Chemotherapy For Acute Lymphoblastic Leukemia Research Articles

Effects of asparaginase-associated pancreatitis in children with haematological tumours.

Asparaginase-associated pancreatitis (AAP) is a major challenge for continuing asparaginase therapy. We aimed to investigate the acute and long-term complications and survival rates related to first and second AAP episodes in Chinese children with haematological malignancies. We retrospectively analysed clinical data of children with pancreatitis who received asparaginase chemotherapy for acute lymphoblastic leukaemia (ALL), acute mixed cell leukaemia, and non-Hodgkin's lymphoma at Shanghai Children's Medical Center from November 2013 to November 2023. Of the 76 children included in the study, 12 had local complications (15.79%), with no deaths recorded. Systemic complications manifested in 28 patients (36.84%), resulting in 3 deaths (3.95%). Four patients (5.26%) developed long-term complications (chronic pancreatitis or insulin-dependent diabetes mellitus). No significant differences in local or long-term complications were recorded between children in the asparaginase re-exposed (n=39) and non-re-exposed (n=45) groups. Among the re-exposed patients, eight (25.81%) experienced a second attack without fatalities or complications. Survival analysis of intermediate- to high-risk patients revealed a significantly higher event-free survival (EFS) rate for the re-exposed group than for the non-re-exposed group. The second AAP episode's occurrence and severity had no relation to the first AAP episode's severity, and the second AAP episode was significantly less severe than the first (p<0.001). The second AAP episode's occurrence is unrelated to the first AAP episode's severity, and the second AAP episode's severity is significantly lower than that of the first. Further, asparaginase therapy could improve EFS in children with intermediate and high-risk ALL.

Effect of Smart Pill Box on Improving Adherence to 6-Mercaptopurine Maintenance Therapy in Pediatric ALL

Abstract Introduction 6-Mercaptopurine (6-MP) forms the backbone of maintenance chemotherapy for acute lymphoblastic leukemia (ALL). A Children's Oncology Group study found 3.9-fold increased risk of relapse in children with 6-MP adherence less than 90%. Objective This article estimates the impact of smart pill box in improving adherence to 6-MP during maintenance phase chemotherapy in children with ALL. Material and Methods It is a prospective interventional study done at pediatric oncology clinic of a tertiary care hospital. Participants being 40 newly diagnosed children with ALL. Baseline adherence was assessed and impact of smart pill box was estimated after using it for 60 days. Subjective and objective assessment of baseline adherence and adherence after intervention was done by subjecting the parents of the children to Morisky Medication Adherence Score 8 (MMAS-8) and measurement of patient's red blood cells (RBC) 6-MP metabolites (6-thioguanine [TGN] and 6-methylmercaptopurine [MMP]) levels, respectively, pre- and postintervention. Results The mean age was 7.39 ± 4.29 years. NUDT15*3 polymorphism was present in 10.26%, and none had TPMT polymorphism. Baseline assessment of adherence to 6-MP by MMAS-8 revealed low, medium, and high adherence in 7.5, 35, and 57.5%, respectively. Baseline 6-TGN and 6-MMP levels by cluster analysis revealed poor adherence in 10%. Following intervention, mean MMAS-8 improved from 7.34 ± 0.78 to 7.66 ± 0.55 (p-value &lt; 0.015) and the median 6-TGN level improved from 150 to 253 pmol/8 × 108 RBCs (p-value &lt; 0.001). Conclusion Nonadherence to 6-MP is widely prevalent in Indian children. Simple measures like smart pill box can improve adherence.

Development and validation of a predictive model for tumor lysis syndrome in childhood acute lymphoblastic leukemia

