Treatment Of Childhood Acute Lymphoblastic Leukemia Research Articles

Thrombin Generation Profile Using ST-Genesia after PEG-asparaginase in Pediatric Patients with Acute Lymphoblastic Leukemia.

Venous thromboembolism (VTE) etiology in children with acute lymphoblastic leukemia (ALL) is multifactorial. The use of global assays of hemostasis as a thrombin generation test (TGT) is useful to individualize VTE risk in adult patients. This prospective cohort study aimed to evaluate the usefulness of an automated TGT to evaluate VTE risk during ALL treatment in children. TGT (automated analyzer ST Genesia; ThromboScreen) and pro- and anticoagulant plasma proteins were analyzed during ALL treatment in pediatric patients following LAL-SEHOP-PETHEMA-2013 guidelines. Results were compared with a series of pediatric normal controls and evaluated according to pegylated asparaginase PEG-ASP administration and to VTE risk factors. The study included 67 patients: males n = 35, B-ALL (n = 60). None had a VTE during the evaluated period. Compared to healthy controls, the normalized endogenous thrombin potential (N-ETP) ratio in patients was higher and ETP inhibition (ETP-inh) was lower, especially after PEG-ASP administration. Plasmatic protein C and protein S levels decreased after PEG-ASP administration, but antithrombin mean level did not. A bivariant analysis showed that ETP-inh was lower in patients >10 years old (p = 0.05) and in those with non-O blood type (p = 0.005). A linear mixed model also showed a higher TGT prothrombotic profile in patients with inherited thrombophilia. TGT could be a biomarker of a high VTE risk in ALL pediatric patients. Non-O blood group and inherited thrombophilia were associated with a significantly higher thrombotic profile, and an increased profile was also observed after administration of PEG-ASP.

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Relationship between subtype-specific minimal residual disease level and long-term prognosis in children with acute lymphoblastic leukemia.

Minimal residual disease (MRD) based risk stratification criteria for specific genetic subtypes remained unclear in childhood acute lymphoblastic leukemia (ALL). Among 723 children with newly diagnosed ALL treated with the Chinese Children Leukemia Group CCLG-2008 protocol, MRD was assessed at time point 1 (TP1, at the end of induction) and TP2 (before consolidation treatment) and the MRD levels significantly differed in patients with different fusion genes or immunophenotypes (P all < 0.001). Moreover, the prognostic impact of MRD varied by distinct molecular subtypes. We stratified patients in each molecular subtype into two MRD groups based on the results. For patients carrying BCR::ABL1 or KMT2A rearrangements, we classified patients with MRD < 10-2 at both TP1 and TP2 as the low MRD group and the others as the high MRD group. ETV6::RUNX1+ patients with TP1 MRD < 10-3 and TP2 MRD-negative were classified as the low MRD group and the others as the high MRD group. For T-ALL, We defined children with TP1 MRD ≥ 10-3 as the high MRD group and the others as the low MRD group. The 10-year relapse-free survival of low MRD group was significantly better than that of high MRD group. We verified the prognostic impact of the subtype-specific MRD-based stratification in patients treated with the BCH-ALL2003 protocol. In conclusion, the subtype-specific MRD risk stratification may contribute to the precise treatment of childhood ALL.

Micafungin twice-a-week for prophylaxis of invasive Aspergillus infections in children with acute lymphoblastic leukaemia: A controlled cohort study

ObjectivesInvasive Aspergillus infections during the early phase of childhood acute lymphoblastic leukemia (ALL) treatment come with morbidity and mortality. The interaction with vincristine hampers first-line azole prophylaxis. We describe the efficacy of an alternative twice-a-week micafungin regimen for Aspergillus prophylaxis. MethodsNewly diagnosed paediatric patients with ALL treated according to the ALL-11 protocol received micafungin twice-a-week (9 mg/kg/dose [max. 300 mg]) during the induction course (first 35 days of treatment) as part of routine care. A historical control cohort without Aspergillus prophylaxis was used. During the first consolidation course (day 36-79), standard itraconazole prophylaxis was used in both groups.The percentage of proven/probable Aspergillus infections during the induction/first consolidation course was compared between the cohorts. The cumulative incidence of proven/probable Aspergillus infections was estimated using a competing risk model. For safety evaluation, liver laboratory chemistry values were analysed. ResultsA total of 169 and 643 paediatric patients with ALL were treated in the micafungin cohort (median age: 4 years [range 1-17]) and historical cohort (median age: 5 years [range 1-17]). The percentage of proven/probable Aspergillus infections was 1·2% (2/169) in the micafungin cohort versus 5·8% (37/643) in the historical cohort (p=0.013; Fisher's exact test). The differences in estimated cumulative incidence were assessed (p=0·014; Gray's test). Although significantly higher ALT/AST values were reported in the micafungin cohort, no clinically relevant side effects were observed. ConclusionsTwice-a-week micafungin prophylaxis during the induction course significantly reduced the occurrence of proven/probable Aspergillus infections in the early phase of childhood ALL treatment.

