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Background: Pediatric acute lymphoblastic leukemia (ALL) patients have excellent survival outcomes, yet remain at increased risk for impaired physical function due to multiple chemotherapy-associated conditions including myopathy, peripheral neuropathy, bone toxicities, and fatigue. While initiating physical therapy (PT) early in treatment is likely to improve physical function and overall health of children with ALL, there are no published recommendations to guide PT service delivery for this population. In fact, utilization of PT and factors associated with utilization during planned and unplanned hospitalizations are not known. We sought to determine patterns of inpatient PT utilization in pediatric ALL patients, and its association with patient and hospital factors. Methods: Leveraging the Premier Healthcare Database, we conducted a cohort study that included participants hospitalized with ALL at 0-21 years of age from January 1, 2010 through March 31, 2017. Patients who underwent bone marrow transplant or had traumatic injuries unrelated to ALL therapy were excluded. The primary outcome was receipt of inpatient PT, identified by billing claims, within one year of first hospitalization. A multivariable logistic regression model was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of sociodemographic and clinical variables associated with PT. Results: Our cohort included 5,488 pediatric ALL patients admitted to 330 hospitals (42.3% female, 56.0% White, median age 7 years). Among these patients, 1,491 (27.2%) received PT within one year of their first admission, with 840 (15.3%) receiving PT during their first admission (Figure). For inpatient hospital stays in which participants received PT, the median length of stay was 9 (interquartile range [IQR] 4-18) days, and the median number of PT encounters per stay was 2 (IQR 1-4). Of 426 patients who had a diagnosis of peripheral neuropathy (n=334), myopathy (n=35), or avascular necrosis (n=74), 251(58.9%) received PT within a year of their first ALL admission. Compared with patients 0-4 years old, those aged 5-9 were less likely to receive PT (OR=0.71, 95% CI: 0.60-0.84), while those aged 10-14 (OR=1.38, 95% CI: 1.15-1.66) and 15-21 (OR=1.44, 95% CI: 1.20-1.73) were more likely to receive PT (Table). Patient factors associated with receiving PT included Hispanic ethnicity (OR=1.22, 95% CI: 1.01-1.46) and a history of an intensive care unit stay (OR=2.67, 95% CI: 2.28-3.11). Patients at teaching hospitals (OR= 1.64, 95% CI 1.39-1.89) were more likely to receive PT than those at non-teaching hospitals, while patients at rural hospitals (OR=0.39, 95% CI: 0.27-0.56) were less likely to receive PT than those at urban hospitals. Compared to patients treated by a pediatric hematologist/oncologist, patients treated by a non-hematology/oncology pediatric (OR=0.53, 95% CI:0.44-0.63) or adult (OR=0.46, 95% CI:0.37-0.57) specialist were less likely to receive PT. PT utilization also varied significantly by geographic region, and hospital size, while patient sex and insurance coverage did not appear to impact PT utilization (Table). Conclusions: Less than 30% of pediatric ALL patients receive inpatient PT within a year of their first hospitalization. Interventions to increase inpatient PT services to pediatric ALL patients and address disparities in PT utilization would be desirable to improve the physical function and long-term health of survivors. Figure 1 Figure 1. Disclosures Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding.

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

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 1–17 years. 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 250 IU/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.

Objective Steroids play an essential role in treating pediatric acute lymphoblastic leukemia (ALL). The downside is that these drugs can cause severe side effects, such as adverse psychological reactions (APRs) and sleep problems, which can compromise health‐related quality of life. This study aimed to systematically review literature to identify risk factors for steroid‐induced APRs and sleep problems in children with ALL. Methods A systematic search was performed in six databases. Titles/abstracts were independently screened by two researchers. Data from each included study was extracted based on predefined items. Risk of bias and level of evidence were assessed, using the Quality in Prognosis Studies tool and the Grading of Recommendations Assessment, Development and Evaluation tool, respectively. Results Twenty‐four articles were included. APR measurement ranged from validated questionnaires to retrospective record retrieval, sleep measurement included questionnaires or actigraphy. Overall, quality of evidence was very low. Current evidence suggests that type/dose of steroid is not related to APRs, but might be to sleep problems. Younger patients seem at risk for behavior problems and older patients for sleep problems. No studies describing parental stress or medical history were identified. Genetic susceptibility associations remain to be replicated. Conclusions Based on the current evidence, conclusions about risk factors for steroid‐induced adverse psychological reactions or sleep problems in children with ALL should be drawn cautiously, since quality of evidence is low and methods of measurement are largely heterogeneous. A standardized registration of steroid‐induced APRs/sleep problems and risk factors is warranted for further studies in children with ALL.

High-dose methotrexate (HDMTX) is an important component of treatment in pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Optimal rescue therapy is essential for the safe administration of HDMTX. A cost-effective strategy that does not compromise safety is necessary for low- and middle-income countries. Consecutive admissions for HDMTX in children with ALL and LL over 12 months were analyzed. The dose of HDMTX was 3 g/m

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease whose prognostic factors include minimal residual disease (MRD) and cytogenetic abnormalities. To explore the significance of MRD in ALL subtypes, we analyzed the outcomes of 1126 children treated with risk-stratified therapy based on sequential MRD monitoring. MRD distributions and treatment outcomes differed between distinct leukemia subtypes. Patients with ETV6-RUNX1 or hyperdiploidy had the best prognosis (5-year OS: 97 ± 1.5% and 89.2 ± 2.7%). However, hyperdiploidy patients with MRD ≥ 10% on day 15 had a higher risk of relapse (36.4%) than those with ETV6-RUNX1. TCF3-PBX1 patients had the fastest disease clearance (negative MRD rate on day 33: 92.1%), but the overall prognosis was intermediate (5-year OS: 82.5%). Patients with high-risk characteristics and ALL-T had inferior outcomes: even with undetectable MRD on day 33, cumulative incidence of relapse was 19.9% and 23.4%, respectively. Moreover, those with poor early-treatment response and detectable week-12 MRD had a worse prognosis. After adjusting for other risk factors, re-emergent MRD was the most significant adverse prognostic indicator overall. Sequential MRD measurement is important for MRD-guided therapy, and integration of MRD values at different timepoints based on leukemia subtype could allow for more refined risk stratification.

