Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subtype of B-lineage ALL (B-ALL) that displays a gene expression profile (GEP) similar to Philadelphia chromosome-positive ALL (PhALL). It has a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, frequently accompanied by abnormal transcription factors related to lymphatic development. Children with Ph-like ALL account for 15% of children with high-risk B-ALL. It has adverse clinical features and a poor prognosis. Tyrosine kinase inhibitors combined with chemotherapy can significantly improve the prognosis of children with PhALL, suggesting that targeted therapy based on the molecular cytogenetic abnormalities of Ph-like ALL has good research prospects. This paper expounds the genetic alterations, pathogenesis, clinical features, diagnostic measures, and potential therapeutic approaches of Ph-like childhood ALL based on recent research progress in Ph-like ALL.
Humans ; Janus Kinase 2 ; genetics ; PAX5 Transcription Factor ; genetics ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; drug therapy ; genetics ; Proto-Oncogene Proteins c-abl ; genetics

OBJECTIVEThe study was aimed to investigate the feasibility and clinical significance of quantitative detection of minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) by real-time quantitative polymerase chain reaction (RQ-PCR).

METHODSClonal IgH gene rearrangements of samples at diagnosis were identified by standard PCR assay with consensus primers. Monoclonal IgH gene rearrangements were analyzed using DNAPLOT software. Upstream primers were designed with the Primer Express software and allele specific oligonucleotide developed complementary to the V-D or D-J junction. Samples at diagnosis were serially diluted to generate the patient specific standard curves. RQ-PCR method was used to quantify the MRD of the follow up samples collected at five time points during chemotherapy. To check the quantity and quality of DNA, the investigators used RQ-PCR analysis for the albumin gene.

RESULTSTotally 16 monoclonal IgH gene rearrangements were identified from 34 patients with B-ALL. The analysis of the 16 monoclonal rearrangements showed that the most frequently used V segment was from V3 family and J segment from J4 and J6. The RQ-PCR sensitivity of 10(-4) to 10(-5) was mostly reached. Non-specific amplification was seen in 6 patients. The number of inserted and deleted nucleotides did not appear to be related to the sensitivity (P > 0.05). The correlation coefficients of all 16 standard curves were excellent (> or = 0.99). The mean slope of the standard curves was -3.4 +/- 0.37 and the mean intercept was 24.3 +/- 2.95. MRD analysis of follow up samples from the 16 patients showed an association between high degree of MRD and relapse. There was no apparent relationship between MRD degree at the end of induction chemotherapy and other high risk factors of ALL (P > 0.05).

CONCLUSIONThe study showed that the above approach with RQ-PCR was applicable to clinical detection of MRD in childhood ALL. Quantitative and dynamic study of MRD was of prognostic importance.

Child ; Gene Rearrangement, B-Lymphocyte ; Humans ; Neoplasm, Residual ; diagnosis ; genetics ; Polymerase Chain Reaction ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; drug therapy ; genetics ; Prognosis

CD4 Antigens ; metabolism ; CD56 Antigen ; metabolism ; Dendritic Cells ; pathology ; Diagnosis, Differential ; Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor ; Hematologic Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; surgery ; Humans ; Immunohistochemistry ; Leukemia, Myeloid ; pathology ; Lymphoma, Extranodal NK-T-Cell ; pathology ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; pathology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ; pathology ; Skin Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; surgery

OBJECTIVETo study the clinical characteristics, risk factors and therapeutic outcome of Philadelphia chromosome-positive adult acute lymphoblastic leukemia (Ph(+)aALL).

METHODSThe clinical data of 117 newly diagnosed adults with Ph(+)ALL in our hospital between January 1995 and December 2009 were retrospectively analyzed. And their prognoses were followed up.

