Unilateral Hydronephrosis and Renal Damage after Acute Leukemia

A 14-year-old boy presented with asymptomatic right hydronephrosis detected on routine yearly ultrasound examination. Previously, he had at least two normal renal ultrasonograms, 4 years after remission of acute myeloblastic leukemia, treated by AML-BFM-93 protocol. A function of the right kidney and no damage on the left was confirmed by a DMSA scan. Right retroperitoneoscopic nephrectomy revealed 3 renal arteries with the lower pole artery lying on the pelviureteric junction. Histologically chronic tubulointerstitial nephritis was detected. In the pathogenesis of this severe unilateral renal damage, we suspect the exacerbation of deleterious effects of cytostatic therapy on kidneys with intermittent hydronephrosis

Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

PurposeMethotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing.Methods and resultsSummed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were r(s)=0.68 and r(s)=0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all r(s)0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (pPeer reviewe

Impact of body mass index on relapse in children with acute lymphoblastic leukemia treated according to Nordic treatment protocols

Objectives High body mass index (BMI) is associated with poorer survival in childhood acute lymphoblastic leukemia (ALL), but the actual impact on the risk of relapse still needs to be clarified. We evaluated the impact of BMI at diagnosis on the risk of relapse in children with ALL treated according to Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols. Method In a multicenter study, we collected data on BMI at diagnosis and outcome of 2558 children aged 2.0-17.9 years diagnosed between 1992 and 2016. Patients were divided into four groups according to International Obesity Task Force (IOTF) childhood BMI cut-offs: underweight, = 30 kg/m(2). Results In Cox multivariate regression analyses, an increased risk of relapse was observed in children aged 10-17.9 years with unhealthy BMI at diagnosis (underweight hazard ratio HR: 2.90 [95% confidence interval: 1.24-6.78],P = .01; overweight, HR: 1.95 [1.11-3.43],P = .02, and obese HR: 4.32 [95% 2.08-8.97],P <.001), compared to children with healthy weight. BMI had no impact on relapse in children under 10 years of age. Conclusion High BMI, and especially obesity at diagnosis, is an independent adverse prognostic factor for relapse in older children with ALL.Peer reviewe

Characteristics of white blood cell count in acute lymphoblastic leukemia : A COST LEGEND phenotype-genotype study

Background White blood cell count (WBC) as a measure of extramedullary leukemic cell survival is a well-known prognostic factor in acute lymphoblastic leukemia (ALL), but its biology, including impact of host genome variants, is poorly understood. Methods We included patients treated with the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-2008 protocol (N = 2347, 72% were genotyped by Illumina Omni2.5exome-8-Bead chip) aged 1-45 years, diagnosed with B-cell precursor (BCP-) or T-cell ALL (T-ALL) to investigate the variation in WBC. Spline functions of WBC were fitted correcting for association with age across ALL subgroups of immunophenotypes and karyotypes. The residuals between spline WBC and actual WBC were used to identify WBC-associated germline genetic variants in a genome-wide association study (GWAS) while adjusting for age and ALL subtype associations. Results We observed an overall inverse correlation between age and WBC, which was stronger for the selected patient subgroups of immunophenotype and karyotypes (rho(BCP-ALL )= -.17, rho(T-ALL )= -.19; p < 3 x 10(-4)). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (rho = .43, p << 2 x 10(-6)). However, when the spline-adjusted WBC residuals were used as phenotype, no GWAS significant associations were found. Based on available annotation, the top 50 genetic variants suggested effects on signal transduction, translation initiation, cell development, and proliferation. Conclusion These results indicate that host genome variants do not strongly influence WBC across ALL subsets, and future studies of why some patients are more prone to hyperleukocytosis should be performed within specific ALL subsets that apply more complex analyses to capture potential germline variant interactions and impact on WBC.Peer reviewe

Changes in body mass index during treatment of childhood acute lymphoblastic leukemia with the Nordic ALL2008 protocol

Funding Information: Christina Egnell is supported by funding from the Swedish Childhood Cancer Foundation (Barncancerfonden, grant numbers TJ2018‐0093; PR2019‐0075; TJ2019‐0048). This work is part of the Danish nation‐wide research program Childhood Oncology Network Targeting Research, Organisation & Life expectancy (CONTROL) and supported by the Danish Cancer Society (R‐257‐A14720) and the Danish Childhood Cancer Foundation (2019‐5934 and 2020‐5769). Publisher Copyright: © 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.Objectives: Children with acute lymphoblastic leukemia (ALL) have a tendency to gain weight during treatment. As overweight and obesity associate with health problems, prophylactic interventions are warranted. Therefore, it is important to identify the children most prone to gain weight. Methods: Patients aged 2.0–17.9 years at ALL diagnosis were identified from the NOPHO ALL2008 registry. Registry data was complemented with height and weight at the end of therapy from questionnaires. Body mass index (BMI) was classified according to international age- and sex-adjusted International Obesity Task Force BMI cut-offs. BMI values were transformed into standard deviation scores (SDS) to calculate the difference in BMISDS during treatment. Results: Data on BMI change were available for 765 children. Overweight and obesity doubled during treatment: 9.7% were overweight and 2.1% obese at diagnosis and 21.8% and 5.4% at the end of therapy, respectively. The mean BMISDS change was +0.64. Younger (2.0–5.9 years) and healthy weight children were most prone to become overweight (mean change in BMI SDS +0.85 and + 0.65, respectively). Conclusions: Younger children (2.0–5.9 years) with healthy weight at diagnosis were most prone to becoming overweight and therefore are an important group to target while considering interventions.Peer reviewe

