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Mycobacterial infections, both tuberculosis and nontuberculous, are more common in patients with haematological malignancies and haematopoietic stem cell transplant recipients than in the general population-although these infections remain rare. Mycobacterial infections pose both diagnostic and therapeutic challenges. The management of mycobacterial infections is particularly complicated for patients in haematology because of the many drug-drug interactions between antimycobacterial drugs and haematological and immunosuppressive treatments. The management of mycobacterial infections must also consider the effect of delaying haematological management. We surveyed the management practices for latent tuberculosis infection (LTBI) in haematology centres in Europe. We then conducted a meticulous review of the literature on the epidemiology, diagnosis, and management of LTBI, tuberculosis, and nontuberculous mycobacterial infections among patients in haematology, and we formulated clinical guidelines according to standardised European Conference on Infections in Leukaemia (ECIL) methods. In this Review, we summarise the available literature and the recommendations of ECIL 8 for managing mycobacterial infections in patients with haematological malignancies.

Purpose: Dasatinib is a dual Src/Abl inhibitor recently approved for Bcr-Abl+ leukemias with resistance or intolerance to prior therapy. Because Src kinases contribute to multiple blood cell functions by triggering a variety of signaling pathways, we hypothesized that their molecular targeting might lead to growth inhibition in acute myeloid leukemia (AML).Experimental Design: We studied growth factor–dependent and growth factor–independent leukemic cell lines, including three cell lines expressing mutants of receptor tyrosine kinases (Flt3 or c-Kit) as well as primary AML blasts for responsiveness to dasatinib.Results: Dasatinib resulted in the inhibition of Src family kinases in all cell lines and blast cells at ∼1 × 10−9 mol/L. It also inhibited mutant Flt3 or Kit tyrosine phosphorylation at ∼1 × 10−6 mol/L. Mo7e cells expressing the activating mutation (codon 816) of c-Kit were most sensitive to growth inhibition with a GI50 of 5 × 10−9 mol/L. Primary AML blast cells exhibited a growth inhibition of −6 mol/L. Cell lines that showed growth inhibition at ∼1 × 10−6 mol/L showed a G1 cell cycle arrest and correlated with accumulation of p21 and p27 protein. The addition of rapamycin or cytotoxic agents enhanced growth inhibition. Dasatinib also caused the apoptosis of Mo7e cells expressing oncogenic Kit.Conclusions: Although all of the precise targets for dasatinib are not known, this multikinase inhibitor causes either growth arrest or apoptosis in molecularly heterogeneous AML. The addition of cytotoxic or targeted agents can enhance its effects. Clin Cancer Res; 16(4); 1149–58

Supplementary Data from Dasatinib Inhibits the Growth of Molecularly Heterogeneous Myeloid Leukemias

Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. Cytotoxicity is mediated by DNA incorporation of thioguanine nucleotides (DNA-TG). We investigated the association of DNA-TG to relapse risk in 1 910 children and young adults with non-high risk ALL. In a cohort-stratified Cox regression analysis adjusted for sex, age, and white cell count at diagnosis, the relapse-specific hazard ratio (HRa) per 100 fmol/μg increase in weighted mean DNA-TG (wmDNA-TG) was 0.87 (95% CI 0.78-0.97; p = 0.013) in the 839 patients who were minimal residual disease (MRD) positive at end of induction therapy (EOI), whereas this was not the case in EOI MRD-negative patients (p = 0.76). Validation analysis excluding the previously published Nordic NOPHO ALL2008 pediatric cohort yielded a HRa of 0.92 (95% CI 0.82-1.03; p = 0.15) per 100 fmol/μg increase in wmDNA-TG in EOI MRD-positive patients. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68-0.99; p = 0.044) per 100 fmol/μg increase in wmDNA-TG. The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone.

Paediatric patients with cancer and those undergoing haematopoietic cell transplantation are at high risk of bacterial infections. The 8th European Conference on Infections in Leukaemia (ECIL-8) convened a Paediatric Group to review the literature and to formulate recommendations for the use of antibiotics according to the European Society of Clinical Microbiology and Infectious Diseases grading system. The evaluation of antibacterial prophylaxis included mortality, bloodstream infection, febrile neutropenia, emergence of resistance, and adverse effects as endpoints. Initial antibacterial therapy and antibiotic de-escalation or discontinuation focused on patients with a clinically stable condition and without previous infection or colonisation by resistant bacteria, and on patients with a clinically unstable condition or with previous infection or colonisation by resistant bacteria. The final considerations and recommendations of the ECIL-8 Paediatric Group on antibacterial prophylaxis, initial therapy, and de-escalation strategies are summarised in this Policy Review.

6-mercaptopurine(6MP)/methotrexate maintenance therapy is essential to reduce relapse of childhood acute lymphoblastic leukemia (ALL). Common germline variants in TPMT cause low activity of thiopurine methyltransferase (TPMT) and higher 6MP metabolite (TGN) levels. Higher levels of TGNs incorporated into DNA (DNA-TG) and low TPMT activity have previously been associated with a lower relapse risk. We explored if TPMT geno- or phenotype was associated with DNA-TG levels and relapse rate in NOPHO ALL2008. TPMT genotype, repeated phenotyping, and DNA-TG measurements were collected in 918 children with non-high risk ALL (NOPHO ALL2008 maintenance therapy study). Maintenance therapy started with 6MP at 50 and 75 mg/m2 for TPMT heterozygous and wildtype patients and was adjusted to a target WBC of 1.5 − 3.0 × 109/L. Of 918 patients, 78 (8.5%) were TPMT heterozygous and 903 had at least one TPMT measurement (total 3063). Mean TPMT activities were higher with wildtype than heterozygous TPMT (N = 752, 16.6 versus 9.6 U/mL ery., p

Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.

