Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia.

Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1-45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.

Evaluation of oncofertility care in childhood cancer patients: the EU-Horizon 2020 twinning project TREL initiative.

Background: The 5-year survival rate of childhood cancer exceeds 80%, however, many survivors develop late effects including infertility. The aim of this study was to evaluate the current status of oncofertility care at Vilnius University Hospital Santaros Klinikos (VULSK) within the framework of the EU-Horizon 2020 TREL project. Methods: All parents or patients aged 12-17.9 years treated from July 1, 2021 until July 1, 2022 were invited to complete an oncofertility-care-evaluation questionnaire. After completing the questionnaire, patients were triaged to low-risk (LR) or high-risk (HR) of gonadal damage using a risk stratification tool (triage). Data was assessed using descriptive statistics. Results: Questionnaires were completed by 48 parents and 13 children triaged as 36 (59%) LR and 25 (41%) HR patients. Most HR respondents (21/25, 84%) were not counseled by a fertility specialist. Six boys (4 HR, 2 LR) were counseled, none of the girls was counseled. Three HR boys underwent sperm cryopreservation. Only 17 (27.9%, 9 HR, 8 LR) respondents correctly estimated their risk. All counseled boys (n = 6) agreed the risk for fertility impairment had been mentioned as compared to 49.1% (n = 27) of uncounseled. All counseled respondents agreed they knew enough about fertility (vs. 42%). Conclusions: Respondents counseled by a fertility specialist were provided more information on fertility than uncounseled. HR patients were not sufficiently counseled by a fertility specialist. Based on the current experience oncofertility care at VULSK will be improved.

Development and Integration of Patient-Reported Measures into E-Health System: Pilot Feasibility Study.

Patient-centered care is recognized as a key element in recent healthcare management strategies. However, the integrated collection of patient feedback capturing the entire journey of patients with complex medical conditions remains understudied. Herein, we aimed to describe the development of an instrument prototype for the collection of PROMs and PREMs that would encompass a whole patient journey at a single time point. We further describe the process of its integration into a hospital's information system (HIS) and the results of a pilot feasibility study in adult patients with kidney and hematological diseases. We developed an instrument consisting of original PREM and generic EQ-5D-5L questionnaires. E-questionnaires were handled with REDCap software (version 12.5.14) and integrated into the HIS. Patients refusing to use e-questionnaires (48%) were offered paper administration and were older (64 vs. 50 years). The overall response rate for e-questionnaires was 57.1% with a median completion time of 2.0 and 3.7 min for PROM and PREM, respectively. Psychological and social services and primary care setting (diagnosis establishment and involvement in continuous care) were identified as most problematic. The majority of PREM dimensions encompassing different levels of care significantly correlated with PROM responses. Our data indicate the feasibility and potential relevance of the proposed approach, although wider-scale studies in diverse settings are needed.

Integrated Collection of Patient-Reported Outcomes and Experiences in Children with Kidney and Hematological Diseases: A Pilot Study.

We aimed to explore the feasibility and potential relevance of integrated electronic collection of patient-reported outcome and experience measures (PROM and PREM) in children with special healthcare needs (CSHCN) by using the example of children with kidney and hematological diseases. We performed a cross-sectional, single-center study of children <18 years of age. Children (≥10 years) and their parents received Generic PedsQL Core Scale 4.0 and custom PREM surveys to their email addresses via the REDCap platform, and the results were integrated into the hospital's electronic health records system. A total of 192 patients (98 with kidney diseases and 94 with hematological diseases) were enrolled. The overall response rate was 51%, and the median time for completion of each proxy questionnaire was approximately three minutes. The lowest PROM scores were observed in the emotional and school functioning dimensions. More favorable experiences in the diagnosis establishment process were associated with higher scores in physical, social, school functioning, and total PROM scores. A better evaluation of the hospital's environment was associated with higher social functioning, while better information provision correlated with higher physical functioning and total PROM scores. Our data indicates that integrated electronic collection of PROMs and PREMs in the population of CSHCN is feasible, but efforts to increase the response rate are needed. The associations between PROMs and PREMs suggest that future studies exploring targeted interventions at the healthcare service level to improve subjective patient outcomes are needed.