RESULTSThere were 117(16.1%) of 727 aALL patients diagnosed as Ph(+)aALL. Among the 117 cases, 64.1% patients were classified as pre-B immunophenotype and 31.3% as common B immunophenotype, 37.5% patients with co-expression of myeloid antigens (CD13 or CD33), and 98.4% patients with positive CD34. The complete remission (CR) rate after 1 or 2 cycles of induction chemotherapy was 62.2% in Ph(+)aALL group versus 82% in Ph(-)aALL group (P = 0.000). The median disease-free survival time of Ph(+) group was 6 months and the median survival time was 9 months. Sole karyotype abnormality subgroup t(9;22) accounted for 53% of all Ph(+)aALL patients and additional karyotype abnormality subgroup, t(9;22) plus other chromosome variation, accounted for 47%. Patients in sole karyotype abnormality subgroup had slightly lower CR rate (59.6% vs 62.5%, P = 0.768), longer median survival time (7 months vs 4 months, P = 0.158), and higher 3-year overall survival rate (27.3% vs 14.4%, P = 0.271). For the myeloid antigen co-expressed patients and the only lymphocytic antigen expressed ones, CR rate was 56.0% and 61.5% (P = 0.750), the median survival time was 5 months and 4 months (P = 0.182), and the 3-year overall survival rate was 16.0% and 15.0% (P = 0.354), respectively. In the imatinib plus combination chemotherapy treatment group, 81.3% patients achieved CR, compared with that of 58.3% in patients treated with only traditional combination chemotherapy (P = 0.083). The median survival time was 9.5 months and 6 months (P = 0.003) in these two subgroup, and 3-year overall survival rate was 52.2% and 10.3% (P = 0.029), respectively. For the patients receiving allo-HSCT after CR and that receiving traditional consolidation chemotherapy, the median survival time was 15 months and 6 months (P = 0.000), and the 3-year overall survival rate was 62.0% and 10.3% (P = 0.000), respectively. For the patients receiving imatinib as consolidation-maintenance treatment and that receiving allo-HSCT, the median survival time was 12 months and 15 months (P = 0.300), and the 3-year overall survival rate was 64.7% and 62% (P = 0.505), respectively.

CONCLUSIONOf all adult ALL patients, the Ph(+) subgroup accounted for about 16.1%, which have unfavorable prognosis such as lower CR rate and shorter survival duration under traditional chemotherapy. Neither additional chromosome abnormalities to t(9;22) nor co-expression of myeloid antigen had negative effect on CR rate and survival duration. Addition of imatinib to the therapy was beneficial to improve the CR rate and survival duration. Either receiving imatinib as consolidation-maintenance treatment or allo-HSCT after complete remission can improve long-term survival rate of Ph(+) adult ALL group significantly.

Adult ; Benzamides ; Female ; Humans ; Imatinib Mesylate ; Male ; Philadelphia Chromosome ; Piperazines ; therapeutic use ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; drug therapy ; genetics ; Prognosis ; Pyrimidines ; therapeutic use ; Retrospective Studies

This study was aimed to explore the relation between folylpolyglutamate synthetase (FPGS) rs10760502 polymorphism and prognosis and methotrexate (MTX)-related toxicities in pediatric B-cell acute lymphoblastic leukemia (B-ALL). Sequenom MassARRAY was used to genotype rs10760502. The χ(2) test, Kaplan-Meier method and Cox regression models were used to analyze the data. The results indicated that A allele carriers (GA+AA) had poor relapse free survival (RFS, log-rank: P = 0.004) and event free survival (EFS, log-rank: P = 0.022) compared with the GG genotype carriers. Multivariate Cox-regression analysis results showed that A allele is an independent prognosis factor for poor RFS [hazard ratio (HR), 20.173; 95% CI, 2.535-160.545; P = 0.005] and EFS (HR, 8.133; 95% CI, 1.718-38.512; P = 0.008). No relationship was found between any MTX toxicity and rs10760502 polymorphism. It is concluded that FPGS rs10760502G>A polymorphism may affect the treatment outcome of B-ALL patients.
Adolescent ; Child ; Child, Preschool ; Female ; Genotype ; Humans ; Infant ; Leukemia, B-Cell ; diagnosis ; drug therapy ; genetics ; Male ; Methotrexate ; adverse effects ; Peptide Synthases ; genetics ; Polymorphism, Genetic ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; Prognosis

No abstract available.
Antineoplastic Agents/therapeutic use ; Base Sequence ; DNA/chemistry/genetics/metabolism ; DNA Mutational Analysis ; Fusion Proteins, bcr-abl/*genetics ; Genotype ; Humans ; Imatinib Mesylate/therapeutic use ; Karyotyping ; Male ; Multiplex Polymerase Chain Reaction ; Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*diagnosis/drug therapy/*genetics