Methotrexate (MTX) during maintenance therapy is essential for curing acute lymphoblastic leukemia (ALL), but dosing strategies aiming at adequate treatment intensity are challenged by interindividual differences in drug disposition. To evaluate genetic factors associated with MTX metabolism, we performed a genome-wide association study in 447 ALL cases from the Nordic Society for Pediatric Haematology and Oncology ALL2008 study, validating results in an independent set of 196 patients. The intergenic single-nucleotide polymorphism rs1382539, located in a regulatory element of DHFR, was associated with increased levels of short-chain MTX polyglutamates (P = 1.1 × 10−8) related to suppression of enhancer activity, whereas rs35789560 in FPGS (p.R466C, P = 5.6 × 10−9) was associated with decreased levels of long-chain MTX polyglutamates through reduced catalytic activity. Furthermore, the FPGS variant was linked with increased relapse risk (P = .044). These findings show a genetic basis for interpatient variability in MTX response and could be used to improve future dosing algorithms.

PURPOSE Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS). METHODS Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method. RESULTS Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3. CONCLUSION In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

aintenance therapy containing methotrexate and 6-mercapto-purine is essential to cure acute lymphoblastic leukemia (ALL). Cytotoxicity is elicited by incorporation of thioguanine nucleotides into DNA (DNA-TG), and higher leukocyte DNA-TG is associated with increased relapse-free survival. As 6-thioguanine provides 6-fold higher cytosolic levels of thioguanine nucleotides than does 6-mercaptopurine, we added low-dose 6-thioguanine to methotrexate/6mercaptopurine maintenance therapy to explore if this combination results in significantly higher DNA-TG. The target population of the “Thiopurine Enhanced ALL Maintenance therapy” (TEAM) study was 30 patients with non-high-risk ALL, aged 1-45 years on methotrexate/6-mercaptopurine maintenance therapy receiving no other systemic chemotherapy. Incremental doses of 6-thioguanine were added to methotrexate/6-mercaptopurine maintenance therapy (starting 6-thioguanine dose: 2.5 mg/m2/day, maximum: 12.5 mg/m2/day). The primary endpoint was DNA-TG increments. Thirty-four patients were included, and 30 patients completed maintenance therapy according to the TEAM strategy. Of these 30 patients, 26 (87%) tolerated 10.0-12.5 mg/m2/day as the maximum 6-thioguanine dose. TEAM resulted in significantly higher DNA-TG levels compared to those in both TEAM patients before their inclusion in TEAM (on average 251 fmol/mg DNA higher [95% confidence interval: 160-341; P

Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved. Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP aged 1.0 to 17.9 y) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.

LBA2 Background: 5-year survival of RR-ES is about 15%. rEECur, the first randomized controlled trial in this setting, is defining standard care, balancing efficacy and toxicity. Methods: Patients aged 4-50 with RR-ES were randomly assigned to topotecan and cyclophosphamide (TC), irinotecan and temolozomide (IT), gemcitabine and docetaxel (GD), or high-dose ifosfamide (IFOS). Primary outcome was event-free survival (EFS) for the phase III comparison. Secondary outcomes included overall survival (OS), toxicity, and quality of life (QoL). A probability-based Bayesian approach was used with multiple pairwise comparisons. At the first and second interim assessments, patients allocated to GD and IT, respectively, had worse objective response (OR) and EFS than the other arms, halting recruitment to both. The final intent-to-treat assessment of the original four arms was a phase III evaluation of TC and IFOS. Results: 451 patients recruited between 18/12/14 and 31/08/21, were randomly assigned to TC (163 patients), IT (127 patients), GD (72 patients), and IFOS (83 patients). Median age was 19 years (range 4-49). Patients had: refractory disease (18%), first recurrence (66%), > first recurrence (17%). Initial disease site was bone in 70%. Sites of progression were: primary site only (15%), pleuropulmonary metastases only (34%), and other metastatic (51%). Baseline renal function was similar in both. Median follow-up (reverse Kaplan-Meier method) was 40 months. For the phase III comparison between TC and IFOS (both, 73 patients), median EFS was 3.7 months (95% CI, 2.1-6.2) for TC and 5.7 months (95% CI, 3.8-7.0) for IFOS. Median OS was 10.4 months (95% CI, 7.5-15.5) for TC and 16.8 months (95% CI, 11.1-25.8) for IFOS. Given the observed data, the posterior probability that EFS and OS were better after IFOS than after TC (ie Pr [true hazard ratio < 1 | data]) was 95% for both. A greater survival difference was observed for patients aged under 14 than those aged ≥ 14 for EFS and OS. Subgroup analyses favored IFOS for all minimization factors. The main grade 3/4 adverse events (% patients with an event) for TC (left-hand values) compared with IFOS were: febrile neutropenia (26% vs. 25%), infections (8% vs. 14%), vomiting (1% vs. 1%), nausea (0% vs. 3%), diarrhea (1% vs. 1%), encephalopathy (0% vs. 7%), and renal toxicity (0% vs. 8%). Descriptive statistics of quality of life scores appeared to favor the IFOS arm over the TC arm in children but not in adults. Conclusions: The first randomized trial in RR-ES has shown that high-dose ifosfamide is more effective in prolonging survival than TC, having previously beaten GD and IT, and should be considered as a control arm in future randomized phase II/III studies in RR-ES if combination with IFOS is logical. rEECur is the first study to provide comparative toxicity and survival data for the four most commonly used chemotherapy regimens in RR-ES. Clinical trial information: ISRCTN36453794.

