scholarly journals Emerging Pharmacotherapies for Adult Patients with Acute Lymphoblastic Leukemia

2012 ◽  
Vol 6 ◽  
pp. CMO.S7262 ◽  
Author(s):  
Lydia Lee ◽  
Adele K. Fielding
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Sustained Remission ◽  
The Novel ◽  
Durable Response ◽  
Treatment Regimes ◽  
The Face ◽  
Pediatric All ◽  
Relapsed Disease ◽  
Failure Of Induction

Acute lymphoblastic leukemia (ALL) treatment regimes are amongst the longest, most intensive and complex used in hemato-oncology. Despite this, while treatment of pediatric ALL is a success story, we are far from being able to ensure a durable response in adult ALL. This is not due to failure of induction therapy as a complete remission (CR) is achieved in over 90% of patients. However the challenge remains in ensuring a sustained remission. Furthermore in the face of relapsed disease, salvage therapies currently offer a poor chance of a good outcome. This article reviews the novel agents which show the most promise in the treatment of adult ALL.

Targeting Kinase-activating Genetic Lesions to Improve Therapy of Pediatric Acute Lymphoblastic Leukemia

2018 ◽  
Vol 25 (24) ◽  
pp. 2811-2825 ◽  
Author(s):  
Raffaella Franca ◽  
Natasa K. Kuzelicki ◽  
Claudio Sorio ◽  
Eleonora Toffoletti ◽  
Oksana Montecchini ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Fusion Gene ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Point Of View ◽  
Lymphoid Cells ◽  
Gene Encoding ◽  
Pediatric All ◽  
Blast Cells ◽  
Tk Inhibitors

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, characterized by an abnormal proliferation of immature lymphoid cells. Thanks to risk-adapted combination chemotherapy treatments currently used, survival at 5 years has reached 90%. ALL is a heterogeneous disease from a genetic point of view: patients’ lymphoblasts may harbor in fact several chromosomal alterations, some of which have prognostic and therapeutic value. Of particular importance is the translocation t(9;22)(q34;q11.2) that leads to the formation of the BCR-ABL1 fusion gene, encoding a constitutively active chimeric tyrosine kinase (TK): BCR-ABL1 that is present in ~3% of pediatric ALL patients with B-immunophenotype and is associated with a poor outcome. This type of ALL is potentially treatable with specific TK inhibitors, such as imatinib. Recent studies have demonstrated the existence of a subset of BCR-ABL1 like leukemias (~10-15% of Bimmunophenotype ALL), whose blast cells have a gene expression profile similar to that of BCR-ABL1 despite the absence of t(9;22)(q34;q11.2). The precise pathogenesis of BCR-ABL1 like ALL is still to be defined, but they are mainly characterized by the activation of constitutive signal transduction pathways due to chimeric TKs different from BCR-ABL1. BCR-ABL1 like ALL patients represent a group with unfavorable outcome and are not identified by current risk criteria. In this review, we will discuss the design of targeted therapy for patients with BCR-ABL1 like ALL, which could consider TK inhibitors, and discuss innovative approaches suitable to identify the presence of patient’s specific chimeric TK fusion genes, such as targeted locus amplification or proteomic biosensors.

Role of Matrix Metalloproteinase MMP-2, MMP-9 and Tissue Inhibitor of Metalloproteinase (TIMP-1) in Clinical Progression of Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Maha Saleh ◽  
Mohamed Khalil ◽  
Mona S. Abdellateif ◽  
Emad Ebeid ◽  
Eman Z. Kandeel
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Count ◽  
Cancer Progression ◽  
Lymphoblastic Leukemia ◽  
Multivariate Logistic Regression Analysis ◽  
Blast Cell ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All

