Lymphoblastic Leukemia In Children Research Articles

The treatment development for T cell acute lymphoblastic leukemia in children, adolescents, and young adults

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10%-15% of pediatric ALL, and its frequency increases during the adolescent and young adult (AYA) periods. The improvements in pediatric T-ALL outcomes have been achieved through the treatment intensification strategies addressing the cranial radiotherapy omission issue. Furthermore, pediatric-inspired regimens have been adopted for AYA patients with T-ALL, improving outcomes. In Japan, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-T11/JALSG T-ALL-211-U trial has been conducted for newly diagnosed patients with T-ALL aged <25 years and has been shown to have excellent outcomes. While early T cell precursor ALL is not an obvious poor prognostic factor in recent treatment strategies for pediatric T-ALL, the minimal residual disease (MRD) has been recognized as the most reliable prognostic indicator. Therefore, MRD is now widely used in T-ALL clinical trials for risk stratification and stem cell transplantation indications. Further progress in the novel therapeutic approaches can potentially improve the outcomes of pediatric and AYA patients with T-ALL.

Treatment strategy for B cell precursor acute lymphoblastic leukemia in children

Over the last 60 years, treatment outcomes for pediatric B cell precursor acute lymphoblastic leukemia have improved dramatically, resulting in long-term survival in approximately 90% of cases. These advancements are the results findings of Biological studies, their acceptance as prognostic factors for treatment responses, including MRD, and the accumulation of clinical trials including many randomized controlled trials. Further improvements in the cure rate and reduction of short-term and long-term complications will be issued in the future. To address such issues, new drugs such as immunotherapy and molecular targeted therapy, as well as more precise stratification, are required, and it is expected that progress will be made by promoting clinical trials in the future.

Treatment strategy for Philadelphia chromosome-positive acute lymphoblastic leukemia in children

Tyrosine kinase inhibitor (TKI)-combined chemotherapy has become the standard option in pediatric Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ALL) treatment. Additionally, hematopoietic cell transplantation (HCT) in the first remission is no longer an absolute indication. However, pediatric Ph+ALL remains refractory leukemia, with a disease-free survival rate of approximately 60% for patients without HCT in the first remission due to treatment-related death or relapse after chemotherapy. Further outcome improvement will require an intensified targeted therapy with second- or third-generation TKIs or less toxic immunotherapies, as well as improved safety, with reduced conventional chemotherapy. Continuous attention to these issues in clinical trials will change pediatric Ph+ALL from intractable to manageable leukemia in the future.

T-cell acute lymphoblastic leukemia in children, adolescents, and young adults

T-cell acute lymphoblastic leukemia in children, adolescents, and young adults

Current status and perspectives of relapsed acute lymphoblastic leukemia in children

Current status and perspectives of relapsed acute lymphoblastic leukemia in children

Korisnost ponovljenih merenja nivoa leka nakon infuzije visoke doze metotreksata za planiranje lečenja kod pedijatrijske leukemije

Introduction: Although high-dose Methotrexate (MTX) is a successful chemotherapeutic agent used in the treatment of acute lymphoblastic leukemia in childhood, life-threatening toxic effects are rarely seen. Therefore, frequent follow-up of drug levels is recommended. The study researched the necessity of drug level measurement and a minimum safe number of measurements. Materials and Methods: The files of pediatric patients with Acute Lymphoblastic Leukemia receiving high-dose MTX treatment in a single center between 2018 and 2021 were retrospectively reviewed. The treatment protocol was: 3000 mL/m2 alkaline hydration fluid was continued until the 72nd hour together with 2 gr/m2 continuous MTX infusion in the low-risk group and 5 gr/m2 in moderate and high-risk groups, and 15 mg/m2 /dose folinic acid was given at the 42nd, 48th and 54th hours. Findings: 456 MTX treatments were evaluated in 114 patients. Similar results (p &gt; 0.05) were obtained in the MTX level measurements performed at the 24th, 42nd, 48th, and 54th hours after MTX administration. In the repeated measurements, the data at the 42nd hour were similar (p = 0.021). The number of cases that were &gt; 150 µmol/L at the 24th hour of methotrexate infusion and above 1 µmol/L at the 42nd, 48th, and 52nd hours were found to be similar in the repeated measurements. Conclusion: Although recommended, frequent follow-up of MTX levels might not always indicate toxicity. In centers with limited laboratory facilities, the MTX level measured at the 42nd hour in the first treatment might be a practical approach to guide the management of other MTX treatments.

