Childhood Acute Lymphoblastic Leukemia Research Articles

Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL.

Systemic combination chemotherapy and intrathecal chemotherapy markedly increased the survival rate of children with ALL. In the past two decades, the use of minimal (measurable) residual disease (MRD) measurements early in therapy improved risk group stratification with subsequent treatment intensifications for patients at high risk of relapse, and enabled a reduction of treatment for low-risk patients. The recent development of more sensitive MRD technologies may further affect risk stratification. Molecular genetic profiling has led to the discovery of many new subtypes and their driver genetic alterations. This increased our understanding of the biological basis of ALL, improved risk classification, and enabled implementation of precision medicine. In the past decade, immunotherapies, including bispecific antibodies, antibody-drug conjugates, and cellular therapies directed against surface proteins, led to more effective and less toxic therapies, replacing intensive chemotherapy courses and allogeneic stem-cell transplantation in patients with relapsed and refractory ALL, and are now being tested in newly diagnosed patients. It has taken 50-60 years to increase the cure rate in childhood ALL from 0% to 90% by stepwise improvements in chemotherapy. This review provides an overview of how the developments over the past 10-15 years mentioned above have significantly changed the diagnostic and treatment approach in ALL, and discusses how the integrated use of molecular and immunotherapeutic insights will very likely direct efforts to cure those children with ALL who are not cured today, and improve the quality of life for survivors who should have decades of life ahead. Future efforts must focus on making effective, yet very expensive, new technologies and therapies available to children with ALL worldwide.

The effect of the plasma methotrexate concentration during high-dose methotrexate therapy in childhood acute lymphoblastic leukemia

Two hundred and thirty-one acute lymphoblastic leukemia (ALL) children with 1376 high-dose methotrexate (HD-MTX) courses (3–5 g/m2) were enrolled to analyze the influence of the plasma MTX concentration (C MTX) in ALL. The 24-h target peak C MTX (C 24h) was set at 33 μmol/l for low-risk (LR) and 65 μmol/l for intermediate/high-risk (IR/HR) groups. The median C 24h was 42.0 μmol/l and 69.7 μmol/l for LR and IR/HR groups, respectively. MTX excretion delay was observed in 14.6% of courses, which was more frequent in IR/HR groups (56.9% vs. LR group 40.2%, p = .014) and T-ALL patients (82.6% vs. B-ALL 47.1%, p = .001). MTX-related toxicities were more common in courses with MTX excretion delay. However, survival between the patients who failed to reach the target C 24h or not, with or without MTX excretion delay, was comparable. These findings suggest that, owing to the effectiveness of risk stratification chemotherapy, C MTX does not exert an independent influence on the prognosis of childhood ALL.

Treatment of newly diagnosed paediatric acute lymphoblastic leukaemia on BFM-based chemotherapy protocol: Feasibility and outcome from a tertiary care center in India

BackgroundData on outcomes in children with acute lymphoblastic leukaemia (ALL) who are on Berlin-Frankfurt-Munster (BFM)-based chemotherapy protocol is scarce from India. We share experience on the survival of children with ALL treated on the modified IC BFM 2002 protocol. MethodsChildren (1–18 years) diagnosed with ALL between January 1, 2011 and January 1, 2021 at BLK-MAX Super Specialty Hospital were analyzed retrospectively. Patients were treated with modified IC BFM 2002 protocol. Data on the type of leukaemia, risk status, minimal residual disease (MRD), cytogenetic, and molecular genetics were collected. Disease free survival (DFS) and overall survival (OS) were calculated. ResultsHundred (88 B-cell, 12 T-cell) patients with ALL were evaluated. The median age at presentation was 6.5 years. According to the BFM risk stratification, 35 children were standard-risk, 45 were intermediate and 20 were high-risk. Bone marrow aspiration for MRD by flow cytometry on day 33 of induction chemotherapy was performed in 61 patients. One patient died on day 50 of induction. Day 78 MRD was performed in 60 patients. Day 78 MRD positivity was used for treatment escalation. There were 18 deaths. DFS as on 1st July 2023 for standard, intermediate and high-risk patients was 89%, 85% and 55% respectively. Overall survival in all risk groups was 82%. ConclusionTreating childhood ALL with BFM-based chemotherapy protocol is feasible in developing countries without major modifications and with results comparable to those reported in Western literature.