Metabolomic Insights into the Pathogenesis and Prognostic Potential of Adult Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) comprises hematological malignancies affecting B or T cell precursors (BCP-ALL or T-ALL). Despite considerable progress made over the past three decades in the treatment of childhood ALL [5-year disease survival rate (5-y DFS): 90%], the prognosis of adult ALL remains relatively poor (5-y DFS: 50-70%). Hence, gaining a deeper understanding of the pathogenic factors is of timely importance. Recent advancements in next-generation genome sequencing technologies have facilitated the refinement of disease diagnosis and prognosis. However, due to the inherent genetic diversity among patients, additional tools are needed to unravel the complex etiological basis and improve risk stratification for personalized therapeutic interventions, particularly in adult ALL. Metabolomics offers a powerful approach that enables the comprehensive exploration of cellular states by analyzing metabolites quantitatively and qualitatively, which reflects altered enzyme kinetic activities and changes in metabolic reactions. It was previously reported that most bone marrow metabolites could be detected in plasma in BCP-ALL (81%). In this study, we reported an integrated analysis of serum metabolites using liquid chromatography/mass spectrometry as well as the metabolic gene expression profiles from RNA-sequencing data of bone marrow blasts, generating a comprehensive metabolic information dataset (CMID) in 211 adult ALL patients (BCP-ALL: n=160; T-ALL: n=51) who participated in our recent clinical trial (ChiCTR-ONRC-14004968). The graphical abstract is depicted in Figure 1A. Serum metabolomic landscape of adult ALL was obtained at various time points during treatment, including samples at diagnosis (Day 0, D0, n=198), during the induction phase (D14, n=177 and D28, n=147) and the early consolidation phase (Cons, n=58). These samples were subject to comparison to those from 164 age/sex-matched healthy controls (HC). Using CMID, we further subtyped BCP-ALL (clusters BC1 and BC2, and a special cluster of Ph + ALL) and T-ALL (clusters TC1 and TC2), revealing that BC2 and TC1 were associated with relatively favorable outcome, compared respectively to BC1 (OS: P&amp;lt;0.05) and TC2 (OS: P&amp;lt;0.05). Regarding serum metabolomic profiles over the treatment course, we found a number of featured disturbances ( Figure 1B). Aberrant lipid-related metabolisms, such as steroid metabolism, were detectable throughout different phases. In contrast, the metabolism of amino acids and a number of metabolites pumped by ATP-binding cassette transporter were severely impacted by therapeutic agents during the induction phase (on D14). Notably, at the time of diagnosis, primary bile acid biosynthesis was enriched, consistent with a previous study on pediatric ALL. In our functional experiment, inhibiting the synthesis of bile acid precursors such as cholesterol with Simvastatin suppressed leukemic cell viability in 10 ALL cell lines, indicating a potential role of this pathway in leukemogenesis. In addition, we identified arachidonic acid (AA) metabolism enrichment in the favorable BC2 subgroup. Coincidentally, glycerophospholipid metabolism, which provides substrates for AA synthesis, was also enriched in the TC1 subgroup, together with an active AA metabolism. Increasing data suggests that AA metabolites act as immunoregulators in cancer, thus we hypothesize that they could play a role in ALL prognosis by regulating the immune reaction against leukemic cells in the hematopoietic microenvironment. In our further efforts to address the correlation between CMID-based subtypes and known genetic events in Ph --BCP-ALL and T-ALL leukemogenesis, we discovered that some favorable genetic markers (ZNF-384/362 fusions and high ploidy) tended to fall into BC2, while NRAS mutations were only observed in TC1. On the other hand, both CMID-based subtypes and genetic events-based ones stand as independent factors in multivariate Cox analysis for risk stratification of BCP-ALL, demonstrating an added value of the CMID subtypes in the prognosis of adult BCP-ALL. Our work has thus highlighted the significance of altered metabolome in ALL pathogenesis, proved its clinical relevance for prognosis stratification, and identified its potential vulnerabilities for improving tailored therapy.

