Lymphoblastic Leukemia In Children Research Articles

Reflections on the importance of strict adherence to treatment protocols: acute lymphoblastic leukaemia in children in the 1970s in the US and the UK

Reflections on the importance of strict adherence to treatment protocols: acute lymphoblastic leukaemia in children in the 1970s in the US and the UK

Amsacrine, Etoposide and Methylprednisolone As Part of the Therapy Intensification in Children with Acute Lymphoblastic Leukemia: A Retrospective Analysis in the Trial Coall 08-09

BackgroundThe combination of amsacrine, etoposide and methylprednisolone (AEP) is regarded as a salvage treatment option in pediatric acute lymphoblastic leukemia (ALL). A recent study already showed a significant response after the treatment with AEP in children with recurrent/refractory ALL without AEP-related mortality, an acceptable morbidity and moderate myelotoxicity. [1] The CoALL study group, that investigates the treatment of childhood ALL, has implemented this block as a part of a therapy intensification in the current CoALL 08-09 protocol, for patients with a high MRD load ( B-Precursor > 10-³ at the end of induction (EOI), T-ALL >10-³ after the first consolidation block) stratified to the High Risk intensified arm or for patients without remission at the EOI defined as late responder.We examined the toxicity profile and the efficacy of this block in patients that have been treated within the current study.Patients and MethodsSo far 67 of 624 patients enrolled into the CoALL 08-09 trial, received the combination of amsacrine, etoposide and methylprednisolone as they have been treated according to the High Risk intensified arm (36 c-ALL, 8 pre-B-ALL, 3 pro-B-ALL, 8 T-ALL) or as they were specified as late responder (3 c-ALL, 1 pre-B-ALL, 1 pro-B-ALL, 7 T-ALL). The patients were characterized by a median age of 11 years and a median MRD value of 7x10-3 (B-ALL)/ 1x10-2 (T-ALL). All patients had received one cycle amsacrine 100mg/m²/day i.v. for 2 days, etoposide 500mg/m²/day i.v. for 2 days and methylprednisolone 1000mg/m²/day p.i. for 4 days at the end of the consolidation phase.ResultsBeside a profound myelosuppression 29 of the 67 enrolled patients exhibited toxicities after receiving AEP, mostly reflected by fever in neutropenia. In two cases septicemia was reported as a serious adverse event.Only three fungal infections, two occurrences of mucositis, four cases of a diabetic metabolic state and two cases of cardiac arrhythmia were reported. There was no osteonecrosis and no steroid-related psychosis reported within this patient cohort. No treatment related death occurred. The median treatment interval was 28 days, 8 days longer than the so far reported median treatment interval.A Kaplan-Meier analysis for event free (EFS) and the overall survival (OS), showed a trend in favor of the current cohort compared to patients of the predecessor trial and a comparable MRD load EOI (pOS: 87.7 SE 4.9 vs 76.3 SE 4.4; pEFS:78.8 SE 6.2 vs 61.1 SE 5.1 p= 0.1) . These patients were treated within the High Risk standard arm without the AEP treatment element.ConclusionTreatment intensification with AEP was well tolerated, without an excess of infectious complications in these heavily pretreated patients. AEP treatment intensification shows a trend towards an improved event-free survival.[1] Horstmann, M. A., Hassenflug, W.-A., zur Stadt, U., Escherich, G., Janka, G., & Kabisch, H. (January 2006). Amsacrine combined with etoposide and high-dose methylprednisolone as salvage therapy in acute lymphoblastic leukemia in children. Haematologica, S. 1701-3. DisclosuresNo relevant conflicts of interest to declare.

MicroRNA expression profiles discriminate childhood T- from B-acute lymphoblastic leukemia.