BackgroundTumor lysis syndrome (TLS) frequently manifests shortly after induction chemotherapy for acute lymphoblastic leukemia (ALL), with the potential for swift progression. This study endeavored to develop a nomogram to predict the risk of TLS, utilizing clinical indicators present at the time of ALL diagnosis. MethodsWe retrospectively gathered data from 2243 patients with ALL, spanning December 2008 to December 2021, utilizing the clinical research big data platform of the National Center for Clinical Research on Children's Health and Diseases. The Least Absolute Shrinkage and Selection Operator (LASSO) method was employed to filter variables and identify predictors, followed by the application of multivariate logistic regression to construct the nomogram. ResultsThe LASSO regression identified six critical variables among ALL patients, upon which a nomogram was subsequently constructed. Multifactorial logistic regression revealed that an elevated white blood cell count (WBC), serum phosphorus <2.1 mmol/L, potassium <3.5 mmol/L, aspartate transaminase (AST) ≥50 U/L, uric acid (UA) ≥476μmol/L, and the presence of acute kidney injury (AKI) at the time of initial diagnosis were significant risk factors for the development of TLS in ALL patients (P<0.05). The predictive model achieved an area under the receiver operating characteristic curve (AUC) of 0.824 [95 % CI (0.783, 0.865)], with an internal validation AUC of 0.859 [95 % CI (0.806, 0.912)]. The Hosmer-Lemeshow goodness-of-fit test confirmed the model’s robustness (P=0.687 for the training cohort; P=0.888 for the validation cohort). Decision curve analysis (DCA) indicated that the predictive model provided substantial clinical benefit across threshold probabilities ranging from 10 % to 70 %. ConclusionsA nomogram incorporating six predictive variables holds significant potential for accurately forecasting TLS in pediatric patients with ALL.

Insights into Readmission Trends Following Inpatient Chemotherapy for Acute Lymphoblastic Leukemia: A 30-Day Analysis

Insights into Readmission Trends Following Inpatient Chemotherapy for Acute Lymphoblastic Leukemia: A 30-Day Analysis

Prediction of tumor lysis syndrome in childhood acute lymphoblastic leukemia based on machine learning models: a retrospective study.

Tumor lysis syndrome (TLS) often occurs early after induction chemotherapy for acute lymphoblastic leukemia (ALL) and can rapidly progress. This study aimed to construct a machine learning model to predict the risk of TLS using clinical indicators at the time of ALL diagnosis. This observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data were collected from pediatric ALL patients diagnosed between December 2008 and December 2021. Four machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction. The study included 2,243 pediatric ALL patients, and the occurrence of TLS was 8.87%. A total of 33 indicators with missing values ≤30% were collected, and 12 risk factors were selected through LASSO regression analysis. The CatBoost model with the best performance after feature screening was selected to predict the TLS of ALL patients. The CatBoost model had an AUC of 0.832 and an accuracy of 0.758. The risk factors most associated with TLS were the absence of potassium, phosphorus, aspartate transaminase (AST), white blood cell count (WBC), and urea levels. We developed the first TLS prediction model for pediatric ALL to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200060616). https://www.chictr.org.cn/, identifier ChiCTR2200060616.

Frailty in Children and Adolescents with Lymphoblastic Leukemia or Lymphoma Receiving Maintenance Chemotherapy - a Pilot Study