Abstract Background: Matrix metalloproteinases (MMPs) play a crucial role in cancer progression and metastasis, however their role in pediatric Acute lymphoblastic leukemia (ALL) is still unrevealed.Methods: The diagnostic, prognostic and predictive value of tissue inhibitor of metalloproteinase (TIMP-1), MMP-2, MMP-9 and CD34+CD38- CSCs were assessed in bone marrow (BM) samples of 76 ALL children using Flow Cytometry analysis. Results: There was a significant increase in TIMP-1 [1.52 (0.41-10) versus 0.91(0.6-1.12); respectively, P<0.001], and CSCs CD84+CD38- [1 (0.03-18.6) versus 0.3 (0.01-1.1), P<0.001] expression in ALL patients compared to controls. While there were no significant differences regarding MMP-2 and MMP-9 expression between the two groups. The sensitivity, specificity, AUC of MMP-2 were (80.3%, 53.3% and 0.568, P=0.404), and that of MMP-9 were (53.9%, 40% and 0.660, P=0.053). While that of TIMP-1 were (78.9%, 100% and 0.892, P<0.001), and that of CSCs CD34+ CD38- were (78.9%, 73.3% and 0.855, P<0.001). There was a significant association between MMP-2 overexpression and MRD at day-15, increased BM blast cell count at diagnosis and at day-15, (P=0.020, P=0.047 and P=0.001). Increased TIMP-1 expression associated with the high-risk disease (P<0.001), increased BM blast cell count at diagnosis and at day-15 (P=0.033 and P=0.001), as well as MRD at day 15 and day 42 (P<0.001 for both). CD34+CD38- CSCs associated with MRD at day-15, increased BM blast cell count at diagnosis and at day-15 (P=0.015, P=0.005 and P=0.003). TIMP-1 overexpression associated with shorter DFS and OS rates (P=0.009 and P=0.048). Multivariate logistic regression analysis showed that both TIMP-1 [OR: 4.224, P=0.046], and CD34+CD38- CSCs [OR: 6.873, P=0.005] are independent diagnostic factors for pediatric ALL.Conclusion: TIMP-1 and CD34+CD38- CSCs could be useful independent diagnostic markers for pediatric ALL. Also, TIMP-1 is a promising prognostic marker for poor outcome of the patients.

scholarly journals “SOCIOECONOMIC FACTORS AFFECTING SURVIVAL IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA FROM NORTH-EAST INDIA”

2020 ◽  
pp. 1-3
Author(s):  
Partha Sarathi Roy ◽  
Munlima Hazarika ◽  
Rakesh Kumar Mishra ◽  
BhargabJyoti Saikia ◽  
Gaurav Kumar
Keyword(s):  
Overall Survival ◽  
Developing Countries ◽  
Acute Lymphoblastic Leukemia ◽  
Socioeconomic Factors ◽  
Lymphoblastic Leukemia ◽  
Childhood All ◽  
Female Ratio ◽  
Risk Of Death ◽  
Lower Socioeconomic ◽  
Pediatric All

Acute lymphoblastic leukemia (ALL) is a highly curable childhood cancer with a survival rate of nearly 80% in developed countries but is around 45% in developing countries. This retrospective study analyzed the association between demographic and socioeconomic factors with survival in pediatric ALL. All confirmed cases of pediatric ALL (age <18 years) registered at Dr. B Borooah Cancer Institute between 2010 to 2017 were analyzed using data collected from hospital-based cancer registry and case records. Seventy-five confirmed cases of pediatrics ALL were eligible for the study. The median age of presentation was six years with a male: female ratio 1.9:1. Overall survival at 4-years was 43.8%, with a median survival of 25 months. A trend for higher 4-year overall survival was seen in female children (54.1% versus 37.9%, p=0.097). Patients from rural areas (44% versus 39.5%, p=0.308), with higher maternal education (83.3% versus 41.1%, p=0.161) and patients who did not abandon treatment (49.1% versus 31.2%, p=0.497) had better survival, but the differences were not significant. Four years overall survival in upper-middle, lower-middle, upper-lower, and lower class were 85.7%, 74.9%, 38.1%, and 7.7% respectively (upper-middleversus lower socioeconomic class, p=0.0001).Multivariate analyses confirmed a statistically significant relationship between socioeconomic status and survival, with the upper-middle group had a 90% decreased risk of death compared to the lower socioeconomic group. There is an urgent need for a proper definition of the problems of childhood ALL to introduce appropriate policies for improving survival in developing countries.