Thromboprophylaxis with Intermediate Dose Low Molecular Weight Heparin in Adults Undergoing Induction with L-Asparaginase for Acute Lymphoblastic Leukemia

Introduction Adolescents and young adults (AYA, defined as age 15-39 years) with acute lymphoblastic leukemia (ALL) have a poorer prognosis than their pediatric counterparts. To replicate the success of ALL treatment in children, pediatric-inspired regimens have been incorporated into the treatment of AYA and often include the use of L-asparaginase. Rates of thrombosis in adults receiving L-asparaginase for treatment of ALL have been reported to be as high as 34%, compared to only about 5% in pediatric patients. The risk of thrombosis is elevated primarily during the induction phase of treatment. Several strategies have been studied in adults, including antithrombin III replacement, fresh frozen plasma replacement, and prophylactic dosing of anticoagulation, however no clear guidelines exist on how to prevent thrombosis in these high-risk patients. To prevent L-asparaginase-induced thrombotic events, our institution implemented a standard practice of 1mg/kg/day of low molecular weight heparin (LMWH), a dose in-between prophylactic and therapeutic dosing, administered to all adults with ALL who were treated with L-asparaginase during induction chemotherapy. In this current study, we report data from patients who have been treated with this strategy from 2012 to present, focusing on the antithrombotic efficacy and safety of 1mg/kg/day LMWH in this population. Methods This retrospective chart review included 62 patients who received prophylactic anticoagulation with the LMWH enoxaparin (1mg/kg/day) while undergoing induction chemotherapy with L-asparaginase for ALL at the Oregon Health &amp; Science University from 2012 to present. Anticoagulation with enoxaparin was initiated with the first dose of L-asparaginase and continued until the day of discharge or day 30 of induction. The primary outcome was the incidence of thrombosis within the first 30 days of L-asparaginase administration. Minor and major bleeding events, as defined by the International Society of Thrombosis and Haemostasis (ISTH), were recorded. Statistical analysis with univariate regression models was performed to evaluate the association of thrombotic events with demographic, disease and treatment variables. Results Sixty-two patients received 1mg/kg/day LMWH prophylaxis during ALL induction between January 2012 and June 2023 (43 with B-ALL and 19 with T-ALL). Median age at induction was 25.7 years (range 18-39 years). A majority of patients (83.9%) received the maximum dose of 2500mg/m 2 of L-asparaginase. Four patients (6.5%; 95% CI 1.8%-15.7%) experienced a thrombotic event within the first 30 days of induction with L-asparaginase; 3 of the events were catheter-associated and were treated supportively or with catheter removal, and 1 patient developed a distal lower extremity deep vein thrombosis related to myositis. Median time to thrombosis was 13.5 days (range 11-22 days). There were no significant associations between development of thrombotic events with age, gender, B- or T-cell precursor, or dose of L-asparaginase. No thrombosis-related deaths or major bleeding events occurred. Conclusions Prophylactic anticoagulation with intermediate dose 1mg/kg/day LMWH in adults with ALL undergoing induction chemotherapy with L-asparaginase is a safe and an effective strategy to prevent serious thrombotic events. Our institutional rate of 6.5% of patients experiencing thrombotic events during induction with L-asparaginase, with all of the events being clinically low risk, compares favorably to historically reported rates in adults and approaches the low rates reported in children. Further prospective research is warranted.

Mapping Chemo-Resistance Profiles of Pediatric Acute Leukemia through Integration of Ex-Vivo Drug Screens with Molecular Data