Top Ten Contributions of Pediatric Hematology/Oncology to the Diagnosis and Treatment of Acute Lymphoblastic Leukemia.

Monumental progress has occurred in the diagnosis and treatment of childhood acute lymphoblastic leukemia dating back to the classic paper of Farber and colleagues in 1948. This historical review from the perspective of an individual, familiar with many of the waystations on this superhighway, will offer an admittedly personal review of the top 10 major contributions to the field. Fortunately, there have been many more additional advances beyond these 10 as we have witnessed an impressive improvement in overall survival from a few months 75 years ago to a cure rate of 85% in the world's more advanced countries. Other workers in the field assuredly would create a different list and ranking of these advances but the takeaway summation of the make-up and order of these lists is that advances have yielded improved and prolonged responses, a rational understanding of factors, both clinical and biological, that predict response and prognosis, the application of those factors to tailor therapy's intensity and duration to those factors and to discover and design modalities and targets of therapy that target our much more complete understanding of this most common malignancy of infants and children. On a very personal note, I vividly recall an early, ill-advised decision to devote my academic career to hematology/oncology, with one glaring exception, acute lymphoblastic leukemia, and other malignancies. The stark realities of clinical practice and the harsh unmet needs and mostly unanswered challenges redirected my path that resulted in participation in many of these advances, making my own journey so gratifying and that of most of our patients so favorable.

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.

FRI225 Clinical Course Of Late-onset Adrenal Insufficiency Due To Treatment Of Childhood Acute Lymphoblastic Leukemia

Abstract Disclosure: M. Iwabuchi: None. Background: Some people who were treated for cancer during childhood may develop endocrine problems as because of changes in the function of endocrine system. Acute lymphoblastic leukemia is the most common type of cancer and leukemia in children and components of ALL treatment are induction, consolidation, maintenance, and central nervous system prophylaxis. It is recommended that people who had irradiation in a dose of 40 Gy or higher to the central area of the hypothalamic-pituitary axis should have a blood test done to check the cortisol level and should be done yearly for at least 15 years since this complication can occur many years after irradiation. Clinical Case: A man in his 40s was admitted with symptoms of diarrhea, low-grade fever, and drowsiness. The serum sodium level that caused his symptoms decreased to 100 mEq/L and was adequately corrected. Endocrinological examination confirmed the diagnosis of central adrenal insufficiency. Soon after starting hormonal replacement therapy with hydrocortisone, his general conditions improved. After establishing our relationship, he confessed to having a history of ALL in childhood. According to his medical records at the time, he underwent induction therapy with vincristine-prednisone in 1977, maintenance therapy with 6-mercaptopurine, and radiation therapy to the central nervous system of 25 Gy in 1983. In 2023, 40 years have passed since radiation therapy. He was able to lead a normal life on oral hydrocortisone 20 mg/day without recurrence of adrenal insufficiency. Clinical Lesson: A 40-old male survivor of ALL developed adrenal insufficiency in 30 years after cranial irradiation during childhood. Undiagnosed adrenal insufficiency is often the cause of death. We should consider childhood cancer survivors have the risk of a central adrenal insufficiency. The Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (COG LTFU Guidelines) are a resource for healthcare professionals who provide ongoing care to survivors of pediatric malignancies. The screening recommendations in these guidelines are appropriate for asymptomatic survivors of childhood, adolescent, or young adult cancer presenting for routine exposure-based medical follow-up. It is recommended that people who had irradiation in a dose of 40 Gy or higher to the central area of the hypothalamic-pituitary axis should have a blood test done to check the cortisol level and should be done yearly for at least 15 years since this complication can occur many years after irradiation. This case highlights the importance of long-term follow-up of cancer survivors after irradiation and the delayed presentation of adrenal insufficiency. This is the first report of the subsequent treatment course of late-onset adrenal insufficiency that developed 30 years after irradiation for childhood central nervous system ALL. Presentation: Friday, June 16, 2023

Day Care in Infancy and Risk of Childhood Acute Lymphoblastic Leukaemia: Findings from UK Case - Control Study

Day Care in Infancy and Risk of Childhood Acute Lymphoblastic Leukaemia: Findings from UK Case - Control Study

Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015.

