Acute lymphocytic leukemia (ALL) is one of the most common malignancies, especially in young people. Combination chemotherapy for ALL typically includes corticosteroids (Kantarjian et al., 2000). Hyperglycemia is a well-recognized complication of corticosteroids, and chemotherapy-induced diabetes (CID) is not uncommon (27.5%-37.0%) during the treatment of ALL (Hsu et al., 2002; Weiser et al., 2004; Alves et al., 2007). Besides the effect of corticosteroids, potential factors triggering hyperglycemia in ALL also include direct infiltration of the pancreas by leukemia cells and β cell dysfunction induced by chemotherapeutic agents such as L-asparagine (Mohn et al., 2004).
Adolescent ; Adult ; Age Factors ; Aged ; Antineoplastic Agents/adverse effects* ; Diabetes Mellitus/chemically induced* ; Female ; Humans ; Male ; Middle Aged ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality* ; Young Adult

Adolescent ; Busulfan ; therapeutic use ; Child ; Child, Preschool ; Cyclophosphamide ; therapeutic use ; Cyclosporine ; therapeutic use ; Female ; Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Infant ; Leukemia ; drug therapy ; mortality ; therapy ; Leukemia, Myeloid, Acute ; drug therapy ; mortality ; therapy ; Male ; Mycophenolic Acid ; therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; mortality ; therapy ; Retrospective Studies ; Treatment Outcome

OBJECTIVETo study the effects of minimal residual disease (MRD) level on day 33 of remission induction and IKZF1 genotype on the survival of children with B-lineage acute lymphoblastic leukemia (B-ALL).

METHODSA total of 152 children with newly-diagnosed B-ALL who had complete remission after the first cycle of the chemotherapy and had complete follow-up information were enrolled in this study. According to the MRD detection by flow cytometry on day 33 of remission induction, they were divided into three groups: standard-risk (SR) group (MRD <10; n=60), intermediate-risk (IR) group (10≤ MRD <10; n=55), and high-risk (HR) group (MRD ≥10; n=37). Nested RT-PCR was used to determine the IKZF1 genotype of all children before chemotherapy. The effects of MRD level on day 33 of remission induction and IKZF1 genotype on the recurrence-free survival (RFS) of children with B-ALL were analyzed.

RESULTSThere were 7 common IKZF1 subtypes in all the 152 children with B-ALL: IK1, IK2/3, IK4, IK6, IK8, IK9, and IK10. Of the 152 children, 130 had functional subtypes of IKZF1 and 22 had non-functional subtypes of IKZF1. During the follow-up period, relapse occurred in 26 (17%) children, and the recurrence rate was highest in the HR group (P<0.05). However, there was no significant difference in the recurrence rate between the SR group and the IR group (P>0.05). The cumulative recurrence rate of the children with non-functional subtypes of IKZF1 was significantly higher than that of those with functional types of IKZF1 (P<0.01). The predicted 5-year RFS rates in the SR, IR, and HR groups were (94.2±2.9)%, (86.7±3.8)%, and (56.2±4.5)% respectively (P<0.05). The 5-year RFS rate of the children with functional subtypes of IKZF1 was significantly higher than that of those with non-functional subtypes of IKZF1 (P<0.01). There was no significant difference in the predicted 5-year RFS rate between the children with functional subtypes of IKZF1 and those with non-functional subtypes of IKZF1 in the SR group (P>0.05). However, the predicted 5-year RFS rate of the children with functional subtypes of IKZF1 was significantly higher than that of those with non-functional subtypes of IKZF1 in the IR group and the HR group (P<0.05).

CONCLUSIONSB-ALL children with non-functional subtypes of IKZF1 have a high recurrence rate, and the recurrence rate will be even higher in B-ALL children with non-functional subtypes of IKZF1 and MRD ≥10 on day 33 of chemotherapy.

Antineoplastic Combined Chemotherapy Protocols ; Child ; Child, Preschool ; Female ; Genotype ; Humans ; Ikaros Transcription Factor ; genetics ; Male ; Neoplasm, Residual ; genetics ; mortality ; therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; mortality ; therapy ; Prognosis ; Recurrence ; Remission Induction ; Survival