MicroRNAs (miRNAs) play a critical role on biological and cellular processes; the search for functional markers may be of importance for differential diagnosis, prognosis, and development of new therapeutic regimens. In this context, we evaluated the bone marrow miRNA profile of Brazilian children exhibiting T- or B-cell acute lymphoblastic leukemia (T-ALL or B-ALL), using massive parallel sequencing, using the HiSeq 2500 platform (Illumina). The differential expression analysis was conducted considering a leave-one-out approach and FDR≤0.05. Machine learning algorithms were applied to search for the disease subset biomarkers. Target prediction, functional enrichment, and classification of biological categories were also performed. Sixteen miRNAs were differentially expressed between T- and B-ALL, of which 10 (miR-708-5p, miR-497-5p, miR-151a-5p, miR-151b, miR-371b-5p, miR-455-5p, miR-195-5p, miR-1266-5p, miR-574-5p, and miR-425-5p) were downregulated and six (miR-450b-5p, miR-450a-5p, miR-542-5p, miR-424-5p, miR-629-5p, and miR-29c-5p) were upregulated in childhood T-ALL. These miRNAs may be used for distinguishing childhood lymphoblastic leukemia subtypes, since it provided the clear separation of patients in these two distinct groups. Six relevant biological pathways were identified according to their role in leukemia, namely, viral carcinogenesis, cell cycle, and B-cell receptor signaling pathways for induced miRNAs and TGF-beta signaling, apoptosis, and NF-kappa B signaling for the repressed miRNAs, of which several miRNA gene targets participate in cell differentiation and hematopoiesis processes. Machine learning analysis pointed out miR-29c-5p expression as the best discriminator between childhood T- and B-ALL, which is involved in calcium signaling, critical for B-cell lymphocyte fate. Further studies are needed to assure the role of the 16 miRNAs and miR-29c-5p on acute lymphoblastic leukemia subtypes and on disease prognosis.

Comparative methodological studies of L-asparaginase encapsulation into erythrocytes

Background. L-asparaginase is an enzyme, widely used in the therapy of acute lymphoblastic leukemia in children and adults, but its use is limited due to a wide range of side effects and anaphylactic reactions. L-asparaginase loaded into erythrocytes can solve these problems. This enzyme is protected from the immune system and plasma proteases due to erythrocyte membrane, but continues to work inside the cell because its membrane is permeable to L-asparagine. Thus, the half-life of the drug increases and anaphylactic reactions reduce. The encapsulation of L-asparaginase into erythrocytes can be performed by various osmotic methods. Each of them is characterized by the amount of encapsulated enzyme, the cell yield, as well as by the quality indices of the survived erythrocytes. An important parameter of each method is the possibility to provide sterility of this dosage form for the clinical use.The aim of the study was the comparing of three osmotic methods of L-asparaginase encapsulation into erythrocytes (hypo-osmotic lysis, dialysis and flow dialysis) to select the most promising method for clinical use.Materials and methods. A suspension of erythrocytes of healthy donors (hematocrit 60–70%) was mixed with L-asparaginase from E. сoli. The procedures of hypotonic reversible lysis, dialysis in dialysis bags, or flow dialysis using pediatric dialyzers were performed. The physiological osmolality was restored in suspensions after the procedure by the addition of a hypertonic solution, and they were incubated for 30 min at 37 °C. Then the cells were washed in isotonic phosphate-buffered saline with pH 7.4. Activity of L-asparaginase, volume, hematocrit, hematological indices and osmotic cell fragility of erythrocytes were measured in the suspensions of erythrocytes before and after the enzyme encapsulation procedure.Results. An optimal osmolality of the hypotonic buffer for each method was selected and was equal to 90–110 mOsm/kg. The yields of encapsulation were 4.2 ± 2.0, 6.0 ± 2.3 and 16.2 ± 2.2 % for hypotonic lysis, dialysis and flow dialysis, respectively. The hematological indices of the obtained erythrocyte-carriers differed from the corresponding parameters of the initial erythrocytes, but did not differ significantly for different methods.Conclusion. Comparative investigation of mentioned above parameters allowed choosing the method of flow dialysis as the most promising for clinical use.