This study was aimed to investigate the clinical features and therapy of Ph(+) acute lymphoblastic leukemia (Ph(+)ALL) combined with invasive aspergillosis. A series of examination, including routine blood and bone marrow picture analysis, chest roentgenography, cranial computerized tomography and detection of cell genetics etc were carried out for a Ph(+)ALL patient combined with invasive aspergillosis. This patient received chemotherapy with DVCP, idarubicin and imatinib mesylate and was treated with sporanox and amphotericin B (Amb; including Amb-L) and cerebrotomy for drainage because the invasive aspergillosis occurred during myelosuppression. The results showed that patient gained complete remission and the invasive aspergillosis was controlled successfully. It is concluded that patient with Ph(+)ALL has poor prognosis despite intensive conventional chemotherapy, imatinib mesylate may prove to be an effective treatment for Ph(+)ALL. Because detection rate of the fungus is very low, itraconazole in combination with surgical excision of focus is the best treatment of lung and brain invasive aspergillosis.
Antifungal Agents ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Aspergillosis ; diagnosis ; drug therapy ; Benzamides ; Brain Diseases ; complications ; microbiology ; Humans ; Imatinib Mesylate ; Itraconazole ; therapeutic use ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; complications ; Lung Diseases, Fungal ; drug therapy ; etiology ; Piperazines ; administration & dosage ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; complications ; genetics ; microbiology ; Pyrimidines ; administration & dosage

OBJECTIVEAcute lymphoblastic leukemia (ALL) is the most common childhood cancer, while glucocorticoid (GC) is a critical component in multi-agent chemotherapy protocols currently used for the treatment of ALL. The purpose of this study was to investigate the relationship between the glucocorticoid induction test and the clinical features and the prognosis of Chinese childhood ALL.

METHODThe study recruited 309 hospitalized patients (187 male and 122 female) with childhood ALL, the sex, age, initial WBC count, immunophenotype, chromosome and gene expression were recorded. After diagnosis, all patients received GC induction test for 7 days. Then they were divided into prednisone good response (PGR) group and prednisone poor response (PPR) group according to the peripheral lymphoblast count on D8. Early responses to chemotherapy and treatment outcomes of the patients in the two groups were also analyzed.

RESULTOf the 309 patients, 263 belonged to PGR group and 46 belonged to PPR group. Initial WBC count was higher in PPR group than in PGR group (86.30×10(9)/L vs. 30.97×10(9)/L, P < 0.01) . B lineage ALL showed more sensitive to GC than T-ALL (86.6% vs. 60%, P < 0.05). Different initial-risk-group's sensitivity to GC differed from one another (high-risk:51.4%, medium-risk: 82.7%, standard risk: 93.7%, P < 0.0125). There was no significant difference between two groups in chromosomal karyotypes (P > 0.05). BCR-ABL positive ALL showed lower sensitivity to GC (P < 0.05) , while MLL, TEL-AML1, E2A-PBX1 positive rates in two groups were of no statistical significance (P > 0.05). Bone marrow was reviewed on D15 and D33, and the CR rates in PGR group were significantly higher than that in PPR group (D15: 60.5% vs. 32.6%, D33: 94.6% vs. 73.3%, P < 0.01) ; Minimal residual disease (MRD) levels were examined on D33, W12, and both were much lower in PGR group (D33: P < 0.01, W12: P < 0.05). Of the PGR group 215 patients (81.7%) remained continuously in complete remission (CCR) while only 28 cases (60.9%) in PPR group did so. The CCR rate was much higher in PGR group than that in PPR group (P < 0.01).

CONCLUSIONClosely related to clinical features and the outcomes of treatment, GC induction test is also an important prognostic factor in Chinese childhood ALL.

Adolescent ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Biomarkers, Tumor ; Child ; Child, Preschool ; Female ; Glucocorticoids ; administration & dosage ; therapeutic use ; Humans ; Infant ; Leukocyte Count ; Male ; Neoplasm, Residual ; drug therapy ; genetics ; Oncogene Proteins, Fusion ; genetics ; Polymerase Chain Reaction ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; diagnosis ; drug therapy ; genetics ; mortality ; Predictive Value of Tests ; Prognosis ; Remission Induction ; Survival Rate

