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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.

Bone marrow minimal residual disease (MRD) is the strongest predictor of relapse in children with acute lymphoblastic leukemia (ALL). 6-mercaptopurine (6MP) in ALL therapy has wide inter-individual...

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.

Truncation of asparaginase treatment due to asparaginase-related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1 to 17 years, diagnosed with ALL between July 2008 and February 2016, treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (including extended asparaginase exposure [1000 IU/m2 intramuscularly weeks 5-33]). Patients were included with delayed entry at their last administered asparaginase treatment, or detection of SI, and followed until relapse, death, secondary malignancy, or end of follow-up (median, 5.71 years; interquartile range, 4.02-7.64). In a multiple Cox model comparing patients with (n = 358) and without (n = 1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (HR; aHR) was 1.33 (95% confidence interval [CI], 0.86-2.06; P = .20). In a substudy including only patients with information on enzyme activity (n = 1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI, 6.9-15.4) vs 6.7% (95% CI, 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI, 1.05-2.74, P=.03). The unadjusted bone marrow relapse-specific HR was 1.83 (95% CI, 1.07-3.14, P=.03) and 1.86 (95% CI, 0.90- 3.87, P=.095) for any central nervous system relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible. This trial was registered at www.clinicaltrials.gov as #NCT03987542.

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

Introduction: Asparaginase is an essential part of the treatment of acute lymphoblastic leukemia (ALL). Hypersensitivity occurred in 16.8% (clinical allergy (13.8%) or silent inactivation (3.0%)) of patients treated with pegylated asparaginase (PEG-asp) in the NOPHO ALL2008 cohort (Hoejfeldt et al 2018). Hypersensitivity (clinical allergy or silent inactivation) is the most common cause of truncated asparaginase therapy, and truncated treatment has been associated with decreased event-free survival (Silverman et al 2001). Asparaginase encapsulated in erythrocytes (eryaspase) is an alternative formulation of asparaginase aiming to prolong the half-life of asparaginase and to reduce toxicity e.g. hypersensitivity, since the erythrocyte membrane prevents activation of the immune system and protects asparaginase against elimination. A phase 2 study has demonstrated prolonged asparaginase enzyme activity (AEA) and significantly reduced incidence of hypersensitivity in patients with ALL, who had a prior exposure to other asparaginase preparations (NCT01518517). The aim of the NOR-GRASPALL 2016 study is to evaluate the safety and efficacy of eryaspase in combination with multiagent chemotherapy according to the NOPHO ALL2008 protocol and the ALLTogether Pilot study. Antileukemic treatment in these protocols include 4-8 doses of PEG-asp as first line treatment. Methods: NOR-GRASPALL 2016 is a phase 2 multinational multicentre trial conducted in the Nordic/Baltic countries. It is a single-arm study for non-high-risk patients with ALL and hypersensitivity to PEG-asp. Eryaspase (150 U/kg) is scheduled to complete the intended course of asparaginase (1-7 doses). AEA-measurements are used as biomarkers for treatment efficacy. Results: Since August 2017, 36 children and two adults were included in the study. Median age was 6.0 years (IQR: 3.3;8.7). 37 patients (97.4%) had clinical allergy to PEG-asp of whom 59.5% (n=22) had a severe allergic reaction. One patient (3.3%) was included due to silent inactivation. AEA-measurements were available in all patients but one (n=37), and in none of these patients AEA was detectable following PEG-asp treatment. In total, 171 doses of eryaspase were administered. A total of 34 of the 36 patients (94.7%) had AEA >100 U/L and 27 patients (71.1%) had AEA-levels >400 U/L 14 days after first eryaspase administration (expected nadir). The median AEA-level was 798 U/L [IQR: 387;864]. In total 90.7% of all samples collected 14 days after eryaspase administration had AEA >100 U/L and 69.3% had AEA >400 U/L. The median AEA-level was 621U/L [IQR: 331;962]. Adverse events with relation to eryaspase were reported in 8 of 36 patients (22%). Six patients experienced a possible allergic reaction to eryaspase; one patient had a severe allergic reaction, three patients developed a rash and two patients had "drug fever", deemed related to eryaspase. Three of these six patients (50%) had low AEA-levels after developing allergic symptoms, the remaining patients (50%) had AEA-levels comparable with all other patients in the study. Four patients experienced adverse events related to eryaspase; two patients with mild hyperlipidaemia and two with hepatoxicity. No other severe adverse events with relation to eryaspase have been reported. Final study results will be provided at the meeting. Conclusion: Eryaspase consistently demonstrated prolonged AEA in patients who developed hypersensitivity reactions to PEG-asp. Treatment with eryaspase was well tolerated. We conclude that eryaspase is a promising alternative to PEG-asp in case of hypersensitivity. Disclosures Schmiegelow: Jazz Pharmaceuticals: Other: Speaker and/or Advisory Board Honoraria ; Amgen: Other: Speaker fee; Medscape: Other: Speaker fee; Servier: Other: Educational grant. Speaker and/or Advisory Board Honoraria . Albertsen:Erytech Pharma: Other: Sponsor of the investigator initiated study: NOR-GRASPALL 2016. No financial benefits..

Relapse following truncation of Asparaginase in NOPHO ALL2008.