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area.

The efficacy and toxicity of L-asparaginase in the treatment of acute lymphoblastic leukemia in children

L-asparaginase, an enzyme used as an anticancer drug, was one of the first drugs included in the treatment protocols for acute lymphoblastic leukemia. It has become widely used when an important metabolic feature of leukemia cells – their high demand for asparagine to maintain viability – was discovered. Three L-asparaginase preparations are currently used in clinical practice: native E. coli asparaginase, pegylated E. coli asparaginase (PEG-asparaginase), and native E. chrysanthemi-derived asparaginase, which have different half-lives, immunogenic profiles, and the spectrum and frequency of toxic effects. One of the main factors limiting the use of L-asparaginase is its high immunogenicity which can cause acute allergic reactions and the phenomenon of silent inactivation. The development of the immune response leads to an accelerated asparaginase clearance and a shortening of its half-life. To monitor the effectiveness of therapy with L-asparaginase, therapeutic drug monitoring of serum asparaginase activity can be used. When choosing management strategies for patients experiencing acute hypersensitivity reactions to L-asparaginase, the following factors should be taken into consideration: the severity of reaction, the number of previous exposures to L-asparaginase and serum asparaginase activity. The use of PEG-asparaginase is the best first-line treatment strategy for children acute lymphoblastic leukemia, its advantages include a significant reduction in the risk of developing acute allergic reactions, higher therapeutic efficacy and, as a result, improved treatment outcomes.

Risk factors for overweight and obesity after childhood acute lymphoblastic leukemia in North America and Switzerland: A comparison of two cohort studies.

After childhood acute lymphoblastic leukemia (ALL), sequelae include overweight and obesity, yet with conflicting evidence. We compared the prevalence of overweight and obesity between ≥5-year ALL survivors from the North American Childhood Cancer Survivor Study (CCSS) and the Swiss Childhood Cancer Survivor Study (SCCSS) and described risk factors. We included adult childhood ALL survivors diagnosed between 1976 and 1999. We matched CCSS participants (3:1) to SCCSS participants by sex and attained age. We calculated body mass index (BMI) from self-reported height and weight for 1287 CCSS and 429 SCCSS participants; we then compared those with siblings (2034) in North America and Switzerland (678) siblings. We assessed risk factors for overweight (BMI 25-29.9 kg/m2 ) and obesity (≥30 kg/m2 ) using multinomial regression. We found overweight and obesity significantly more common among survivors in North America when compared with survivors in Switzerland [overweight: 30%, 95% confidence interval (CI): 27-32 vs. 24%, 21-29; obesity: 29%, 27-32 vs. 7%, 5-10] and siblings (overweight: 30%, 27-32 vs. 25%, 22-29; obesity: 24%, 22-26 vs. 6%, 4-8). Survivors in North America [odds ratio (OR) = 1.24, 1.01-1.53] and Switzerland (1.27, 0.74-2.21) were slightly more often obese than siblings. Among survivors, risk factors for obesity included residency in North America (5.8, 3.7-9.0); male (1.7, 1.3-2.3); attained age (≥45 years: 5.1, 2.4-10.8); Non-Hispanic Black (3.4, 1.6-7.0); low household income (2.3, 1.4-3.5); young age at diagnosis (1.6, 1.1-2.2). Cranial radiotherapy ≥18 Gray was only a risk factor for overweight (1.4, 1.0-1.8); steroids were not associated with overweight or obesity. Interaction tests found no evidence of difference in risk factors between cohorts. Although treatment-related risk for overweight and obesity were similar between regions, higher prevalence among survivors in North America identifies important sociodemographic drivers for informing health policy and targeted intervention trials.