Introduction While novel approaches for treatment of acute lymphoblastic leukemia (ALL) in children have resulted in significant improvements in survival rates, survivors are faced with potentially life-long challenges as a result of the highly toxic treatment and the outcome for patients who relapse remains poor. The current risk-adapted treatment for ALL in children includes multiple drugs administered sequentially or in combination, with little variation in timing or intensity. Factors that affect varying treatment response between patients and cellular mechanisms that underly response to individual drugs are still under exploration. In this study, we investigate the relationship between ex-vivo drug resistance, transcriptomes, epigenomes and clinical outcome, with the aim of better understanding underlying determinants of treatment response. Methods Pediatric patients diagnosed with B-ALL between 1992 and 2008 in the Nordic countries were included in the study (n = 598). For these patients, ex-vivo drug response to ten clinically used drugs was determined using the fluorometric microculture cytotoxicity assay (FMCA). Clinical data, including follow-up information (overall survival and relapse free survival) was available for all patients. Additionally, DNA-methylation (450K array, n = 383) and gene expression profiling (RNA-seq, n = 119) was performed on a subset of diagnostic patient samples. The patients were stratified into low, medium and high resistance groups based on ex-vivo drug response. The low and high resistance groups were compared with regard to differentially methylated CpG sites or expressed genes associated with individual drug response profiles. Results Overall survival was significantly lower for patients with higher ex-vivo drug resistance to dexamethasone, doxorubicin and thioguanine compared to patients that displayed sensitivity to these drugs (p &amp;lt; 0.05). Similarly, relapse free survival was significantly lower for patients with ex-vivo resistance to cytarabine, dexamethasone, doxorubicin, prednisolone and thioguanine (p &amp;lt; 0.05). After adjusting for sex and risk group, according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) protocol, in a Cox proportional hazards model, higher hazard ratios for relapse were observed in the highly resistant group across all drugs. We identified distinct DNA methylation and gene expression patterns in patients with low and high resistance, indicating the presence of predetermined molecular resistance fates. These resistance patterns included 665 genes that were differentially expressed (absolute log2FC &amp;gt; 1, Benjamini-Hochberg adjusted p value &amp;lt; 0.05) and 1 422 CpG sites with differential methylation status (absolute mean β-value difference &amp;gt; 0.2, Benjamini-Hochberg adjusted p value &amp;lt; 0.05) in resistant compared to sensitive groups, for one or multiple drugs. With the aim of identifying the genes with the largest impact on drug resistance, we selected the most differentially expressed genes and the genes with the largest difference in methylation status between resistant and sensitive samples. Among these, we identified ~20 putative genes of interest for future studies into resistance mechanisms based on potential functional prioritization. Conclusion Our findings confirm that drug response profiles are associated with outcome in pediatric ALL, reflecting response in vivo. We show molecular evidence for differentiating low- and high-resistant types based on diagnostic gene expression and DNA methylation profiles, suggesting contribution of certain molecular signatures to drug response. Our data integrating molecular data with drug response profiles may help identifying such changes of importance in drug resistance mechanisms.

Outcome of neutropenic enteropathy during induction phase of treatment of childhood acute lymphoblastic leukemia

BackgroundNeutropenic enteropathy is one of the important causes of death during intensive phase of chemotherapy in children with acute lymphoblastic leukemia (ALL). It follows a prolonged course of neutropenia and carries a mortality rate up to 30%. The study aimed to find out the outcomes of typhlitis during induction phase of treatment of childhood ALL. Material and methodsThis prospective case control study was conducted in the Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from November 2018 to January 2021. Children (<19 years) with ALL who developed neutropenic enteropathy during induction phase of chemotherapy without any comorbid condition were included in this study. The clinico-radiological diagnosis of neutropenic enteropathy was based on a standard diagnostic criteria. Complete blood count, serum electrolytes, albumin, blood culture, stool culture, abdominal X-ray and ultrasonogram were performed in all the cases. ResultsThirty-six patients developed neutropenic enteropathy. 8 (22.2%) died. Thrombocytopenia (p = 0.001), hypoalbuminemia (Odd ratio 21.0, p < 0.001), positive blood culture (Odds ratio 6.11, p = 0.026). ConclusionThis study found a mortality rate of 22.2% amongst the pediatric patients with ALL who developed neutropenic enteropathy during induction chemotherapy. Thrombocytopenia, hypoalbuminemia, and a positive blood culture predicted mortality.

Hyperlipidemia in children and adolescents with acute lymphoblastic leukemia: A systematic review and meta-analysis.

The established association between acute lymphoblastic leukemia (ALL) and hyperlipidemia has, in some studies, been linked to toxicities such as pancreatitis, thrombosis, and osteonecrosis. However, a systematic review investigating the incidence, management, and clinical implications of hyperlipidemia during childhood ALL treatment is lacking. Systematically assess the incidence of hyperlipidemia during ALL treatment, explore associations with risk factors and severe toxicities (osteonecrosis, thrombosis, and pancreatitis), and review prevalent management strategies. A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Data synthesis was descriptive, and a meta-analysis of hypertriglyceridemia and risk of severe toxicities was performed. We included 13 studies with 3,425 patients. Hyperlipidemia incidence varied widely (6.7%-85%) but with inconsistent definitions and screening strategies across studies. Evidence regarding risk factors was conflicting, but age (>10 years) and treatment with asparaginase and glucocorticosteroids seem to be associated with hyperlipidemia. Hypertriglyceridemia (grade 3/4) increased the risk for osteonecrosis (odds ratio (OR): 4.27, 95% confidence interval (CI): 2.77-6.61). No association could be established for pancreatitis (OR: 1.60, 95% CI: 0.53-4.82) or thrombosis (OR: 2.45, 95% CI: 0.86-7.01), but larger studies are needed to confirm this. The overall evidence of this systematic review is limited by the small number of studies and risk of bias. Our review suggests that hypertriglyceridemia increases the risk for osteonecrosis. However, larger studies are needed to explore the clinical implications of hyperlipidemia and randomized trials investigating hyperlipidemia management and its impact on severe toxicities.