Background: Increased survivorship of childhood cancer has revealed a number of long-term morbidities related to treatment. Evidence suggests that cancer and its treatment may accelerate normal loss of physiologic capacity that occurs during aging.The advanced physiologic aging and related morbidities often seen in childhood cancer survivors suggests that these patients may present with signs of early-onset frailty. Frailty is a measure of global infirmity and impaired physical function and has been correlated with adverse health outcomes and elevated incidence of mortality in the general population. Research into the incidence and applicability of the frailty phenotype in children being treated for cancer may aid in the identification of the most vulnerable patients and identify those who may require intervention. The purpose of this study is to explore the frailty phenotype in children and adolescents receiving maintenance chemotherapy for acute lymphoblastic leukemia or lymphoma. Methods: We prospectively recruited children and adolescents (aged 5-18 years-old) diagnosed with acute lymphoblastic leukemia or lymphoma in the first cycle of their maintenance chemotherapy. Frailty was assessed twice: at an initial visit in cycle 1 maintenance treatment (V1), and 6-months following the initial assessment (V2). The frailty phenotype consists of 5 domains, which were assessed using developmentally appropriate measures: 1) Slowness: 6-minute walk test; 2) Weakness: Handgrip strength dynamometry - calibrated to the size of the participant's hand; 3) Exhaustion/Fatigue: The PedsQL TM Multidimensional Fatigue Scale; 4) Body Composition: InBody 270 body composition analyzer; and 5) Physical activity/Energy expenditure: Self-administered physical activity questionnaire for older children (PAQ-C) and physical activity questionnaire for adolescents (PAQ-A).Each assessment was scored individually and “Frailty points” were assigned based on age and sex-based normative z-scores or survey scores, and a composite “Frailty Score” ranging from 0=least frail to 25=most frail. Wilcoxon signed-rank test was used to compare V1 and V2 frailty scores. Results:The analysis sample consisted of 19 participants (mean age 9.1 [SD=3.4] years old; 63% female) who completed V1 and 7 participants that completed V2. Diagnoses of participants who completed V1 include precursor B-Cell acute lymphoblastic leukemia (n=15), T-Cell acute lymphoblastic leukemia (n=3), and T-Cell lymphoblastic Lymphoma (n=1). Median V1 z-scores and survey scores per domain are as follows: Slowness: z-score -3.11 [-4.02, -2.48]; Weakness: z-score -1.48 [-2.06, -1.38]; Exhaustion/Fatigue: score 58.3 [46.5, 70.8]; Body composition: z-score (total body fat) 0.90 [0.47, 1.79]; Physical activity/Energy expenditure: score 2.26 [1.73, 2.54]. Domain specific frailty score for V1 are displayed in Figure 1. Of the 7 participants with a V2 frailty assessment, paired analysis demonstrated significant improvement in Exhaustion/Fatigue (median score V1=56.94, V2=70.83 [p=0.016]). However, improvements in weakness, body composition, and physical activity/energy expenditure did not reach statistical significance. Median slowness z-scores at V2 were similar to V1. Median composite frailty score improved from 12 to 11 in V2 but was not statistically significant (p=0.054). Comparison of V1 and V2 overall composite scores are displayed in Figure 2. Conclusion: Children and adolescents receiving maintenance chemotherapy for acute lymphoblastic leukemia or lymphoma scored poorly in all five domains of frailty. We observed some improvements in exhaustion/fatigue, and trending improvements in subdomain and composite frailty scores in the small sample of participants with V1 and V2 assessments. Given that frailty has been shown to persist into adulthood in survivors of childhood cancer, the frailty assessment may be an effective tool for identifying patients who may require additional intervention. Initial and follow-up frailty measurements for this study are currently ongoing.

B-331 Homogeneous Enzyme Immunoassay for the Quantitative Determination of Methotrexate

Abstract Background Methotrexate (MTX), a classical antifolate, can be safely administered over a wide dose range as maintenance chemotherapy for acute lymphoblastic leukemia and treatment of nononcologic diseases including rheumatoid arthritis or psoriasis. When combined with leucovorin (LV) rescue, high-dose MTX (HDMTX; doses of 1000–33 000 mg/m2) is usually administered as a prolonged i.v. infusion for a variety of cancers, including acute lymphoblastic leukemia, lymphoma, osteosarcoma, breast cancer, and head and neck cancer. HDMTX can be safely administered to patients with normal renal function by vigorously hydrating and alkalinizing the patient to enhance the solubility of MTX in urine. Serum levels may reach 1000 μmol/L or more. Pharmacokinetically guided LV rescue by monitoring MTX serum levels is required to prevent potentially lethal MTX toxicity. Ability to measure MTX accurately at 0.050 μmol/L enables clinical determination of non-toxic status Methods The ARK™ Methotrexate II Assay is a homogeneous enzyme immunoassay for the quantitative determination of methotrexate in human serum or plasma on automated clinical chemistry analyzers. The assay was evaluated on the Beckman AU680 analyzer. The assay consists of two reagents, six-level calibrators, and six-level (0.070, 0.400, 0.800, 5.0, 50.0, 500.0 μmol/L) quality controls. Performance of the assay was determined by assessing precision, limit of quantitation, linearity, endogenous substances interference, high sample dilution (1:10 serial dilutions), on-board auto dilution (at 1:10 and 1:50), cross-reactivity, and method comparison. Results Within-lab precision (%CV) for control levels were 3.00% (0.070 µmol/L), 1.40% (0.400 µmol/L), 2.05% (0.800 µmol/L), 1.58% (5.0 µmol/L), 2.30% (50.0 µmol/L), and 1.62% (500.0 µmol/L). Limit of Detection and Quantitation: LoD was 0.004 µmol/L and LoQ was 0.030 µmol/L (4.87% CV, 113.6% analytical recovery). The ARK Methotrexate II Assay showed less than 8% deviation from linearity over the range 0.030 to 1.300 µmol/L. Endogenous substances did not interfere with measurement of MTX at the levels tested. High sample manual dilution (2.0, 20.0, 200.0, 1200.0, 5.0, 50.0, and 500.0 µmol/L) and on-board auto dilution (1:10 and 1:50) results were within 10% of nominal values. Cross-reactivity to compounds (potentially co-administered drugs, folate derivatives, and compounds of similar structure) tested was &amp;lt;10% interference. The major metabolite, 7-hydroxy MTX, at 50 µmol/L produced less than 10% interference for MTX levels of 0.050 and 0.500 µmol/L. Passing Bablok analysis of the results for 90 patient specimens of ARK MTX II Assay compared to liquid chromatography with tandem mass spectrometry (LC-MS/MS) was 1.03 + 0.00 (r2 = 0.98). Conclusion The ARK™ Methotrexate Assay II quantitated methotrexate accurately and precisely in serum and plasma. Performance on the Beckman AU680 automated clinical chemistry analyzer demonstrated excellent precision, recovery, and clinical accuracy vs LC-MS/MS.

Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia.

Most patients with acute lymphoblastic leukemia (ALL) are treated with chemotherapy as primary care. Although the treatment response is usually positive, resistance and relapse often occur via unknown mechanisms. The purpose of this study was to identify factors associated with chemotherapy resistance in ALL. Here, we present clinical and experimental evidence that overexpression of nucleolin (NCL), a multifunctional nucleolar protein, is linked to drug resistance in ALL. NCL mRNA and protein levels were compared between cell lines and patient samples using qRT-PCR and immunoblotting. NCL mRNA levels were compared between patients of different disease stages from our clinic patients' specimens and publicly available ALL patient datasets. Cells and patient-derived xenograft mouse experiments were performed to assess the effect of NCL inhibition on ALL chemotherapy effectiveness. Analysis of patient specimens, and publicly available RNA-sequencing datasets revealed a strong correlation between the abundance of NCL and disease relapse or poor survival in B-ALL. Altering NCL expression results in changes in drug sensitivity in ALL cell lines. High levels of NCL upregulated components of the ATP-binding cassette transporters via activation of the ERK pathway, resulting in a decrease in drug accumulation inside the cells. Targeting NCL with AS1411, an NCL-binding oligonucleotide aptamer, significantly increased the sensitivity of ALL cell lines and cells/patient-derived ALL xenograft mice to chemotherapeutic drugs and prolonged mouse survival. Our results highlight NCL as a prognostic marker in B-ALL and a potential therapeutic target to combat chemotherapy resistance in ALL.

Experiences of Parenting a Child Receiving Dexamethasone During Maintenance Chemotherapy for Acute Lymphoblastic Leukemia.

Background: The purpose of this research was to understand the experience of parenting a child receiving dexamethasone during maintenance chemotherapy for acute lymphoblastic leukemia (ALL). Previous research has shown that dexamethasone's high level of toxicity causes many physical, behavioral, and emotional side effects, which reduce the quality of life during ALL treatment. Less is known about the experience of parenting a child receiving dexamethasone and the impact on the parent-child relationship. Methods: In-depth semi-structured interviews were conducted with 12 parents and data was analyzed using Interpretative Phenomenological Analysis. Results: Four superordinate themes emerged: "a child on steroids is not your child": the behavioral and emotional changes in the child and their relationships; "you have to do what you have to do": adapting parenting to manage dexamethasone; "it breaks your heart … it's a horrible medicine": the emotional impact of parenting a child on dexamethasone; and, "it's the worst week ever": finding ways to cope with the challenges of dexamethasone. Discussion A preparatory intervention for parents beginning the dexamethasone journey focused on likely challenges, managing boundary setting and discipline, and their own emotional struggles, could be beneficial. Research into the impact on siblings could further understand the systemic influence of dexamethasone and help develop further interventions.