Purpose To assess the impact of maintenance therapy and the additional impact of dexamethasone treatment on cancer-related fatigue and sleep-wake rhythms in pediatric acute lymphoblastic leukemia (ALL) patients and to determine the association between these outcomes. Methods A national cohort of pediatric ALL patients (≥ 2 years) was included (± 1 year post-diagnosis). Patients receiving dexamethasone were assessed twice (assessment with and without dexamethasone). Actigraphy assessments were used to calculate sleep-wake outcomes with nonparametric methods. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Sleep-wake rhythms and cancer-related fatigue were compared between patients participating in the assessment without dexamethasone and healthy children (linear regression) and between assessments with and without dexamethasone (mixed models). Using linear regression, associations between sleep-wake outcomes and cancer-related fatigue were determined during assessments with and without dexamethasone. Results Responses were collected for 125 patients (113 assessments with and 81 without dexamethasone). The sleep-wake rhythm was less stable (p = 0.03) and less robust (p = 0.01), with lower physical activity levels (p p p = 0.001) and cancer-related fatigue more severe (p ≤ 0.001) during assessments with dexamethasone compared to without dexamethasone. Sleep-wake outcomes were significantly associated with cancer-related fatigue during periods without dexamethasone, but not during periods with dexamethasone. Conclusion Sleep-wake rhythms are disturbed, physical activity levels lower, and cancer-related fatigue levels higher during maintenance therapy. Interventions aimed to enhance sleep-wake rhythms during maintenance therapy could improve cancer-related fatigue. Families should be supported in coping with the additional burden of dexamethasone treatment to improve well-being of ALL patients.

Remoteness is associated with worse survival in adults with cancer. We aimed to determine whether remoteness is associated with cancer outcomes in pediatric acute lymphoblastic leukemia (ALL). Canadian children with ALL entered in the CYP-C registry were included. The predictive impact of remoteness on overall survival (OS), relapse, and treatment-related complications (infections, thrombosis, bleeding, and osteonecrosis) was estimated using multivariate regression models. We included 1383 children, of whom 277 (20.0%) lived remotely (200 km from the pediatric oncology center). The median latency to see a pediatric oncologist was longer in children living remotely. The 5-year OS (95% CI) was similar for both groups (remote: 95.2% [93.7-96.3%] vs close: 94.1% [90.5-95.2%]). No difference was found in the relapse rate between both groups and in treatment-related complications. Remoteness did not affect survival in pediatric ALL. Further research is needed to determine which models of healthcare organization optimize cancer outcomes and patients' satisfaction.

Approximately 30–40% of relapses in pediatric acute lymphoblastic leukemia (ALL) are extra-medullary. KMT2A gene rearrangements are common in patients with infantile ALL. Chloromas are rare tumors composed of collections of acute leukemic cells that typically involve the bone or skin. Exceptionally uncommon, chloromas invade the peripheral nervous system, a phenomenon termed “neuroleukemiosis.” We describe A 6-year-old girl with a history of pre-B ALL with CNS involvement and KMT2A rearrangement diagnosed initially at 4 months of age. During continuation therapy she developed a scalp mass that was confirmed to be a leukemic relapse. She underwent re-induction chemotherapy followed by blinatumomab with subsequent remission and proceeded to allogeneic hematopoietic cell transplant (HCT). Three years following HCT, she presented with brachial plexus palsy and was found to have a lymphoblastic chloroma invading the brachial plexus. Review of existing literature shows relapse in pediatric ALL patients presenting as brachial plexus chloroma has only been documented once before. It has long been suggested that KMT2A gene rearrangements play a role in development of chloromas in patients with AML, however it is still unclear what role KMT2A has in ALL. Here we report a rare case of ALL relapse that presented as a left arm palsy secondary to a leukemic chloroma invading the brachial plexus and aim to explore the potential role of KMT2A in the formation of ALL chloromas.

Treatment of acute lymphoblastic leukemia (ALL) in children during the last 50 years has changed significantly, which has increased the survival of patients from 10–15 % in the early 60s to 80–85 % by the mid-2000s. Such results have been achieved through the development of new polychemotherapy regimens, the introduction of neuroleukemia prophylaxis, the strengthening of standard chemotherapy by increasing the dose and / or frequency of chemotherapeutic drugs administration, and the definition of criteria for patient stratification into prognostic risks groups and the development of principles of risk-adopted therapy.However, inspite of the overall success of pediatric acute lymphoblastic leukemia therapy, some variants of acute lymphoblastic leukemia associated with poor prognosis, especially acute lymphoblastic leukemia with BCR-ABL1 and MLL rearrangements. Besides the prolonged persistence of minimal residual disease is also an unfavorable prognostic factor requiring therapy intensification.In the current issue we present the main steps in the evolution of programmed chemotherapy of children with acute lymphoblastic leukemia. Great attention was paid for modern risk-stratifying criteria with an emphasis on minimal residual disease.

Introduction Hypersensitivity reactions (HSRs) to rituximab occur during the first infusion in 29% to 40% of patients. Commonly, these hypersensitivity reactions are the result of a release of cytokines, although IgE mediated reactions have also been reported. Case Report A 7-year-old female patient with diagnosis of CD-20 positive acute lymphoblastic B-cell leukemia was included in a pilot study that consisted of two doses of rituximab treatment in the induction to remission phase by the pediatric hematology service; 30 minutes after the first administration of 300 mg of rituximab the patient started with generalized rash, nausea, vomiting, tachycardia, dyspnea, foreign body sensation in throat, oxygen desaturation until 89% and hypotension; therefore, the infusion of rituximab was suspended, and intramuscular epinephrine was administered as well as intravenous hydrocortisone and chlorphenamine and supplemental oxygen supply with adequate resolution of symptoms. Management & Outcome Intradermal skin testing with rituximab at the concentration 1 mg/ml (dilution 1:10), was positive. Desensitization to rituximab was indicated by our service with 4 bags – 16 steps protocol with an initial concentration dose of 1/1,000 of the total dose. The patient was premedicated 1 hour prior with intravenous chlorphenamine, methylprednisolone and ondansetron. Intravenous prophylactic fluids with normal saline solution were administered during the infusion. The procedure was carried out with close monitoring of vital signs in a course of 6.67 hours, without presenting hypersensitivity reactions. Discussion HSR to rituximab may be induced by the activation of mast cells and basophils. Desensitization protocols are developed when there is no alternative drug for the underlying condition.

The number of individuals undergoing unrelated cord blood transplantation (UCBT) has increased in recent years; however, information on prognostic factors is limited. We retrospectively analyzed data from 475 children and adolescents receiving UCBT with myeloablative conditioning for acute lymphoblastic leukemia (ALL) in complete remission (CR), based on a nationwide registry. In the total patient cohort, 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 61.1% and 67.7%, respectively. UCBT at first CR and UCBT after 2007 were associated with good survival, while grade II-IV acute graft-versus-host disease (GVHD) was associated with low relapse rate but did not affect survival. Analysis according to human leukocyte antigen (HLA) disparity revealed that tacrolimus-based GVHD prophylaxis resulted in higher OS and lower relapse rate and nonrelapse mortality (NRM) than cyclosporine-based GVHD prophylaxis in patients transplanted with 6/6 and ≤4/6 HLA-matched umbilical cord blood. Furthermore, grade II-IV acute GVHD was associated with good LFS and low relapse rate, without high NRM, in patients receiving 5/6 HLA-matched UCBT. These data indicate that prognostic factors for ALL differ depending on HLA disparity in UCBT.