KIF11 serves as a cell cycle mediator in childhood acute lymphoblastic leukemia.

To identify key gene in childhood acute lymphoblastic leukemia (ALL) through weighted gene co-expression network analysis (WGCNA), and their enriched biological functions and signaling pathways. Array data of the GSE73578 dataset, involving 46 childhood ALL samples, were acquired from the Gene Expression Omnibus (GEO) database. Hub modules associated with childhood ALL were screened out by WGCNA. Enriched biological functions and signaling pathways were then identified by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Hub genes were selected by overlapping those between down-regulated genes in GSE73578, GSE4698 and the hub module. Guilt by association (GBA) was adopted to verify the function of the identified KIF11 gene and to predict its target genes. Regulatory effects of KIF11 on the proliferation and cell cycle progression of ALL in vitro were determined by cytological experiments. WGCNA showed that the yellow module was the most relevant to childhood ALL treatment, containing 698 genes that were enriched in cell division, mitotic nuclear division, DNA replication and DNA repair, cell cycle, DNA replication and the P53 signaling pathway. The KIF11 gene was screened out and predicted as a cell cycle mediator in childhood ALL. Knockdown of KIF11 in ALL cells inhibited cell proliferation and arrested cell cycle progression in G2/M phase. The KIF11 gene is critical in the treatment process of childhood ALL, which is a promising therapeutic target for childhood ALL.

Causes of death and treatment-related mortality in newly diagnosed childhood acute lymphoblastic leukemia treatment with Chinese Children's Cancer Group study ALL-2015.

To investigate the possible risk factors for death at post-treatment in children with acute lymphoblastic leukemia (ALL). A multivariate competing risk analysis was performed to retrospectively analyze the data of children with ALL who died after treatment with CCCG-ALL-2015 in China and to determine the possible risk factors for death at post-treatment in children with ALL. Age at the first diagnosis of ≥10 years; final risk level of high-risk; D19 minimal residual disease (MRD) (≥0.01%) and D46 MRD (≥0.01%); genetic abnormalities, such as KMT2A-rearrangement, c-Myc rearrangement, and PDGFRB rearrangement; and the presence of CNS3 (all P values, <0.05) were identified as independent risk factors, whereas the risk level at the first diagnosis of low-risk (LR) and ETV6::RUNX1 positivity was considered as independent protective factors of death in children with ALL. Among the 471 cases of death, 45 cases were treated with CCCG-ALL-2015 only, and 163 (34.61%) were treatment-related, with 62.42% due to severe infections. 55.83% of treatment-related mortality (TRM) occurred in the early phase of treatment (induction phase). TRM has a significant impact on the overall survival of pediatric patients with ALL. Moreover, the CCCG-ALL-2015 regimen has a better safety profile for treating children with ALL, with rates close to those in developed countries (registration number: ChiCTR-IPR-14005706; date of registration: June 4, 2014).

L-Asparaginase as the gold standard in the treatment of acute lymphoblastic leukemia: a comprehensive review.

L-Asparaginase is an antileukemic drug long approved for clinical use to treat childhood acute lymphoblastic leukemia, the most common cancer in this population worldwide. However, the efficacy and its use as a drug have been subject to debate due to the variety of adverse effects that patients treated with it present, as well as the prompt elimination in plasma, the need for multiple administrations, and high rates of allergic reactions. For this reason, the search for new, less immunogenic variants has long been the subject of study. This review presents the main aspects of the L-asparaginase enzyme from a structural, pharmacological, and clinical point of view, from the perspective of its use in chemotherapy protocols in conjunction with other drugs in the different treatment phases.

A comparison of hypersensitivity reactions between intravenous and intramuscular applications of native E. coli asparaginase in children with acute lymphoblastic leukemia.