Highlights • First study to establish in real-time STRN-ALK fusion positive pediatric patient-derived cancer cells (PDCs). • Ex vivo sensitivity testing of PDCs to 527 oncology drugs was analysed by high-throughput drug testing. • Comparison of efficacies of eight ALK inhibitors towards PDCs both in 2D and 3D. • Drug combination synergies identified between ALK and MEK and ALK and PI3K/mTOR inhibitors. • Our precision medicine platform supported successful clinical use of crizotinib in patient treatment., Genetic rearrangements involving the anaplastic lymphoma kinase (ALK) gene create oncogenic drivers for several cancers, including malignant peritoneal mesothelioma (MPeM). Here, we report genomic and functional precision oncology profiling on a rare case of a 5-year old patient diagnosed with wide-spread and aggressive MPeM, driven by STRN-ALK rearrangement. We established genomically representative patient-derived cancer cells (PDCs) from the tumor sample and performed high-throughput drug sensitivity testing with 527 oncology compounds to identify potent inhibitors. As expected, the PDCs were overall sensitive to the ALK inhibitors, although the eight different inhibitors tested had variable efficacy. We also discovered other effective inhibitors, such as MEK/ERK inhibitors and those targeting pathways downstream of ALK as well as Bcl-xl inhibitors. In contrast, most cytotoxic drugs were not very effective. ALK inhibitors synergized with MEK and PI3K/mTOR inhibitors, highlighting potential combinatorial strategies to enhance drug efficacy and tackle drug resistance. Based on genomic data and associated functional validation, the patient was treated with the ALK inhibitor crizotinib in combination with conventional chemotherapy (cisplatin and gemcitabine). A complete disease remission was reached, lasting now for over 3 years. Our results illustrate a rare pediatric cancer case, and highlight the potential of functional precision oncology to discover pathogenetic drivers, validate dependency on driver signals, compare different inhibitors against each other and potentially enhance targeted treatments by drug combinations. Such real-time implementation of functional precision oncology could pave the way towards safer and more effective personalized cancer therapies for individual pediatric cancer patients with rare tumors.

Red blood cell transfusions are an essential part of supporting care in leukemia treatment. We examined the prevalence of iron overload and its effects on organ function and childhood growth in pediatric patients after allogeneic HSCT for acute lymphoblastic leukemia. Twenty-three patients were included (median age 12.6, range 7.5-21.4 years). Body iron load was determined using laboratory tests, hepatic and cardiac MRI, and by calculating iron received from transfusions. We performed multivariate analysis to determine association of body iron load with liver enzymes, cardiac function, insulin resistance, and growth. Median plasma ferritin was 344 (range 40-3235) ng/mL and exceeded 1000 ng/mL in three patients (13%). In MRI, 11 patients (48%) had hepatic iron overload and 1 patient (4%) myocardial iron overload. In cardiac MRI, 8 patients (35%) had significant but subclinical decrease in ejection fraction (median z-score -1.7, range -3.1-0.14), but cardiac function did not associate with iron status. Alanine transaminase associated with transfused iron per time unit (P = .001) after the median follow-up of 4.5 years. No correlation was found between iron load and growth or insulin resistance. Iron overload is common in children transplanted for ALL, but iron overload associated organ dysfunction is not present at early age. We recommend evaluation of iron load for all patients at least once during follow-up after transplantation.

Paediatric patients with cancer and those undergoing allogeneic haematopoietic cell transplantation have an increased susceptibility to invasive fungal diseases. In addition to differences in underlying conditions and comorbidities relative to adults, invasive fungal diseases in infants, children, and adolescents are unique in terms of their epidemiology, the validity of current diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of phase 3 clinical trials to provide data to guide evidence-based interventions. To re-examine the state of knowledge and to further improve invasive fungal disease diagnosis, prevention, and management, the 8th European Conference on Infections in Leukaemia (ECIL-8) reconvened a Paediatric Group to review the literature and to formulate updated recommendations according to the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and European Confederation of Medical Mycology (ECMM) grading system, which are summarised in this Review.

Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.

Aim To analyse incidence, treatment and outcomes of paediatric liver malignancies in Finland during 1987-2017. Methods Medical records and national cancer registry data of 47 children with liver malignancies were reviewed. Survival was calculated with the Kaplan-Meier method. Results During follow-up, liver malignancy incidence remained stable at 1.1:10(6). Altogether, 42 patients with hepatoblastoma (n = 24), hepatocellular carcinoma (n = 11) and undifferentiated embryonal sarcoma (n = 7) underwent surgery at median age 4.6 (interquartile range, 2.0-9.6) years and were followed up for 13 (7.0-19) years. Cumulative 5-year survival was 86% for hepatoblastoma, 41% for hepatocellular carcinoma and 67% for undifferentiated embryonal sarcoma. Five-year survival was decreased among hepatoblastoma patients aged >= 2.4 years (73% versus 100%, P = .040), with PRETreatment EXTent of disease IV (PRETEXT, 60% vs 100%, P = .004), and with recurrent disease (67% vs 88%, P = .029). Recurrent/residual disease associated with decreased 5-year survival in hepatocellular carcinoma (0% vs 83%, P = .028). Survival was similar among 19 transplanted and 23 resected patients. In total, 14 deaths occurred either for the underlying malignancy (n = 8), adverse effects of chemotherapy (n = 5) or unrelated reasons (n = 1). Conclusion Outcomes for PRETEXT I-III hepatoblastoma and un-metastasized hepatocellular carcinoma were encouraging. Adverse effects of chemotherapy significantly contributed to mortality.