SARS-CoV-2 Infection Mimicking Neutropenic Fever during Chemotherapy for Acute Lymphoblastic Leukemia: A Case Report

SARS-CoV-2 Infection Mimicking Neutropenic Fever during Chemotherapy for Acute Lymphoblastic Leukemia: A Case Report

Vincristine induced peripheral neuropathy in children undergoing chemotherapy for acute lymphoblastic leukaemia during induction

Background: Vincristine is an anticancer agent administered to all children with acute lymphoblastic leukemia (ALL), and peripheral neuropathy is the major dose-limiting toxicity of this therapy. As cure rates of childhood ALL exceeds 80%, therefore treatment-related toxicities need to be reduced. Thus, the aim of this study was to determine the prevalence and risk factors of vincristine-induced peripheral neuropathy (VIPN) in children with ALL undergoing induction chemotherapy. Methods: A case-control study was conducted from September 2017 to August 2018 in the Department of Paediatric Haematology and Oncology at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. Eighty newly diagnosed ALL and 35 acute myeloid leukemia (AML) cases aged 5 to 17 years with no pre-existing neurological abnormality were recruited. To assess the peripheral neuropathy, we used pediatric-modified total neuropathy score and National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version-04 grade. Results: Among ALL patients, 29.2% developed peripheral neuropathy compared to 10% in AML control group (P=0.04). Higher proportion (57.1%) of peripheral neuropathy was found in age below 10 years (P&lt;0.001). There was no significant association of peripheral neuropathy with sex and body mass index of the patients. Conclusion: Almost 3 in 10 patients developed VIPN during the induction therapy which is significantly higher in age below 10 years compared to ≥ 10 years.

Revaccination of children with acute lymphoblastic leukemia following completion of chemotherapy

Intensive chemotherapy for acute lymphoblastic leukemia (ALL) may affect the immune system and potentially the immune memory causing antibodies provided by vaccination to disappear. There are disagreements regarding the guidelines for posttreatment immunization strategy. Ninety-six children (aged 1-18 years at diagnosis) who completed chemotherapy for ALL were recruited. Antibody levels in the patient's serum against measles, varicella, polio, pertussis, hepatitis A, and hepatitis B were tested after completion of chemotherapy in patients who were fully vaccinated against these agents. Children who did not have positive serology to specific agents were revaccinated with a single dose accordingly. Antibody concentrations were measured again at least 4weeks after revaccination. Positive antibody levels varied between the different agents. The highest percentage of positive serology was against polio (87%) and the lowest against pertussis (4%) (p<.001). There were significant differences between patients with high risk (HR) and non-HR ALL regarding serology status for some vaccines. After revaccination, the levels of response to each booster dose were significantly different: 100% after booster dose for varicella and polio, and only 34% after pertussis booster. Loss of humoral protection for vaccine preventable diseases is a common finding among patients with ALL. Revaccination with one dose of vaccine after completion of chemotherapy achieved seroconversion in 34-100% of the patients depending on the type of vaccine. We recommend this revaccination schedule to all children who completed ALL therapy and were previously fully vaccinated.

Requirement for ER-mitochondria Ca2+ transfer, ROS production and mPTP formation in L-asparaginase-induced apoptosis of acute lymphoblastic leukemia cells.

Acute lymphoblastic leukemia (aLL) is a malignant cancer in the blood and bone marrow characterized by rapid expansion of lymphoblasts. It is a common pediatric cancer and the principal basis of cancer death in children. Previously, we reported that L-asparaginase, a key component of acute lymphoblastic leukemia chemotherapy, causes IP3R-mediated ER Ca2+ release, which contributes to a fatal rise in [Ca2+]cyt, eliciting aLL cell apoptosis via upregulation of the Ca2+-regulated caspase pathway (Blood, 133, 2222-2232). However, the cellular events leading to the rise in [Ca2+]cyt following L-asparaginase-induced ER Ca2+ release remain obscure. Here, we show that in acute lymphoblastic leukemia cells, L-asparaginase causes mitochondrial permeability transition pore (mPTP) formation that is dependent on IP3R-mediated ER Ca2+ release. This is substantiated by the lack of L-asparaginase-induced ER Ca2+ release and loss of mitochondrial permeability transition pore formation in cells depleted of HAP1, a key component of the functional IP3R/HAP1/Htt ER Ca2+ channel. L-asparaginase induces ER Ca2+ transfer into mitochondria, which evokes an increase in reactive oxygen species (ROS) level. L-asparaginase-induced rise in mitochondrial Ca2+ and reactive oxygen species production cause mitochondrial permeability transition pore formation that then leads to an increase in [Ca2+]cyt. Such rise in [Ca2+]cyt is inhibited by Ruthenium red (RuR), an inhibitor of the mitochondrial calcium uniporter (MCU) that is required for mitochondrial Ca2+ uptake, and cyclosporine A (CsA), an mitochondrial permeability transition pore inhibitor. Blocking ER-mitochondria Ca2+ transfer, mitochondrial ROS production, and/or mitochondrial permeability transition pore formation inhibit L-asparaginase-induced apoptosis. Taken together, these findings fill in the gaps in our understanding of the Ca2+-mediated mechanisms behind L-asparaginase-induced apoptosis in acute lymphoblastic leukemia cells.

