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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.

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.

Objective Pediatric acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer among children. This study was conducted to describe and correlate the clinical characteristics and outcomes of treatment of patients with pediatric ALL in the main referral hospital in Palestine. Results Complete data of 69 patients were included in this analysis. The majority (79.7%) of the patients had B-ALL phenotype. After induction chemotherapy, remission was experienced by the vast majority of the patients and 5 (7.2%) experienced relapses. Cytogenetics for patients with B-ALL phenotype indicated that 10 (18.2%) patients had t(12, 21) translocation, 5 (9.1%) had hyperdiploidy, 4 (7.3%) had t(1, 19) translocation, and 2 (3.6%) had t(9, 22) translocation. The initial white blood cells (p value

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

A Leucemia Linfoide Aguda (LLA) concentra cerca de 80% de todos os casos em criancas, tornando-se o caso mais comum na faixa etaria pediatrica. Alteracoes geneticas tem implicacoes terapeuticas e sao importantes nos esquemas de tratamento. O objetivo deste trabalho e reunir informacoes das alteracoes geneticas encontradas na populacao brasileira e seus efeitos fenotipicos nos pacientes diagnosticados com LLA. Trata-se de uma revisao sistematica, com base no modelo PRISMA ( Preferred Reporting Items for Systematic Reviews and Meta-Analyses ) , incluindo artigos nos bancos de dados SciELO , Pubmed e Google Scholar com os descritores “Leucemia Linfoide Aguda”, “Pediatria”, “Genetica” e “Brasil” entre os anos 2009 a 2019. Os resultados indicam que a presenca da alteracao na expressao dos genes HDAC3, HDAC7, HADC9 e TIMP1 estao associados a taxa de sobrevida > 5 anos. Um alelo variante do gene IKZF1 conferiu maior risco de desenvolvimento de LLA-B. A baixa expressao do gene ABCG2 foi associado ao pior prognostico e esta relacionada a resposta a quimioterapia. Criancas com hiperdiploidia tem maior frequencia de mutacoes no gene MAPK . A presenca da hiperexpressao dos genes BLVRB e IGFBP7 foram relacionados a leucocitose < 50.000 mm³ no diagnostico. Niveis elevados de MAN1A1 estao associados a LLA entre 1 e 9 anos. Os genes KRAS e NRAS quando mutados e relacionados a translocacao MLL-AFF1 conferiram pior taxa de sobrevivencia global. As alteracoes geneticas descritas nos estudos analisados nesta revisao, mostram a importância e relevância de algumas dessas alteracoes no prognostico destes pacientes, reforcando a importância da investigacao destas alteracoes como forma de possibilitar condutas clinicas e terapias-alvo dirigidas mais adequadas ao manejo clinico destes pacientes.

Objective: The purpose of this study was to evaluate the cytogenetic and fluorescent in situ hybridization (FISH) profile in children with acute lymphoblastic leukemia (ALL), referred to a university hospital in a 5-year 6-month period. Subjects and Methods: Cytogenetic analysis of the bone marrow aspirate specimens of 91 patients was performed by standard Giemsa (G)-banding and interphase FISH (iFISH). Results: The frequency of chromosomal abnormalities detected by G-banding was 29.5%, and the frequency of nonrandom abnormalities with independent prognostic significance identified by iFISH was 46.4%. The abnormality with the highest frequency was gain of RUNX1 (n = 18, 21.4%), followed by ETV6/RUNX1 fusion (n = 7, 8.3%), and gain of KMT2A (n = 6, 7.1%). Additionally, rarely reported gains of ETV6, PBX1, and ABL1 were observed at a frequency of 6% (n = 5), and the deletion of ETV6 and TCF3 was seen at a frequency of 3.6% (n = 3) and 2.3% (n = 2), respectively. A 10-year old with intrachromosomal amplification of chromosome 21 was also observed. Conclusions: This study strengthens and widens the current knowledge of the cytogenetic landscape of pediatric ALL.

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.