Source at https://doi.org/10.1002/cam4.1917. Classification of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T-ALL patients were characterized by genome-wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2-1, and novel genes in T-ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP− subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL-TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP−), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T-ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies.

11524 Background: Survival for RR-ES at 5 years remains < 15%, so novel treatments are needed. Almost all Phase II trials for RR-ES use response as the primary outcome measure. It is unclear whether response is a valid surrogate for survival outcomes. Methods: Patients (pts) were eligible if they had RR-ES and were evaluable for imaging response (primary outcome) if they had measurable disease by RECIST 1.1. The randomization was initially between four chemotherapy regimens: topotecan-cyclophosphamide, irinotecan-temozolomide, gemcitabine-docetaxel (GD), high-dose ifosfamide. Response was assessed after 2, 4 (primary) and 6 cycles of therapy and was classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD). PFS and OS were secondary outcomes. Survival from each assessment point by response status was analyzed, by Cox models, with hazard ratios (HR) given for PR v. SD and CR+PR v. SD. Results: From 2015-19, 241 pts with response data were entered. The relationship between response status and PFS and OS is shown in the table (HR < 1.0 indicates better outcome for PR or CR+PR than SD). Both PFS and OS were similar for pts with PR or CR+PR compared to those with SD. OS was inferior for patients with PD (all p < 0.01) (PFS is by definition zero for patients with PD at that timepoint). Small numbers mean CR results are not reliable. Results were consistent across all treatments and between refractory and relapsed disease. At the first interim assessment the GD arm was dropped, with risk ratios for response compared to the other three arms (blinded as still open) of 0.3, 0.5 and 0.5. If a new outcome – disease control (CR+PR+SD) – is defined, the risk ratios are 0.7, 0.8 and 0.7; i.e. still inferior for GD, but less so. Conclusions: Response does not correlate with survival outcomes in RR-ES, so considering PR, or even CR, a success and SD a failure when evaluating treatments may be misleading. We propose PFS as a better primary outcome for future trials and it will be introduced as such in the rEECur trial. Clinical trial information: ISRCTN36453794 . [Table: see text]

11523 Background: Ewing 2008R1 (EudraCT2008-003658-13, Sponsor UKM) was conducted in 12 countries. It evaluated the effect of zolendronic acid (ZOL) maintenance therapy on event-free (EFS, primary endpoint) and overall survival (OS) from randomization in standard risk Ewing Sarcoma (EwS). Methods: Phase III, open label, prospective, multi-center, randomized controlled clinical trial. Eligible patients (pts) had localized EwS with either good histological response to induction chemotherapy and/or small tumors ( < 200ml). Pts received 6 cycles VIDE induction and 8 VAI (male) or 8 VAC consolidation (female) and were randomized to receive either 9 cycles of maintenance ZOL or no further treatment (control;ctrl). ZOL cycles started parallel to the 6th consolidation cycle. Randomization was stratified by tumor site (pelvis/no pelvis). Two-sided adaptive inverse-normal 4-stage design, changed after the 1st interim analysis via Müller-Schäfer method. Initial sample size 448 pts, type I error rate 5%, power 80%. Results: 284 pts were randomized between 2009 and 2018 (142 ZOL / 142 ctrl). With a median follow-up of 3.9 years, the primary endpoint EFS was not significantly different between the ZOL and ctrl group in the adaptive design (HR 0.74, 95% CI 0.43-1.28, intention to treat). 3-year (3y) EFS rates were 84.0% (95% CI 77.7-90.8%) for ZOL vs 81.7% (95% CI 75.2-88.8%) for ctrl. Results were similar in the per protocol collective. Cause-specific HR for local recurrence in ZOL was csHR 0.30 (95% CI 0.08 -1.09; p = 0.07), for metastatic progress/new metastases csHR 1.0 (CI 0.5-2.2), for combined relapse/progress csHR 0.3 (95% CI 0.1-1.7), for second malignancies csHR 4.0 (95% CI 0.45-36.1) compared to ctrl. The 3y OS was 92.8% (95% CI 88.4-97.5%) for ZOL and 94.6% (95% CI 90.9-98.6%) for ctrl. For ZOL the 5y OS was 87.3% (95% CI 80.7-94.5%) and 89% (95% CI 83.7-95.9%) for ctrl. Noticeable more renal, neurological and gut toxicities were observed for ZOL (p < 0.05), with severe renal toxicities occurring more often in the ZOL arm (p = 0.003). Conclusions: In patients with standard risk localized Ewing Sarcoma there is no benefit from maintenance treatment with zoledronic acid, but significant side effects were observed. Clinical trial information: NCT00987636 .

Source at https://doi.org/10.1186/s13148-018-0466-3. © The Author(s). 2018 Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients. Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1–18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data. Results: Among the 137 patients that later relapsed, patients with a CIMP− profile (n = 42) at initial diagnosis had an inferior overall survival (pOS5years 33%) compared to CIMP+ patients (n = 95, pOS5years 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors. Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.