Changes in Nutritional Status during Induction Phase and Their Association with Fever and Minimal Residual Disease in Paediatric Acute Lymphoblastic Leukaemia.

Background and objectives: Acute lymphoblastic leukaemia (ALL) is associated with a cytokine imbalance and oxidative stress, which can be aggravated by malnutrition. Malnutrition, defined by the World Health Organisation (WHO) as obesity or undernutrition, can affect treatment complications and outcomes. Therefore, we aimed to analyse the change in the body mass index (BMI) z-score during induction, as well as evaluate the impact of childhood malnutrition on fevers at an ALL presentation and early response to therapy. Methods: An observational cohort study of 50 consecutive children with ALL, diagnosed in 2019-2022, was performed. Patients were divided into age groups of 0-5, 6-11, and 12-17 years. BMI-for-age z-scores were used to define undernutrition and overnutrition according to WHO growth standards. Results: The number of patients with an abnormal BMI increased from 3 (6%) at diagnosis to 10 (20%) at the end of induction (from 2 (4%) to 6 (12%) in overweight/obese, and from 1 (2%) to 4 (8%) in underweight patients). At the end of induction, all overweight/obese patients were 0-5 years old. On the other hand, a statistically significant decrease in the mean BMI z-score among patients aged 12-17 was observed (p = 0.005). The mean BMI z-score differed statistically significantly among children aged 0-5 presenting with and without fever (p = 0.001). The minimal residual disease (MRD) level at the end of induction was not related to BMI at diagnosis. Conclusions: Despite the use of steroids, adolescents are prone to losing weight during an ALL induction, in contrast to preschool children, who tend to gain weight under the same treatment. BMI at diagnosis was related to a fever of ≥38 °C (at ALL presentation) in the 0-5 age group. The results emphasise the importance of careful nutritional status monitoring, with younger and older children as important target groups for weight gain and weight loss interventions, respectively.

Case Report: Specific ABL-Inhibitor Imatinib Is an Effective Targeted Agent as the First Line Therapy to Treat B-Cell Acute Lymphoblastic Leukemia With a Cryptic NUP214::ABL1 Gene Fusion.

Acute lymphoblastic leukemia (ALL) with recurrent genetic lesions, affecting a series of kinase genes, is associated with unfavorable prognosis, however, it could benefit from treatment with tyrosine kinase inhibitors (TKI). NUP214::ABL1 fusion is detected in 6% of T-cell acute lymphoblastic leukemia (T-ALL), and is very rare in B-ALL. We present a case of adolescent with B-ALL and a cryptic NUP214::ABL1 fusion which was initially missed during diagnostic screening and was detected by additional RNA sequencing. Treatment with specific ABL-inhibitor Imatinib was added later in therapy with a good effect. Initial treatment according to conventional chemotherapy was complicated by severe side effects. At the end of Consolidation, the patient was stratified to a high risk group with allogeneic hematopoietic stem cell transplantation because of insufficient response to therapy. At that time, targeted RNA sequencing detected NUP214::ABL1 gene fusion which was previously missed due to a small microduplication in the 9q34 chromosome region. Gene variant analysis revealed no TKI-resistant ABL1 mutations; therefore, treatment with Imatinib was added to target the NUP214::ABL1 fusion protein. A negative minimal residual disease was achieved, and treatment was downgraded to intermediate risk protocol. Combining routine genetic assays with next-generation sequencing methods could prevent from missing atypical gene alterations. Identification of rare targetable genetic subtypes is of importance in order to introduce targeted therapy as early as possible that may improve survival and reduce toxicity. Treatment with ABL1 inhibitor imatinib mesylate revealed as a highly effective targeted therapy against the leukemia driving protein kinase.

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

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.

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/m2/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m2/day. A total of 778 patients will be included in TEAM during ~ 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. TRIAL REGISTRATION: EudraCT, 2018-001795-38. Registered 2020-05-15, Clinicaltrials.gov , NCT04307576 . Registered 2020-03-13, https://clinicaltrials.gov/ct2/show/NCT04307576.