Unusual Presentations of Acute Lymphoblastic Leukemia in Children: A Study of 9 Patients

Background: Acute lymphoblastic leukemia is the most common malignancy in children below 15 years of age. Bone marrow, CNS and the gonads are the three major sites of failure or relapse in acute lymphoblastic leukemia. Occasionally, leukemic cells can infiltrate the unusual sites and present with some unusual manifestations either at initial (diagnosis) presentation or during the course of disease. This study presents 9 such rare cases of unusual manifestations of acute lymphoblastic leukemia. Aim: To report the unusual presentation and management of acute lymphatic leukemia in children either at initial diagnosis or during the course of disease. Methods: Between 2000-2012, 1800 patients with acute lymphoblastic leukemia were treated at the Gujarat Cancer & Research Institute, Ahmedabad, a tertiary cancer care center and one of the largest regional cancer center of India. Among these patients a total of 317 cases were found to develop relapse at bone marrow, CNS, testicles etc. Out of these patients, a total of 9 patients were detected to have very unusual manifestations of the disease, either at initial presentation or during the course of their disease. These patients had parotid salivary gland involvement (1), maxillary sinus (2), bilateral blindness due to retinal detachment (1), bilateral facial nerve palsies (1), multiple symmetrical involvement of bones of both upper and lower extremities (1), small bone of the hand (4th metacarpal bone) (1), massive splenomegaly (1) and torsion of the testicle (1). The manifestations of such unusual clinical presentations, their evaluation, management and ultimate outcome is being presented in this presentation along with review of the literature. Results: Acute lymphoblastic leukemia can present with very unusual manifestation during initial diagnosis or later. Conclusion: ALL may occasionally present in some unusual way. Such uncommon presentation can create a diagnostic dilemma as well as difficulty in management. All such presentations require special attention from the treating consultant and team for the better outcome. We strongly recommend that all such rare presentations must be reported to enhance the understanding of the disease and enhance the literature.

Treatment outcomes of children with acute lymphoblastic leukemia in a middle-income developing country: high mortalities, early relapses, and poor survival

ObjectiveAcute lymphoblastic leukemia is the most common childhood cancer, yet surprisingly, very few studies have reported the treatment outcomes and the relapse rate of patients from low/middle-income countries. MethodThis study was a 5-year retrospective cohort study. It was conducted at Oncology Center of Mansoura University in Egypt and aimed to estimate the treatment outcomes and the relapse rates of newly diagnosed acute lymphoblastic leukemia in children. ResultsTwo hundred children suffering from acute lymphoblastic leukemia were studied; forty-six patients (23%) died during induction and most of those deaths were related to infection. Forty-one patients (27%) relapsed out of the 152 patients who achieved complete remission. The most common site of relapse was the bone marrow, followed by the isolated central nervous system, 53.7% and 31.7%, respectively. Seventy-eight percent of relapses occurred very early/early rather than later. The majority of relapse patients’ deaths were related to infection and disease progression. The 5-year overall survival rate for patients was 63.1% (82.1% for non-relapsed compared to 36.6% for relapsed patients). ConclusionThere was a high incidence of induction deaths related to infection and high percentages of very early/early relapses, with high mortalities and low 5-year overall survival rates. These findings suggest the urgent need for modification of chemotherapy regimens to be suitable for the local conditions, including implementation of supportive care and infection control policies. There is also a requirement for antimicrobial prophylaxis during induction period combined with the necessary increase in government healthcare spending to improve the survival of acute lymphoblastic leukemia in Egyptian children.

Anthropometry in Long-Term Survivors of Acute Lymphoblastic Leukemia in Childhood and Adolescence

Anthropometry in Long-Term Survivors of Acute Lymphoblastic Leukemia in Childhood and Adolescence

Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome.

Children with Down syndrome (DS) more commonly have acute lymphoblastic leukemia (ALL) and a lower survival rate than those without Down syndrome (WDS). We analyzed the clinical, demographic, and biological characteristics and treatment response of children with DS-ALL versus those WDS-ALL. Patients and methods: Patients with ALL between January 1990 and November 2016. The demographic and biologic characteristics and treatment response were compared using the χ² and Wilcoxon rank-sum tests. The overall survival and event-free interval (EFI) were analyzed using the Kaplan-Meier and log-rank tests. 1795 patients were included; 54 had DS. Patients with DS-ALL were older (p= 0.0189). All had B-cell precursor immunophenotype and a lower incidence of recurrent abnormalities (p < 0.0001). They showed a better response rate to prednisone (p= 0.09) and a higher mortality in induction and complete remission (p < 0.0001). All deaths of patients with DS-ALL were treatment-related. The event-free survival (EFS) was 47% (± 8%) versus 73% (± 1%) (p= 0.006) and the EFI was 54% (± 9%) versus 75% (± 1%) (p= 0.0297) among patients with DS-ALL versus those WDS-ALL, respectively. The rate of relapse was similar in both groups (p= 0.6894). The EFI of patients with DS-ALL was lower in the group aged 6-9 years: 39% (± 19%) (p= 0.7885). A lower survival was observed among children aged 6-9 years with DS-ALL. Although these children showed a better early response, their EFS and EFI were lower due to treatment-related mortality.