Teema : lastenlääkkeet. English summary

11007 Background: 5-year survival of RR-ES is about 15%. Several chemotherapy regimens are used, but without robust evidence. rEECur, the first randomised controlled trial in this setting, is defining a standard of care, balancing efficacy and toxicity. Methods: Patients aged 4 to 50 with RR-ES and fit to receive chemotherapy were randomised 2, 3 or 4 ways between topotecan & cyclophosphamide (TC), irinotecan & temolozomide (IT), gemcitabine & docetaxel (GD) or high-dose ifosfamide (IFOS). Primary outcome measure was objective response (OR) after 4 cycles by RECIST 1.1. Secondary outcomes included PFS, OS and toxicity. A probability-based Bayesian approach was used. The first interim assessment to determine which arm should be closed occurred when 50 evaluable patients had been recruited to 3 arms and evaluated for the primary outcome measure. Results: 242 patients (89% RECIST-evaluable) recruited between 18/12/14 and 21/06/18 were randomised to TC (n=75), IT (71), GD (66) and IFOS (30). Median age was 21 years (range 4 to 49). Patients had: refractory ES (20%), 1st recurrence (63%), >1st recurrence (17%); initial primary disease arose in bone in 60%; disease progression sites were primary site (17%), pleuropulmonary (29%) or other metastatic (54%). Median follow up was 11.3 months. Outcomes in the GD arm were: response rate 11.5% (95% CI: 4.4 to 23%), median PFS 3.0 months (95% CI: 1.6 to 8.0), median OS 13.7 months (95% CI: 10.1 to 23.9). The table shows, for each pairwise comparison of GD with the other arms (randomly labelled A, B, C to maintain blinding of open arms), the probabilities given the observed data that OR, PFS and OS were better for GD than for each other arm (RR: relative risk, HR: hazard ratio). For OR and PFS, all comparisons favoured the other arms. There were fewer grade 3/4 adverse events with GD than with the other arms pooled (58% v. 74%). Conclusions: rEECur has shown that GD is a less effective treatment than TC, IT or IFOS in reducing tumour burden or prolonging PFS in RR-ES. Recruitment continues to the remaining arms. Clinical trial information: ISRCTN36453794. [Table: see text]

Physical fitness is an essential feature of overall health. Our objective was to compare the physical performance between nontransplanted acute lymphoblastic leukemia (ALL) patients (study patients), healthy controls, and ALL patients after stem cell transplantation (SCT). Forty-five ALL patients (median age, 13.3 y) treated without cranial irradiation were compared with 34 ALL patients (12.0 y) treated with SCT and total body irradiation and 522 age-matched and sex-matched controls. Their physical performance was assessed by 6 muscle tests measuring speed and dynamic endurance, flexibility, acceleration, maximal speed, and speed differentiation. The patients were tested at a minimum of 3 years after treatment. The muscle test results of the study patients did not differ from that of the healthy controls. The study patients had normal body mass indexes (BMI). Only 42% of them exercised at least once a week. Those who exercised >3 times a week and those with a BMI below median had better results. SCT patients had inferior results in 4 out of 6 tests. The physical performance of nontransplanted ALL patients did not differ from that of healthy controls. A higher physical exercise activity and a BMI below median positively correlated with better muscle performance, supporting the importance of encouraging ALL survivors to exercise and avoid obesity.

Summary Background Adjustment of mercaptopurine and methotrexate maintenance therapy of acute lymphoblastic leukaemia by leucocyte count is confounded by natural variations. Cytotoxicity is primarily mediated by DNA-incorporated thioguanine nucleotides (DNA-TGN). The aim of this study was to establish whether DNA-TGN concentrations in blood leucocytes during maintenance therapy are associated with relapse-free survival. Methods In this substudy of the NOPHO ALL2008 phase 3 trial done in 23 hospitals in seven European countries (Denmark, Estonia, Finland, Iceland, Lithuania, Norway, and Sweden), we analysed data from centralised and blinded analyses of 6-mercaptopurine and methotrexate metabolites in blood samples from patients with non-high-risk childhood acute lymphoblastic leukaemia. Eligible patients were aged 1·0–17·9 years; had been diagnosed with non-high-risk precursor B-cell or T-cell leukaemia; had been treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol; and had reached maintenance therapy in first remission. Maintenance therapy was (mercaptopurine 75 mg/m 2 once per day and methotrexate 20 mg/m 2 once per week, targeted to a leucocyte count of 1·5–3·0 × 10 9 cells per L). We measured DNA-TGN and erythrocyte concentrations of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates. The primary objective was the association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival. The secondary endpoint was the assessment of DNA-TGN concentration and 6-mercaptopurine and methotrexate metabolites during maintenance therapy phase 2. Findings Between Nov 26, 2008 and June 14, 2016, 1509 patients from the NOPHO ALL2008 study were assessed for eligibility in the DNA-TGN substudy, of which 918 (89%) of 1026 eligible patients had at least one DNA-TGN measurement and were included in the analyses. Median follow-up was 4·6 years (IQR 3·1–6·1). Relapse-free survival was significantly associated with DNA-TGN concentration (adjusted hazard ratio 0·81 per 100 fmol/μg DNA increase, 95% CI 0·67–0·98; p=0·029). In patients with at least five blood samples, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentration (all p Interpretation Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration, and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts. Funding Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordic Foundation.