Background: Immunocompromised patients are at increased risk of infections, especially those living in poor hygienic conditions. Aims and Objectives: This study aims to assess the effect of weight, immunization status of the child at the start of treatment along with the socioeconomic status (SES), and demographic parameters, i.e., type of house, sanitary facility (SF), and source of drinking water on the duration of induction phase of chemotherapy (delayed if the patient received chemotherapy for >29 days). Materials and Methods: 110 pediatric acute lymphoblastic leukemia patients aged 1.5–14 years who underwent induction of remission from June 2015 to February 2018 were included. The immunization status and weight of the child were recorded at the start of treatment. SES was assessed using modified Kuppuswami scale and a questionnaire was used to determine various sociodemographic parameters. Results: The patients not immunized as per age (P = 0.000) and having poor demographic parameters, i.e., mud house (P = 0.000), absence of SF (P = 0.013), and nonfiltered drinking water (P = 0.005), had significant delay. The duration of induction phase of chemotherapy was not delayed with poor SES (P = 0.832). Although the duration was delayed in patients with weight ≥10 percentile, it was not statistically significant (P = 0.079). On analyzing the three demographic parameters together as Water-Sanitary Facility-Housing (WaSH) Score (0–4), the duration was also significantly delayed if the patients had WaSH score

Minimal residual disease (MRD) monitoring has a strong prognostic value in childhood lymphoblastic leukemia (ALL) and is currently utilized in all major pediatric ALL protocols. MRD monitoring is done by multiparameter flow cytometry, IG/TCR quantitative PCR or reverse transcriptase quantitative PCR of leukemic fusion transcripts providing a reliable measurement of treatment response. However, occasionally bone marrow (BM) aspirates may not yield representative material or be misinterpreted due to treatment-induced changes in MRD marker profile, undetected subclones at diagnosis, contamination with peripheral blood or cell adhesion and stroma cell interactions posing a risk for underestimating MRD levels and misclassifying resistant disease that may be detected by traditional BM morphology methods, immunohistochemistry, karyotyping and FISH. We present four cases with high MRD levels where MRD monitoring failed to provide the correct stratification information. Through these cases, we discuss the continued need to consider all available information including BM smears, touch imprints and trephine biopsy preparations not only at diagnosis but throughout remission monitoring in pediatric ALL.

Contains fulltext : 248362.pdf (Publisher’s version ) (Open Access) INTRODUCTION: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended. METHODS: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy. RESULTS: We observed a dynamic clonal evolution in all cases, with relapse almost exclusively originating from a subclone at diagnosis. We identified several driver mutations that may have influenced the outgrowth of a minor clone at diagnosis to become the major clone at relapse. For example, a minimal residual disease (MRD)-based standard-risk patient with ETV6-RUNX1-positive leukemia developed a relapse from a TP53-mutated subclone after loss of the wildtype allele. Furthermore, two patients with TCF3-PBX1-positive leukemia that developed a very early relapse carried E1099K WHSC1 mutations at diagnosis, a hotspot mutation that was recurrently encountered in other very early TCF3-PBX1-positive leukemia relapses as well. In addition to alterations in known relapse drivers, we found two cases with truncating mutations in the cohesin gene RAD21. CONCLUSION: Comprehensive genomic characterization of diagnosis-relapse pairs shows that very early relapses in BCP-ALL frequently arise from minor subclones at diagnosis. A detailed understanding of the therapeutic pressure driving these events may aid the development of improved therapies.

Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26–8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71–13.75; p = 0.003).

Introduction Due to bone fragility, children with acute lymphoblastic leukemia (ALL) have a 6-fold greater fracture risk during therapy compared to peers. Osteoporotic fractures are a concern, as they lead to adverse health outcomes including pain, loss of height due to vertebral deformity, and (transient) disability. In previous studies, lower lumbar spine bone mineral density (LS BMD) at ALL diagnosis was found to be prognostic for the occurrence of future fractures. However, routinely performing dual-energy X-ray absorptiometry (DXA) in each newly diagnosed child is not universally feasible. The aim of this study is to develop and validate an easy to use clinical risk prediction model for low lumbar spine bone mineral density (LS BMD Z-score ≤-2.0) at diagnosis, as an important indicator for fracture risk and further treatment-related BMD aggravation. Methods Children treated for ALL according to the Dutch Childhood Oncology Group (DCOG-ALL9; model development) protocol (n=249; median age: 7.6 years [range: 4.0-16.6 years]) and children from the Canadian STeroid-Associated Osteoporosis in the Pediatric Population (STOPP; model validation) cohort (n=99; median age: 7.3 years [range: 4.0-16.6 years]) were included in this study. Multivariable logistic regression analyses were used to develop the prediction model for low LS BMD at diagnosis, defined as a Z-score ≤-2.0 (evaluated with DXA). Candidate predictors included sex, age, height and weight Z-scores at diagnosis of ALL. The receiver operating characteristic area under the curve (AUC) was assessed for model performance. To confirm the association between low LS BMD at diagnosis and bone fragility during and shortly following ALL therapy, we performed multivariable logistic regression analyses. The dependent variables were: one or more symptomatic fractures from ALL diagnosis to 12 months following treatment cessation and low LS BMD at cessation of treatment. In addition, because of homogeneity in the intended glucocorticoid doses, we combined data from the DCOG-ALL9 and STOPP cohorts and performed multivariable pooled cohort analyses (meta-analysis). Potential associations between the six-month cumulative glucocorticoid dose and fractures that occurred in the first year of therapy, were explored. Furthermore, we assessed potential associations between the cumulative glucocorticoid dose at cessation of therapy, and the endpoints 'low LS BMD at therapy cessation' and 'fractures that occurred during treatment and within 12 months following treatment cessation'. Results The prediction model for low LS BMD at diagnosis included weight Z-scores (β = -0.70) and age (β = -0.10) at diagnosis. This model had an AUC of 0.71 (0.63 to 0.78) in the DCOG-ALL9 cohort, and resulted in correct identification of 71% of patients with low LS BMD at ALL diagnosis. Validation on the STOPP cohort showed an AUC of 0.74 (95% CI = 0.63 to 0.84). To calculate the probability of low LS BMD at ALL diagnosis for an individual patient, an online calculator is available at http://lsbmd-risk-calculator.azurewebsites.net/ We confirmed that low LS BMD at diagnosis is associated with LS BMD at treatment cessation (OR = 5.9; 95% CI = 3.2 to 10.9) and with symptomatic fractures (OR = 1.7; 95% CI = 1.3 to 2.4) that occurred from diagnosis until 12 months following treatment cessation. In pooled meta-analysis, lower LS BMD at diagnosis (OR = 1.6, 95% CI = 1.1 to 2.4) and six-month cumulative glucocorticoid dose (OR = 1.9, 95% CI = 1.1 to 3.3, for every gram increase) were associated with symptomatic fractures that occurred in the first year of therapy. Higher cumulative glucocorticoid dose at cessation of therapy (OR = 1.5, 95% CI = 1.2 to 2.0, for every gram increase), lower LS BMD Z-scores at diagnosis (OR = 7.9, 95% CI = 4.8 to 13.1) and higher age at diagnosis (OR = 1.6, 95% CI = 1.4 to 1.8), were associated with low LS BMD at cessation of therapy. Conclusion We developed and successfully validated a risk prediction model for low LSBMD at diagnosis in children aged 4-18 years with ALL. This is important because low LS BMD at diagnosis was strongly associated with bone fragility and fractures during and shortly following treatment for ALL. Our easy to use prediction model, can facilitate awareness and early identification of bone fragility in individual pediatric ALL patients, without performing DXA examination. Disclosures No relevant conflicts of interest to declare.