The event-free survival (EFS) for pediatric acute lymphoblastic leukemia (ALL) has shown remarkable improvement in the past several decades. In Korea also, a recent study showed 10-year EFS of 78.5%. Much of the improved outcome for pediatric ALL stems from the accurate identification of prognostic factors, the designation of risk group based on these factors, and treatment of appropriate duration and intensity according to risk group, done within the setting of cooperative clinical trials. The schema of first-line therapy for ALL remains mostly unchanged, although many groups have now reported on the elimination of cranial irradiation in all patients with low rates of central nervous system relapse. Specific high risk subgroups, such as Philadelphia chromosome-positive (Ph+) ALL and infant ALL continue to have significantly lower survival than other ALL patients. The introduction of tyrosine kinase inhibitors into therapy has led to enhanced outcome for Ph+ ALL patients. Infant ALL patients, particularly those with MLL rearrangements, continue to have poor outcome, despite treatment intensification including allogeneic hematopoietic cell transplantation. Relapsed ALL is a leading cause of mortality in pediatric cancer. Recent advances in immunotherapy targeting the CD19 of the ALL blast have shown remarkable efficacy in some of these relapsed and refractory patients. With improved survival, much of the current focus is on decreasing the long-term toxicities of treatment.
Cell Transplantation ; Central Nervous System ; Child ; Cranial Irradiation ; Disease-Free Survival ; Humans ; Immunotherapy ; Infant ; Korea ; Mortality ; Precursor Cell Lymphoblastic Leukemia-Lymphoma* ; Protein-Tyrosine Kinases ; Recurrence ; Transplants

OBJECTIVETo investigate the neurocognitive function of children with acute lymphoblastic leukemia (ALL) and long-term disease-free survival and related influencing factors.

METHODSA total of 40 ALL children with long-term disease-free survival were enrolled as study group, and 40 healthy children were enrolled as control group. The Chinese Wechsler Intelligence Scale for Children (C-WISC), continuous performance test (CPT), and Stroop test software were used for the evaluation of all children. Neurocognitive function was compared between groups and influencing factors were analyzed.

RESULTSCompared with the control group, the study group had significantly lower full intelligence quotient, verbal intelligence quotient, and performance intelligence quotient in C-WICS (P<0.05) and significantly higher numbers of mistakes and misses in CPT (P<0.05). There were no significant differences in the numbers of correct answers, mistakes, and misses of word-color consistency between the study group and the control group (P>0.05), while the study group had significantly higher numbers of mistakes and misses of word-color contradiction and irrelevance (P<0.05). The total dose of high-dose methotrexate and ALL risk classification were associated with the reduction in intelligence quotient, and children's younger age at diagnosis of ALL was associated with the higher numbers of misses and mistakes. Girls tended to have a significantly lower performance intelligence quotient than boys (P<0.05).

CONCLUSIONSALL children with long-term disease-free survival have neurocognitive impairment, which may be associated with the dose of chemotherapeutic drugs, age at diagnosis, and sex.

Adolescent ; Child ; Child, Preschool ; Cognition ; drug effects ; Disease-Free Survival ; Female ; Humans ; Infant ; Intelligence Tests ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; mortality ; psychology

OBJECTIVETo study the expression of β-integrin family members in children with T-cell acute lymphoblastic leukemia (T-ALL) and their significance.

METHODSQuantitative real-time PCR analyses were performed to assess the expression levels of β-integrin family members in bone marrow samples from 22 children with newly-diagnosed T-ALL and 21 controls (16 children with non-malignant hematologic disease and 5 healthy donors with bone marrow transplantation). Jurkat cells were treated with integrin inhibitor arginine-glycine-aspartate (Arg-Gly-Asp, RGD) peptide. The cell viability and apoptosis rate were determined by CCK8 assay and flow cytometry respectively.

RESULTSThe mRNA levels of integrins β, β, and βwere significantly lower in children with T-ALL than in controls (P<0.05). In T-ALL patients, high integrin βexpression was associated with lower white blood cell counts (<100×10/L), minimal residual disease (MRD) positivity, and day 33 bone marrow negative remission (P<0.05). In T-ALL patients, higher integrin βexpression was associated with relapse of T-ALL (P<0.05). Based on survival curve analysis, higher integrin βexpression was related to lower event-free survival and overall survival rates. RGD peptide treatment inhibited the proliferation of Jurkat cells and increased their apoptosis rate (P<0.05).

CONCLUSIONSβ-Integrin may play a role in the occurrence and development of T-ALL by affecting cell proliferation and apoptosis. The expression of integrin β5 is closely related to the risk of relapse of T-ALL. The expression of integrin β3 is closely related the treatment response and prognosis of T-ALL.

Child ; Child, Preschool ; Female ; Humans ; Integrin beta Chains ; genetics ; physiology ; Jurkat Cells ; Male ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; etiology ; metabolism ; mortality ; RNA, Messenger ; analysis

OBJECTIVETo explore the clinical characteristics and prognosis of children and adolescents over 10 years of age with acute lymphoblastic leukemia (ALL).

METHODSA total of 86 newly diagnosed ALL children and adolescents over 10 years of age (62 cases of B-ALL and 24 cases of T-ALL) were enrolled. Clinical characteristics, therapeutic effect and prognostic factors were retrospectively analyzed. Event-free survival (EFS) and overall survival (OS) rates were estimated by the Kaplan-Meier method. Prognostic factors were evaluated by COX regression analysis.