Screening of Translocation Ets-Leukemia-Acute-Myeloid-Leukemia-1 Fusion Gene and Expression Pattern of Multidrug Resistance Protein Protein in Children with Acute Lymphoblastic Leukemia

The study aimed to investigate the positive rate of TEL-AML 1 fusion gene in acute lymphoblastic leukemia (ALL) children and the clinical characteristics of ALL patients with TEL-AML 1 fusion gene positively expressed, as well as the expression level of MRP-1. 40 ALL children were selected, with their medical records collected. The TEL-AML 1 fusion gene was screened by nested RTPCR. Bone marrow specimens were taken for G-banded karyotype analysis and flow cytometry immunophenotyping of the marrow chromosome. A semi-quantitative RT-PCR method was used to study the mRNA expression level of MRP 1. The results showed that the positive rate of TEL-AML 1 fusion gene in ALL patients was 22.5% (9/40). The positive group exhibited lower gene expression level, the hepatosplenomegaly degree, the total number of peripheral white blood cells, the absolute count of naive cells, and the Hb level at the first visit, indicating that the tumor burden of children in the positive group was lower. The complete remission rate of the positive group was higher (P &lt; 0.05). The mRNA expression level of MRP 1 gene positive group was lower. In conclusion, patients with positive TEL-AML 1 fusion gene were more sensitive to chemotherapeutic drugs, and their treatment responses and prognosis were better.

Quantitative Determination of Serum Level of TLR4, TLR7 and TLR9 in Pediatric Acute Lymphoblastic Leukemia (ALL) Patients in Basrah, Iraq

Acute Lymphoblastic Leukemia (ALL) is one of most frequent malignancy detected in children, accounting for three quarters of all leukemia occurrences in children. Toll-Like Receptors (TLRs) have been shown to be expressed or up regulated in tumors (solid) and tumor cell lines, but their expression level or role in the etiology and progression of acute lymphoblastic leukemia in children is not studied widely. This study intended to explore the association of serum level of TLR4, TLR7, and TLR9 in children with acute lymphoblastic leukemia. A case control study was conducted on patients (pediatric) with ALL who have been admitted to Basrah Children Specialty Hospital, Basrah, Iraq. Three ml of serum samples were collected for the measurement of TLRs concentration by using Sandwich Enzyme-Linked Immuno Sorbent Assay (ELISA). The mean level of TLR4, TLR7 and TLR9 in patients were higher than the control group. However, the difference was statistically significant for TLR4 and TLR7 (P-value less than 0.005) but not for TLR9. The mean value of TLRs are higher in the newly diagnosed group than the relapse. The higher serum concentration of TLR4, TLR7 and TLR9 in patients, whether new or in relapse, compared to control group might be part of the immune-evasion mechanism developed by the malignant cells that plays a serious role in leukomogenicity and disease advancement.

A Review of Acute and Long-Term Neurological Complications Following Haematopoietic Stem Cell Transplant for Paediatric Acute Lymphoblastic Leukaemia.

Despite advances in haematopoietic stem cell transplant (HSCT) techniques, the risk of serious side effects and complications still exists. Neurological complications, both acute and long term, are common following HSCT and contribute to significant morbidity and mortality. The aetiology of neurotoxicity includes infections and a wide variety of non-infectious causes such as drug toxicities, metabolic abnormalities, irradiation, vascular and immunologic events and the leukaemia itself. The majority of the literature on this subject is focussed on adults. The impact of the combination of neurotoxic drugs given before and during HSCT, radiotherapy and neurological complications on the developing and vulnerable paediatric and adolescent brain remains unclear. Moreover, the age-related sensitivity of the nervous system to toxic insults is still being investigated. In this article, we review current evidence regarding neurotoxicity following HSCT for acute lymphoblastic leukaemia in childhood. We focus on acute and long-term impacts. Understanding the aetiology and long-term sequelae of neurological complications in children is particularly important in the current era of immunotherapy for acute lymphoblastic leukaemia (such as chimeric antigen receptor T cells and bi-specific T-cell engager antibodies), which have well-known and common neurological side effects and may represent a future treatment modality for at least a fraction of HSCT-recipients.