scholarly journals Effects of TPMT, NUDT15, and ITPA Genetic Variants on 6-Mercaptopurine Toxicity for Pediatric Patients With Acute Lymphoblastic Leukemia in Yunnan of China

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoyan Mao ◽  
Runxiu Yin ◽  
Gaoyuan Sun ◽  
Yan Zhou ◽  
Chunhui Yang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Yunnan Province ◽  
Medical Center ◽  
Lymphoblastic Leukemia ◽  
Free Survival ◽  
Ethnic Populations ◽  
Significant Difference ◽  
Pediatric All ◽  
Medical University ◽  
Tolerable Dose

Background: 6-Mercaptopurine (6-MP) is the cornerstone of current antileukemia regimen and contributes greatly to improve the survival of pediatric acute lymphoblastic leukemia (ALL) patients. However, 6-MP dose-related toxicities limit its application. TPMT, NUDT15, and ITPA are pharmacogenetic markers predicting 6-MP-related toxicities, but their genetic polymorphisms differ from those of ethnic populations. In Yunnan province, a multiethnic region of China, we had no genetic data to predict 6-MP toxicities. In this study, we evaluated the most common variants involved in 6-MP metabolism—TPMT*3C (rs1142345), NUDT15 c.415C&gt;T (rs116855232), and ITPA c.94C&gt;A (rs1127354) variants—in our cohort of pediatric ALL patients.Methods: A total of 149 pediatric ALL patients in the Affiliated Children's Hospital of Kunming Medical University (Yunnan Children's Medical Center) from 2017 to 2019 were enrolled in this retrospective study. We assessed the TPMT*3C (rs1142345), NUDT15 c.415C&gt;T (rs116855232), and ITPA c.94C&gt;A (rs1127354) frequencies and evaluated association between genotypes and 6-MP toxicities, 6-MP dose, and event-free survival (EFS) in these ALL patients.Results: The allele frequencies of TPMT*3C (rs1142345), NUDT15 c.415C&gt;T (rs116855232), and ITPA c.94C&gt;A (rs1127354) were 1.34%, 14.43%, and 18.79%, respectively. Only NUDT15 c.415C&gt;T (rs116855232) was strongly associated with 6-MP toxicity and 6-MP tolerable dose. NUDT15 c.415C&gt;T was related to leukopenia, p = 0.008, OR = 2.743 (95% CI: 1.305–5.768). The T allele was significantly correlated with 6-MP tolerable dose, dose of NUDT15 c.415C&gt;T wild genotype CC 39.80 ± 1.32 mg/m2, heterozygotes CT 35.20 ± 2.29 mg/m2, and homozygotes TT 18.95 ± 3.95 mg/m2. 6-MP tolerable dose between CC and TT had a significant difference, p = 0.009. Between CC and CT, and CT and TT, they had no significant difference. EFS showed no significant difference among NUDT15 c.415C&gt;T genotypes.Conclusion:NUDT15 c.415C&gt;T (rs116855232) was an optimal predictor for 6-MP toxicity and tolerable dose in pediatric ALL patients from Yunnan province, a multiethnic region in China, and would play an important role in precise therapy for ALL.

Improving pneumococcal vaccination rates in pediatric acute lymphoblastic leukemia/lymphoblastic lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18666-e18666
Author(s):  
Simone Chang ◽  
Alexandra Cheerva ◽  
Michael Angelo Huang ◽  
Kerry McGowan ◽  
Esther E Knapp ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Pneumococcal Vaccination ◽  
Vaccination Rate ◽  
Lymphoblastic Lymphoma ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Vaccination Rates ◽  
Targeted Interventions ◽  
Pediatric All