Pharmacogenomics and pharmacotranscriptomics contribute to more efficient and safer treatment of many diseases, especially malignancies. Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy during childhood. Glucocorticoids, prednisone and dexamethasone, represent the basis of chemotherapy in pediatric ALL. Therapy causes side effects in 75% of patients and 1–3% of pediatric ALL patients die because of therapy side effects rather than the disease itself. Due to this fact, pharmacogenomics and pharmacotranscriptomics have gained key positions in this field. There is a growing knowledge of pharmacogenomics and pharmacotranscriptomics markers relevant for the success of the glucocorticoid treatment of children with ALL. New technologies, such as next-generation sequencing (NGS) have created a possibility for designing panels of pharmacogenomics and pharmacotranscriptomics markers related to the response to glucocorticoid drugs. Optimization of these panels through population pharmacogenomic studies leads to new knowledge that could open the doors widely to pre-emptive pharmacogenomic testing.

Prognosis of acute lymphoblastic leukemia (ALL) in adults is inferior to children. Hence, ALL is still a challenging disease to be cured in adult population. Aberrant genetic alterations have been observed previously in ALL, while the patterns of differential gene alteration have not much been comprehensively determined in the adult and pediatric ALL on a genome-wide scale. This study was attempted to investigate the biological differences in genomic profiling between the adults and children with ALL, and the relationship between the genomic heterogeneity and prognosis. The results showed the similar common mutation types in two populations but the increased prevalence of genetic alterations in adult ALL. The median number of detected gene mutations was 17 (range: 1–53) per sample in adult ALL and 4.5 (range: 1–19) in pediatric ALL(P2 = 0.5853, P

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors’ late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy’s long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines’ possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect’s vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.

BACKGROUND Recent shifts from radiation to chemotherapy-based treatment for acute lymphoblastic leukemia (ALL) have contributed to reduced long-term morbidity. Despite this, ALL survivors remain at increased risk for long-term cognitive impairments. AIM To identify demographic and treatment factors associated with school performance in pediatric survivors of ALL. METHODS We collected standardized test scores for reading, math, and science obtained in a school setting from grades 3-11 in 63 ALL survivors (46.0% boys). Most participants were assessed across multiple grades (median number of grades n = 5, range 1-7), and 269 observations were considered in the analyses. Treatment exposures were extracted from medical records. Socio-economic status was estimated using participation in free/reduced lunch programs at school. Mixed effects linear regression models were conducted to determine factors associated with school performance. RESULTS ALL survivors' scores were comparable to state norms on reading, math, and science performances. On multivariable analysis, participation in free/reduced lunch programs was significantly associated with lower reading scores (β = -12.52; 95% CI -22.26:-2.77, p = .01). Exposure to radiation during treatment was also associated with lower reading test scores (β = -30.81, 95% CI -52.00:-9.62, p = .01). No significant associations between demographics and treatment parameters were observed for math and science test scores. CONCLUSIONS We utilized population-based achievement tests conducted from grades 3-11 to characterize school performance in ALL survivors. Our results imply that survivors with low socio-economic status and those exposed to radiation during treatment could benefit from early monitoring and intervention to maximize academic success.

Targeted therapy has revolutionized the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) with specific genetic abnormalities. It is still being described as a new landmark therapeutic approach. The main purpose of the use of molecularly targeted drugs and immunotherapy in the treatment of ALL is to improve the treatment outcomes and reduce the doses of conventional chemotherapy, while maintaining the effectiveness of the therapy. Despite promising treatment results, there is limited clinical research on the effect of target cell therapy on the potential toxic events in children and adolescents. The recent development of highly specific molecular methods has led to an improvement in the identification of numerous unique expression profiles of acute lymphoblastic leukemia. The detection of specific genetic mutations determines patients’ risk groups, which allows for patient stratification and for an adjustment of the directed and personalized target therapies that are focused on particular molecular alteration. This review summarizes the knowledge concerning the toxicity of molecular-targeted drugs and immunotherapies applied in childhood ALL.

Introduction: Cytomegalovirus (CMV) infections in developing countries are experienced at an early age. This study was performed to investigate the frequency of reactivation and risk factors of infection acquired at an early age of nontransplant acute lymphoblastic leukemia (ALL) patients receiving immunosuppressive therapy with weekly monitoring of CMV levels in Turkey. Materials and Methods: This was a retrospective, single-center study of 172 pediatric patients (102 boys and 70 girls) with ALL. All patients were monitored routinely for CMV-DNA at the initial presentation of leukemia and twice a week during chemotherapy. The CMV immunoglobulin (Ig)M/IgG titers were measured at admission. Results: CMV seropositivity at baseline was 90,11%. The overall prevalence of CMV infection (viremia) was 70.34%, 116 of whom were seropositive for CMV IgG and 5 of whom were negative for CMV at the time of ALL diagnosis. Reactivation was more common than de novo CMV infections (P=0.000). CMV seropositivity at the beginning of the leukemia diagnosis was found to be an independent predictor for developing CMV infection (P=0.001). A total of 60 CMV infection episodes were treated with antivirals. Four of these included organ involvement. The duration of CMV-DNA viremia episodes was longer in patients with CMV-DNA >= 1000 copies/mL (n=45) than in those with lower CMV-DNA levels (P=0.002). Infection was shown not to be associated with chemotherapy phase. Conclusion: This study suggests the importance of monitoring for CMV infections in developing countries because of frequent reactivations in seropositive ALL patients. It should be kept in mind that low CMV-DNA levels may also lead to organ involvement.