Összefoglaló. Bevezetés: A gyermekkori akut lymphoblastos leukaemia kezelése napjainkban 80% feletti túlélést tesz lehetővé, de fontos cél a kezelés okozta mellékhatások kivédése és a gyermekek hosszú távú életminőségének javítása is. Célkitűzés: A kemoterápia csontrendszerre kifejtett mellékhatásainak vizsgálata és a prognosztikai tényezők feltárása, a rizikófaktorok összegyűjtése. Módszerek: Retrospektív vizsgálatunkba a Semmelweis Egyetem II. Gyermekgyógyászati Klinikáján 2007 és 2016 között kezelt 215, akut lymphoblastos leukaemiás gyermek közül a csontelváltozást észlelt betegeket vontuk be a következő, csontrendszert érintő megbetegedésekkel: 38 gyermeknél csökkent csontásványianyag-tartalom, 5 főnél osteonecrosis, 3 főnél osteomyelitis és 2 fő esetében patológiás fractura volt detektálható. Különböző követési időpontokban gyűjtöttünk oszteodenzitometriai adatokat, D-vitamin-, foszfát-, alkalikusfoszfatáz- és lipidszinteket is. Eredmények: Az oszteodenzitometriai értékek már a diagnóziskor csökkent értéket mutatnak, az intenzív vénás kemoterápia hatására pedig további csökkenés figyelhető meg (a lumbális gerinc Z-score-értéke a kezelés kezdetén: –1,5 ± 1,02, az intenzív vénás kezelés végén –1,8 ± 0,5). A Z-score-értékek a fenntartó terápia végére javuló tendenciát mutattak (–1,6 ± 0,5; pKövetkeztetés: Kiemelendő, hogy a gyógyult gyermekek utánkövetése, az oszteodenzitometriai mérések és a laborparaméterek ellenőrzése rendkívül fontos, mivel csontelváltozásokkal a leukaemiás betegek esetén számolni kell. Orv Hetil. 2020; 161(49): 2086–2093. Summary. Introduction: Current treatment of pediatric acute lymphoblastic leukemia allows survival above 80%, but it is also very important to prevent treatment-related side effects and to improve long-term quality of life. Objective: Our aim was to assess the side effects of chemotherapy on the skeletal system and to identify prognostic and risk factors. Methods: Between 2007 and 2016, 215 children were treated with acute lymphoblastic leukemia at the 2nd Department of Paediatrics, Semmelweis University. In our retrospective study, we analyzed data of these children with skeletal-related side-effects (38 children with reduced bone mineral density, 5 with osteonecrosis, 3 with osteomyelitis and 2 with pathologic fracture). Results: Osteodensitometric data, vitamin D, phosphate, alkaline phosphatase and lipid levels were collected at different follow-up times. Osteodensitometric values were already reduced at the time of diagnosis (lumbar spine Z-score: –1.5 ± 1.02) and intensive venous chemotherapy caused further decrease (–1.8 ± 0.5). Z-score showed an improving tendency at the end of the maintenance therapy (–1.6 ± 0.5; pConclusion: In summary, we can conclude that follow-up of these children, osteodensitometric measurements and monitoring of laboratory parameters are extremely important, as bone abnormalities can occur in leukemia patients. Orv Hetil. 2020; 161(49): 2086–2093.

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.

Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability

Total body irradiation (TBI)/cyclophosphamide (CY) is a standard-of-care conditioning regimen in allogeneic hematopoietic stem cell transplant (HSCT) for pediatric acute lymphoblastic leukemia (ALL). This study sought to identify whether the addition of thiotepa (TT) to TBI/CY improves HSCT outcomes for pediatric patients with ALL. A retrospective analysis was performed on 347 pediatric ALL patients who underwent HSCT between 1995 and 2015, with 242 receiving TBI/CY/TT and 105 patients receiving TBI/CY. There were no statistical differences in age, donor source, or complete remission status between the 2 groups. Comparison of the TBI/CY/TT versus TBI/CY groups demonstrated no difference in transplant-related mortality at 1 (11% versus 11%), 5 (13% versus 16%), or 10 years (16% versus 16%). There was lower relapse in the TBI/CY/TT group at 1 (14% versus 26%), 5 (24% versus 36%), 10 (26% versus 37%), and 15 years (26% versus 37%) (P= .02) but was not statistically significant on multivariate analysis. The TBI/CY/TT group showed a trend toward improved disease-free survival (DFS) at 5 (59% versus 47%), 10 (56% versus 46%), and 15 years (49% versus 40%) (P = .05) but was not statistically significant on multivariate analysis. Comparing overall survival at 5 (62% versus 53%), 10 (57% versus 50%), and 15 years (50% versus 44%) demonstrated no statistical difference between the 2 groups. The addition of thiotepa to TBI/CY demonstrated no increase in transplant-related mortality for pediatric ALL HSCT but was unable to demonstrate significant benefit in disease control. Minimal residual disease status remained the key risk factor impacting both relapse and DFS. More studies are warranted to better clarify the benefits of using thiotepa in conditioning for ALL HSCT.