Revisiting the complete blood count and clinical findings at diagnosis of childhood acute lymphoblastic leukemia: 10-year experience at a single center

BackgroundHeterogeneity regarding clinical and laboratory findings at diagnosis of acute lymphoblastic leukemia exists. The frequency of complete blood count abnormalities and its combinations, symptoms and physical findings were investigated in Hispanic children from an open population at the diagnosis of acute lymphoblastic leukemia. MethodsThe patient charts and electronic records of under 16-year-old children diagnosed with acute lymphoblastic leukemia over 10 years at a regional hematology center of a university hospital were analyzed to retrieve data concerning the complete blood count at first evaluation. Type and distribution of abnormal data, frequency of symptoms and physical findings at presentation were documented. ResultsThe records of 203 children aged 0–15 years diagnosed with acute lymphoblastic leukemia from 2006 to 2016 were revisited. The results of the blood workup showed a median white blood cell count of 7120×109/L (range: 450–600,000×109/L), and a median hemoglobin concentration of 7.5g/dL (range: 2.4–15.3g/dL), whereas the median platelet count was 47,400×109/L (range: 4000–544,000×109/L). Leukocytosis and leukopenia were present in 36.6% and 36.1% of cases, respectively; anemia was diagnosed in 82.9% children. The order of frequency for major clinical symptoms was fatigue 62%, fever 60%, bone and joint pain 39%, hyporexia 33% and weight loss 21%, while main physical findings were hepatomegaly 78%, splenomegaly 63%, lymphadenopathy 57%, pallor 48%, and purpura 30%. ConclusionData differing from those classically expected at diagnosis of acute lymphoblastic leukemia in children were documented in a cohort of Hispanic children over one decade with a wide spectrum of complete blood count abnormalities, forms of presentation and frequency of physical findings.

Abstract 222: Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome

Abstract Purpose: Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) compared to children without DS. While genome-wide association studies (GWAS) have identified several susceptibility loci in childhood ALL, studies of ALL in children with DS are lacking. Therefore, we conducted the first GWAS of DS-ALL. Methods: We analyzed independent cohorts of: 1) 226 newly diagnosed DS-ALL cases from Children's Oncology Group (COG) ALL trials (2000-2013) and 436 DS controls from the National Down Syndrome Project (NDSP), 2) 124 additional COG ALL cases (2011-2015) and 336 additional NDSP DS controls, 3) 20 DS-ALL cases and 275 DS controls from Michigan neonatal bloodspots, and 4) 157 DS-ALL cases and 145 DS controls largely from neonatal bloodspots from California and Washington. Genotyping was performed with Affymetrix or Illumina single nucleotide polymorphism (SNP) arrays. STRUCTURE software was used to define European (372 cases, 1,056 controls), Hispanic (140 cases, 136 controls), and African (15 cases, 62 controls) genetic ancestry. After genome-wide imputation and quality control, ancestry- and cohort-specific associations were evaluated at &amp;gt;6,000,000 autosomal SNPs with minor allele frequency ≥1%. Associations were meta-analyzed across cohort and ancestry groups, assuming additive allelic effects. Results: Genome-wide significant (p&amp;lt;5x10-8) association signals were identified for known ALL susceptibility loci, including rs58923657 near IKZF1 (Odds Ratio [OR]=2.02, p=5.32x10-15), CDKN2A missense mutation rs3731249 (OR=3.63, p=3.91x10-10), rs3781093 near GATA3 (OR=1.73, p=2.89x10-8), and rs7090445 near ARID5B (OR=1.57, p=2.93x10-8). A novel potential risk locus was identified at chromosome 20q11.21 (rs78019519, OR=3.17, p=5.11x10-7) with consistent effects observed across each cohort and ancestry group. This SNP is in the promoter region of the oncogene TPX2 and is also associated with expression of HM13 in whole blood in the Genotype-Tissue Expression (GTEx) Portal. Conclusion: We confirmed that known ALL susceptibility loci in children without DS, including IKZF1, CDKN2A, GATA3, PIP4K2A and ARID5B, also confer risk of ALL in children with DS, with CDKN2A showing the largest effect size. We also identified a potentially novel locus associated with ALL susceptibility in DS at chromosome 20q11.21. Additional investigation of these loci is ongoing and may advance our understanding of DS-ALL etiology and biology. Citation Format: Austin L. Brown, Adam J. de Smith, Michael E. Scheurer, Noah A. Kallsen, Shanna A. Peyton, Gareth E. Davies, Erik A. Ehli, Michael E. Zwick, Naomi Winick, Kelly Maloney, Anne L. Angiolillo, Reuven Schore, MIchael M. Burke, Wanda L. Salzer, Nyla A. Heerema, Andrew J. Carroll, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Elizabeth A. Raetz, Elanor Feingold, Stephanie L. Sherman, Wenjian Yang, Meenakshi Devidas, Kyle Walsh, Andrew T. DeWan, Maria S. Pombo-de-Oliveira, Jeffrey W. Taub, Daniel Sinnett, Jasmine Healy, Jillian M. Birch, Lisa F. Barcellos, Helen Hansen, Ivan Smirnov, Charles G. Mullighan, Stephen P. Hunger, Ching-Hon Pui, Mignon Loh, Joe L. Wiemels, Xiaomei Ma, Catherine Metayer, Beth A. Mueller, Mary V. Relling, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 222.