Premature discontinuation of asparaginase reduces cure rate in contemporary acute lymphoblastic leukemia (ALL) treatment. One of the commonest causes of asparaginase truncation is asparaginase-associated pancreatitis (AAP). We prospectively registered AAP during treatment of 2,448 consecutive Nordic/Baltic ALL patients aged 1.0-45.9 years treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol (7/2008-10/2018). The Day 280 cumulative incidence of first-time AAP (including 99% (167/168) of AAP events at this time point) was 8.3% (95% confidence interval (CI) 7.0-9.9) with a median time of 104 days (interquartile range (IQR) 70-145) from ALL diagnosis to AAP, with a median of 10 days (IQR 6-13) from last asparaginase exposure, and after a median number of five asparaginase doses (IQR 3-7, max 14 doses). All patients received polyethylene glycol conjugated Escherichia coli-derived asparaginase as standard treatment. Eighty-five percent (140/164, unknown in N=4) of AAP events were severe (AAP-associated symptoms and/or pancreatic enzymes >3x upper normal limit lasting >72 hours or with hemorrhagic pancreatitis, pancreatic abscess, or pseudocyst). Four age groups were defined: 1.0-4.9, 5.0-8.9, 9.0-16.9, and 17.0-45.9 years-each containing approximately 25% of the AAP events. Compared with patients aged 1.0-4.9 years, adjusted (sex, immunophenotype, and white blood cell count) hazard ratios (HR) of AAP were associated with higher age (5.0-8.9 years: HR 2.3, 95% CI 1.5-3.6, P Of 168 AAP patients, 34 (20%) were re-challenged with asparaginase. Fifty percent (17/34) developed a second episode of AAP-41% being severe (7/17). The median time to a second AAP event from asparaginase re-exposure was 29 days (IQR 16-94) and occurred after a median of two asparaginase doses (range 0-7). Neither age group nor severity of the first AAP was associated with increased hazard of a second AAP event. None of the patients with a second AAP were further re-exposed to asparaginase, and none died of the second AAP. Among a total of 196 ALL relapses, 21 patients have had AAP including 17 patients with asparaginase truncation. However, the hazard of relapse (age- and sex-adjusted) was not increased among AAP patients with asparaginase truncation versus AAP patients with asparaginase re-exposure (5.0-year cumulative incidence of relapse: 13.2% versus 14.2%) (HR 1.0, 95% CI 0.3-3.1, P=1.0). When analyzing time to relapse among AAP patients versus non-AAP patients, no difference in hazard of relapse was found (HR 2.0, 95% CI 0.8-4.9, P=.2). In conclusion, adolescents and young adults tolerated asparaginase treatment as well as children; however, the risk of AAP was higher for patients older than 5.0 years of age with no difference with increasing age. Despite a low AAP-related mortality, the morbidity was considerable and most profound for patients aged 9.0-16.9 years. Since asparaginase re-exposure was associated with a high risk of a second AAP event and neither AAP development nor AAP-related asparaginase truncation was associated with increased relapse risk, asparaginase re-exposure should be attempted only in patients with a high risk of leukemic relapse. Finally, there is an unmet need for preventive strategies toward AAP. Disclosures Wolthers: Novo Nordisk: Employment.

Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that can be classified into an extrinsic or intrinsic type. A high percentage of patients, especially adults with the extrinsic type of AD, have been reported to show antibodies to antinuclear proteins (ANA). We aimed to study the prevalence of ANA in children with AD and to evaluate clinical differences between patients with ANA-positive and ANA-negative AD. Methods A total 346 serum samples from children with active AD (mean age 5.8 years) and 117 hospital controls without known skin, inflammatory, or immune-mediated disease (mean age 7.9 years) were tested for IgG ANA with indirect immunofluorescence on HEp-2 cells, total serum IgE levels, and IgE type antibodies to food allergen panels. Results In total, 47 patients with AD (13.6%) and 15 subjects in the control group (12.8%) were ANA positive at screening dilution 1:10 (P > 0.05). In patients with AD, ANA was found already at the age of 2 years, significantly more often in females (P

Background Atopic dermatitis (AD) is a multifactorial chronic inflammatory skin disease presenting with a relapsing clinical pattern similar to chronic autoimmune disease. Several human transglutaminases have been defined and keratinocyte transglutaminase (TG1) and epidermal transglutaminase (TG3) expressed in the epidermis are associated with epidermal barrier dysfunction. Since impairments to the epidermal barrier represent an important factor in AD, we hypothesized that IgA autoantibodies specific for TG1 (IgA-anti-TG1) and TG3 (IgA-anti-TG3) may affect AD development during childhood. Methods Active AD patients (n = 304), 28 patients with biopsy-confirmed coeliac disease (CD), 5 patients with active AD and CD, and 55 control patients without CD and skin diseases were enrolled into the study. IgA-anti-TG1 and IgA-anti-TG3 reactivity was determined using an enzyme-linked immunosorbent assay. IgA-anti-TG2 were defined using a fluoroenzyme immunoassay. Results IgA-anti-TG1 antibodies were found in 2% and IgA-anti-TG3 antibodies in 3% of patients with active AD. Two out of the 5 patients with AD and concomitant CD had IgA-anti-TG1 and IgA-anti-TG2 antibodies. In CD patients, 36% of individuals presented with elevated IgA-anti-TG1 antibodies and 18% presented with elevated IgA-anti-TG3 antibodies and all CD patients presented with IgA-anti-TG2 antibodies (significantly different from AD patients and controls, p Conclusions IgA-anti-TG1 and IgA-anti-TG3 seropositivity was rare in active AD but frequent in CD patients. The level of circulating antibodies related to skin lesions could be studied by determining the levels of IgA-anti-TG1 and IgA-anti-TG3 in skin biopsies of AD patients.

Asparaginase-associated Pancreatitis in Acute Lymphoblastic Leukemia: Results from the NOPHO ALL2008 Treatment of Patients 1–45 Years

NOR-GRASPALL 2016: Asparaginase encapsulated in erythrocytes – a promising alternative to PEG-asparaginase in case of hypersensitivity. Line Stensig Lynggaard