e18666 Background: Pediatric Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma (ALL/LLy) is the most common pediatric cancer. Invasive pneumococcal disease (IPD) is prevalent in this population and the Centers for Disease Control and Prevention recommends pneumococcal vaccination to decrease morbidity and mortality. Despite these recommendations, vaccination rates remain low and the incidence of IPD among children with hematologic malignancy is significantly higher compared to the average pediatric population. An interventional study was designed to improve the vaccination rate and reduce the incidence of IPD in our institution. Methods: A plan-do-study-act (PDSA) model of quality improvement (QI) was used. Chart review at our institute was done for the 6-month period of January 2020 - June 2020 and baseline rates for pneumococcal polysaccharide (PPSV23) vaccination were calculated. Patients were included if they were ≥ 2 years old, diagnosed with ALL/LLy, and undergoing maintenance. A multidisciplinary team performed the root cause analysis. Immunization records were obtained and reviewed and targeted interventions were implemented. The interventions used are outlined in Table. The percentage of pediatric ALL/LLy patients per month in maintenance who received age-appropriate pneumococcal vaccinations was monitored before and after the interventions. Results: Analysis of the 6-month retrospective cohort (n=36) showed a baseline vaccination rate of 5.5%. During the subsequent 6-month phase with interventions, 40 patients were prospectively enrolled. Demographics showed a mean age of 10.2 years (range, 2-21) and a predominantly male (66.7%) cohort. B-cell ALL/LLy comprised the majority (78.9%); the rest included T-cell ALL/LLy and mixed phenotype acute leukemia. As seen in Table, the percentage receiving at least 1 pneumococcal vaccine increased from 5.5% to 84.8% over the first 3 months, this plateaued around 81%. Completion of the series mirrored this and increased to 74.2%. Pre-visit planning and cues proved to be the most helpful interventions. Conclusions: Use of a PDSA model successfully improved pneumococcal vaccination rates in the pediatric ALL/LLy population. We suggest these results can be achieved with planning and implementation of the outlined interventions. [Table: see text]

scholarly journals Where do we stand in the treatment of relapsed acute lymphoblastic leukemia?

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 129-136 ◽  
Author(s):  
Elizabeth A. Raetz ◽  
Teena Bhatla
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Salvage Therapy ◽  
Lymphoblastic Leukemia ◽  
Disease Recurrence ◽  
New Agents ◽  
Promising Tool ◽  
Unique Biology ◽  
Genomic Analyses ◽  
Relapsed Disease

Abstract Acute lymphoblastic leukemia (ALL) is the most common and one of the most treatable cancers in children. Although the majority of children with ALL are now cured, 10%-20% of patients are predicted to relapse and outcomes with salvage therapy have been disappointing, with approximately only one-third of children surviving long-term after disease recurrence. Several prognostic factors have been identified, with timing of recurrence relative to diagnosis and site of relapse emerging as the most important variables. Despite heterogeneity in the elements of salvage therapy that are delivered in trials conducted internationally, outcomes have been remarkably similar and have remained static. Because most intensive salvage regimens have reached the limit of tolerability, current strategies are focusing on identifying new agents tailored to the unique biology of relapsed disease and identifying methods to develop these agents efficiently for clinical use. Recently, high-resolution genomic analyses of matched pairs of diagnostic and relapse bone marrow samples are emerging as a promising tool for identifying pathways that impart chemoresistance.

scholarly journals Methionine synthase A2756G polymorphism influences pediatric acute lymphoblastic leukemia risk: a meta-analysis

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Li-Min Ma ◽  
Hai-Ping Yang ◽  
Xue-Wen Yang ◽  
Lin-Hai Ruan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Population Based ◽  
Methionine Synthase ◽  
China National Knowledge Infrastructure ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All ◽  
And Control