Development of a questionnaire to evaluate female fertility care in pediatric oncology, a TREL initiative.

BACKGROUND: Currently the five-year survival of childhood cancer is up to 80% due to improved treatment modalities. However, the majority of childhood cancer survivors develop late effects including infertility. Survivors describe infertility as an important and life-altering late effect. Fertility preservation options are becoming available to pre- and postpubertal patients diagnosed with childhood cancer and fertility care is now an important aspect in cancer treatment. The use of fertility preservation options depends on the quality of counseling on this important and delicate issue. The aim of this manuscript is to present a questionnaire to determine the impact of fertility counseling in patients suffering from childhood cancer, to improve fertility care and evaluate what patients and their parents or guardians consider good fertility care. METHODS: Within the framework of the EU-Horizon 2020 TREL project, a fertility care evaluation questionnaire used in the Netherlands was made applicable for international multi-center use. The questionnaire to be used at least also in Lithuania, incorporates patients' views on fertility care to further improve the quality of fertility care and counseling. Results evaluate fertility care and will be used to improve current fertility care in a national specialized pediatric oncology center in the Netherlands and a pediatric oncology center in Lithuania. CONCLUSION: An oncofertility-care-evaluation questionnaire has been developed for pediatric oncology patients and their families specifically. Results of this questionnaire may contribute to enhancement of fertility care in pediatric oncology in wider settings and thus improve quality of life of childhood cancer patients and survivors.

Does minimal central nervous system involvement in childhood acute lymphoblastic leukemia increase the risk for central nervous system toxicity?

Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) implicates enhanced intrathecal chemotherapy, which is related to CNS toxicity. Whether CNS involvement alone contributes to CNS toxicity remains unclear. We studied the occurrence of all CNS toxicities, seizures, and posterior reversible encephalopathy syndrome (PRES) in children with ALL without enhanced intrathecal chemotherapy with CNS involvement (n = 64) or without CNS involvement (n = 256) by flow cytometry. CNS involvement increased the risk for all CNS toxicities, seizures, and PRES in univariate analysis and, after adjusting for induction therapy, for seizures (hazard ratio [HR] = 3.33; 95% confidence interval [CI]: 1.26-8.82; p = 0.016) and PRES (HR = 4.85; 95% CI: 1.71-13.75; p = 0.003).

Asparaginase encapsulated in erythrocytes as second-line treatment in hypersensitive patients with acute lymphoblastic leukaemia.

Asparaginase is essential in treating acute lymphoblastic leukaemia (ALL). Asparaginase-related hypersensitivity causes treatment discontinuation, which is associated with decreased event-free survival. To continue asparaginase treatment after hypersensitivity, a formulation of asparaginase encapsulated in erythrocytes (eryaspase) was developed. In NOR-GRASPALL 2016 (NCT03267030) the safety and efficacy of eryaspase was evaluated in 55 patients (aged 1-45 years; median: 6.1 years) with non-high-risk ALL and hypersensitivity to asparaginase conjugated with polyethylene glycol (PEG-asparaginase). Eryaspase (150 u/kg) was scheduled to complete the intended course of asparaginase (1-7 doses) in two Nordic/Baltic treatment protocols. Forty-nine (96.1%) patients had asparaginase enzyme activity (AEA) ≥100 iu/l 14 ± 2 days after the first eryaspase infusion [median AEA 511 iu/l; interquartile range (IQR), 291-780], whereas six of nine (66.7%) patients had AEA ≥100 iu/l 14 ± 2 days after the fourth infusion (median AEA 932 iu/l; IQR, 496-163). The mean terminal half-life of eryaspase following the first infusion was 15.3 ± 15.5 days. Few asparaginase-related adverse events were reported; five patients (9.1%) developed clinical allergy associated with enzyme inactivation. Replacement therapy was successfully completed in 50 patients (90.9%). Eryaspase was well tolerated, and most patients had AEA levels above the therapeutic target after the first infusion. The half-life of eryaspase confirmed that a 2-week schedule is appropriate.