Minimal residual disease (MRD) status is the strongest independent prognostic factor for patients with pediatric acute lymphoblastic leukemia (ALL). Monitoring of the MRD status allows risk-adapted therapy as its absence or presence guides patient therapy and can result in significant treatment reduction or intensification, respectively. MRD assays should be sensitive (exceeding a threshold of 10−4 per current guidelines), specific, widely applicable, rapid, and technically feasible. Classical MRD assays that are widely used in pediatric ALL include multiparameter flow cytometry (MFC), which identifies aberrant immunophenotypes, and real-time quantitative polymerase chain reaction (RQ-PCR), which detects fusion transcripts or clonal immunoglobulin/ T-cell receptor (IG/TCR) gene rearrangements. These assays have sensitivities of 10−3 to 10−5 and have been standardized internationally. However, each assay has its own pitfalls such as false negatives caused by immunophenotypic shifts in MFC, relatively limited applicability of the fusion transcript PCR, and the technical complexity associated with designing PCR for quantifying clonal IG/TCR gene rearrangements using allele-specific oligonucleotides. Next-generation flow cytometry, next-generation sequencing, and droplet digital PCR are expected to replace classical MRD assays, given their higher sensitivities (10−5 to 10−6) and accuracies as well as greater technical feasibilities. Before their incorporation into the standard practice for care for children with ALL, these assays require further exploration to ascertain whether their higher sensitivities are clinically relevant. Furthermore, standardization and quality assurance programs should be devised to enhance the clinical adoption of these new assays. Lastly, new targets should be identified to improve the monitoring of MRD; moreover, both the methodology and clinical significance of MRD evaluation should be revisited in the era of immunotherapy.

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.

BACKGROUND: To analyze the expression and clinical significance of murine double minute 2 (MDM2), lysosome-associated membrane protein (LAMP1) and P-glycoprotein (P-gp) in children with acute lymphoblastic leukemia (ALL). METHODS: Thirty-three children with ALL who were admitted to our hospital between January 2017 and January 2018 were enrolled as the ALL group. The expression of MDM2, LAMP1 and P-gp was compared between the two groups, as well as between ALL patients with different clinical characteristics. Logistic regression was used to analyze the risk factors that affect the prognosis and survival of ALL patients. Kaplan-Meier survival curves were used to analyze the correlations of MDM2, LAMP1 and P-gp on the prognosis and survival of ALL patients. RESULTS: The expression levels of MDM2, LAMP1 and P-gp in the ALL group were higher than those in the control group (P

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.

B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic disorder characterized by the abnormal proliferation and accumulation of immature B-lymphoblasts arrested at various stages of differentiation. Despite advances in treatment, a significant percentage of pediatric patients with precursor B-ALL still relapse. Therefore, alternative therapies are needed to improve the cure rates for pediatric patients. TPEN (N, N, N’, N’-tetrakis(2-pyridylmethyl)-ethylenediamine).is a pro-oxidant agent capable of selectively inducing apoptosis in leukemia cells. Consequently, it has been suggested that TPEN could be a potential agent for oxidative therapy. However, it is not yet known whether TPEN can selectively destroy leukemia cells in a more disease-like model, for example, the bloodstream and bone marrow (BM), in vitro. This investigation is an extension of a previous study that dealt with the effect of TPEN on ex vivo isolated/purified refractory B-ALL cells. Here, we evaluated the effect of TPEN on whole BM from nonleukemic patients (control) or pediatric patients diagnosed with de novo B-ALL or refractory B-ALL cells by analyzing the hematopoietic cell lineage marker CD34/CD19. Although TPEN was innocuous to nonleukemic BM (n=3), we found that TPEN significantly induced apoptosis in de novo (n = 5) and refractory B-ALL (n = 6) leukemic cell populations. Moreover, TPEN significantly increased the counts of cells positive for the oxidation of the stress sensor protein DJ-1, a sign of the formation of H2O2, and significantly increased the counts of cells positive for the pro-apoptotic proteins TP53, PUMA, and CASPASE-3 (CASP-3), indicative of apoptosis, in B-ALL cells. We demonstrate that TPEN selectively eliminates B-ALL cells independent of age, diagnosis status (de novo or refractory), sex, karyotype, or immunophenotype. Understanding TPEN-induced cell death in leukemia cells provides insight into more effective therapeutic oxidation-inducing anticancer agents.