Loss of protective anti-HBs titers and seroconversion to hepatitis B vaccination in children during chemotherapy for acute lymphoblastic leukemia.

This study aimed to evaluate loss of protective anti-hepatitis B (HBs) titers and seroconversion to hepatitis B vaccine (HBV) during chemotherapy in children with acute lymphoblastic leukemia (ALL). Anti-HBs titers were done at diagnosis. Patients were divided into two groups. Group I (protective titers >10mIU/ml) received single double dose of HBV as booster. Titers were repeated at three time points: end of phase 1b, beginning of re-induction, and start of maintenance chemotherapy. Group II (nonprotective titers <10mIU/L) received hepatitis B immunoglobulin (HBIG), prior to start of chemotherapy, followed by three double doses of HBV as booster. Titers were repeated at two time points: prior to first dose, and 4weeks after third dose of vaccine. Total 125 patients were included: 88 in group I; 37 in group II. Among group I patients, 98.7%, 90%, and 84% retained protective titers at the three points, respectively. Subgroup analysis showed that those with initial titers greater than 100mIU/L retained protective titers better than those with titers between 11 and 100mIU/L (p = .0001). Among group II patients, 62% and 64% attained protective titers at the two points, respectively. HBV boosters helped maintain protective titers during intensive ALL chemotherapy in immunized children having titers more than 10mIU/L, and more so if titer was more than 100mIU/L. Therefore, we propose that cut off for protective anti-HBs titers be changed to greater than or equal to 100mIU/L. Titers between 11 and 100mIU/L may require combined active and passive immunization. Around one-third of group II patients who fail to attain protective titers may need frequent doses of HBIG.

Mechanistic Study of Wee1 Kinase Inhibition with AZD1775 Exposes Drug Targetable Vulnerabilities in Acute B-Lymphoblastic Leukemia

Targeted therapies exploiting vulnerabilities of cancer cells hold promise for improving patient outcome and reducing side effects of chemotherapy. Despite a high response rate to induction chemotherapy in acute lymphoblastic leukemia (ALL) there is an urgent need to identify effective combination therapy to overcome treatment resistance that associates with disease relapse. ALL cells are acutely highly sensitive to the WEE1 inhibitor AZD1775 that compromises the G2/M-phase cell cycle checkpoint. Here, we show that AZD1775 selectively inhibits recovery of proliferation in KMT2A/MLL-rearranged (MLL-r) ALL, a group of leukemias that respond poorly to current chemotherapy and have dismal prognosis compared to other leukemia subgroups. This vulnerability could be distinguished by elevated WEE1 expression in MLL-r ALL and through biochemical analysis of the resulting mitotic catastrophe upon WEE1 inhibition as assessed by PARP cleavage and flow cytometric analysis of DNA metabolism. Extensive genomics profiling of the drug response by joint single-cell transcriptome and chromatin accessibility profiling revealed that AZD1775 led to a strong p53-driven gene regulatory response resulting in induction of apoptosis and senescence and disrupts a crucial hematopoietic TF-network involving RUNX1, MYC and GATA2. We further demonstrate that RUNX1 protein was degradaded in a CDK-dependent manner. Leukemia relapse may arise from rare cells that escape treatment through genetic mutations, transcriptional reprogramming or signaling rewiring. We here demonstrate that upon the pre-mature mitosis entry resulting from AZD1775 treatment, a rapid transcriptional reprogramming is triggered involving activation of NfKB and transcription factors regulating lipid metabolism, BCL6 and pre-BCR signaling that resulted in a small surviving cell population. Single-cell characterization of the AZD1775 response in a MLL-r patient-derived xenograft (PDX) model supported the in vivo relevance of this drug resistance mechanism. Informed by the genomic profiles, sequential administration of AZD1775 with inhibitors of pre-BCR signaling or fatty acid synthesis was designed to target the resistant cell state and this approach effectively prevented cell survival and recovery of ALL cells. Collectively, our findings provide new insights into the tight connectivity of gene regulatory programs associated with cell survival and cell fate regulation in response to drugs targeting cell cycle regulation and provide a rationale for combination therapies with low toxicity drugs such as dasatinib or fatostatin to counteract drug resistance that occurs through cell state switching.