PURPOSE In the DCOG ALL-11 protocol, polyethylene glycol–conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are reported. PATIENTS AND METHODS After induction with 3 fixed intravenous doses of 1,500 IU/m2 PEGasparaginase, medium-risk patients (n = 243) received 14 individualized doses that targeted trough levels of 100-250 IU/L, standard-risk patients (n = 108) received 1 individualized dose, and high-risk patients (n = 18) received 2-5 fixed administrations (1,500 IU/m2). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m2 Erwinia asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied. RESULTS The final median PEGasparaginase dose was lowered to 450 IU/m2. Overall, 97% of all trough levels of nonallergic patients were > 100 IU/L. Asparagine was < 0.5 μM in 96% and 67% of the PEGasparaginase and Erwinia asparaginase levels > 100 IU/L, respectively. Ten percent developed a neutralizing hypersensitivity reaction to PEGasparaginase, of which 40% were silent inactivations. The cumulative incidence of grade 3-4 pancreatitis, central neurotoxicity, and thromboses was 12%, 4%, and 6%, respectively, and not associated with asparaginase activity levels. During medium-risk intensification, 50% had increased ALT and 3% hyperbilirubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hypertriglyceridemia. Hypertriglyceridemia occurred less in intensification compared with ALL-10 (37% v 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification. CONCLUSION TDM of asparaginase results in a significant reduction of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine depletion. In addition, with TDM, silent inactivation and allergic-like reactions were identified. However, the effect of reduced asparaginase activity levels on toxicity is limited.

Background: Acute lymphoblastic leukemia (ALL), a common pediatric malignant neoplasia, showed high relapse rate after induction therapy. Some miRNAs have been shown to regulate normal hematopoiesis and their disruption could contribute to leukemogenesis: Recently, specific miRNA, including miR-181a, was shown to be involved in the pathogenesis of ALL, serving as a biomarker for diagnosis and relapse of ALL. Aim of the Study: To evaluate miR-181a expression level as a predictive marker for children with acute lymphoblastic leukemia. Patients and Methods: 40 pediatric ALL patients were included in this study. miR-181a expression was assessed at diagnosis before start of treatment. Samples were either peripheral blood or bone marrow aspirate sample. Patients were evaluated clinically and laboratory after the induction therapy. Results: The remission rate was significantly higher in patients with high miR-181a expression compared to those with low expression (p Conclusion: The expression level of miR-181a was significantly higher in remission group than in non-remission group was and predict good response to induction therapy.

Background Treatment stratification based on bone marrow minimal residual disease (MRD) at set time points has resulted in considerably improved survival in pediatric acute lymphoblastic leukemia (ALL). Treatment response is assessed using bone marrow samples. MicroRNAs (miRs) easily traffic among fluid spaces and are more stable than most other RNA classes. We examined the role of circulating miRs as putative less invasive MRD biomarkers. Methods In an exploratory experiment, expression of 46 preselected miRs was studied in platelet-free blood plasma samples of 15 de novo, 5 relapsed ALL patients and 10 controls by Custom TaqMan Array Advanced MicroRNA Card. Based on their high expression in ALL compared to controls, and on the reduction observed along the induction therapy, four miRs were selected for further analyses: miR-128-3p, -181a-5p, -181b-5p and 222-3p. Their expression was measured by qPCR at 4 time points in 27 de novo ALL patients treated in the ALL IC-BFM 2009 study. Results The expression of all 4 miRs significantly decreased over the first week of therapy (miR-128-3p: log2 fold change − 2.86; adjusted p 3.6 × 10−7; miR-181b-5p: log2 fold change − 1.75; adjusted p 1.48 × 10−2; miR-181a-5p: log2 fold change -1.33; adjusted p 3.12 × 10−2; miR-222-3p: log2 fold change − 1.25; adjusted p 1.66 × 10−2). However, no significant further reduction in miR expression was found after the 8th day of therapy. Measured drop in expression of 2 miRs at day 8 strongly correlated with day 15 bone marrow flow cytometry MRD results (miR-128-3p: Pearson’s r = 0.88, adjusted p = 2.71 × 10−4; miR-222-3p: r = 0.81, adjusted p = 2.99 × 10−3). Conclusion In conclusion, these circulating miRs might act as biomarkers of residual leukemia. MiR-128-3p and miR-222-3p in blood predict day 15 flow cytometry MRD results 7 days earlier. Although, their sensitivity falls behind that of bone marrow flow cytometry MRD at day 15.

Background A retrospective analysis was performed to investigate the survival outcomes in pediatric acute lymphoblastic leukemia (ALL) based on time period. We hypothesized that improvement has been obtained with the time-dependent therapeutic era and rise in the gross domestic product (GDP) and Human Development Index (HDI). Materials and methods Data from 710 children who were treated for ALL between 1958 and 2018 at a single pediatric center were analyzed for probability of 5-year overall survival (pOS), event-free survival (pEFS) and relapse risk (pRR). Time periods were defined by the treatment protocols used in seven consecutive therapeutic eras. Results Over the 60-year period analyzed, pOS increased from 1.2% to 90.7%, pEFS from 1.2% to 86.6%, and pRR decreased from 98.8% to 9.9% for patients treated in the past decade. Risk of mortality for patients who received chemotherapy and hematopoietic cell transplant was reduced to 9.9% in the recent era, however, no statistically significant survival difference was found between patients treated with stem cell transplant and those not. Conclusion The therapeutic era, related to improved GDP and HDI, was a statistically significant predictor of increased OS from ALL.

Monitoring serum immunoglobulin G (IgG) levels in pediatric oncology patients and treating subtherapeutic levels with intravenous immunoglobulin (IVIG) may prevent infections; however, evidence is limited. This retrospective study assessed pediatric acute lymphoblastic leukemia patients diagnosed 2006 to 2011 to evaluate if monitoring/supplementing IgG would reduce febrile illnesses during maintenance chemotherapy. A subject was categorized as "ever IgG monitored" if they had ≥1 IgG levels checked and their risk days were stratified into not IgG monitored days and IgG monitored days. IgG monitored days were further stratified into IgG monitored with IVIG supplementation, monitored with no IVIG supplementation (IgG level >500 mg/dL) and monitored with no IVIG supplementation days (IgG level

The purpose of this study was to evaluate the impact of switching patients being treated for acute lymphoblastic leukemia (ALL) from vincristine to bortezomib.A total of 20 patients with ALL were switched from vincristine to bortezomib (1.3 mg/m/dose) because of worsening neuropathy despite physical therapy interventions (n=18) or at increased risk of neuropathy (n=2). Relapse rates were compared with 56 vincristine-only patients matched by prognostic factors. Maintenance blood counts in bortezomib patients were compared with cooperative group data using vincristine during maintenance. In addition, 6 evaluable patients were assessed for neuropathy using the pediatric-modified total neuropathy score. Neuropathy scores were collected during treatment with vincristine and after switching to bortezomib.After a median follow-up of 3.5 years the relapse rate in patients switched to bortezomib was nonsignificantly different than those remaining on vincristine. Patients on monthly bortezomib had statistically significantly lower platelet counts that did not require transfusions or dose adjustment. Total neuropathy for all 6 cases decreased significantly when switched to bortezomib from vincristine (P=0.015), with motor neuropathy declines in 5 of 6 subjects.Bortezomib substitution for vincristine in ALL treatment is a potential strategy to mitigate severe vincristine neuropathy. These findings should be confirmed in a randomized clinical trial to further assess benefits and risks of this approach.