Impact of XRCC3 rs861539 and XPD rs13181 gene polymorphisms on childhood acute lymphoblastic leukemia in Egyptian patients

Abstract Background There is mounting evidence that the genotypes of DNA repair proteins and susceptibility to certain malignancies are related. Few studies, however, have examined the role of the homologous repair gene X-ray repair cross-complementing group 3 (XRCC3) genotype and xeroderma pigmentosum complementation group D (XPD) in the development or prognosis of acute lymphoblastic leukaemia (ALL). Aim of the study In this study, we investigated the impact of XRCC3 rs861539 and XPD rs13181 polymorphisms on the risk of ALL. To the best of our knowledge, this is the first report of XRCC3 and XPD polymorphisms in ALL Egyptian patients. Methods Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) was used to analyse XRCC3 rs861539 and XPD rs13181 gene polymorphisms in 96 patients with ALL and in 103 disease-free controls, who were of a similar age. Results ALL risk is lower in individuals with the homozygous variant TT genotype at XRCC3 rs861539. The heterozygous variant CT genotype of XRCC3 was connected to increased disease risk of ALL in males. Additionally, C allele frequency was noticeably higher than T allele frequency in pre B ALL. In this investigation, there was no correlation between the XPD Lys751 rs13181 polymorphism and risk of ALL. Conclusion Our research reveals that genetic variation in the genes for DNA repair may influence ALL susceptibility.

OC 38.2 Acquired Abnormalities in the Hemostatic System during Induction Chemotherapy in Treatment of Childhood Acute Lymphoblastic Leukemia (ALL): A Biomarker Sub-Study of the PREVAPIX-ALL Trial

OC 38.2 Acquired Abnormalities in the Hemostatic System during Induction Chemotherapy in Treatment of Childhood Acute Lymphoblastic Leukemia (ALL): A Biomarker Sub-Study of the PREVAPIX-ALL Trial

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.

Gene-Environment Analyses Reveal Novel Genetic Candidates with Prenatal Tobacco Exposure in Relation to Risk for Childhood Acute Lymphoblastic Leukemia.

Associations between maternal tobacco exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have yielded mixed results. This may be due to biases in self-reported smoking or other differences in individual-level risk factors. We utilized a biological marker of maternal tobacco exposure to evaluate the association between maternal tobacco exposure during pregnancy, genetics, and subsequent childhood ALL risk in two large population-based studies of childhood ALL in California. Maternal exposure to tobacco smoke was assessed with a validated methylation marker (cg05575921) of the aryl hydrocarbon receptor repressor (AHRR) gene in newborn dried blood spots. We adjusted for sex, birthweight, gestational age, mode of delivery, year of birth, AHRR quantitative trait locus (mQTL) rs77111113, and a polygenetic risk score for childhood ALL. We additionally adjusted for principal components in a gene-environment interaction testing method that incorporates gene-only and environment-only effects along with interactions. AHRR hypomethylation overall was not associated with childhood ALL. In gene-environment interaction testing, several genetic variants displayed significant interaction with AHRR hypomethylation and childhood ALL. Our results suggest that novel candidates in PTPRK and DPP6 may play a role in tobacco-related leukemogenesis. Further research is necessary to better understand the effects of tobacco and these variants on childhood ALL risk. Despite the lack of an overall "main effect," tobacco exposure during pregnancy affects childhood ALL risk depending on specific genetic variants.

Clinical characteristics and risk factors of acute lymphoblastic leukemia in children with severe infection during maintenance treatment.

Infection is the most common adverse event of acute lymphoblastic leukemia (ALL) treatment and is also one of the main causes of death. To investigate the clinical characteristics and risk factors of severe infections during the maintenance phase of ALL treatment, we conducted a retrospective study. A total of 181 children were eligible and 46 patients (25.4%) suffered from 51 events of severe infection, most of which occurred in the first half year of the maintenance phase (52.9%). The most common infection was pulmonary infection (86.3%) followed by bloodstream infection (19.6%). The main symptoms of ALL patients with pulmonary infection were fever, cough, and shortness of breath. The main manifestations of computer tomography (CT) were ground glass shadow (56.8%), consolidation shadow (27.3%), and streak shadow (25%). Multivariate binary logistic regression analysis showed that agranulocytosis, agranulocytosis ≥7 days, anemia, and low globulin level were independent risk factors for severe infection during the maintenance phase (all p < 0.05). Taken together, blood routine examinations and protein levels should be monitored regularly for ALL patients in the maintenance phase, especially in the first 6 months. For ALL patients with risk factors, preventive anti-infective or supportive therapies can be given as appropriate to reduce the occurrence of severe infections.