Asparaginase is an indispensable drug in treating childhood acute lymphoblastic leukemia (ALL). Hypersensitivity reactions (HSR) are the most common side effects and interfere with the antineoplastic activity of the drug. This study aims to compare the intramuscular (IM) and intravenous (IV) administration routes of Native Escherichia coli Lasparaginase (L-ASNase) in terms of hypersensitive reactions. L-ASNase was randomly administered IV or IM to newly diagnosed ALL patients and HSR was monitored in all patients for 1 h following the end of the IV infusion and for 2 h following the end of the IM administration of L-ASNase. Based on a retrospective review of clinical charts, reactions were identified. In order to determine the severity of each allergic reaction, we used the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 for allergic reactions. A total of 1032 doses of L-ASNase were administered to 85 patients (42 males and 43 females) during the study period. Among 85 patients, 30 reactions were recorded, which means that 35% of the patients reacted. According to the CTCAE, twenty-nine out of 30 reactions (97%) were grade 2, while one (3%) was grade 4. In terms of individual doses, there was a non-significant trend toward increased incidence of reactions with IV administration (3.8% versus 0.9%, p = 0.064). The rate of reactions was higher in patients who received all IV doses (n: 60) as compared to those who received all IM doses (n: 25) (31.7% vs. 3.5%; chi-square= 8.415, p value=0.04). Based on the risk groups and HSR incidence, it was found that high risk group (HRG) patients were significantly more likely to develop HSR compared to the standart risk group (SRG) and intermediate risk group (MRG) patients (chi-square p = 0.003, CI: 95%; odds ratio: 3.12 and 5.91, respectively). In conclusion, IM administration of L-ASNase causes significantly less HSR to L-ASNase than the IV route. Patients with HRGALL have a higher risk of HSR. Since L-ASNase is still used in many developing countries and there are problems in the supply of Erwinia chrysanthemi ASNase (Erwinia), LASNase can be administered IM to reduce the frequency of HSR.

Treating childhood acute lymphoblastic leukemia relapse post haploidentical stem cell transplant with car-T cell therapy

Treating childhood acute lymphoblastic leukemia relapse post haploidentical stem cell transplant with car-T cell therapy

Acute complications observed during intensive chemotherapy in pediatric patients with acute lymphoblastic leukemia: Single-center experience.

In childhood acute lymphoblastic leukemia (ALL), very promising results were obtained thanks to the developments in treatment strategies in recent years. However, acute complications during treatment continue to be the important causes of mortality and morbidity. In this study, acute complications that develop during the treatment of ALL in childhood were evaluated. Medical records of 47 patients treated according to (ALL Intercontinental Berlin-Frankfurt-Münster) 2009 protocol between 2016 and 2021 were evaluated retrospectively. Of 47 patients, 28 (59.6%) were male and 19 (40.4%) were female. The mean age at diagnosis was 5.9±4.2 years. Forty-four patients (93.6%) were pre-B cell ALL, 3 patients (6.4%) were pre-T cell ALL. Of 47 patients, 9 (19.1%) were high risk, 32 (68.1%) were intermediate risk, and 6 (12.8%) were standard risk. Acute complications developed in 38 patients (80.8%). Among these complications, infectious complications are the most common and these were followed by gastrointestinal complications, drug-related reactions, thrombotic, neurological, and endocrine/metabolic complications, respectively. In terms of complications that may develop, the threshold of suspicion should be kept low, and patients should be treated with the same medical team in fully equipped centers with a multidisciplinary approach. Inpatient treatment strategies should be applied especially in the early stages of treatment. The importance of inpatient treatment strategy, especially in the early stages of treatment, is emphasized.

Genetic and Epigenetic Cis-Regulatory Disruptions Impacting the Canonical Wnt Signaling Repressor TLE1 Gene Promote Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and despite improved survival rates, more children die of ALL than any other cancer. Glucocorticoids (GCs) are a mainstay of contemporary, multi-drug chemotherapy in the treatment of childhood ALL. Resistance to GCs is predictive of ALL relapse and poor clinical outcomes, and therefore represents a major hurdle limiting further improvements in survival rates. While advances have been made in identifying genes implicated in GC resistance, there remains an insufficient understanding of the impact of cis-regulatory disruptions in GC resistance. This is particularly relevant for GCs, which function through the activation of the glucocorticoid receptor (GR) nuclear receptor transcription factor. To better understand the role of cis-regulatory disruptions in GC resistance we comprehensively mapped the dynamic gene regulatory response to GCs in two human ALL cell lines using functional genomic (RNA-seq, ChIP-seq, ATAC-seq and HiChIP) and massively parallel reporter (ATAC-STARR-seq) assays at multiple time points within a 24-hour window. In total, over 100 independent datasets were generated and integrated. We identified thousands of GR binding sites and GC-responsive changes to chromatin state, including the formation of over 250 GC-responsive super-enhancers and depletion of AP-1 bound cis-regulatory elements implicated in cell proliferation and anti-apoptotic processes. Our results further show that GR mediates gene regulatory effects in ALL cells at GC-responsive chromatin sites through long-range looping interactions with GC-responsive gene promoters. Notably, GC-responsive chromatin sites were also enriched for functionally active cis-regulatory elements. By integrating our GC response maps with inherited DNA sequence variants and differentially accessible chromatin sites associated with GC resistance in primary ALL cells from patients enrolled on St. Jude clinical trials, we identified two GR-bound cis-regulatory elements at the canonical Wnt signaling repressor TLE1 gene locus that were genetically or epigenetically disrupted in GC-resistant patient samples. Functional evaluation of these two GR binding sites using CRISPR genome or CRISPR interference epigenome editing validated their impact on GC resistance and TLE1 gene expression. To better understand the relationship between GC signaling and canonical Wnt signaling, we further performed TOP-flash luciferase reporter assays, cellular drug viability assays and transcriptomic drug response profiling which identified mutual antagonism between these two signaling pathways. Collectively, these data uncovered genetic and epigenetic cis-regulatory disruptions of canonical Wnt signaling as a novel mechanism impacting GC resistance in childhood ALL and further suggest that therapeutic inhibition of canonical Wnt signaling could improve GC sensitivity in patients with resistant disease.