This study purposed to investigate the correlation of expression level of e2a-pbx1 (immunoglobulin enhancer binding factor-Pre-B leukemia) with clinical characteristics and early response to treatment in children patients with acute lymphoblastic leukemia (ALL). The expression level of e2a-pbx1 at primary diagnosis in 45 children with ALL, and on day 33 after induction of remission in 23 children with ALL were detected by real-time quantitative polymerase chain reaction (RQ-PCR). The corelation of e2a-pbx1 expression level at primary diagnosis, MRD level with clinical characteristics and early response to treatment were all observed and explored. The expression level of e2a-pbx1 and clinical characteristics at primary diagnosis were compared between MRD negative and MRD positive patients. The results showed that the expression level of e2a-pbx1 was correlated with the blast percentage in peripheral blood at primary diagnosis. The MRD level at day 33 after induction of remission in 23 children were not related to the expression level of e2a-pbx1 at primary diagnosis and the clinical characteristics. The expression level of e2a-pbx1 at primary diagnosis in MRD positive patients was higher than that in MRD negative patients, while their age was significantly lower than that of patients with MRD negative. The blast percentage in peripheral blood at diagnosis of patients with presenting leukocyte count < 25 x 10(9)/L was significantly lower than that of patients with presenting leukocyte count >or= 25 x 10(9)/L, while the platelet count was higher. It is concluded that the expression level of e2a-pbx1 at primary diagnosis indicates the load of tumor in patients. In patients whose MRD were positive, the expression level of e2a-pbx1 at primary diagnosis is high and their age is young. The platelet count is low in the patients with high load of tumor at primary diagnosis.
Adolescent ; Child ; Child, Preschool ; Chromosomes, Human, Pair 1 ; Chromosomes, Human, Pair 19 ; Female ; Homeodomain Proteins ; genetics ; metabolism ; Humans ; Infant ; Male ; Neoplasm, Residual ; diagnosis ; genetics ; Oncogene Proteins, Fusion ; genetics ; metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics ; Translocation, Genetic ; Treatment Outcome

Therapy-related ALL (t-ALL) is a rare secondary leukemia that develops after chemotherapy and/or radiotherapy for primary malignancies. Chromosomal 11q23 abnormalities are the most common karyotypic alterations in t-ALL. The t(11;19)(q23;p13) aberration is extremely rare and has not been confirmed at the molecular genetic level. Here, we report a case of t-ALL with t(11;19)(q23;p13.3) and MLL-MLLT1 (alias ENL) gene rearrangement confirmed by cytogenetic analysis, multiplex reverse transcription-PCR (multiplex RT-PCR), and DNA sequencing in a patient who had undergone treatment for breast cancer. A 40-yr-old woman developed acute leukemia 15 months after undergoing 6 cycles of adjuvant chemotherapy (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2), radiation therapy (dose, 5,900 cGy), and anticancer endocrine therapy with tamoxifen. The complete blood cell counts and bone marrow examination showed increased blasts and the blasts showed B lineage immunophenotype (positive for CD19, CD34, and cytoplasmic CD79a). Cytogenetic analysis revealed the karyotype 47,XX,+X,t(11;19)(q23;p13.3)[4]/46,XX[16]. FISH analyses, multiplex RT-PCR, and DNA sequencing confirmed the MLL-MLLT1 gene rearrangement. The patient underwent induction chemotherapy with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) and achieved complete remission. Subsequently, she underwent consolidation chemotherapy, but died of brain ischemia in the pons and the region of the middle cerebral artery. To our knowledge, this is the first case report of t-ALL with t(11;19)(q23;p13.3) and the MLL-MLLT1 gene rearrangement.
Adult ; Antineoplastic Agents/therapeutic use ; Base Sequence ; Breast Neoplasms/drug therapy/radiotherapy ; *Chromosomes, Human, Pair 11 ; *Chromosomes, Human, Pair 19 ; Combined Modality Therapy ; Cyclophosphamide/therapeutic use ; Doxorubicin/therapeutic use ; Female ; Gene Rearrangement ; Humans ; Immunophenotyping ; Karyotyping ; Molecular Sequence Data ; Myeloid-Lymphoid Leukemia Protein/*genetics ; Neoplasm Proteins/*genetics ; Nuclear Proteins/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*diagnosis/genetics ; Sequence Analysis, DNA ; Tamoxifen/therapeutic use ; Transcription Factors/*genetics ; *Translocation, Genetic