Evaluation of hematological and biochemical factors of hypertension during the induction chemotherapy for childhood acute lymphoblastic leukemia

Background: Acute lymphoblastic leukemia (ALL) is a prevalent childhood cancer, accounting for approximately 25% of all pediatric cancer cases. The incidence of hypertension in ALL patients is significantly higher compared to the general pediatric population, emphasizing the need for a better understanding and management of this condition. The aim of the study was to evaluate hematological and biochemical factors of hypertension during the induction of chemotherapy for childhood ALL. Methods: This prospective observational study was conducted in the Department of Pediatric Hematology and Oncology at BSMMU from July 2017 to June 2018. The study included 93 newly diagnosed cases of ALL in children aged 1 to 17.9 years, excluding those below 1 year and above 18 years, known cases of hypertension, patients with pre-existing hypertension before chemotherapy, and old or relapse cases of ALL. Results: The study found that 17.2% of the study population experienced renal derangement during the induction remission phase, while the majority (82.8%) did not. The presence of renal derangement was not significantly associated with hypertension. However, patients who developed tumor lysis syndrome (TLS) had a higher percentage (12.5%) of hypertension compared to the non-hypertensive group (1.3%). Febrile neutropenia, convulsion, and coagulopathy were also observed in patients who developed hypertension more frequently. The median time to detect hypertension during induction chemotherapy was on day 8, with a mean duration of 13.6 days. Conclusions: In this study, hypertension is observed in 17.2% of patients during induction chemotherapy for ALL with higher frequency in the second week and associations with tumor lysis syndrome, febrile neutropenia, convulsion, and coagulopathy.

Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL.

High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain. We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs. Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% v 86.8%; P = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% v 8.8%; P = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17. Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.

Relationship between cardiac mechanical properties and cardiac magnetic resonance imaging at rest in childhood acute lymphoblastic leukemia survivors.

The characterization of cardiac mechanical properties may contribute to better understanding of doxorubicin-induced cardiotoxicity. Our study aims to investigate the relationship between cardiac mechanical properties, T1 and T2 relaxation times and partition coefficient.Fifty childhood acute lymphoblastic leukemia survivors underwent a cardiac magnetic resonance (CMR) at rest on a 3T MRI system and included a standard ECG-gated 3(3)3(3)5 MOLLI sequence for T1 mapping and an ECG-gated T2-prepared TrueFISP sequence for T2 mapping. Partition coefficient, ejection fraction, end-diastolic volume (EDV) and end-systolic volume (ESV) were calculated. CircAdapt model was used to study cardiac mechanical performance (left ventricle stiffness (LVS), contractility (LVC) and pressure (Pmin and Pmax), cardiac work efficiency (CWE) and ventricular arterial coupling).In the whole cohort, our results showed that LVC (R2 = 69.2%, r = 0.83), Pmin (R2 = 62.9%, r = 0.79) and Pmax can be predicted by significant CMR parameters, while T1 (R2 = 23.2%, r = 0.48) and partition coefficient (R2 = 13.8%, r = 0.37) can be predicted by significant cardiac mechanical properties. In SR group LVS (R2 = 94.8%, r = 0.97), LVC (R2 = 93.7%, r = 0.96) and Pmin (R2 = 90.6%, r = 0.95) can be predicted by significant cardiac mechanical properties, while in HR + DEX group CWE (R2 = 49.8%, r = 0.70) can be predicted by significant cardiac mechanical properties. Partition coefficient (R2 = 72.6%, r = 0.85) can be predicted by significant CMR parameters in SR group.Early characterization of cardiac mechanical properties from CMR parameters has the potential to early detect doxorubicin-induced cardiotoxicity.

Super Enhancer Regulatory Gene FYB1 Promotes the Progression of T Cell Acute Lymphoblastic Leukemia by Activating IGLL1.

Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.

Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWASs), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study, we constructed and evaluated genomic PRS models based on either non-Latino White (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR2= 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR2= 0.116 ± 0.026) or multi-ancestry samples (PseudoR2= 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR2= 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWASs may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligogenic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.