RESULTSOf 86 patients, 62 were in medium risk, and 24 in high risk. At diagnosis, 53 patients (62%) had hepatomegaly, 50 patients (58%) had splenomegaly, and 46 patients (54%) had lymphoadenopathy. Twenty-nine patients (34%) showed high leukocyte counts (≥50×10/L) at diagnosis. The karyotype analysis was performed on 78 patients. The percentage of hyperdiploidy was 19% (15 cases), and that of hypodiploidy was 5% (4 cases). Eleven patients (14%) had abnormalities of chromosome structure. Of them, one patient was Philadelphia chromosome-positive, and another patient had the t (1; 19) chromosomal translocation. Three patients (4%) were positive for TEL/AML1, 3 (4%) were positive for E2A/PBX1, 6 were positive for BCR/ABL (7%), and 4 (5%) were positive for SIL/TAL1. During 4 weeks of induction therapy, 85 patients (99%) achieved complete remission (CR). In 86 patients, the 5-year anticipated EFS and OS were (64±6)% and (75±5)% respectively. The 5-year EFS and OS in the medium risk group were significantly higher than those in the high risk group (P<0.05). The 5-year EFS in B-ALL patients was significantly higher than that in T-ALL patients (P<0.05). COX multivariate analysis showed that white blood counts at diagnosis and minimal residual disease (MRD) after induction therapy were independent prognostic factors.

CONCLUSIONSChildren and adolescents with ALL over 10 years of age often have clinical characteristics of unfavorable prognosis. White blood counts at diagnosis and MRD after induction therapy may be important factors for the long-term prognosis.

Adolescent ; Child ; Female ; Humans ; Leukocyte Count ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; mortality ; Prognosis ; Proportional Hazards Models

Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; mortality ; therapy ; Protein Kinase Inhibitors ; therapeutic use ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Survivors ; Transplantation, Homologous ; Treatment Outcome

OBJECTIVETo study the prognostic value of hematogones (HGs) for childhood B-lineage acute lymphoblastic leukemia (B-ALL) during consolidation chemotherapy.

METHODSA retrospective analysis was conducted for 196 children with newly-diagnosed B-ALL. They were divided into high-risk group (n=55), intermediate-risk group (n=69), and low-risk group (n=72) by risk stratification, and into complete remission group (n=165) and relapse group (n=31) by clinical outcome. The European BIOMED-1 standard flow cytometry for minimal residual disease (MRD) was used to determine the number of HGs during consolidation chemotherapy. The Kaplan-Meier survival curve was used to assess event-free survival (EFS).

RESULTSThe high-risk group had a significantly lower number of HGs than the intermediate-risk and low-risk groups (P<0.05). The number of HGs in the complete remission group was significantly higher than in the relapse group (P<0.05). The children with HGs ≤1.0% had a significantly lower EFS than those with HGs <1.0% (P<0.05).

CONCLUSIONSHGs can be used to assess the treatment outcome and prognosis in children with B-ALL, and proliferation of HGs reflects the good effect of chemotherapy in such children.

Adolescent ; Bone Marrow ; pathology ; Child ; Child, Preschool ; Female ; Flow Cytometry ; Humans ; Infant ; Male ; Neoplasm, Residual ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; mortality ; pathology ; Prognosis ; Retrospective Studies

OBJECTIVETo identify the incidence of PAX5 deletion in childhood B-lineage acute lymphoblastic leukemia (B-ALL) without reproducible chromosomal abnormalities and to investigate the association between PAX5 abnormalities and prognosis of ALL.

METHODSMultiplex ligation-dependent probe amplification was used to determine the copy numbers of PAX5 gene in children newly diagnosed with B-ALL without reproducible chromosomal abnormalities between April 2008 and April 2013 and controls (children with non-hematologic diseases or tumors). The patients were classifiied into deletion group and non-deletion group based on the presence of PAX5 deletion.

RESULTSEighteen (21%) out of 86 children with B-ALL had PAX5 deletion. The deletion group had a significantly higher total white blood cell count at diagnosis than the non-deletion group (P=0.001). The Kaplan-Meier analysis demonstrated that the deletion group had a significantly lower disease-free survival (DFS) rate than the non-deletion group (0.69±0.12 vs 0.90±0.04; P=0.017), but there was no significant difference in the overall survival rate between the two groups (P=0.128). The Cox analysis showed that PAX5 deletion was a risk factor for DFS (P=0.03).

CONCLUSIONSPAX5 deletion is an independent risk factor for DFS in B-ALL children without reproducible chromosomal abnormalities.

Acute Disease ; Adolescent ; Cell Lineage ; Child ; Child, Preschool ; Chromosome Aberrations ; Disease-Free Survival ; Female ; Gene Deletion ; Humans ; Infant ; Male ; PAX5 Transcription Factor ; genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; mortality