Longitudinal investigation of suicidal ideation and associated factors during pediatric acute lymphoblastic leukemia chemotherapy.

This study describes the prevalence of suicidal ideation (SI) during acute lymphoblastic leukemia (ALL) therapy and investigates the influence of clinical factors and physical symptoms on SI. The Children's Depressive Inventory (CDI-2) was administered to ALL patients (diagnosed 2012-2017) at start of consolidation, delayed intensification (DI), maintenance cycle 1 (MC1), and maintenance cycle 2 (MC2) in a multi-site study. SI was present if patients endorsed the item "I want to kill myself." Logistic regression models evaluated associations between SI and sociodemographic factors; depressive symptoms; and below average, average, and above average symptom clusters identified using latent class analysis of pain, nausea, fatigue, and sleep. Participants (n=175) were 51% male, 75% high-/very high-risk disease, with a median age of 11.2years at diagnosis (range: 7-18years). Overall, 14.9% of patients (75% under age 12years) endorsed SI during treatment, including 4% at start of consolidation, 9% at DI, 8% at MC1, and 4% at MC2. Non-Hispanic Other patients were 10.9-times (95% CI: 2.30-53.40) more likely than non-Hispanic Whites to endorse SI (p=0.003). The frequency of SI was higher in patients experiencing above average (53.3%) compared to below average (4.1%, p=0.003) symptoms. Depressive symptoms were consistently associated with SI. SI during the initial year of childhood ALL was more prevalent in children under the age of 12years, from ethnic groups not typically associated with increased risk, and who endorsed increased physical and depressive symptoms. Findings highlight the need for improved screening of mental health problems to mitigate symptoms of distress.

Real‐world effectiveness of antifungal prophylaxis with posaconazole as the primary agent in patients with haematological malignancies

Patients undergoing induction/reinduction chemotherapy for haematologic malignancies (HM) are at risk for invasive fungal infections (IFIs). In 2015, Duke University Hospital (DUH) implemented a new standardised fungal prophylaxis protocol for adult patients undergoing induction chemotherapy for acute lymphocytic leukaemia, acute myelocytic leukaemia and myelodysplastic syndrome. This study assessed the impact of protocol implementation on (1) use of antifungal prophylaxis, throughout the at-risk period and (2) patient outcomes such as IFI and mortality. Retrospective, observational study of adult HM patients admitted to DUH for induction/reinduction chemotherapy pre- (7/1/2013-12/31/2014) and post- (1/1/2015-10/31/2016) implementation of standardised antifungal prophylaxis protocol (which recommended posaconazole as the first-line agent). Patients were followed for up to 100 days after initiation of induction chemotherapy to evaluate use of antifungal prophylaxis and patient outcomes. 218 patients with haematologic malignancies were included (90 pre, 128 post). Use of antifungal prophylaxis increased from 81.1% (pre) to 97.7% (post) (p < .0001). Overall, 71% received posaconazole as initial antifungal prophylaxis (64.4% pre, 75.7% post). Approximately one-fourth of patients (25.6%, pre vs 26.6%, post) developed an IFI (proven/probable or possible using modified EORTC definitions) (p=.868); 100-day mortality remained stable (18.9% pre vs 18.8% post, respectively, p=.979). Lack of antifungal prophylaxis and older age (≥60 years) were associated with higher risk of IFI. Implementation of a standardised protocol with posaconazole as the primary agent was associated with increased use of antifungal prophylaxis among patients undergoing induction/reinduction chemotherapy for haematologic malignancies in our hospital. Lack of antifungal prophylaxis was an independent predictor of IFIs, underscoring the importance of prophylaxis in this at-risk population.