Acute central nervous system toxicity during treatment of pediatric acute lymphoblastic leukemia : phenotypes, risk factors and genotypes

Publisher Copyright: © 2022 Ferrata Storti Foundation Published under a CC BY-NC license.Central nervous system (CNS) toxicity is common at diagnosis and during treatment of pediatric acute lymphoblastic leukemia (ALL). We studied CNS toxicity in 1, 464 children aged 1.0-17.9 years, diagnosed with ALL and treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol. Genome-wide association studies, and a candidate single-nucleotide polymorphism (SNP; n=19) study were performed in 1, 166 patients. Findings were validated in an independent Australian cohort of children with ALL (n=797) in whom two phenotypes were evaluated: diverse CNS toxicities (n=103) and methotrexate-related CNS toxicity (n=48). In total, 135/1, 464 (9.2%) patients experienced CNS toxicity for a cumulative incidence of 8.7% (95% confidence interval: 7.31-10.20) at 12 months from diagnosis. Patients aged ≥10 years had a higher risk of CNS toxicity than had younger patients (16.3% vs. 7.4%; P<0.001). The most common CNS toxicities were posterior reversible encephalopathy syndrome (n=52, 43 with seizures), sinus venous thrombosis (n=28, 9 with seizures), and isolated seizures (n=16). The most significant SNP identified by the genome-wide association studies did not reach genomic significance (lowest P-value: 1.11x10-6), but several were annotated in genes regulating neuronal functions. In candidate SNP analysis, ATXN1 rs68082256, related to epilepsy, was associated with seizures in patients <10 years (P=0.01). ATXN1 rs68082256 was validated in the Australian cohort with diverse CNS toxicities (P=0.04). The role of ATXN1 as well as the novel SNP in neurotoxicity in pediatric ALL should be further explored.Peer reviewe

Thiopurine Enhanced ALL Maintenance (TEAM) : study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0-45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol

Background: A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance. Methods: TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0-45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5-12.5 mg/m(2)/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m(2)/day. A total of 778 patients will be included in TEAM during similar to 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse,TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients. Discussion: TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms.Peer reviewe

Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia : Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age

PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse. (C) 2019 by American Society of Clinical OncologyPeer reviewe

High white blood cell count at diagnosis of childhood acute lymphoblastic leukaemia: biological background and prognostic impact. Results from the NOPHO ALL-92 and ALL-2000 studies

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPrognostic impact of peripheral blood white blood cell count (WBC) at the diagnosis of childhood acute lymphoblastic leukaemia (ALL) was evaluated in a population-based consecutive series of 2666 children aged 1-15 treated for ALL between 1992 and 2008 in the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden). Ten-year event-free (pEFS(10 y)) survival and overall (pOS(10 y)) survival were 0.75 ± 0.01 and 0.85 ± 0.01, respectively. Although treatment intensity was determined by WBC, non-remission and relapsed patients still had significantly higher WBC than those in remission for B-cell precursor (BCP) (median WBC: 24.8 vs. 14.0 vs. 8.3 × 10(9) /L, P < 0.001), but not for T-lineage (T-ALL) (median WBC: 127.8 vs. 113.0 vs. 86.8 × 10(9) /L, P = 0.22). pEFS was inversely related to WBC for BCP (P < 0.001), but not for T-ALL. WBC was not associated with risk of event for BCP or T-ALL for patients with minimal residual disease at the end of induction (MRD(d29) ) <10(-3). In contrast, for MRD(d29) ≥ 10(-3) and <5% leukaemic blasts in bone marrow at day 29, the pEFS(5 y) for WBC < 100.0 (N = 152) vs. ≥ 100.0 (N = 19) was 0.76 vs. 0.50 (P = 0.001). That was the case both for BCP (pEFS(5 y) 0.76 vs. 0.58) and for T-ALL (pEFS(5 y) 0.71 vs. 0.38). Whether the inferior EFS for the subset of patients with high WBC and slow initial response to treatment reflects rare or overlooked cytogenetic aberrations as well as the factors that determine WBC levels at diagnosis awaits exploration