Readiness for hospital discharge in primary caregivers for children with acute lymphoblastic leukaemia.

To investigate existing status and factors affecting the readiness for hospital discharge in primary caregivers for children with acute lymphoblastic leukaemia in China. Acute lymphoblastic leukaemia is the most common childhood cancer, but there is not enough research on the readiness for hospital discharge. A cross-sectional study was performed by convenience sampling and questionnaire survey. A self-developed questionnaire of general and clinical characteristics of patients, self-developed questionnaire of general status of family and primary caregivers, questionnaire of readiness of hospital discharge scale and social support rating scale for primary caregivers were delivered to 264 primary caregivers of childhood acute lymphoblastic leukaemia patients. Data collection was carried out 24h before discharge at bedside. In this study, the STROBE checklist was followed. In total, 253 patients aged 0-16years, including their primary caregivers in the hospital, were included from November 2016 to August 2017. Based on the readiness scale, the total mean score of readiness was 157.36. Based on the social support scale, the total mean score was 42.17. According to multivariate analysis, periods of chemotherapy (p<.001), complications (p=.019), family economic situation (p=.023), understanding of leukaemia (p<.001), objective support (p=.004), subjective support (p<.001) and availability of support (p=.045) were the main influencers of readiness. The readiness for hospital discharge in primary caregivers for childhood lymphoblastic leukaemia patients is not satisfactory in China. This study has implications for public health administration, asking for better community services and disease education. In addition, more effort should be made to provide high-quality family and primary caregiver assessments and discharge education by nurses.

Chimeric Antigen Receptor T Cell Therapy followed by Unrelated Cord Blood Transplantation for the Treatment of Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia in Children and Young Adults: Superior Survival but Relatively High Post-Transplantation Relapse

Several studies have indicated that chimeric antigen receptor (CAR) T cell therapy followed by allogeneic hematopoietic stem cell transplantation is beneficial for treating patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL). Whether consolidative unrelated cord blood transplantation (UCBT) is suitable in R/R B-ALL after CAR-T therapy remain uncertain. We aimed to assess the efficacy and safety of CAR-T therapy before UCBT in children and young adults with R/R B-ALL. We retrospectively analyzed 43 patients aged <18 years with R/R B-ALL who underwent single-unit UCBT at the First Affiliated Hospital of the University of Science and Technology of China between February 2012 and November 2020. Among them, 21 patients achieved complete remission (CR) following CAR-T therapy before UCBT (the CAR-T group), and the remaining 22 patients remained in nonremission (NR) without prior CAR-T therapy before UCBT (the NR group). The clinical outcomes in the 2 groups were analyzed. The median time from CAR-T therapy to UCBT was 62 days (range, 42 to 185 days). There were no significant between-group differences in the incidences of grade II-IV acute graft-versus-host disease (GVHD), grade III-IV acute GVHD, and 2-year extensive chronic GVHD. Compared with the NR group, the CAR-T group had a lower 2-year cumulative incidence of transplantation-related mortality and higher probabilities of 2-year overall survival, leukemia-free survival, and GVHD-free relapse-free survival (P=.037, .005, .028, and .017, respectively). However, the 2-year cumulative incidence of relapse (CIR) was comparably high in the 2 groups (26.7% in the CAR-T group and 38.3% in the NR group; P=.41). In the CAR-T group, patients who were minimal residual disease (MRD)-positive before UCBT had a higher CIR compared with those who were MRD-negative before UCBT (66.7% versus 19.2%; P=.006). CAR-T therapy followed by UCBT produces superior survival in R/R B-ALL, but treated patients still have a high post-transplantation relapse rate.