Asparaginase is an important component of multi-agent chemotherapy for the treatment of pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy). Hypersensitivity to the PEGyla...

The purpose of this study is a comprehensive analysis of BCR-ABLl-like pediatric acute lymphoblastic leukemia (ALL) and to point out the difference between BCR-ABLl-like and Ph-like ALL in children. It was shown the genetic heterogeneity of BCR-ABLl-like ALL including cases with tyrosine kinase fusion genes, activating mutations in JAK-STAT, RAS. We also described various diagnostic options and prognostic role of BCR-ABL1-like ALL in children.

The remarkable improvement in the prognosis of children with acute lymphoblastic leukemia (ALL) has been mainly achieved through the administration of risk-adapted therapy, including allogeneic hematopoietic stem cell transplantation (HSCT). This paper reviews the current indications to HSCT in ALL children, as well as the type of donor and conditioning regimens commonly used. Finally, it will focus on future challenges in immunotherapy. As our comprehension of disease-specific risk factors improves, indications to HSCT continue to evolve. Future studies will answer the year-old question on the best conditioning regimen to be used in this setting, while a recent randomized controlled study fixed the optimal anti-thymocyte globulin dose in unrelated donor HSCT. HSCT, the oldest immunotherapy used in clinical practice, still represents the gold standard consolidation treatment for a number of pediatric patients with high-risk/relapsed ALL. New immunotherapies hold the promise of further improving outcomes in this setting.

Background: Sedation for lumbar punctures (LPs) in pediatric acute lymphoblastic leukemia (ALL) patients has been the standard for decades to reduce pain and anxiety. Recent studies on the potential long-term neurocognitive effects of cumulative propofol exposure has raised concerns about this practice. The recent pandemic introduced additional burdens to patients, with the requirement of a negative COVID-19 test prior to each sedated procedure. Procedure: These factors prompted a quality improvement intervention at our institution where we aimed to reduce post-Induction sedated lumbar punctures (LPs) by 50%. Our intervention included patient and family education followed by a simulation of the procedure for selected patients. Those converted to unsedated LPs were queried for their preference. Comparative cost, clinical time and LP success rates were collected for sedated and unsedated LPs. Results: Following the intervention, the percentage of LPs performed with sedation dropped from 100% to 48.1%. All LPs were successful using both techniques. Most patients who experienced the unsedated LP technique, and their guardians, strongly preferred this approach. Unsedated LPs significantly reduced clinical time (169 vs 83 minutes) for families, decreased expenditures ($5,736.16 reduction per procedure) and improved institutional opportunity cost due to a decrease in last-minute cancellations. Conclusion: We have shown that it is feasible to significantly reduce the use of sedation for LPs in patients with ALL, which has the potential to improve health and patient experience at a lower cost.

Background Children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy experience a relatively high risk of infection. And the disturbance of gut microbiota is generally believed to impair intestinal barrier function and may induce bacterial infections and inflammation. The study aimed to investigate the alterations in the gut microbiota and assess its relationship with chemotherapy-induced pneumonia in pediatric ALL patients. Methods We conducted a case–control study with 14 cases affected by pneumonia and 44 unaffected subjects and characterized the physiological parameters and gut microbiota by microarray-based technique. Results There were significant differences in α- and β-diversity in the affected group compared with the control group. At species level, the LEfSe analysis revealed that Enterococcus malodoratus, Ochrobactrum anthropi and Actinomyces cardiffensis were significantly abundant in the affected subjects. A receiver operating characteristic (ROC) curve yielded the area under the curve (AUC) of 0.773 for classification between the two groups. In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in the bacterial secretion system were more enriched in the affected group than in the control group. Conclusions Gut microbiota alteration was associated with chemotherapy-induced pneumonia in pediatric ALL patients, which provided a new perspective on the personalized clinical care of pediatric ALL.

Vincristine, a key agent in the treatment of many pediatric malignancies, causes sensory, motor and autonomic neuropathy. We report the clinical courses of 5 patients who required cessation of vincristine after developing severe neurotoxicity during treatment for acute lymphoblastic leukemia. All 5 patients lost the ability to ambulate and 3 had additional severe neurotoxic side effects including vision loss and vocal cord dysfunction. Although prior literature reports poor outcomes for children in whom vincristine was discontinued during acute lymphoblastic leukemia therapy, all 5 patients described here achieved and have maintained complete continuous remission.

IntroductionThe present study aimed to compare the efficacy of vindesine with that of leurocristine for pediatric acute lymphoblastic leukemia and their effects on the quality of life.Material and methodsWe included 94 patients with pediatric acute lymphoblastic leukemia admitted to our hospital for treatment and categorized them into two groups: treatment with vindesine (group A, n = 48) and treatment with leurocristine (group B; n = 48). The effective rate, adverse reactions (thrombocytopenia, anemia, peripheral neurotoxic reaction, infection, nausea, and vomiting) and basic clinical conditions (medical expenses and length of hospital stay) of the patients were observed. In addition, IL-6 and TNF-α expressions were determined by ELISA before and after treatment, posttreatment quality of life score was determined by the Karnofsky performance scale (KPS), and the 5-year overall survival was determined in both groups.ResultsGroup A showed no statistical difference in the total efficacy rate and 5-year overall survival after treatment (P > 0.05) and had lower medical expenses, length of hospital stay, IL-6 and TNF-α expressions, and total incidence of adverse reactions and higher KPS scores than group B (P < 0.05).ConclusionsAlthough no statistical difference was observed between vindesine and leurocristine in treating pediatric acute lymphoblastic leukemia, patients administered vindesine had fewer adverse reactions, shorter length of hospital stay, lower medical expenses, and higher quality of life than those administered leurocristine, indicating a potential association with decreased serum IL-6 and TNF-α expressions.