Etiology and Outcome of Seizures in Children during Induction Remission Chemotherapy for Acute Lymphoblastic Leukaemia

AbstractSeizure is one of the most frequent neurological complication and morbid phenomenon among children receiving chemotherapy for acute lymphoblastic leukemia. As overall survival of children with acute lymphoblastic leukemia is improving, now the challenge is to reduce treatment-related adverse effect. However, not much is known about the etiology and natural history of these seizure in our pediatric population. This is a single centered study conducted in the Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University. This prospective observational study was conducted over a period of 1 year from May 2017 to April 2018. A total of 105 patients aged 1 year to 17.9 years newly diagnosed as acute lymphoblastic leukemia were the study population. This study showed that in five (33.3%) patients, the underlying cause was suspected intracranial hemorrhage and it was the most common cause. All these five patients had features of severe sepsis and upper motor neuron sign associated with severe thrombocytopenia. Among them three had coagulopathy. Three (20%) patients had CNS leukemic infiltration. Suspected meningitis was attributed as the possible cause of seizure in two (13.33%) patients. Other identifiable causes were brain abscess in one patient, multiple cerebral infarction in one patient, hypertensive encephalopathy in one patient, and vincristine-induced neurotoxicity in one patient. In one patient no identifiable cause was found. Among 15 patients with seizure five (33.3%) patients were improved and completed induction remission chemotherapy. Ten (66.7%) patients died. In this study, we found sepsis and coagulopathy as the major underlying cause of seizure. Outcome was found very dismal in patients who developed seizure.

Effect of Age and Socioeconomic Factors in the Utilization of Chemotherapy in Acute Lymphoblastic Leukemia (ALL): A SEER Database Study of 16,196 Patients

IntroductionThe use of multiagent chemotherapy in acute lymphoblastic leukemia (ALL) has resulted in improvement in overall survival (OS), albeit to a different extent across various age groups. This large database study aims to assess the disparity in the utilization of chemotherapy in ALL in the real-world setting. Materials and MethodsUsing the Surveillance, Epidemiology, and End Results database, patients with ALL diagnosis from 2006 to 2016 were identified. Baseline characteristics were compared between the groups who did vs. did not receive chemotherapy using χ2 test. Multivariable logistic regression was used to evaluate the association between various sociodemographic factors and the receipt of chemotherapy in the entire cohort and in different age groups. ResultsOut of 16,196 patients, 1258 patients (8%) did not receive chemotherapy. There was a steady increase in the number of patients who did not receive chemotherapy with advancing age: 2.5% (0-18 years), 5.2% (19-40 years), 9.3% (41-65 years), and 36.2% (>65 years). There was an upward trend in the receipt of chemotherapy in patients >65 years over the last decade. In multivariate analysis, the likelihood of receiving chemotherapy decreased with advancing age, single or widowed status, low income and educational status, and lack of insurance. Insurance status was an independent predictor of receipt of chemotherapy across each age category. ConclusionA significant proportion of patients >65 years do not receive chemotherapy in the United States. Age, marital status, income, education, and insurance status contribute to the disparity in utilization of chemotherapy.

Frequency and Risk Factors of Seizures in Children During Induction Remission Chemotherapy for Acute Lymphoblastic Leukemia (ALL)

Background: Seizure is one of the most common CNS complications among patients receiving chemotherapy for acute lymphoblastic leukemia (ALL). Seizures are seen in 8-13% of patients with ALL. Most seizure occurs during the induction and consolidation phases of treatment. However, not much is known about the risk factors of these seizure.&#x0D; Materials &amp; Method: This prospective observational study was conducted in the department of Pediatric Hematology and Oncology, BSMMU. One hundred and five newly diagnosed admitted children with ALL aged &gt;1 year to &lt;18 years, from May 2017 to March 2018 for induction remission chemotherapy and who fulfilled the criteria of case definition were enrolled into this study.&#x0D; Results: This study showed that seizure frequency was14.3% in children with ALL getting induction remission chemotherapy. Female patients developed seizures more than males which was statistically significant by univariate analysis (p = 0.029) but was not found to be a risk factor by multivariate analysis (p = 0.059). All the seizures developed in B-lineage ALL but there was no statistically significant association between lineage of ALL with development of seizures.&#x0D; Conclusions: In this study slightly higher frequency of seizure in ALL patients on induction remission chemotherapy was found than previous studies (14.3% vs. 13%). Females developed seizures more than males.&#x0D; BANGLADESH J CHILD HEALTH 2021; VOL 45 (2) : 94-98