A Case Report of Confirmed COVID-19 In Acute Lymphoblastic Leukemia in Childhood

Introduction: Confirmed COVID-19 case is defined as positive reverse transcriptase polymerase chain reaction (RT-PCR) tests of viral RNA in person with or without clinical symptoms. Patients with leukemia may be at a higher risk to developing COVID-19 infection associated with their underlying disease and chemotherapy treatment, and also also developed severe disease more rapidly compared with healthy person. The aim of this case report is to describe an 11-year-old girl with confirmed COVID-19 and comorbidities of acute lymphoblastic leukemia. Case Presentation: A girl 11 years 10 months old was clinically diagnosed as confirmed COVID-19 and Acute Lymphobalstic Leukimia (ALL) based on positive RT-PCR SARS CoV2 swab test and bone marrow puncture (BMP). The main complaint was weakness since 2 days ago, she had slight anosmia and dry cough since 1 days. The history of fever, dyspnoea, and spontaneous bleeding were absent. She had normal urination and defecation. Hepatosplenomegaly was found on physical examination. The laboratory result found the complete blood count (CBC) slightly leukopenia, antibody of COVID-19 test was reactive IgG and positive swab RT-PCR SARS CoV2 test. The first BMP result was ALL FAB L2. From the chest x-ray showed infiltrates in both of lungs. Conclusion: This is a case reported of Acute Lymphoblastic Leukemia with confirmed COVID-19 in a girl 11 years 10 months old and diagnostic approach based on RT-PCR SARS CoV2 and BMP.

Acute lymphoblastic leukemia in children and SALL4 and BMI-1 gene expression.

Sal-like protein 4 transcription factor (SALL4) and B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1) gene were reported to cause treatment failure and relapse in several malignancies. We aimed to evaluate the prognostic value of SALL4 and BMI-1 in children with acute lymphoblastic leukemia (ALL). This prospective cohort study was carried out on 60 children with ALL as the patient group and 60 age- and sex-matched children as the control group. We evaluated the expression pattern of both SALL4 and BMI-1 genes in the peripheral blood using real-time reverse transcriptase-polymerase chain reaction in children with ALL at initial diagnosis before chemotherapy. We followed up with the patient group for 2 years for relapse or death. Both SALL4 and BMI-1 were overexpressed in ALL children compared to the control group. Moreover, the expression of SALL4 and BMI-1 in patients with relapse was significantly higher than those with complete remission. The best cut-off of SALL4 and BMI-1 to predict relapse were >2.21 and 0.55 yielding sensitivity of 92.3% and 84.6%, respectively. Patients with overexpression of SALL4 and BMI-1 had significantly shorter overall and disease-free survival. SALL4 and BMI-1 could be useful prognostic markers in children with ALLto predict relapse.

Upregulation of leukemia-induced non-coding activator RNA (LUNAR1) predicts poor outcome in pediatric T-acute lymphoblastic leukemia

T-cell Acute Lymphoblastic Leukemia (T-ALL) accounts for around 10–15% of all lymphoblastic leukemia in children. Previous studies have proven that dysregulation of Leukemia-induced non-coding activator RNA-1 (LUNAR1) expression promotes T-ALL cell growth by enhancing the NOTCH1/IGF-1R signaling pathway. We aimed to investigate the prognostic value of LUNAR1 in pediatric T-ALL, in addition, to find out its association with NOTCH1 and IGF-1R. The LUNAR1, NOTCH1, and IGF-IR gene expression were measured in peripheral blood (PB) samples of l85 children with T-ALL and forty non-leukemic samples as a control group. Cox regression analysis revealed that overexpression of LUNAR1, NOTCH1, and IGF-IR was significantly correlated with poor prognosis, short overall survival, and progression-free survival. We concluded that LUNAR1 could serve as an independent prognostic biomarker for T-ALL in children.

