Bisphosphonate treatment in children with acute lymphoblastic leukemia and osteonecrosis - radiological and clinical findings in a national cohort

Background: Osteonecrosis (ON) is a recognized complication of childhood ALL, but its optimal management remains unestablished. This study evaluated the effect of bisphosphonate (BP) treatment on the evolution of ON lesions in childhood ALL. Material and Methods: We included a national cohort of ALL patients diagnosed with symptomatic ON before 18 years of age and treated with BPs (N = 10; five males). Patients were followed both clinically and with serial MRIs. ON lesions were graded according to the Niinimaki classification. Results: The 10 patients had a total of 55 ON lesions. The median age was 13.3 years at ALL diagnosis and 14.8 years at ON diagnosis. Four patients had received HSCT before the ON diagnosis. BPs used were pamidronate (N = 7), alendronate (N = 2) and ibandronate (N = 1). The duration of BP treatment varied between 4 months and 4 years. In 4/10 patients, BP treatment was given during the chemotherapy. BPs were well-tolerated, with no severe complications or changes in kidney function. At the end of follow up 13/55 (24%) ON lesions were completely healed both clinically and radiographically; all these lesions were originally graded 3 or less. In contrast, ON lesions originally classified as grade 5 (joint destruction; N = 4) remained at grade 5. All grade 5 hip joint lesions needed surgical treatment. During BP treatment, the pain was relieved in 7/10 patients. At the end of follow-up, none of the patients reported severe or frequent pain. Conclusion: BP treatment was safe and seemed effective in relieving ON-induced pain in childhood ALL. After articular collapse (grade 5) lesions did not improve with BP treatment. Randomized controlled studies are needed to further elucidate the role of BPs in childhood ALL-associated ON.Peer reviewe

Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

Publisher Copyright: © 2021, The Author(s).Purpose: Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods: We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results: Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion: A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.Peer reviewe

Altered MicroRNA Profile in Osteoporosis Caused by Impaired WNT Signaling

Context: WNT signaling is fundamental to bone health, and its aberrant activation leads to skeletal pathologies. The heterozygous missense mutation p.C218G in WNT1, a key WNT pathway ligand, leads to severe early-onset and progressive osteoporosis with multiple peripheral and spinal fractures. Despite the severe skeletal manifestations, conventional bone turnover markers are normal in mutation-positive patients. Objective: This study sought to explore the circulating microRNA (miRNA) pattern in patients with impaired WNT signaling. Design and Setting: A cross-sectional cohort study at a university hospital. Participants: Altogether, 12 mutation-positive (MP) subjects (median age, 39 years; range, 11 to 76 years) and 12 mutation-negative (MN) subjects (35 years; range, 9 to 59 years) from two Finnish families with WNT1 osteoporosis due to the heterozygous p.C218G WNT1 mutation. Methods and Main Outcome Measure: Serum samples were screened for 192 miRNAs using quantitative polymerase chain reaction. Findings were compared between WNT1 MP and MN subjects. Results: The pattern of circulating miRNAs was significantly different in the MP subjects compared with the MN subjects, with two upregulated (miR-18a-3p and miR-223-3p) and six downregulated miRNAs (miR-22-3p, miR-31-5p, miR-34a-5p, miR-143-5p, miR-423-5p, and miR-423-3p). Three of these (miR-22-3p, miR-34a-5p, and miR-31-5p) are known inhibitors of WNT signaling: miR-22-3p and miR-34a-5p target WNT1 messenger RNA, and miR-31-5p is predicted to bind to WNT1 3'UTR. Conclusions: The circulating miRNA pattern reflects WNT1 mutation status. The findings suggest that the WNT1 mutation disrupts feedback regulation between these miRNAs and WNT1, providing insights into the pathogenesis of WNT-related bone disorders. These miRNAs may have potential in the diagnosis and treatment of osteoporosis.Peer reviewe

Pienentynyt ferritiinipitoisuus lapsella: Niukat rautavarastot ilman anemiaa

Laadukas tutkimusnäyttö puuttuu rautalisän hyödystä lapsille, joilla ei ole raudanpuuteanemiaa.Lapsia ei tulisi seuloa raudanpuutteen varalta, eikä diagnoosia tehdä yksin seerumin ferritiinipitoisuuden perusteella.Jos lapsella on raudanpuutteeseen sopivia oireita ja ferritiinipitoisuus on pienempi kuin 15 µg/l, suun kautta otettavan rautalisän voi aloittaa, mikäli lapsella ei ole raudan kertymiselle altistavaa sairautta. Hoidon vastetta tulee seurata.Lapselle suoneen annosteltavan rautalääkityksen tarpeen arvioiminen ja toteutus kuuluvat erikoissairaanhoitoon

Lapsena syövän sairastaneiden myöhäisseurannassa yhtenäinen perusta

Lapsena ja nuorena syövän sairastaneiden myöhäisvaikutusten seurannan pohjaksi on luotu kolmiportainen riskiluokitus. Sen mukainen myöhäisseuranta on käynnistetty jokaisessa yliopistosairaalassa

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

Asymptomatic Right Atrial Thrombosis After Acute Lymphoblastic Leukemia Treatment

Right atrial thrombosis is a rare, but potentially serious complication of acute lymphoblastic leukemia treatment. We conducted a retrospective multicenter study to assess the incidence, treatment, and outcome of asymptomatic right atrial thrombosis detected at routine echocardiography of children after acute lymphoblastic leukemia treatment in the Nordic and Baltic countries. Eleven (2.7%, 95% confidence interval, 1.4-4.9) of 406 patients had asymptomatic right atrial thrombosis, ranging from 10 to 25 mm at detection. Three patients were treated with anticoagulation. None of the thromboses affected cardiac function, and they showed neither sign of progress nor spontaneous or treatment-related regress at follow-up.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