Effect of two additional doses of intrathecal methotrexate during induction therapy on serious infectious toxicity in pediatric patients with acute lymphoblastic leukemia

Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P<0.001; Odds Ratio 2.86 [95% Confidence Interval 1.99-4.13]). In a multivariate regression model, treatment with additional IT MTX proved to be the strongest risk factor for life-threatening infections (Odds Ratio 2.85 [1.96-4.14]). Fatal infections occurred in 16 (0.3%) and 38 (1.6%) patients treated with three or five IT MTX doses, respectively (P<0.001). As the relevance of additional intrathecal MTX in induction for relapse prevention in CNS2 patients is unclear, doses of intrathecal therapy have been reduced for these patients. (Clinicaltrials.gov identifiers: NCT01117441 and NCT00613457)

Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p <5 x 10(-8)) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p <1 x 10(-6)), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 x 10(-7)) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 x 10(-7)) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.Peer reviewe

Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups

Treatment and Survival in Acute Leukemia: A New South Wales Study Comparing Adolescents and Young Adults with Children and Adults

Objective. To investigate age differences in treatment and survival from acute lymphoblastic (ALL) and acute myeloid leukemia (AML). Methods. 1053 ALL/566 AML patients diagnosed in 2003-2015 on the New South Wales Cancer Registry were included. Treatment within 12 months from diagnosis was assessed using linked registry, hospital, and health-insurance data. Differences by age at diagnosis in treatment and survival were investigated using socio-demographically adjusted regression analyses, with adolescents and young adults (AYA, 15-24 years) as the reference category. Results. Children were less likely than AYA to start ALL treatment \u3e3 days from diagnosis (adjusted odds ratio (aOR 0.39, 95% CI 0.27-0.57)) and to have multiple treatment types (aOR 0.22, 95% CI 0.14-0.34). For AML, aOR of treatment start \u3e3 days was 0.16 (95% CI 0.09-0.29) for children compared with AYA, with no age differences in treatment types. Five-year disease-specific survival for ALL was 84%. Children were less likely than AYA to die from ALL (adjusted subhazard ratio (aSHR 0.32, 95% CI 0.22-0.50)). For AML, the corresponding survival was 73% without an age difference. Children having multiple treatment types for ALL had an increased risk of mortality at aSHR 2.67 (95% CI 1.53-4.67), but not adults at 1.26 (95% CI 0.67-2.47) (interaction p = 0.017). Time from diagnosis to initial treatment start and initial treatment type were not associated with mortality outcomes after adjusting for socio-demographic variables. Conclusion. Children with ALL had better survival. ALL Mortality were negatively associated with multiple treatment types

First electrical characterization of 3D detectors with electrodes of the same doping type.

7nonenoneA. POZZA; M. BOSCARDIN; BOSISIO L.; G.-F. DALLA BETTA; C. PIEMONTE; S. RONCHIN; N. ZORZIA., Pozza; M., Boscardin; Bosisio, Luciano; G. F., DALLA BETTA; C., Piemonte; S., Ronchin; N., Zorz

First electrical characterization of 3D detectors with electrodes of the same doping type

The 3D silicon radiation detectors are very promising devices to be used in environments requiring extreme radiation hardness, such as the super-LHC experiment at CERN. A drawback of this detector is the very long and non-standard fabrication process, which makes the mass production of these devices very critical. A possible simplification of the manufacturing process relies on a new type of 3D architecture, called 3D-single-type-column detector, that we have introduced in previous works. In this paper we report on the fabrication process of the first batch of detectors and on selected results from the electrical characterization of 3D test structures, covering leakage current, capacitance and breakdown voltage measurements

Study of the signal formation in single-type column 3D silicon detectors

Because of their superior radiation resistance, three-dimensional (3D) silicon sensors are receiving more and more interest for application in the innermost layers of tracker systems for experiments running in very high luminosity colliders. Their short electrode distance allows for both a low depletion voltage and a high charge collection efficiency even at extremely high radiation fluences. In order to fully understand the properties of a 3D detector, a thorough characterization of the signal formation mechanism is of paramount importance. In this work the shape of the current induced by localized and uniform charge depositions in a single-type column 3D detector is studied. A first row estimation is given applying the Ramo theorem, then a more complete TCAD simulation is used to provide a more realistic pulse shape

Electro-optical measurements of 3D-stc detectors fabricated at ITC-irst

In the past two years 3D silicon radiation detectors have been developed at Fondazione Bruno Kessler - FBK, Trento, Italy (formerly ITC-irst). As a first step toward full 3D devices, simplified structures featuring columnar electrodes of one doping type only were fabricated. This paper reports the electrooptical characterization of 3D test diodes made with this approach. Experimental results and TCAD simulations provide good insight into the charge collection mechanism and response speed limitation of these structures