Background PEG-asparaginase is critical in pediatric acute lymphoblastic leukemia (ALL) therapy but is highly immunogenic. Severe allergic reactions lead to substitution of further PEG-asparaginase with Erwinia. Erwinia is associated with more frequent dosing, increased expense, and limited availability. Premedication may reduce rates of allergic reactions. Procedures This Markov model evaluated the cost-effectiveness of three strategies: premedication plus therapeutic drug monitoring (TDM), TDM alone, and no premedication or TDM. We modeled two scenarios: a standard-risk (SR) B-ALL patient receiving two asparaginase doses and a high-risk (HR) patient receiving seven asparaginase doses. The model incorporated costs of asparaginase, premedication, TDM and clinic visits, and lost parental wages associated with each additional Erwinia dose. We incorporated a five-year time horizon with a societal perspective. Outcomes were Erwinia substitutions avoided and differences in quality-adjusted life years (QALYs). Probabilistic and one-way sensitivity analyses evaluated model uncertainty. Results In both scenarios, premedication was the least costly strategy. In SR and HR scenarios, premedication with monitoring resulted in 8% and 7% fewer changes to Erwinia compared with monitoring alone and 3% and 2% fewer changes compared with no premedication/monitoring, respectively. Premedication resulted in the most QALYs gained in the SR patients. Individual variation of model inputs did not change premedication/monitoring favorability for either scenario. In probabilistic sensitivity analyses, premedication/monitoring was favored in >87% of iterations in both scenarios. Conclusion Compared with other strategies, premedication use and asparaginase level monitoring in children with B-ALL is potentially cost-saving.

Objectives The objective of this review was to identify sources of variability in cost-effectiveness analyses of chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel and axicabtagene ciloleucel, evaluated by health technology assessment (HTA) agencies, focusing on young compared with older patients. Methods HTA evaluations in pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma (DLBCL) were included from Australia, Canada, England, Norway, and the United States. Key clinical evidence, economic approach, and outcomes (costs, quality-adjusted life-years [QALYs] and incremental cost-effectiveness ratios) were summarized. Results Fourteen HTA evaluations were identified (5 ALL, 9 DLBCL [4 tisagenlecleucel, 5 axicabtagene]). Analyses were naive comparisons of prospective single-arm studies for the CAR-Ts with retrospective cohort studies for the comparators. Key clinical evidence and economic model approaches were generally consistent by CAR-T and indication, although outcomes varied. Notably, incremental QALYs varied substantially in ALL (3.67-10.6 QALYs gained), whereas variation in DLBCL was less (1.21-1.97 [tisagenlecleucel], 1.97-3.40 [axicabtagene]). Discounting of costs and outcomes varied, with the highest QALYs generated for tisagenlecleucel in ALL (10.95) associated with the lowest discount rate (1.5%) and vice versa (4.97 QALYs; 5% discount rate). The approach to extrapolation of overall survival data varied, even where the same empirical data were used. Conclusion Modeled, long-term treatment benefit in young patients may be associated with greater uncertainty compared with adults because of potential life-long benefits with cell and gene therapies. This reflects the methodological challenges identified by HTA agencies associated with single-arm, short-term studies.

Minimal residual disease (MRD) is the most powerful prognostic factor in pediatric acute lymphoblastic leukemia (ALL). Real-time quantitative polymerase chain reaction (RQ-PCR) represents the gold standard for molecular MRD assessment and risk-based stratification of front-line treatment. In the protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP) and the Berlin-Frankfurth-Munschen (BFM) group AIEOP-BFM ALL2009 and ALL2017, B-lineage ALL patients with high RQ-PCR-MRD at day+33 and positive at day+78 are defined slow early responders (SERs). Based on results of the AIEOP-BFM ALL2000 study, these patients are treated as high-risk also when positive MRD signal at day +78 is below the lower limit of quantification of RQ-PCR ("positive not-quantifiable," POS-NQ). To assess whether droplet digital polymerase chain reaction (ddPCR) could improve patients' risk definition, we analyzed MRD in 209 pediatric B-lineage ALL cases classified by RQ-PCR as POS-NQ and/or negative (NEG) at days +33 and/or +78 in the AIEOP-BFM ALL2000 trial. ddPCR MRD analysis was performed on 45 samples collected at day +78 from SER patients, who had RQ-PCR MRD ≥ 5.0 * 10-4 at day+33 and POS-NQ at day+78 and were treated as medium risk (MR). The analysis identified 13 of 45 positive quantifiable cases. Most relapses occurred in this patients' subgroup, while ddPCR NEG or ddPCR-POS-NQ patients had a significantly better outcome (P < 0.001). Overall, in 112 MR cases and 52 standard-risk patients, MRD negativity and POS-NQ were confirmed by the ddPCR analysis except for a minority of cases, for whom no differences in outcome were registered. These data indicate that ddPCR is more accurate than RQ-PCR in the measurement of MRD, particularly in late follow-up time points, and may thus allow improving patients' stratification in ALL protocols.

INTRODUCTION Invasive fungal infections (IFIs) are significant causes of morbidity and mortality in leukemia patients. This study investigated antifungal treatment and prophylaxis features according to leukemia risk groups and treatment phases in pediatric acute lymphoblastic leukemia (ALL) patients who received Berlin-Frankfurt-Munster-based protocols. MATERIALS AND METHODS We retrospectively examined ALL patients' data between the ages of 1 and 18 and treated them with Berlin-Frankfurt-Munster-ALL protocols between June 2013 and December 2016. RESULTS A total of 446 febrile neutropenic attacks in 85 children were evaluated. Seventy-two patients received antifungals in 151 infection attacks, while 13 patients did not receive any antifungal treatment during chemotherapy. Empirical, preemptive, or proven treatments were given to 74.8%, 21.2%, and 4% of patients, respectively. The frequency of antifungal therapy increased linearly and significantly from the standard-risk group to the intermediate-risk (IR) group, high-risk (HR) group, and relapsed group. IR patients needed more antifungal therapy while receiving induction, whereas HR patients needed more throughout the induction and HR consolidation blocks than other phases. During induction, IR patients received antifungal therapy similar to HR patients' treatment in the induction and HR consolidation blocks. CONCLUSIONS Antifungal therapy requirements increased as the severity and intensity of chemotherapy increased for all leukemia risk groups. The requirement of antifungal therapy for IR patients receiving induction was similar to that of HR patients; further studies are needed to evaluate the potential advantages of using primary antifungal prophylaxis in IR patients.

Background Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, representing 25% of all new cancer diagnoses. Advances in genomic sequencing have demonstrated that inherited genetic risk factors play a larger role in leukemia development than previously appreciated. Aim We identified a father–daughter dyad with childhood B‐cell ALL and aimed to investigate whether the pair shared a gene associated with leukemia predisposition. Methods We performed whole exome sequencing on their leukemia and germline samples and RNA‐seq on their leukemia samples. Results We discovered a novel germline chromosomal structural variant in chromosome 1q32.2 within the TRAF3IP3 gene. TRAF3IP3 regulates B‐cell lymphopoiesis, and this mutation likely resulted in a predisposition to leukemia by causing expansion of immature B‐cell precursors which are highly vulnerable to secondary somatic mutations. Based on the lack of concordance in the somatic mutational profiles between this dyad's leukemia samples, we suspect that the acquired somatic mutations rather than this germline mutation are what dictated their leukemia phenotypes, which we confirmed through RNA‐seq by comparing to sporadic cases of B‐cell ALL. Conclusion This research may have identified a novel gene involved in leukemogenesis which may also be involved in de novo cases of ALL. Additional studies are needed to further characterize this TRAF3IP3 structural variant, the co‐occurring somatic mutations within these leukemia samples and their combined role in leukemogenesis.