Profile of Acute Lymphoblastic Leukemia in Children Under 2 Years of Age

Abstract Context: Acute lymphoblastic leukemia (ALL) shows substantial differences in clinical and laboratory features and treatment responsiveness in different subgroups. Pediatric ALL &lt;2 years is associated with worse outcome. Infantile ALL is characterized by high white blood cell (WBC) counts, bulky extramedullary disease, translocations of 11q23 locus. There is paucity of data on ALL under 2 years of age. Aims: This study aims to analyze clinical, hematological, biochemical, immunophenotypical parameters, and treatment responsiveness of ALL under 2 years. Settings and Designs: It is a retrospective data analysis conducted at a Tertiary Care Cancer Centre in South India. The study population includes all pediatric ALL, registered at this institute during January 2009 to December 2013, who were under 2 years at the time of presentation. Materials and Methods: There were 122 cases of ALL under 2 years of age of whom 48 refused treatment, and four were lost to follow-up. Thus, 70 cases are eligible for analysis. Details on clinical, hematological, biochemical, radiological, immunophenotypical, and cytogenetic features were collected from case records, hospital cancer registry, and analysis done using SPSS version 20. Kaplan–Meier curves plotted for survival analysis. Results:: Male:female ratio was 1.26:1 (infants - 1:1; 1–2 years group - 1.3:1). The most common clinical features were hepatomegaly (95%) and fever (89%). Hemoglobin level &gt;11 gm% was seen in 12%, WBC counts above 50,000 in 26% and platelets below 20,000 in 20%. Elevated lactate dehydrogenase presents in 64% and uric acid in 12%. Immunophenotype done in 44 children; precursor-B ALL-41, precursor-T ALL-3. Central nervous system -positive disease and 11q23 translocation were noted in one infant each. Conclusions: Infants with ALL are associated with poor prognosis. Children in the 1–2 years are associated with significantly better outcome. WBC counts &gt;50,000 are associated with poor prognosis among infants. Treatment refusal/abandonment rate is 43% in the study population which is comparable to that in literature.

Hematopoietic stem cell transplantation for isolated extramedullary relapse of acute lymphoblastic leukemia in children.

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

L-Asparaginase: a feasible therapeutic molecule for multiple diseases.