Treatment of acute lymphoblastic leukemia in children by ALL IC-BFM 2002 protocol: results of multicenter retrospective study

By the whole history of pediatric acute lymphoblastic leukemia (ALL) treatment protocols development, one of the World ideologist of original science-based therapeutic approaches was German group BFM (Berlin–Frankfurt–Münster). It is not surprisingly that modern ALL treatment protocols, developed by BFM group are high-effective and use in many countries. Understanding the probability of recovery of overwhelming ALL patients majority treated by ALL IC-BFM 2002 protocol, the Scientific-Practical Board of Ministry of Health of Russia in 2020 adopted a protocol as clinical recommendation for pediatric ALL treatment (ID:529).It the current issue BFM ALL treatment protocols evolution is presented and first Russian multicenter experience in pediatric ALL treatment by ALL IC-BFM 2002 protocol. It was 408 pediatric and adolescents patients with primary ALL included the study. All of them were treated by ALL IC-BFM 2002 protocol from 01.11.2003 to 12.05.2021. Survival rate was estimated on 01.06.2021.ALL IC-BFM 2002 demonstrated a high efficiency in multicenter retrospective study. 15-year event-free survival was 83.7 ± 2.1 %, relapsefree survival – 88 ± 1.8 % and overall survival – 93.4 ± 1.4 %. So, ALL IC-BFM 2002 protocol could be realized in Russian clinics and give results similar to world’s leading medical centers.

Effectiveness of T-Cell Replete Haploidentical Hematopoietic Stem Cell Transplantation for Refractory/Relapsed B Cell Acute Lymphoblastic Leukemia in Children and Adolescents.

Background: The prognosis of refractory/relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains dismal owing to acquired resistance to chemotherapeutic agents. This study aimed to evaluate the efficacy of T-cell replete HLA haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) for pediatric refractory/relapsed BCP-ALL (RR-BCP-ALL).Methods: Nineteen pediatric patients with RR-BCP-ALL underwent TCR-haplo-HSCT between 2010 and 2019 at the Fukushima Medical University Hospital. The disease status at TCR-haplo-HSCT included complete remission (CR) in eight patients and non-CR with active disease in 11 patients. Total body irradiation-based, busulfan-based, and reduced-intensity conditioning regimens were employed in 11, 6, and 2 patients, respectively. Low-dose anti-thymocyte globulin (thymoglobulin, 2.5 mg/kg) was used in all patients. Graft-vs.-host disease (GVHD) prophylaxis was administered with tacrolimus, methotrexate, and prednisolone.Results: All patients received peripheral blood stem cells as the stem cell source. The HLA disparities in graft vs. host directions were 2/8 in one, 3/8 in five, and 4/8 in 13 patients. Among 18 patients who achieved primary engraftment, acute GVHD occurred in all 18 evaluable patients (grade II, 9; grade III, 8; grade IV, 1), and chronic GVHD was observed in 10 out of 15 evaluable patients. Three patients died because of transplant-related mortality. The 3-year overall survival (OS) and leukemia-free survival rates were 57.4 and 42.1%, respectively. Compared to patients older than 10 years in age (N = 10), those younger than 10 years in age (N = 9) showed an excellent OS rate (3-year OS rate: patients < 10 years old, 100%; patients > 10 years old, 20% [95% confidence interval, 3.1–47.5]; p = 0.002).Conclusions: We suggest that TCR haplo-HSCT with low-dose ATG conditioning has the potential to improve the transplantation outcomes in patients with RR-BCP.

Cerebral venous thrombosis in acute lymphoblastic leukemia in children treated with asparaginase

Cerebral venous thrombosis is a rare disease in children, but is one of the most serious complications of leukemia acute infantile lymphoblastic. We report the case of a child with acute childhood lymphoblastic leukemia, treated with L-asparaginase, who developed cerebral venous thrombosis.

A Risk Scoring Model for High-Dose Methotrexate-Induced Liver Injury in Children With Acute Lymphoblastic Leukemia Based on Gene Polymorphism Study.