Introduction Acute lymphoblastic leukemia (ALL) is the first pediatric cancer where the assessment of early response to therapy by minimal residual disease (MRD) monitoring has demonstrated its importance to improve risk-based treatment approaches. The most standardized tools to study MRD in ALL are multiparametric flow cytometry (MFC) and realtime-quantitative polymerase chain reaction (RQ-PCR) amplification-based methods. In recent years, MRD measurement has reached greater levels of sensitivity and standardization through international laboratory networks collaboration. Areas covered We herewith describe how to assess and apply the prognostic impact of MRD in treatment decisions, with specific focus on pediatric ALL. We also highlight the role of MRD monitoring in the context of genetically homogeneous subgroups of pediatric ALL. However, some queries remain to be addressed and emerging technologies hold the promise of improving MRD detection in ALL patients. Expert opinion Emerging technologies, like next generation flow cytometry, droplet digital PCR, and next generation sequencing appear to be important methods for assessing MRD in pediatric ALL. These more specific and/or sensitive MRD monitoring methods may help predict relapse with greater accuracy, and are currently being used in clinical trials to improve pediatric ALL patient outcome by optimizing patient stratification and earlier MRD-based interventional therapy.

In the study of acute myeloid leukemia (AML), TLS-ERG (also called FUS-ERG or TLS/FUS-ERG) was found to be closely associated with extramedullary disease (EMD), with very poor prognosis. However, the occurrence of TLS-ERG in acute lymphoblastic leukemia (ALL) is very rare. Till date, only 20 cases of ALL with TLS-ERG gene have been reported, of which six are children. Therefore, many clinical aspects of ALL with TLS-ERG gene remain unknown. The aim of this study was to report the clinical features and outcomes of four TLS-ERG-positive pediatric ALL cases. The results showed that all four pediatric patients with this fusion gene achieved an excellent outcome even with a very short-term induction chemotherapy of less than two months. These findings indicated that children with TLS-ERG-positive ALL have very low risk of leukemia, and can be treated and cured with less intensive chemotherapy.

Objective: This study aimed to investigate the correlation of L-asparaginase (L-asp) activity, anti-L-asp antibody, asparagine and glutamine levels with the risks of adverse events (AEs), especially anaphylaxis, in pediatric acute lymphoblastic leukemia (ALL) patients who underwent polyethylene glycol-conjugated L-asp (PEG-asp)-contained treatment. Methods: Plasma samples were collected from 91 pediatric ALL patients who underwent PEG-asp-contained treatment on the 7th day after drug administration. Plasma L-asp activity, anti-L-asp antibody level, asparagine level and glutamine level were detected. Meanwhile, AEs related to PEG-asp administration were recorded. Results: AEs occurred in 13 (14.3%) patients, among which 7 (7.7%) patients had anaphylaxis, while another 6 patients had non-anaphylaxis AEs (including 4 (4.4%) patients who had acute pancreatitis, 1 (1.1%) patient who had abdominal pain and diarrhea, as well as 1 (1.1%) patient who had nausea and vomiting). L-asp activity was decreased, while asparagine and glutamine levels were increased in patients with AEs compared to patients without AEs, and ROC curves showed that they were correlated with higher AEs risk. Notably, further analyses revealed that L-asp activity, anti-L-asp antibody, asparagine and glutamine levels were highly correlated with anaphylaxis risk, but they were not associated with the risk of non-anaphylactic AEs. Conclusion: The measurement of L-asp activity, anti-L-asp antibody level, asparagine level and glutamine level might assist the prevention of anaphylaxis-related AEs in pediatric ALL patients who underwent PEG-asp-contained treatment.

The differences in overall morbidity by induction treatment regimen for pediatric Acute Lymphoblastic Leukemia (ALL) are unknown. We examined a cohort of children with ALL who received induction chemotherapy between January 2010 and May 2018. We evaluated 20 clinically-relevant adverse events (AEs) and readmission and ICU admission rates. Outcomes were compared between standard 3- and 4-drug treatment regimens in multivariate analyses using Cox proportional hazard ratios. Among 486 eligible patients, the risks of sepsis (HR=2.16, 95% CI=1.11–4.19), hypoxia (HR=2.08, 95% CI=1.03–4.18), hyperbilirubinemia (HR=2.48, 95% CI=1.07–5.74), hyperglycemia (HR=2.65, 95% CI=1.29–5.42), thromboembolic event (HR=4.50, 95% CI=1.30–15.6), and hyponatremia (HR=7.88, 95% CI=1.26–49.4) were significantly higher during 4-drug induction. Despite no differences in readmission or ICU admission rates, 4-drug induction patients had greater total inpatient days (12 vs. 4 days; p

Persistently elevated absolute neutrophil counts during maintenance for acute lymphoblastic leukemia is a risk factor for relapse and may be related to wild-type thiopurine methyltransferase activity and overly efficient shunting of 6-mercaptopurine to hepatotoxic metabolites (6-methylmercaptopurine nucleotides), leading to low 6-thioguanine nucleotides. 6-mercaptopurine is also metabolized by xanthine oxidase, and therefore allopurinol, an inhibitor of xanthine oxidase, allows for increased 6-thioguanine nucleotides and decreased 6-methylmercaptopurine nucleotide. Here, we report our experience with allopurinol for persistently elevated absolute neutrophil count or hepatotoxicity and suggest an algorithmic approach for checking thiopurine metabolites and initiating allopurinol in acute lymphoblastic leukemia maintenance.

Herein, we describe a 14-year-old female patient with B-cell precursor acute lymphoblastic leukemia who relapsed in early consolidation. Minimal residual disease-negative complete remission was obtained after 1 cycle of inotuzumab ozogamicin therapy. She underwent HLA-haploidentical peripheral blood stem cell transplantation after a myeloablative conditioning regimen. Posttransplant cyclophosphamide, tacrolimus, and mycophenolate mofetil were administered for the prophylaxis of graft-versus-host disease. At 23 months, she was in complete remission. Although the administration of inotuzumab ozogamicin followed by haploidentical peripheral blood stem cell transplantation with posttransplant cyclophosphamide has been limited in children, this strategy may be an effective treatment for pediatric refractory acute lymphoblastic leukemia.