This note highlights our understanding and thinking about the feasibility of l-asparaginase as therapeutics for multiple diseases. l-asparaginase enzyme (l-asparagine amidohydrolase, EC 3.5.1.1) is prominently known for its chemotherapeutic application. It is primarily used in the treatment of acute lymphoblastic leukemia in children. It is also used in the treatment of other forms of cancer Hodgkin disease, lymphosarcoma, acute myelomonocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, reticulosarcoma and melanosarcoma (Lopes et al. Crit Rev Biotechnol 23:1-18, 2015). It deaminates l-asparagine present in the plasma pool causing the demise of tumor cell due to nutritional starvation. The anti-tumorigenic property of this enzyme has been exploited for over four decades and evidenced as a boon for the cancer patients. Presently, the medical application of l-asparaginase is limited only in curing various forms of cancer.

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.

B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) Tcell therapy. In CAR Tcell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered. Despite a narrow range of affinity for BCMA, dramatic differences in CAR Tcell expansion were observed between unique scFvs in a repeat antigen stimulation assay. These results were confirmed by screening in a MM xenograft model, where only the top preforming CARs from the repeat antigen stimulation assay eradicated disease and prolonged survival. The results of this screening identified a highly effective CAR Tcell therapy with properties, including rapid invivo expansion (>10,000-fold, day 6), eradication of large tumor burden, and durable protection to tumor re-challenge. We generated a bicistronic construct including a second-generation CAR and a truncated-epithelial growth factor receptor marker. CAR Tcell vectors stemming from this work are under clinical investigation.

Association between miR146a(rs2910164)G>C polymorphism and susceptibility to acute lymphoblastic leukemia in children

Objective To investigate the association between miR146a(rs2910164)G>C polymorphism and susceptibility to acute lymphoblastic leukemia(ALL) in children. Methods Two hundred blood specimens were obtained from children with ALL as patient group and 100 blood specimens were obtained from healthy children as healthy control group, who were all from Baoding First Central Hospital between March 2010 and October 2016.There were no significant differences in sex and age between patient group and healthy control group(χ2=0.430, P=0.512; χ2=2.839, P=0.092). The distribution of gene frequency of patient group and healthy control group conformed to Hardy-Weinberg equilibrium.miR146a(rs2910164)G>C polymorphism was identified by adopting restriction fragment length polymorphism (RFLP). The relation of genotype and ALL was demonstrated by odds ratio(OR) and 95% credibility interval(CI). Results Gene frequency of miR146a(rs2910164)GG, GC and CC genotypes in patient group and healthy control group was 16.0%, 44.5%, 39.5% and 29.0%, 41.0%, 30.0%, respectively.The GC/CC genotypes were significantly higher in patient group than those in healthy control group(GG genotype as reference, GC genotype: OR=1.967, 95%CI: 1.054-3.672, P=0.037; CC genotype: OR=2.386, 95%CI: 1.239-4.595, P=0.012). Conclusion miR146a(rs2910164)G>C polymorphism is significantly associated with susceptibility to ALL in children. Key words: miR146a(rs2910164)G>C polymorphism; Leukemia, lymphoblastic, acute; Child

Effect of PKA Gene on Acute Lymphoblastic Leukemia in Children and Its Mechanism

To explore the effect of PKA gene on acute T lymphocyte leukemia cells in children and its mechanism. Jurkat and Sup-T1 cells were divided into 2 group: control group (Jurkat and Sup-T1 cells treated with non-specific siRNA) and transfected group (Jurkat and Sup-T1 cells transfected with PKA siRNA). The effects of down-regulating the expression of PKA gene on the viability, proliferotion, migration and cell cycle distribution of Jurkat and Sup-T1 cells in 2 groups were analyzed by CCK-8 assay, transwell experiment, cell colony-formation test and flow cytometry; the cyclin-related protein levels after transfection with PKA siRNA were detected by Western blot. It was revealed that the expression of PKA in Jurkat and Sup-T1 cells decreased to different degree after siRNA transfection(P<0.05). CCK-8 assay showed that the proliferation of Jurkat and Sup-T1 cells in the transfected group was slower than that in the control group(P<0.05). Transwell experiment showed that the migration and invasion ability of Jurkat cells in the transfection group was weaker than that in the control group (P<0.05). The cell colong formation number of Jurkat and Sup-T1 cells in the transfection group decreased significantly (P<0.05). The cell level of Jurkat and Sup-T1 cells in G0/G1 phase increased after tansfection (P<0.05). Western blot assay revealed that the expression levels of CDK2, CyclinD1 and p-Rb in the Jurkat and Sup-T1 cells of the transfection group were suppressed (P<0.05). The down-regulating PKA gene expression can decrease the proliferation and migration of tumor cells, and also can restrict the cell proliferation through related cell cycle proteins.