A study on 70 acute lymphoblastic leukemia (ALL) children (age ≤16 years) treated with high-dose methotrexate (HD-MTX) in Sichuan Provincial People’s Hospital was conducted. The aim of the study was to establish a risk-scoring model to predict HD-MTX-induced liver injury, considering gene polymorphisms’ effects. Data screening was performed through t-test, chi-square test, and ridge regression, and six predictors were identified: age, MTRR_AA, MTRR_AG, SLCO1B1_11045879_CC, albumin_1 day before MTX administration, and IBIL_1 day before MTX administration (p < 0.1). Then, the risk-scoring model was established by ridge regression and evaluated the prediction performance. In a training cohort (n = 49), the area under the curve (AUC) was 0.76, and metrics including accuracy, precision, sensitivity, specificity, positive predictive value, and negative predictive value were promising (0.86, 0.81, 0.76, 0.91, 0.81, 0.88, respectively). In a test cohort (n = 21), the AUC was 0.62 and negative predictive value was 0.80; other evaluation metrics were not satisfactory, possibly due to the limited sample size. Ultimately, the risk scores were stratified into three groups based on their distributions: low- (≤48), medium- (49–89), and high-risk (>89) groups. This study could provide knowledge for the prediction of HD-MTX-induced liver injury and reference for the clinical medication.

Maternal antibiotics exposure during pregnancy and the risk of acute lymphoblastic leukemia in childhood: a systematic review and meta-analysis.

Many epidemiological studies have assessed the association between maternal antibiotic exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL), while reaching inconsistent conclusions. In order to clarify the association, the publications in English that provided information about maternal antibiotic exposure during pregnancy and ALL risk in offspring in the PubMed, Embase, and Web of Science databases were systematically reviewed and we performed a meta-analysis using the random-effect models. Results of pooled analysis showed that maternal antibiotic intake during pregnancy is not associated with childhood ALL risk (pooled odds ratio 1.07, 95% confidence interval 0.98-1.18) without significant heterogeneity (I2 = 13.7%, P = 0.310). This finding was consistent across subgroups stratified by type of study design, measurement method, sample size, study quality, and pregnancy stage. Our findings suggest that maternal antibiotic consumption during pregnancy was not associated with ALL risk in progeny. Further investigations are needed to confirm the results and assess any risk differences of ALL by types of antibiotics.Conclusions: Our findings suggest that maternal antibiotics consumption during pregnancy was not associated with ALL risk in progeny. Further investigations are needed to confirm the results and assess any risk differences of ALL by types of antibiotics. What is Known: • It is not unusual for pregnant woman to receive antibiotics for local or systematic use during pregnancy. • The conclusions regarding the associations between maternal antibiotics use during pregnancy and childhood ALL risk were inconsistent. What is New: • Maternal antibiotics consumption during pregnancy was not associated with the increased ALL risk in offspring. • Further laboratory evidences are needed to confirm the results.

An analysis of childhood acute lymphoblastic leukemia (B-Cell) for incidence of age in the capital city of Punjab

Aim: To evaluate the age presentation of B-cell lymphoblastic leukemia. Study design: The design of the study was cross sectional. Setting of study: PGMI, Chughtai Institute of Pathology. Duration of study: The duration of study was one year i.e., from 1st July 2019 to 31st June 2020. Methods: A sample of 56 patients were included in the study. The selection of the patients was in accordance with the criteria set in the inclusion and exclusion group of the study. All the cases presenting with B-cell lymphoblastic leukemia were analyzed based on age presentation. The quantitative variable of age was recorded in Proforma. The statistical evaluation was done using SPSS version 22. The quantitative age variable was presented as mean + standard deviation Results: The results of the study showed variation of age presentation, ranging from two years to fourteen years (2Y-14Y). The youngest patient at presentation was only 2Y of age. The mean age of presentation however was ranged at 6.28Y. The eldest presentation of B-cell lymphoblastic leukemia was 14Y. The SD value of our quantitative variable of age is 3.29. Conclusion: The rationale of the study helped us determining the peak incidence of age presentation for B-cell lymphoblastic leukemia in children. The age ranged from 2 years to 14 years, with peak at 6 years. We conclude that these results are in close association with the findings in result of the developing countries of the world Keywords: Lymphoblastic leukemia, B-cell, childhood