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.

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

L-asparaginase has been an essential component of paediatric-based multiagent therapy for children diagnosed with haematological cancer. Drug’s effect is based on depletion of asparagine in the circulatory system thus depriving unmatured malignant cells of amino acid. However, some children are faced with silent inactivation or, in worst cases, an allergic reaction to the drug and is recommended to monitor drug activity levels in order to detect these patients and modify the therapy. We had set up the first laboratory for asparaginase-activity testing in Croatia at the Department of Laboratory diagnostics, Children’s Hospital Zagreb. Our aim is to present the first experiences in asparaginase monitoring from March 2018 till October 2020 from the 2 pediatric centers (Zagreb and Split). Children between 1 and 18 years old with diagnosed pediatric acute lymphoblastic leukemia (ALL) or lymphoma (NHL) were included in the prospective L-asparaginase study. Blood samples were collected prior to and during treatment. Serum was separated and frozen prior to shipping. Over 100 samples were processed, among which some were repeatedly measured in order to determine the inter-day precision due to sample thawing. Activities of three commercially available drugs, E. coli-derived asparaginase or Erwinia chrysanthemi asparaginase or E.coli pegylated, PEG-asparaginase were measured in intervals as recommended. Laboratory measurements used plate reader-based indooxine method where L-aspartic beta-hydroxamate (AHA) was a substrate for the enzyme. The reading time was optimized to ensure the best results. 41 patients (38 ALL and 3 lymphoma cases) were included in the study. Among thirty native E. coli asparaginase–treated patients, three (10%) of them developed an allergy and four (13%) of them showed silent inactivation. Patients without hypersensitivity to native drug had serum median trough levels of 281,3 U/L after 48 h. Six patients were treated with Erwinia asparaginase; one developed an allergy and none silent inactivation while others had median through levels 90,3 U/L after 48 h. The PEG asparaginase therapy was given to 4 patients where median trough decline was observed (938,4 U/L, 479,5 U/L, 170,3 U/L for 7, 14 or 21 days, respectively). Serum samples were stabile after second thawing as were no significant difference in asparaginase level after re-testing. Additionally, the absorbance results showed no significant difference between the 10 minutes reading intervals. Here we conclude that therapeutic drug monitoring is important for pediatric patients with hematological cancer. The spectrophotometric-based method showed precise performance and has been added to our routine clinical protocols.

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.

High-dose methotrexate (HD-MTX) is the mainstream therapy of current acute lymphoblastic leukemia (ALL) regimens, but frequent intra- and interindividual differences in the clinical response to HD-MTX lead to chemotherapeutic interruption or discontinuation. The exact mechanism of transport across the cell membrane and the disposition of active methotrexate metabolites—methotrexate polyglutamates (MTXPGs)—are not well described in the literature. The aim of this study was to gain more insight into the plasma distribution of methotrexate and MTXPGs in pediatric patients with ALL and to clarify the obscure pathways of MTXPGs. We prospectively measured the concentrations of MTXPG1–7 in plasma samples from three male pediatric patients treated with HD-MTX and leucovorin rescue according to the IC-BFM 2009 protocol using liquid chromatography–mass spectrometry (LC-MS). Blood samples were obtained at 24, 36, 42, and 48 h after the start of HD-MTX treatment. Noticeable plasma concentrations of MTXPGs with a 2.2-fold interpatient variability were detected. The highest interindividual variability in total plasma MTXPG concentration was observed at 36 h, and ranged from 13.78 to 30.82 μmol/L. Among all patients, the predominant polyglutamate types in relation to the total plasma MTXPG concentration at each time point were MTXPG3 (16.71–30.02%) and MTXPG5 (26.23–38.60%), while MTXPG7 was the least abundant MTXPG (3.22–5.02%). The presence of MTXPGs in plasma of patients with ALL could be related to the action of ABC efflux transporters on blood cells and hepatocytes resulting from the administration of high doses of methotrexate. This study may not draw definitive conclusions, but it does reduce uncertainty about the dynamics of methotrexate and its active metabolites, which may be of vital importance for achieving a clinical response.