Clinical characteristics and outcomes of acute lymphoblastic leukaemia in children treated at a single tertiary hospital in Riyadh, Saudi Arabia

Context: Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer worldwide, and it accounts for 30% of all cancer cases in children of Saudi Arabia. Aim: This study aims to describe the clinical characteristics and outcomes of paediatric ALL. Settings and Design: This case series study was conducted at a single tertiary hospital in Saudi Arabia. Methods: Clinical data and outcomes of all patients diagnosed between 2000 and 2010 were collected from medical charts using a custom data collection sheet. Statistical Analysis: Data were analysed using SPSS. Mann–Whitney test was used to compare the median age of diagnosis between different categories as the age was not normally distributed. Results: This study included 50 patients (median age, 4 years; 58% male). The majority (82%) had pre-B-cell ALL and 18% had T-cell ALL. Thirty-one (62%) patients were in the standard risk category, 18 (36%) in the high-risk category and one (2%) in the very high-risk category. Forty-nine (98%) patients achieved complete remission. The remission status was M1 marrow status in 46 (94%) patients. The overall survival and event-free survival rates were 92% and 74%, respectively, with 4 (8%) deaths due to different complications. Conclusion: This is the first 10-year case series study in a single tertiary institution in Saudi Arabia. The clinical characteristics of children with ALL were similar to those reported in the literature. The use of well-defined treatment protocols improved the survival rates to levels that are comparable to those of developed countries.

The methylenetetrahydrofolate reductase 677T-1298C haplotype is a risk factor for acute lymphoblastic leukemia in children.

The etiology of acute lymphoblastic leukemia (ALL) is complex, linked with both environmental exposures and genetic factors. Functional variants of the methylenetetrahydrofolate reductase (MTHFR) gene result in disturbance in folate metabolism and may affect susceptibility to cancer. The study was performed to evaluate whether MTHFR C677T and A1298C polymorphisms, analyzed separately and together, are associated with the development of ALL in a population under 18 years of age of Caucasian ancestry.The study included 117 pediatric patients (59% males, mean age at diagnosis 7.4 ± 5.2 years) with ALL, confirmed by conventional immunophenotyping surface-marker analysis and 404 healthy control subjects (48.5% men, mean age 37.7 ± 11.3 years). The MTHFR C677T and A1298C genotypes were analyzed using allele discrimination tests with Taq-Man fluorescent probes.The MTHFR 677TT genotype was related to a 2-fold increase in risk of ALL (P = .014). The 677T-1298C haplotype was found in ALL patients but not in controls (frequency 0.598%; P <.0001). The observed frequency of carriers of this rare haplotype was 12%, including 677CT/1298CC (1.7%), 677TT/1298AC (6.0%), and 677CT/1298AC (4.3%) genotypes.The MTHFR 677T allele alone or in combination with the MTHFR 1298C allele significantly increases the risk of development of ALL in Polish population under 18 years of age. Further studies of haplotype composition in subjects with the 677CT/1298AC genotype are necessary to assess the risk of childhood ALL.

A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children.

To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non-high risk precursor B-cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse-free survival at 7years (RFS) was associated with IKZF1 intragenic deletions (P<0·0001); P2RY8-CRLF2 gene fusion (P<0·0004); Day 33 MRD>5×10-5 (P<0·0001) and High National Cancer Institute (NCI) risk (P<0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2+ for patients with 2 or 3 high risk factors. RS0, RS1, and RS2+ groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD-based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL.

MON-P078: Do Nutritional Intakes Affect on Body Mass Index in Survivors of Acute Lymphoblastic Leukemia Children?

MON-P078: Do Nutritional Intakes Affect on Body Mass Index in Survivors of Acute Lymphoblastic Leukemia Children?