BackgroundCarboxypeptidase G2 (CPDG(2)) can be used as rescue treatment in cases of delayed methotrexate elimination (DME) and Mtx-induced nephrotoxicity.ProcedureBetween July 2008 and December 2014, all children (1.0-17.9 years) in the Nordic countries diagnosed with Philadelphia chromosome negative acute lymphoblastic leukemia (ALL) were treated according to the Nordic Organization for Pediatric Hematology and Oncology (NOPHO) ALL 2008 protocol, including administration of six to eight high-dose (5 g/m(2)/24 hr) Mtx (HDMtx) courses. The protocol includes recommendations for CPDG(2) administration in cases of DME (clinicaltrials.gov NCT01305655).ResultsForty-seven of the 1,286 children (3.6%) received CPDG(2) during 50 HDMtx courses at a median dose of 50 IU/kg. In 49% of the cases, CPDG(2) was used during the first HDMtx course. Within a median of 6 hr from CPDG(2) administration, the Mtx concentration decreased by 75% when measured with immune-based methods, and by 100% when measured with high-performance liquid chromatography. The median time from the start of Mtx infusion to plasma levels 0.2 M was 228 hr (range: 48-438). The maximum increase in plasma creatinine was 375% (range: 100-1,310). Creatinine peaked after a median of 48 hr (range: 36-86). Mtx elimination time was shorter in patients with body surface area ConclusionsCPDG(2) administration is highly effective as rescue in case of delayed Mtx clearance. Subsequent HDMtx courses could be administered without events in most of the patients.

Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making. (C) 2016 Wiley Periodicals, Inc.

Trimethoprim-sulfamethoxazole (TMP/SMX) is used in children with acute lymphoblastic leukemia (ALL) to prevent Pneumocystis pneumonia (PCP). We explored to which extent TMP/SMX influenced methotrexate (MTX)/6-mercaptopurine (6MP) dosage, myelosuppression, and event-free survival (EFS) during maintenance therapy. Of 447 study patients treated by the NOPHO ALL92 protocol, 120 patients received TMP/SMX continuously for 2-7 d/wk (TMP/SMX(2-7) ) and 287 patients never received TMP/SMX (TMP/SMX(never) ). Ten patients (all TMP/SMX(never) ) developed PCP, eight of which occurred within 7 months from the start of maintenance therapy. The TMP/SMX(2-7) group received lower oral 6MP doses than TMP/SMX(never) patients (50.6 vs. 63.9 mg/m(2) /d; P

Cancer remains the leading cause of disease-related mortality among children aged 1-14 years in developed countries. Acute lymphoblastic leukaemia (ALL) is the most common malignancy in childhood and accounts for about 25% of all childhood cancers. In Norway about 30-40 children are diagnosed with ALL each year. Treatment comprises of a combination of 6-12 different chemotherapy drugs administered over a period of 2.5 years with additional supportive care. Side effects remain a great challenge for both patients and physicians. One of the most common side effects is immunosuppression which increases the risk of infection. Today, the overall survival rate in childhood ALL is 80-85%. About 75% of deaths related to ALL are caused by the disease itself, most after relapse, but about 25% of deaths are caused by treatment and are classified as treatment-related deaths (TRDs). In this study, the incidence, risk factors and causes of death were investigated for 88 TRDs among 2,700 patients in the Nordic countries Sweden, Denmark, Finland, Iceland and Norway. The incidence of TRD was 3.2%, which was stable in the two protocols, the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 1992 and ALL 2000 protocols. The risk factors identified were female gender, treatment risk-group, T-cell disease, Down syndrome and stem cell transplantation. Seventy-five percent of the deaths were related to infection, 10% to bleeding or thrombosis, 10% to organ failure and 5% to the tumour burden. We have no good explanation as to why some patients experience more severe infections than others, even when receiving the same drugs, drug dosage and supportive care. It is reasonable to believe that genetic factors play a role. In accordance with the increasing understanding of host genetic variation the past 10 years, we investigated 34,000 single nucleotide polymorphisms (SNPs) relevant in childhood ALL in a Danish ALL cohort including 69 children and detected 24 SNPs which associated with infections during induction treatment. Through CART-analysis (classification and regression tree) a four-SNP risk profile were identified as highly predictive of risk of infections during the 50 days induction treatment. The four SNPs belong to the genes R51F1, CBR1, POLDIP3 and CCL11 which regulate drug metabolism, cell-growth and inflammation. If these findings are replicated in larger studies, such knowledge may be useful for developing personalized medicine with more tailored therapy and supportive care, which will hopefully reduce the severity of side effects and increase overall survival. Studies involving multiple biological markers, such as SNPs and short tandem repeats (STRs), often use high-quality DNA extracted from blood samples. However, blood samples are not always easy to obtain from study participants, especially if the patient has died. Archival bone marrow samples from patients with leukaemia are available and represent a potential DNA source. We were interested in exploring whether such archival material is usable for the analysis and identification of multiple markers. DNA from 21 bone marrow smears and 13 bone marrow biopsies were extracted and quantified. Because of small amounts of DNA from each sample whole genome amplification (WGA) was applied. Ten different STR-markers and 34,000 SNPs were analysed and compared with corresponding blood samples. For the STR markers 90% detection rates were obtained. Shorter markers (107bp-242bp) from samples stored 0-3 years gave better results compared with longer markers (219bp-317bp) stored 4-10 years. Multiple SNP analysis was more complicated and only seven of 34 archival samples gave acceptable results (SNP call-rates above 50%). However, in two samples, nearly 100% of SNP-markers were detected. Although increasing the total amount of DNA, WGA reduced the analysis quality. In conclusion, DNA from archival bone-marrow samples might be used in multiple marker analysis, but adjustments of the laboratory set-up are essential to optimize this method.