Corticosteroids and L-asparaginase used in the treatment of pediatric acute lymphoblastic leukemia (ALL) results in Drug induced Diabetes Mellitus (DIDM). Literature on the management of DIDM among children with ALL is sparse and the diagnostic criteria for pediatric diabetes should be carefully applied considering the acute and transient nature of DIDM during ALL therapy. Insulin remains the standard of care for DIDM management and the choice of Insulin regimen (standalone Neutral Protamine Hagedorn (NPH) or basal bolus) should be based on the type and dose of steroids used for ALL and the pattern of hyperglycemia. A modest glycemic control (140-180 mg/dl) to achieve euglycemia and prevent hypoglycemia would be the general approach. This review is intended to suggest a evidence based practical guidance in the diagnosis and management of DIDM during pediatric ALL therapy.

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.

Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. Recently circRNAs were proved associated with malignant hematopoietic differentiation process. However, evidence regarding single-nucleotide polymorphisms (SNP) of circRNA biogenesis key regulator genes and the risk of ALL is still fairly elusive. Methods: To evaluate the novel circRNA biogenesis associated genes SNPs susceptible to ALL, we carried out a case-control study genotyping 6 SNPs in 782 cases of ALL and 1077 controls. Following that, stratified analysis and prognosis analysis were performed. In addition, we detected the gene expression levels of the ALL associated genetic variants. Results: After adjustment for multiple testing, we found two genetic variants, QKI (rs715020 A > G) and ILF3 (rs3810156 C > G), exhibited a significant association with increased susceptibility to ALL. The associations were further validated by stratified analyses. Moreover, rs715020 A > G indeed affected the expression level of QKI, which showed higher mRNA levels. Of note, the polymorphisms QKI rs715020 was identified as a predictor of chemotherapy outcome.Conclusions: Our results suggested that circRNA biogenesis-related genes were associated with the ALL risk and highlight plausible interplay between genetic variants in ALL treatment.

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.

Objective: This study aims to analyze the risk factors that influence the degree of depression in pediatric ALL patients. Patients with ALL, especially children and adolescents, are faced with many psychological and social problems. One of the most common problems of emotional change is depression. It is still unknown what risk factors can affect the degree of depression in pediatric ALL patients. Methods: A cross-sectional analytical observational study was conductedch by collecting interview data and filling out the PHQ-9 questionnaire from pediatric ALL patients treated at Dr. Soetomo Surabaya in the period September 2020-March 2021. The patient's sociodemographic factors, parents' sociodemographic and the patient's clinical condition as a risk factors for the degree of depression were analyzed. The Chi-Square Test, Fischer's Exact Test, and multivariate logistic regression were undertaken. There were 40 samples pediatric ALL patients. Results: Most of the samples (34 patients, 85%) were grouped in the mild depression group (total PHQ score was 0-9). It was found in the results of the multivariate analysis that had been carried out from several variables analyzed, only comorbidities had p=0.007 (p

