect in reducing mortality.

A Case of Acute Sensorineural Hearing Loss as an Initial Manifestation in a Child with Acute Lymphoblastic Leukemia / 대한소아혈액종양학회지

Acute sensorineural hearing loss is unusual as initial manifestations in a child with acute lymphoblastic leukemia (ALL), even though facial or oculomotor nerve palsy as early finding of leukemia was reported. The pathology of sensorineural hearing loss in leukemia showed as leukemic cell infiltration, hemorrhage, infection, and local ischemia due to hyperviscosity. A 12-year-old boy with ALL was admitted due to multiple cervical lymphadenopathy with left sided sensorineural deafness. He complained gross hematuria and purpura on whole body. His initial complete blood cell counts were hemoglobin 11.9 g/dL, hematocrit 34.3%, white blood cells 164,000/muL (segmented neutrophils 3%, lymphocytes 11%, monocytes 2%, immature blast 84%), and platelet 28,000/muL. Pure tone audiogram revealed profound sensorineural hearing loss of the left ear at all frequencies. His brain MRI showed no definite abnormal findings without hemorrhage or infarction in inner ear or temporal lobe. He received induction chemotherapy and total 4 times of transtympanic steroid injection with 1 week interval. His hearing power at complete remission was more improved than admission, but not completely recovered until 5 months. We proposed that hearing impairment might be an initial manifestation in acute leukemia with hyperleukocytosis.

Detection of Minimal Residual Disease Using Real-Time Quantitative Polymerase Chain Reaction in Children with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia / 대한소아혈액종양학회지

PURPOSE: The aim of this study was to detect the bcr-abl/abl mRNA ratio of the patients with Philadelphia chromosome positive childhood acute lymphoblastic leukemia (ALL) after completing chemotherapy or bone marrow transplantation (BMT), by the real-time quantitative polymerase chain reaction (RQ-PCR). It was also to be proved that these quantitative changes of minimal residual disease (MRD) can be used for early detection of relapse and for treatment response. METHODS: The subjectives of this study were 8 patients diagnosed with Philadelphia chromosome positive childhood acute lymphoblastic leukemia (ALL) from January to November in the year 2001. The change of bcr/abl transcript with chemotherapy were evaluated in 6 patients out of them. RESULTS: All of 6 patients reached in hematologically complete remission state by the induction chemotherapy, but the MRD was cytogenetically detected in 5 out of the 6 patients. While the 5 patients were in the hematologically remission state, only 1 patient had the cytogenetical remission after the serial consolidation chemotherapy at the maximum of 6 times. The increased amount of bcr-abl/abl mRNA ratio (up to 10 3) were correlated with the positive real time polymerase chain reaction (RT-PCR) result, but the results of bcr/abl fluorescent in situ hybridization (FISH) were not correlated with the results of RT-PCR and bcr-abl/abl mRNA ratio. The change of bcr/abl transcript was evaluated in 4 patients after BMT. The RT-PCR in 1 month after BMT showed the negative result in all 4 patients in our study. The bcr-abl/abl mRNA ratio in all patients was constantly decreased. However, bcr-abl/abl mRNA ratio in one patient was increased in 6 months after BMT, and the results of second RT-PCR showed positive value, which made the cyclosporine be discontinued immediately. In the 9th month following BMT, the ratio of bcr-abl/abl mRNA was abruptly decreased and the results of second RT-PCR showed the negative value. CONCLUSION: We suggest that RT-PCR or RQ-PCR rather than FISH is more sensitive and effective for detection of MRD. We also observed that Philadelphia chromosome positive childhood ALL could be cured with the BMT, not with the chemotherapy alone, by monitoring MRD.

Ifosfamide and Etoposide in Relapsed Refractory Childhood Acute Lymphoblastic Leukemia / 대한소아혈액종양학회지

BACKGROUND: The prognosis for children with relapsed acute lymphoblastic leukemia remains dismal. Ifosfamide has previously been shown to be active as a single agent and in combination with doxorubicin, etoposide, and teniposide in pediatric solid tumors, recurrent acute lymphoblastic leukemia and adult acute leukemia. We assessed the efficacy and the toxicity of the drug combination with ifosfamide and etoposide in patients with relapsed refractory acute lymphoblastic leukemia. METHODS: Between April 1995 and May 1996, twenty children aged 1 to 14 years with ALL in Catholic Medical Center, all heavily pretreated and in bone marrow relapse, were enrolled in this study. Drugs were given intravenously each day for 5 days at the following doses ; ifosfamide 1.8 g/m2/day, etoposide 100 mg/m2/day and mesna 1440 mg/ m2/day(as a uroprotectant) ; Cycles were repeated every 28 days for two cycles. RESULTS: 1) Twenty heavily pretreated patients were entered on study. At study entry, seventeen patients were in first relapse, two were in second relapse and one was in third relapse. 2) Six patients(30%) achieved complete remission, and eight patients(40%) achieved partial remission. Overall response rate was 70%. 3) Duration of remission ranged from 30 days to 230 days. 4) The toxicity of the regimen was tolerated. Moderate or severe toxicity evaluated on a per cycle basis included : neutropenia 52.5%, thrombocytopenia 45%, hemorrhagic cystitis 12.5% and mucositis 2.5%. 5) Two patients went on to bone marrow transplantation with histocompatibility matched sibling donors while in remission. CONCLUSION: The combination of ifosfamide and etoposide with mesna uroprotection has significant activity in relapsed refractory childhood lymphoblastic leukemia with tolerable toxicity. We recommended bone marrow transplantation after successful reinduction because of short remission duration of this regimen.