Correlation between asparaginase enzyme activity levels and coagulation parameters during childhood acute lymphoblastic leukemia treatment.

Thromboembolism is a serious toxicity in the treatment of acute lymphoblastic leukemia (ALL), but little is known about the correlation between asparaginase enzyme activity (ASA) levels and coagulation parameters. We included 65 non-high risk ALL patients, aged 1-17years. Coagulation parameters and corresponding ASA levels were measured during asparaginase treatment. We found ASA to be negatively correlated with antithrombin and fibrinogen up to ASA levels of 250IU/L, after which these parameters reached a plateau and did not decrease further with further increase of ASA. Patients with silent inactivation of asparaginase had normal coagulation parameters.

ALL-280 Our Experience Treating Childhood Acute Lymphoblastic Leukemia in Armenia

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. The 5-year-survival rate for ALL in high-income countries is close to 85%. However, this rate is much lower in low- or middle-income countries. In Armenia, the 5-year survival rate for children with ALL has greatly increased over time, and it is estimated at about 75%. This study aims to evaluate the clinicopathological features and treatment outcomes for childhood ALL in the Pediatric Cancer and Blood Disorders Center of Armenia (PCBDCA) at the Hematology Center (HC) named after Prof. R. Yeolyan. A retrospective analysis of pediatric patients diagnosed with ALL at PCBDCA from 2010 to 2021 was performed. The total number of pediatric leukemia cases was 333. Among them, 13.5% (45) were acute myeloblastic leukemia (AML) and 86.5% (288) were ALL. Only 79.9% (230) of diagnosed ALL patients received treatment at HC; 1.3% (4) of patients refused treatment and 18.8% (54) received treatment abroad. From 2010 to 2018, the number of patients was 147; 48.6% (107) of them received standardized treatment according to the BFM-2000 intermediate-risk group protocol, and 18.3% (40) of patients were treated with the Moscow-Berlin (MB) protocol. From 2019 to 2021, 73 patients received treatment based on the ALLIC-BFM 2009 protocol in accordance with risk groups; 21.9% (16) of the patients were classified as a high-risk group and 78.1% (57) as an intermediate-risk group, and there were no patients treated as a standard-risk group. From 2010 to 2018, the relapse rate was 19.0% (28), 50% (14) of which were early relapses, and 5.4% (8) were refractory to treatment. The mortality rate was 26.5% (39). Treatment-related mortality (TRM) of all patients was 9.5% (14): 7.5% (3) of the MB protocol and 10.2% (11) of the BFM-2000 protocol. The mortality rate related to the ALLIC-BFM 2009 protocol was 6.8% (5). The relapse rate was 5.5% (4); all were early relapses, and 2.73% (2) were TRM. Armenia is a developing county, and over the decades, there have been treatment and survival overall improvements in children with ALL in Armenia. However, several diagnostic and therapeutic challenges remain to be addressed.

A Retrospective Cohort Study of the Efficacy, Safety, and Clinical Value of 6-TG versus 6-MP Maintenance Therapy in Children with Acute Lymphoblastic Leukemia.