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 Acute Lymphoblastic Leukemia (ALL) is the most common blood disease in children and is responsible for the most deaths amongst children. Due to major improvements in the treatment protocols in the 50-years period, the survivability of this disease has witnessed dramatic rise until this date which is about 90 percent. There are many investigations tending to indicate the efficiency of cranial radiotherapy found out that without that, outcome of the patients did not change and even it improved at some cases. Methods the main aim of this study is predicting cranial radiotherapy treatment in pediatric acute lymphoblastic leukemia patients using machine learning. Scope of this paper is intertwined with predicting the necessity of one of the treatment modalities that has been used for many years for this group of patients named Cranial Radiotherapy (CRT). For this purpose, a case study is considered at Mahak charity hospital. In this paper, our focus is on ALL patients aged 0 to 17 treated at Mahak hospital, one of the best centers for treatment of childhood malignancies in Iran. Dataset analyzed in this study is gathered by the research team from patient's paper-based files. Our dataset consists of 241 observations on patients with 31 attributes after the data cleaning process. Our designed machine learning model for predicting cranial radiotherapy treatment in pediatric acute lymphoblastic leukemia patients is a stacked ensemble classifier of independently strong models with a meta-learner to tune the weights and parameters of the base classifiers. Results The stacked ensemble classifier show highly reasonable performance with AUC of 87.52%. Moreover, the attributes are ranked based on their predictive power and the most important variable for CRT necessity prediction is the disease relapse. Conclusion In order to conclude, derived from previous studies regarding CRT it is not only cost-effective but also more healthy to eradicate the use of CRT for the treatment of childhood ALL. Furthermore, it is valuable to increase the clinical databases by creating more synthetic health databases not only for research purposes but also for physicians to keep track of their patient's status. .

Hypereosinophilia is rare in children and represents primary or secondary conditions, the latter of which is associated with other diseases (parasitic infections and allergic, autoimmune, and neoplastic diseases). In small number of cases (< 1%) it is a part of the clinical presentation of acute lymphoblastic leukemia, the most common malignancy in children. More often hypereosinophilia precedes the symptoms of leukemia and hinders timely diagnosis, exposing patients in a high risk. In this report, a case of a child with acute lymphoblastic leukemia and hypereosinophilia is presented. The patient is a 30-month-old female, whose leukemia is preceded 2 weeks after hypereosinophilia. This symptom made the exact and timely diagnosis of oncological disease difficult. The further course of the disease was standard despite of delayed diagnosis and incomplete induction treatment due to the hepatic chemotoxicity. We present this case due to the rarity of hypereosinophilia in pediatric acute lymphoblastic leukemia. Every experience with such cases would be very useful for the improvement of the diagnosis of these patients. Moreover in our patient we did not find typical cytogenetic or molecular genetic abnormalities for this type of leukemia, and did not observe any clinical signs of organ complications specific for hypereosinophilia. Int J Clin Pediatr. 2020;9(2):59-63 doi: https://doi.org/10.14740/ijcp365

Introduction: Historically, the majority of childhood cancers, including acute lymphoblastic leukemia (ALL), were not thought to have a hereditary basis. However, recent germline genomic studies have revealed that at least 5 - 10% of children with cancer (and approximately 3 - 4% of children with ALL) develop the disease due to an underlying genetic predisposition.Areas covered: This review discusses several recently identified ALL predisposing conditions and provides updates on other more well-established syndromes. It also covers topics related to the evaluation and management of children and family members at increased ALL risk.Expert opinion: Germline predisposition is gaining recognition as an important risk factor underlying the development of pediatric ALL. The challenge now lies in how best to capitalize on germline genetic information to improve ALL diagnosis, treatment, and perhaps even prevention.

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.

A 14 year-old boy with acute lymphoblastic leukemia (ALL) on maintenance chemotherapy presented with vision-threatening cytomegalovirus (CMV) retinitis. Treatment with intavitreal ganciclovir injection (2 mg/0.1 mL) followed by oral ganciclovir resulted in successful resolution of CMV retinitis. Another 13 year-old boy with ALL on maintenance chemotherapy presented with prolonged fever with no response to antibiotics administration. CMV and real-time PCR revealed positive result and a titer of 2,618,700 copies/mL, respectively. Ganciclovir was used for more than the approved duration of treatment, but viral titer frequently recurred with elevated liver enzymes and fever. In these 2 cases of CMV infection, a high index of suspicion and prompt management is important in children receiving ALL chemotherapy.

We present a case of Korean pediatric patient with pre-B cell type acute lymphoblastic leukemia (ALL) with trisomy 5 as a sole cytogenetic anomaly. Here, we compare and describe the present case with previous pediatric case reports and provide a review of the literature. This case report may help elucidate the poor prognostic impact of trisomy 5 as a sole cytogenetic anomaly in pediatric patients with ALL. Additional studies are needed to confirm this hypothesis.

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.