Treatment-related mortality among children with cancer in Denmark during 2001-2021.

BACKGROUND: Survival of children with cancer has markedly improved over recent decades, largely due to intensified treatment regimes. The intensive treatment may, however, result in fatal complications. In this retrospective cohort study, we assessed temporal variation in the incidence of treatment-related death and associated risk factors among children diagnosed with cancer in Denmark during 2001-2021. METHOD: Among all children diagnosed with first incident cancer before age 15 years recorded in the Danish Childhood Cancer Register (n = 3,255), we estimated cumulative incidence of treatment-related death (death in the absence of progressive cancer) within 5 years from diagnosis using Aalen-Johansen estimators and assessed associated risk factors using Cox regression. RESULTS: Among all 3,255 children with cancer, 93 (20% of all 459 deaths) died from treatment. Of these treatment-related deaths, 39 (42%) occurred within 3 months of diagnosis. The 5-year cumulative incidences of treatment-related death were 3.3% during 2001-2010 and 2.5% during 2011-2021 (p = 0.20). During 2011-2021, treatment-related deaths accounted for more than half of all deaths among children with haematological cancers. Risk factors varied according to cancer group and included female sex, age below 1 year at diagnosis, disease relapse, stem cell transplantation, central nervous system involvement, and metastasis at diagnosis. INTERPRETATION: Despite increasing treatment intensities, the incidence of treatment-related death has remained stable during the past 20 years in Denmark. Still, clinical attention is warranted to prevent treatment-related deaths, particularly among children with haematological cancers. Patient characteristics associated with increased treatment-related death risk support patient-specific treatment approaches to avoid these fatalities.

Corrigendum: Cancer data quality and harmonization in Europe: The experience of the BENCHISTA Project - International Benchmarking of Childhood Cancer Survival by Stage.

[This corrects the article DOI: 10.3389/fonc.2023.1232451.].

Cancer data quality and harmonization in Europe: the experience of the BENCHISTA Project - international benchmarking of childhood cancer survival by stage.

Introduction: Variation in stage at diagnosis of childhood cancers (CC) may explain differences in survival rates observed across geographical regions. The BENCHISTA project aims to understand these differences and to encourage the application of the Toronto Staging Guidelines (TG) by Population-Based Cancer Registries (PBCRs) to the most common solid paediatric cancers. Methods: PBCRs within and outside Europe were invited to participate and identify all cases of Neuroblastoma, Wilms Tumour, Medulloblastoma, Ewing Sarcoma, Rhabdomyosarcoma and Osteosarcoma diagnosed in a consecutive three-year period (2014-2017) and apply TG at diagnosis. Other non-stage prognostic factors, treatment, progression/recurrence, and cause of death information were collected as optional variables. A minimum of three-year follow-up was required. To standardise TG application by PBCRs, on-line workshops led by six tumour-specific clinical experts were held. To understand the role of data availability and quality, a survey focused on data collection/sharing processes and a quality assurance exercise were generated. To support data harmonization and query resolution a dedicated email and a question-and-answers bank were created. Results: 67 PBCRs from 28 countries participated and provided a maximally de-personalized, patient-level dataset. For 26 PBCRs, data format and ethical approval obtained by the two sponsoring institutions (UCL and INT) was sufficient for data sharing. 41 participating PBCRs required a Data Transfer Agreement (DTA) to comply with data protection regulations. Due to heterogeneity found in legal aspects, 18 months were spent on finalizing the DTA. The data collection survey was answered by 68 respondents from 63 PBCRs; 44% of them confirmed the ability to re-consult a clinician in cases where stage ascertainment was difficult/uncertain. Of the total participating PBCRs, 75% completed the staging quality assurance exercise, with a median correct answer proportion of 92% [range: 70% (rhabdomyosarcoma) to 100% (Wilms tumour)]. Conclusion: Differences in interpretation and processes required to harmonize general data protection regulations across countries were encountered causing delays in data transfer. Despite challenges, the BENCHISTA Project has established a large collaboration between PBCRs and clinicians to collect detailed and standardised TG at a population-level enhancing the understanding of the reasons for variation in overall survival rates for CC, stimulate research and improve national/regional child health plans.

Proton linear energy transfer and variable relative biological effectiveness for adolescent patients with Hodgkin lymphoma.

Objectives: Proton therapy has a theoretical dosimetric advantage due to the Bragg peak, but the linear energy transfer (LET), and therefore the relative biological effectiveness (RBE), increase at the end of range. For patients with Hodgkin lymphoma, the distal edge of beam is often located within or close to the heart, where elevated RBE would be of potential concern. The purpose of this study was to investigate the impact of RBE and the choice of beam arrangement for adolescent patients with mediastinal Hodgkin lymphoma. Methods: For three previously treated adolescent patients, proton plans with 1-3 fields were created to a prescribed dose of 19.8 Gy (RBE) in 11 fractions (Varian Eclipse v13.7), assuming an RBE of 1.1. Plans were recalculated using Monte-Carlo (Geant4 v10.3.3/Gate v8.1) to calculate dose-averaged LET. Variable RBE-weighted dose was calculated using the McNamara model, assuming an α/ß ratio of 2 Gy for organs-at-risk. Results: Although the LET decreased as the number of fields increased, the difference in RBE-weighted dose (Δdose) to organs-at-risk did not consistently decrease. Δdose values varied by patient and organ and were mostly of the order of 0-3 Gy (RBE), with a worst-case of 4.75 Gy (RBE) in near-maximum dose to the left atrium for one plan. Conclusions: RBE-weighted doses to organs-at-risk are sensitive to the choice of RBE model, which is of particular concern for the heart. Advances in knowledge: There is a need to remain cautious when evaluating proton plans for Hodgkin lymphoma, especially when near-maximum doses to organs-at-risk are considered.

Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study.

BACKGROUND: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. METHODS: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. INTERPRETATION: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

International variation in childhood cancer mortality rates from 2001 to 2015: Comparison of trends in the International Cancer Benchmarking Partnership countries.

Despite improved survival rates, cancer remains one of the most common causes of childhood death. The International Cancer Benchmarking Partnership (ICBP) showed variation in cancer survival for adults. We aimed to assess and compare trends over time in cancer mortality between children, adolescents and young adults (AYAs) and adults in the six countries involved in the ICBP: United Kingdom, Denmark, Australia, Canada, Norway and Sweden. Trends in mortality between 2001 and 2015 in the six original ICBP countries were examined. Age standardised mortality rates (ASR per million) were calculated for all cancers, leukaemia, malignant and benign central nervous system (CNS) tumours, and non-CNS solid tumours. ASRs were reported for children (age 0-14 years), AYAs aged 15 to 39 years and adults aged 40 years and above. Average annual percentage change (AAPC) in mortality rates per country were estimated using Joinpoint regression. For all cancers combined, significant temporal reductions were observed in all countries and all age groups. However, the overall AAPC was greater for children (-2.9; 95% confidence interval = -4.0 to -1.7) compared to AYAs (-1.8; -2.1 to -1.5) and adults aged >40 years (-1.5; -1.6 to -1.4). This pattern was mirrored for leukaemia, CNS tumours and non-CNS solid tumours, with the difference being most pronounced for leukaemia: AAPC for children -4.6 (-6.1 to -3.1) vs AYAs -3.2 (-4.2 to -2.1) and over 40s -1.1 (-1.3 to -0.8). AAPCs varied between countries in children for all cancers except leukaemia, and in adults over 40 for all cancers combined, but not in subgroups. Improvements in cancer mortality rates in ICBP countries have been most marked among children aged 0 to 14 in comparison to 15 to 39 and over 40 year olds. This may reflect better care, including centralised service provision, treatment protocols and higher trial recruitment rates in children compared to older patients.

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.

Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial.

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1-5; 60 mg/m2 prednisone taken orally on days 1-15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high incidence of cancer prone syndromes.

PURPOSE: Historically, cancer predisposition syndromes (CPSs) were rarely established for children with cancer. This nationwide, population-based study investigated how frequently children with cancer had or were likely to have a CPS. METHODS: Children (0-17 years) in Denmark with newly diagnosed cancer were invited to participate in whole-genome sequencing of germline DNA. Suspicion of CPS was assessed according to Jongmans'/McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) criteria and familial cancer diagnoses were verified using population-based registries. RESULTS: 198 of 235 (84.3%) eligible patients participated, of whom 94/198 (47.5%) carried pathogenic variants (PVs) in a CPS gene or had clinical features indicating CPS. Twenty-nine of 198 (14.6%) patients harbored a CPS, of whom 21/198 (10.6%) harbored a childhood-onset and 9/198 (4.5%) an adult-onset CPS. In addition, 23/198 (11.6%) patients carried a PV associated with biallelic CPS. Seven of the 54 (12.9%) patients carried two or more variants in different CPS genes. Seventy of 198 (35.4%) patients fulfilled the Jongmans' and/or MIPOGG criteria indicating an underlying CPS, including two of the 9 (22.2%) patients with an adult-onset CPS versus 18 of the 21 (85.7%) patients with a childhood-onset CPS (p = 0.0022), eight of the additional 23 (34.8%) patients with a heterozygous PV associated with biallelic CPS, and 42 patients without PVs. Children with a central nervous system (CNS) tumor had family members with CNS tumors more frequently than patients with other cancers (11/44, p = 0.04), but 42 of 44 (95.5%) cases did not have a PV in a CPS gene. CONCLUSION: These results demonstrate the value of systematically screening pediatric cancer patients for CPSs and indicate that a higher proportion of childhood cancers may be linked to predisposing germline variants than previously supposed.

Improved Survival of Children, Adolescents, and Young Adults With Head and Neck Soft Tissue Sarcomas in Denmark.