We report a case of a 13-year-old boy with a presumed neck cyst who developed sudden tracheal obstruction and out-of-hospital cardiac arrest. Cardiorespiratory collapse occurred due to an improperly diagnosed mediastinal tumor. This report serves to alert Emergency Physicians and emergency medical services personnel of the rare and rapidly progressive nature of respiratory compromise caused by a mediastinal tumor, which may have lethal consequences if not recognized and treated promptly.

Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320 CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve stratification of ALL patients. The genes highlighted in our study are not enriched to specific pathways, but the gene expression levels are inversely correlated to the methylation levels.

Udgivelsesdato: 2009-Jan We studied the pharmacokinetics of 6-thioguanine (6TG) in 50 children treated for newly diagnosed acute myeloid leukemia, four of them with Down syndrome (DS). They received oral 6TG 100 mg/m2 body surface area twice daily for 4 days. Etoposide, 100 mg/m2/24 h, and cytarabine, 200 mg/m2/24 h, were administered concomitantly by intravenous infusion. On day 5, doxorubicin 75 mg/m2 was given as an 8-h infusion. The concentration of thioguanine nucleotides (TGN) in erythrocytes, the active metabolites of 6TG, was determined by high-performance liquid chromatography. The mean TGN concentration from 72, 95, and 106-h samples was used as a measure of drug exposure for each individual. The median TGN concentration in non-DS children above 2 years of age was 2.30 micromol/mmol Hb (range 0.57-25.3). The TGN concentrations varied widely (30-fold) also after dose normalization. We found no correlation with demographic, clinical, or biochemical parameters, and differences in bioavailability might be the most important explanation to interpatient variability. Children with high TGN concentration tended to have longer treatment interval to the next course, but we found no correlation with our predefined parameters for clinical response, that is, remission and relapse rate. Therefore, 6TG does not seem to be a candidate for therapeutic drug monitoring by TGN measurement, at least not in the setting of short multidrug treatment courses. Children with DS had significantly higher TGN concentrations, indicating that dose reduction might be considered to reach the same drug exposure as in non-DS children.

Background We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL. Results We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations (‘other’ subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5. Conclusions Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients. Electronic supplementary material The online version of this article (doi:10.1186/s13148-014-0039-z) contains supplementary material, which is available to authorized users.

A quarter of cancers diagnosed in those under 18 years of age are leukemias, another quarter being tumors of the central nervous system. The remaining cancers are solid tumors occurring elswehere in the body, most commonly lymphomas, soft tissue and bone sarcomas, neuroblastomas and Wilms tumors. In almost all cases, the treatment of these solid tumors consists of combinations of surgery, cytotoxic drugs and radiotherapy. Although the prognoses have improved, they exhibit variation even within tumor groups. New targeted therapies are being developed, but for the time being they do not have any significant role.

We studied the pharmacokinetics of doxorubicin in 41 children treated for newly diagnosed acute myeloid leukemia. Doxorubicin, 75 mg/m body surface area, was administered by constant i.v. infusion over 8 h. Four children with Down's syndrome (DS), 1.2-2.3 years old, had a median total body clearance of 523 ml/min/m. The median clearance in non-DS children, 0.6-1.8 years old (n=4) and 2.5-17.7 years old (n=33), was 446 and 538 ml/min/m, respectively. Patients who went into complete remission (CR) after induction therapy had a significantly higher median plasma concentration of doxorubicin than those who did not, 249 compared with 180 ng/ml, respectively (P=0.036, analysis restricted to non-DS patients). Doxorubicin plasma concentration was an independent factor for CR, both in univariate (P=0.031) and multivariate analysis including sex, age and white blood cell count at diagnosis (P=0.021). Patients who reached CR had a significantly lower doxorubicin clearance than those who did not, 513 and 657 ml/min/m, respectively (P=0.017). In conclusion, doxorubicin plasma concentration and total body clearance during up-front treatment were correlated to the effect of induction therapy. Prospective studies should be performed to confirm the concentration-effect relationship and explore the possibility of therapeutic monitoring. © 2006 Lippincott Williams & Wilkins.

Translocation t(1;19) is related to low cellular drug resistance in childhood acute lymphoblastic leukaemia

Background As the treatment results of childhood ALL have improved, avoidance of late effects has become increasingly important. Identification of favorable prognostic factors helps to achieve this goal. Procedure We studied the prognostic value of TEL–AML1 fusion and a risk factor composed of age, white blood cell count (WBC), lymphomatous features, and hemoglobin level (Hb). We also compared outcome between two cohorts; cohort 1 (n = 100) diagnosed 1975–1981, and cohort 2 (n = 102) 1989–1991. Both cohorts were retrospectively divided in two groups: very-low-risk (WBC

Summary. We determined the in vitro cellular drug resistance in 370 children with newly diagnosed acute lymphoblastic leukaemia (ALL). The resistance to each of 10 drugs was measured by the fluorometric microculture cytotoxicity assay (FMCA) and was related to clinical outcome. The median follow-up time was 41 months. Riskgroup stratified analyses indicated that in vitro resistance to dexamethasone, doxorubicin and amsacrine were each significantly related to the probability of disease-free survival. In the high-risk (HR) group, increased in vitro resistance to dexamethasone (P ¼ 0AE014), etoposide (P ¼ 0AE025) and doxorubicin (P ¼ 0AE05) was associated with a worse clinical outcome. Combining the results for these drugs provided a drug resistance score with an independent prognostic significance superior to that of any other factor studied, with a relative risk of relapse in the most resistant group 9AE8 times that in the most sensitive group (P ¼ 0AE007). The results in the intermediate-risk (IR) and standard-risk (SR) groups were less clear cut. In conclusion, our data indicate that in vitro testing of cellular drug resistance can be used to predict the clinical outcome in HR ALL, while the final evaluation of the results in IR and SR patients must await longer follow-up.