Objective To explore the efficacy, safety, and clinical value of 6-TG versus 6-MP when treating childhood acute lymphoblastic leukemia (ALL). Methods The study period was from January 2017 to June 2021. The subjects of this study were 100 children with ALL who were treated in our hospital. According to different intervention methods, the children who received 6-MP maintenance therapy were selected as the control group, with a total of 57 cases. Children with TG maintenance therapy were included in the research group, a total of 43 cases. The ICNS recurrence rate, non-ICNS recurrence rate, first remission mortality rate, secondary malignant tumor, and other indicators were compared. Results First of all, we compared the effective rate: complete remission (CR), partial remission, and nonremission in the study group, and the effective rate was 87.5%. In the control group, there were CR, partial remission, and no remission, and the effective rate was 65.5%. The effective rate of the study group was higher, and the difference between groups was statistically significant (P < 0.05). There were 55 cases of failure in the study group, with an incidence of 21.91%. There were 42 cases of total failure events in the control group, the incidence rate was 18.02%, and there exhibited no remarkable difference (P > 0.05). In the study group, 6 cases died in the first remission, with a fatality rate of 2.39%, while there exhibited no death in the control group. The mortality in the first remission period in the study group was lower (P < 0.05). The overall recurrence rate of the study group was 5.57%, while that of the control group was 11.15%. The overall recurrence rate of the study group was lower, and the difference between groups was statistically significant (P < 0.05). The recurrence rate of ICNS was 2.14% in the study group and 2.98% in the control group, and there exhibited no remarkable difference (P > 0.05). The non-ICNS recurrence rate was 3.43% in the study group and 7.17% in the control group. There exhibited no remarkable difference (P > 0.05). The incidence of secondary malignant tumor events was 0.85% in the study group and 1.59% in the control group. There exhibited no remarkable difference (P > 0.05). The incidence of hepatic vein occlusive disease was 7.29% in the study group and 2.39% in the control group. The incidence of hepatic vein occlusive disease in the study group was higher, and the difference between groups was statistically significant (P < 0.05). Finally, we compared the incidence of adverse reactions. In the study group, there were 12 cases of oral mucosal damage, 7 cases of liver function damage, 6 cases of infection, 10 cases of myelosuppression, 9 cases of gastrointestinal reaction, and 4 cases of skin damage; the incidence rate was 23.17%. In the control group, there were 12 cases of oral mucosal damage, 7 cases of liver function damage, 6 cases of infection, 10 cases of myelosuppression, 9 cases of gastrointestinal reaction, and 4 cases of skin damage, with an incidence of 19.12%. There exhibited no remarkable difference in the incidence of adverse reactions (P > 0.05). Conclusion 6-TG maintenance therapy in children with ALL can enhance the overall effective rate, can reduce the first remission mortality and the total recurrence rate, and will not increase the overall incidence of adverse reactions, but the incidence of reversible or irreversible hepatic veno-occlusive disease is remarkably increased, which has a certain clinical value. Background Treatment-related hepatotoxicity and myelosuppression remain formidable challenges for clinicians. Pharmacokinetic studies found that 6-TG has a more direct intracellular activation pathway, shorter cytotoxic time, and stronger potency than 6-MP. Therefore, this study investigated the efficacy, safety, and clinical value of 6-TG and 6-MP in the treatment of children with ALL.

Comparative treatment costs of risk-stratified therapy for childhood acute lymphoblastic leukemia in India.

To evaluate the treatment cost and cost effectiveness of a risk-stratified therapy to treat pediatric acute lymphoblastic leukemia (ALL) in India. The cost of total treatment duration was calculated for a retrospective cohort of ALL children treated at a tertiary care facility. Children were risk stratified into standard (SR), intermediate (IR) and high (HR) for B-cell precursor ALL, and T-ALL. Cost of therapy was obtained from the hospital electronic billing systems and details of outpatient (OP) and inpatient (IP) from electronic medical records. Cost effectiveness was calculated in disability-adjusted life years. One hundred and forty five patients, SR (50), IR (36), HR (39), and T-ALL (20) were analyzed. Median cost of the entire treatment for SR, IR, HR, and T-ALL was found to be $3900, $5500, $7400, and $8700, respectively, with chemotherapy contributing to 25%-35% of total cost. Out-patient costs were significantly lower for SR (p < 0.0001). OP costs were higher than in-patient costs for SR and IR, while in-patient costs were higher in T-ALL. Costs for non-therapy admissions were significantly higher in HR and T-ALL (p < 0.0001), representing over 50% of costs of in-patient therapy. HR and T-ALL also had longer durations of non-therapy admissions. Based on WHO-CHOICE guidelines, the risk-stratified approach was very cost effective for all categories of patients. Risk-stratified approach to treat childhood ALL is very cost-effective for all categories in our setting. The cost for SR and IR patients is significantly reduced through decreased IP admissions for both, chemotherapy and non-chemotherapy reasons.