AIM: The aim of this study was to estimate nationally the survival of children, adolescents, and young adults with head and neck soft tissue sarcomas. MATERIALS AND METHODS: The authors included patients 0 to 21 years of age and diagnosed with rhabdomyosarcoma (RMS) or nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) located in the head and neck between 1980 and 2014. Survival probabilities were estimated using the Kaplan-Meier method. The authors estimated the effect of covariates with univariate and multivariate Cox regression analyses. The cumulative recurrence in RMS was estimated when considering death as a competing risk. RESULTS: We identified 72 patients (50% male individuals, whereas 72% had RMS). Elder patients (older than 15 y) did worse compared with younger patients (log-rank test P=0.001). Patients diagnosed from 1980 to 1999 did worse than patients diagnosed from 2000 to 2014 (log-rank test P=0.02). Similarly, younger (younger than 15 y) patients did significantly better when diagnosed from 2000 to 2014 with reference to those diagnosed from 1980 to 1999 (log-rank test P=0.026). The multivariate hazard ratio was 0.46 (95% confidence interval, 0.23-0.92) for patients diagnosed from 2000 to 2014 with reference to patients diagnosed from 1980 to 1999. The 1-year cumulative recurrence for RMS was 21.2% (95% confidence interval, 12.3%-35.0%). CONCLUSION: Overall survival has improved throughout the study period, which is attributable to advancement in diagnostics, treatment, and the application of standardized guidelines from international protocols.

Survival after cancer in children, adolescents and young adults in the Nordic countries from 1980 to 2013.

BACKGROUND: The present study aimed to assess whether the widespread concern of inferior cancer survival in adolescents and young adults (AYAs) compared with children and adults holds true in a Nordic setting with important differences in healthcare organisation compared with the United States (e.g. free access to healthcare) and the United Kingdom (e.g. young teenagers are treated in paediatric departments). METHODS: Five-year relative survival was calculated for 17 diagnostic groups in patients diagnosed in 2000-2013 in three diagnostic age categories: children (0-14 years), AYAs (15-24 years) and adults (25-34 years). RESULTS: For 13 out of 17 diagnostic groups examined, there was no difference in survival between AYAs and neighbouring age categories. For acute lymphoblastic leukaemias, astrocytomas, rhabdomyosarcomas and non-rhabdomyosarcoma soft tissue sarcomas we found survival in children to be superior to that in AYAs. For these four diagnostic groups, the rate of survival improvement over three calendar periods (1980-1989, 1990-1999 and 2000-2013) was not particularly low in AYAs compared with neighbouring age categories. CONCLUSIONS: The present study suggests that in an affluent setting with free access to healthcare, meaningful differences in survival between AYA patients and either childhood or adult patients are a phenomenon of the past for most AYA cancer diagnostic groups.

Importance of Comprehensive Molecular Profiling for Clinical Outcome in Children With Recurrent Cancer.

Purpose: Pediatric cancers are often difficult to classify and can be complex to treat. To ensure precise diagnostics and identify relevant treatment targets, we implemented comprehensive molecular profiling of consecutive pediatric patients with cancer relapse. We evaluated the clinical impact of extensive molecular profiling by assessing the frequency of identified biological onco-drivers, altered diagnosis, and/or identification of new relevant targeted therapies. Patients and Methods: Forty-six tumor samples (44 fresh-frozen; two formalin-fixed paraffin embedded), two bone marrow aspirates, three cerebrospinal fluid samples, and one archived DNA were obtained from 48 children (0-17 years; median 9.5) with relapsed or refractory cancer, where the disease was rapidly progressing in spite of their current treatment or they had exhausted all treatment options. The samples were analyzed by whole-exome sequencing (WES), RNA sequencing (RNAseq), transcriptome arrays, and SNP arrays. Final reports were available within 3-4 weeks after patient inclusion and included mutation status, a description of copy number alterations, differentially expressed genes, and gene fusions, as well as suggestions for targeted treatment. Results: Of the 48 patients, 33 had actionable findings. The most efficient method for the identification of actionable findings was WES (39%), followed by SNP array (37%). Of note, gene fusions were identified by RNAseq in 21% of the samples. Eleven findings led to clinical intervention, i.e., oncogenetic counseling, targeted treatment, and treatment based on changed diagnosis. Four patients received compassionate use targeted therapy. Six patients experienced direct benefits in the form of stable disease or response. Conclusion: The application of comprehensive genetic diagnostics in children with recurrent cancers allowed for discovery and implementation of effective targeted therapies and hereby improvement of outcome in some patients.

Children with low-risk acute lymphoblastic leukemia are at highest risk of second cancers.

BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy. PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1]. RESULTS: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47). CONCLUSIONS: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

Pharmacokinetics of 6-Thioguanine and 6-Mercaptopurine Combination Maintenance Therapy of Childhood ALL: Hypothesis and Case Report.

Methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia is challenged by treatment-related hepatotoxicity, failure to achieve the myelosuppressive target, and lack of direct parameters for monitoring treatment efficacy or even intensity. Patients with low thiopurine methyltransferase (TPMT) activity have lower levels of hepatotoxic methylated thiopurine metabolites (MeMPs), higher levels of thioguanine nucleotides (TGNs), and reduced relapse rates. Addition of 6-thioguanine to maintenance therapy of a child with ALL and high TPMT activity increased the TGN/MeMP index in erythrocytes 5.5-fold, mimicking the more favorable thiopurine metabolism seen in patients with low TPMT activity.