Background Genetic aberrations provide prognostic information in childhood ALL. The proportion of patients with detectable aberrations can be increased by combining G-banding with comparative genomic hybridization (CGH). Procedure We studied 79 children with ALL by CGH and G-banding, and explored the relationship of these findings to clinical features and outcome. Results CGH revealed DNA copy number changes in 57 patients (72%), 9 of whom had normal karyotype by G-banding. Gains were more frequent than losses, and changes of whole chromosomes more frequent than partial aberrations. Two frequent partial losses were found; at 9p and 12p. The 9 patients with loss at 12p were studied for the deletion of TEL (ETV6) gene and the fusion of TEL and AML1 genes by fluorescent in situ hybridization (FISH). Eight out of the 9 children with loss at 12p harbored the TEL–AML1 translocation and all 9 had the deletion of a nontranslocated TEL allele. All 9 had precursor-B phenotype and L1 morphology, and 8/9 had WBC below 50 × 109/liter. All children were treated according to Nordic ALL protocols, had a good response to treatment based on day 15 bone marrow morphology, and 7 out of the 9 survived in continuous complete remission (median follow-up 74 months). Conclusions CGH is a valuable tool in screening for genetic aberrations in childhood ALL. DNA copy number losses detected at 12p associate with TEL–AML1 fusion as well as with favorable prognostic features. Med Pediatr Oncol 2001; 37:419–425. © 2001 Wiley-Liss, Inc.

SummaryL-asparaginase is an important drug in the treatment of childhood acutelymphoblastic leukaemia (ALL). Treatment is associated with several toxici-ties, including acute pancreatitis. Clinical course, presentation, re-exposureto L-asparginase after pancreatitis and risk of recurrent pancreatitis withinan asparaginase-intensive protocol has been poorly reported. Children (1–17 years) on the ongoing Nordic Society of Paediatric Haematology andOncology (NOPHO) ALL2008 protocol with asparaginase-associated pan-creatitis (AAP) diagnosed between 2008 and 2012 were identified throughthe online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eightor 15 doses of intramuscular pegylated L-asparginase (PEG-asparaginase)1000 iu/m 2 /dose at 2–6 weeks intervals, with a total of 30 weeks of expo-sure to PEG-asparaginase (clinicaltrials.gov no: NCT00819351). Of 786children, 45 were diagnosed with AAP with a cumulative risk of AAP of5 9%. AAP occurred after a median of five doses (range 1–13), and 11 d(median) from the latest administration of PEG-Asparaginase. Thirteenpatients developed pseudocysts (30%) and 11 patients developed necrosis(25%). One patient died from pancreatitis. Twelve AAP patients werere-exposed to L-asparginase, two of whom developed mild AAP once more,after four and six doses respectively. In conclusion, re-exposure to PEG-asparaginase in ALL patients with mild AAP seems safe.Keywords: L-asparaginase, leukaemia, pancreatitis, toxicity, risk factors.

Most cases of childhood leukemia are acute lymphoblastic leukemia, a small proportion being myelogenous leukemia. Chronic myelogenous leukemia is rare in children, whereas chronic lymphocytic leukemia is not encountered. The prognosis of childhood leukemia has improved considerably so that approximately 80 to 90% of those having lymphocytic leukemia and 60 to 70% of those having myelogenous leukemia will recover fully. The challenge is to develop new treatments for disease groups having a poor prognosis and on the other hand to lighten the treatments for leukemias having a good prognosis.

Trimethoprim-sulfamethoxazole (TMP/SMX) is used in children with acute lymphoblastic leukemia (ALL) to prevent Pneumocystis pneumonia (PCP). We explored to which extent TMP/SMX influenced methotrexate (MTX)/6-mercaptopurine (6MP) dosage, myelosuppression, and event-free survival (EFS) during maintenance therapy. Of 447 study patients treated by the NOPHO ALL92 protocol, 120 patients received TMP/SMX continuously for 2-7 d/wk (TMP/SMX(2-7) ) and 287 patients never received TMP/SMX (TMP/SMX(never) ). Ten patients (all TMP/SMX(never) ) developed PCP, eight of which occurred within 7 months from the start of maintenance therapy. The TMP/SMX(2-7) group received lower oral 6MP doses than TMP/SMX(never) patients (50.6 vs. 63.9 mg/m(2) /d; P0.001) but had lower absolute neutrophil counts (ANC) (median 1.7 vs. 2.0 × 10(9) /L; P0.001). In Cox multivariate analysis, higher ANC levels (P=0.04) and male gender (P=0.06) were related to reduced EFS. ANC had no effect on EFS among TMP/SMX(2-7) patients (P=0.40) but did for TMP/SMX(never) patients (P=0.02). The difference in the effect on EFS between TMP/SMX(2-7) and TMP/SMX(never) patients was not significant (P=0.46). EFS did not differ between TMP/SMX(2-7) and TMP/SMX(never) patients (0.83 vs. 0.83; P=0.82). These results suggest that TMP/SMX is effective in preventing PCP and may have an antileukemic effect. TMP/SMX should be given the entire duration of maintenance therapy.