Abstract Plenty of studies have investigated the effect of methionine synthase (MTR) A2756G polymorphism on risk of developing pediatric acute lymphoblastic leukemia (ALL), but the available results were inconsistent. Therefore, a meta-analysis was conducted to derive a more precise estimation of the association between MTR A2756G polymorphism and genetic susceptibility to pediatric ALL. The PubMed, Embase, Google Scholar, Web of Science, ScienceDirect, Wanfang Databases and China National Knowledge Infrastructure were systematically searched to identify all the previous published studies exploring the relationship between MTR A2756G polymorphism and pediatric ALL risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. Sensitivity analysis and publication bias were also systematically assessed. This meta-analysis finally included ten available studies with 3224 ALL cases and 4077 matched controls. The results showed that there was significant association between MTR A2756G polymorphism and risk of pediatric ALL in overall population (AG vs. AA: OR = 1.13, 95%CI = 1.02–1.26, P = 0.02; AG+GG vs. AA: OR = 1.13, 95%CI = 1.02–1.25, P = 0.01; G allele vs. A allele: OR = 1.10, 95%CI = 1.01–1.20, P = 0.03). In the stratification analyses by ethnicity, quality score and control source, significant association was found in Caucasians, population-based designed studies and studies assigned as high quality. In conclusion, this meta-analysis suggests that MTR A2756G polymorphism may influence the development risk of pediatric ALL in Caucasians. Future large scale and well-designed studies are required to validate our findings.

scholarly journals Pharmacogenomic Markers of Methotrexate Response in the Consolidation Phase of Pediatric Acute Lymphoblastic Leukemia Treatment

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 468
Author(s):  
Nikola Kotur ◽  
Jelena Lazic ◽  
Bojan Ristivojevic ◽  
Biljana Stankovic ◽  
Vladimir Gasic ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Allele Frequency ◽  
Methylenetetrahydrofolate Reductase ◽  
Lymphoblastic Leukemia ◽  
Statistical Modelling ◽  
Joint Effect ◽  
Allele Frequency Distribution ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Consolidation Phase ◽  
Pediatric All

Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR- and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients.

scholarly journals Assessment of obesity and hepatic late adverse effects in the Egyptian survivors of pediatric acute lymphoblastic leukemia: single center study

2017 ◽  
Vol 9 (1) ◽  
pp. e2017026 ◽  
Author(s):  
Farida El-Rashedy ◽  
Mahmoud Ahmed El-Hawy ◽  
Sally El Hefnawy ◽  
Mona Mohammed
Keyword(s):  
Hepatitis C ◽  
Acute Lymphoblastic Leukemia ◽  
Adverse Effects ◽  
Liver Enzymes ◽  
Lymphoblastic Leukemia ◽  
Overweight And Obesity ◽  
Direct Bilirubin ◽  
P Value ◽  
Late Adverse Effects ◽  
Pediatric All

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL) with current cure rates reaching 80% emphasizes the necessity to determine treatment related long-term effects. The aim of this study is to estimate the prevalence of overweight, obesity and hepatic late adverse effects in a cohort of ALL survivors treated at the Hematology and Oncology Unit, Pediatrics Department, Menoufia University, Egypt.METHODS: In this case control study, height, weight and body mass index (BMI) were assessed for 35 pediatric ALL survivors and 15 healthy children. These parameters were plotted on the growth and WHO standard deviation charts for both males and females. Overweight and obesity were defined by BMI > 85th and 95th percentile respectively. Laboratory investigations were done in the form of iron profile, liver enzymes, total and direct bilirubin levels, serum urea &creatinine and detection of hepatitis C virus antibodies by ELISA.RESULTS: The weight and BMI were significantly higher in the survivors than controls (P value =0.002 and 0.039 respectively). ALT, total & direct bilirubin, serum ferritin and transferrin saturation were significantly higher in the survivors than the controls (P value = 0.03, 0.036, 0.044, 0.006 and 0.03 respectively). Ten (28.6%) of survivors had hepatitis C antibodies with none (0%) of controls (P value =0.02)CONCLUSIONS: Pediatric ALL survivors are at increased risk of overweight/obesity, hepatic dysfunction in the form of elevated liver enzymes, bilirubin levels and C viral hepatitis. Screening of those survivors for such complications should be considered.Key words: ALL- Survivors – Obesity- Liver.

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