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

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.

Population-based targeted RNA sequencing reveals novel disease-related gene fusions in pediatric and adult T-ALL.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) is a genetically diverse disease characterized by a heterogeneous profile of genetic lesions. Recent transcriptome studies identified a number of new T-ALL-related gene fusions. Novel gene fusions could be employed as disease-specific molecular markers and provide a better understanding of T-ALL biology, proving the need for further omics sequencing studies. METHODS: We performed a population-based analysis of 65 (26 pediatric and 39 adults) Lithuanian T-ALL patients. Targeted RNA sequencing (RNA-seq) was used to detect recurrent and novel T-ALL-related fusion transcripts and gene sequence variants. RT-qPCR was used to calculate the relative gene expression of fusion transcripts. RESULTS: We identified disease-related gene alterations in 57/65 (87.7%) T-ALL cases, of which four patients harbored gene fusions that affect ABL-class or JAK-STAT signaling pathways. Five novel gene fusions were detected in 4/65 (6.2%) T-ALL cases: CD99::ABL2 and ZEB1::GNAS in the same case, CTCF::ENKD1, DIAPH1::JAK2, and CDK6::NEK1. Novel fusion transcripts encode chimeric proteins that can potentially affect T-cell proliferation, apoptosis, and help to maintain leukemic cells. Importantly, novel fusion transcripts were not detected in the clinical remission samples attributing these fusions to the leukemic compartment. CONCLUSIONS: We report a similar incidence rate of recurrent gene alterations affecting T-ALL-related molecular signaling pathways in both Lithuanian T-ALL patients and other T-ALL studies. Our data suggest that newly identified gene fusions are specific to leukemic T-cells and provide new molecular insights on T-ALL pathogenesis. Further research is needed to confirm these findings.

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 (ρBCP-ALL  = -.17, ρT-ALL  = -.19; p < 3 × 10-4 ). Spline functions fitted to age, immunophenotype, and karyotype explained WBC variation better than age alone (ρ = .43, p << 2 × 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.

DNA-thioguanine concentration and relapse risk in children and young adults with acute lymphoblastic leukemia: an IPD meta-analysis.

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.

Obesity as a predictor of treatment-related toxicity in children with acute lymphoblastic leukaemia.

Obesity is associated with poor outcomes in childhood acute lymphoblastic leukaemia (ALL). We explored whether severe treatment-related toxicity and treatment delays could explain this observation. This study included 1 443 children aged 2·0-17·9 years with ALL treated with the Nordic Society of Pediatric Haematology and Oncology (NOPHO) ALL2008 non-high-risk protocol. Prospective treatment-related toxicities registered every three-month interval were used. Patients were classified according to sex- and age-adjusted international childhood cut-off values, corresponding to adult body mass index: underweight, <17 kg/m2 ; healthy weight, 17 to <25 kg/m2 ; overweight, 25 to <30 kg/m2 ; and obese, ≥30 kg/m2 . Obese children had a higher incidence rate ratio (IRR) for severe toxic events {IRR: 1·55 [95% confidence interval (CI) 1·07-2·50]}, liver and kidney failures, bleeding, abdominal complication, suspected unexpected severe adverse reactions and hyperlipidaemia compared with healthy-weight children. Obese children aged ≥10 years had increased IRRs for asparaginase-related toxicities compared with healthy-weight older children: thromboses [IRR 2·87 (95% CI 1·00-8·21)] and anaphylactic reactions [IRR 7·95 (95% CI 2·15-29·37)] as well as higher risk for truncation of asparaginase [IRR 3·54 (95% CI 1·67-7·50)]. The high prevalence of toxicity and a higher risk of truncation of asparaginase may play a role in the poor prognosis of obese children aged ≥10 years with ALL.

Maintenance therapy and risk of osteonecrosis in children and young adults with acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study.

PURPOSE: Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. METHODS: We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. RESULTS: After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. CONCLUSION: Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.