ALBERT

Description: Reduction in bone mineral density (BMD), fractures, altered body composition, deteriorated motor performance and impaired passive ankle dorsiflexion are side-effects of chemotherapy during childhood acute lymphoblastic leukemia (ALL). Because only scarce information is available on the value of regular exercise to prevent these side-effects, we performed a randomized trial to investigate the effects of intervention with an exercise program. At diagnosis 51 ALL patients (median age: 5.4 years) were randomized into a group receiving intervention (including twice-daily high-intensity weight-bearing activities throughout the two-year during treatment period), or a control group receiving standard care. BMD of total body (BMDTB) and lumbar spine (BMDLS) and body composition parameters were measured using dual energy X-ray absorptiometry (DEXA). We measured motor performance with the Bayley Scales of Infant Development and the Movement-ABC, and passive ankle dorsiflexion with a goniometer. The investigators were blinded to the randomization. Repeated measurements analysis (ANOVA) was used. BMD decreased equally in the intervention and control group during treatment (delta-BMDTB: −0.75 SDS vs −0.96 SDS, p=0.65 and delta-BMDLS: −0.15 SDS vs −0.04 SDS, p=0.83), and increased equally during the year after treatment (delta-BMDTB: 0.42 SDS vs 0.35 SDS, p=0.70 and delta-BMDLS: 0.10 SDS vs 0.14 SDS, p=0.84). Body-fat increased during treatment in both groups (delta-fat: 1.04 SDS vs 1.56 SDS, p=0.25). In the intervention group a more rapid decline of body-fat was observed during the year after completion of therapy than in the control group (delta-fat: −1.08 SDS vs −0.49 SDS, p=0.01). Lean body mass (LBM) of both groups decreased equally during treatment (delta-LBM: −0.61 SDS vs −0.12 SDS, p=0.16) and increased equally the year after stop of treatment (delta-LBM: 0.29 SDS vs 0.22 SDS, p=0.66). Both groups showed similar changes in passive ankle dorsiflexion mobility (−5.2º vs −4.6º, p=0.76) and motor performance (0.37 SDS vs 0.68 SDS, p=0.44) during treatment. Adherence to the exercise program varied considerably: 11% of the patients performed exercises daily, 37% more than once a week, 16% once weekly and 36% less than once a week. The exercise program was not more beneficial in preventing reduction in BMD, motor performance and passive ankle dorsiflexion than standard care, most likely due to unsatisfactory compliance. However, the faster recovery after stop of treatment of the excess of body-fat in the intervention group than in the control group may be due to the educational effect of the intervention program.

Description: Abstract 1469 Purpose As survival rates for pediatric acute lymphoblastic leukemia (ALL) have significantly improved, awareness of side effects such as skeletal toxicity becomes increasingly important. As BMD decrease over time might be associated with an increased risk of fractures, we performed repeated measurements of BMD in a large nation-wide study and studied the incidence of fractures in these children treated for ALL. Methods Prospectively, serial measurements (at diagnosis, after 32 weeks, after 2 years (at cessation of therapy) and after 3 years (1 year after cessation of therapy)) of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry (DXA). Using logistic multivariate regression, we evaluated the following putative risk factors for a low BMDLS:age at diagnosis, gender, risk group of ALL treatment, weight and height at diagnosis. Moreover, Kaplan-Meier survival analysis was used to assess the cumulative incidence of fractures in 672 patients treated with the dexamethasone-based DCOG-ALL9 protocol. All reported fractures were symptomatic, and confirmed by X-ray. Cumulative incidences of fractures for different subgroups were compared with the Log-Rank test. Results At diagnosis, mean BMDLS of ALL patients was lower than that of healthy peers (mean BMDLS= −1.10 SDS, P〈 0.001), and this remained significant lower during and after treatment (8 months: BMDLS = −1.10 SDS, P〈 0.001; 24 months: BMDLS = −1,27 SDS, P〈 0.001; 36 months: BMDLS = −0.95 SDS, P〈 0.001). Multivariate linear regression analysis showed that after correction for weight, height and gender, treatment according to the HR treatment arm and older age at diagnosis had a significant negative effect on the decline of BMDLS during treatment (high-risk group: b = −0.50, P

Description: Abstract 3071 Poster Board III-8 Introduction As the survival of pediatric acute lymphoblastic leukemia (ALL) improves, research on treatment-related morbidity, like disturbance of body composition and bone mineral density (BMD), is required. This study investigates pharmacogenetic risk factors for BMD and body composition in pediatric ALL. Methods We determined the influence of SNPs in 4 genes (vitamin-D receptor (VDR: BsmI/ ApaI/ TaqI and Cdx-2/ GATA), collagen type I alpha 1 (SpI), estrogen receptor 1 (ESR1: PvuII/ XbaI) and the glucocorticoid receptor (BclI)) on body composition, BMD and fracture risk during dexamethasone-based pediatric ALL treatment. Anthropometry data of 69 patients (mean age 7.4 (range: 1.6-16.8) year) treated according to the DCOG-ALL9 protocol were evaluated. In patients aged 〉4 years body composition and BMD of the total body (BMD-TB) and the lumbar spine (BMD-LS) were measured repeatedly using dual energy X-ray absorptiometry. To correct for bone size we calculated bone mineral apparent density of the lumbar spine (BMAD-LS) with the model BMAD-LS = BMD-LS x (4/ (n × width)). All values were expressed as standard deviation scores (SDS). Repeated measurements analysis (ANOVA) was used. Results Non-carriers of VDR 5'-end (Cdx-2/ GATA) haplotype 3 revealed a significant larger fat gain than carriers (Δ%fat: non-carriers: +1.76 SDS, carriers: +0.77 SDS, p

Description: Purpose We prospectively studied the incidence and clinical course of hypertriglyceridemia and hypercholesterolemia during very prolonged use of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity levels in children with acute lymphoblastic leukemia (ALL). Also, the incidence of pancreatitis, thrombosis, hyperammonemia and central neurotoxicity and their association with asparaginase activity levels were evaluated. Patients and Methods Patients were treated according to Dutch Childhood Oncology Group (DCOG) ALL-10 medium risk intensification protocol, which includes 15 doses of PEGasparaginase (2,500 IU/m2) for 30 weeks. Erwinia asparaginase (20,000 IU/m2) was administered when an allergy to or silent inactivation of PEGasparaginase occurred. Definitions of silent inactivation of PEGasparaginase and Erwinia asparaginase were previously described (Tong et al., Blood, 2014 Mar;123(13):2026-33). Hypertriglyceridemia, hypercholesterolemia, hyperammonemia, pancreatitis, thrombosis and central neurotoxicity were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Changes over time of triglyceride, cholesterol, and ammonia levels were evaluated using mixed models analysis of variance (ANOVA). Changes related to age and gender were also investigated using mixed models ANOVA. The incidence of toxicities (pancreatitis, thrombosis, central neurotoxicity) related to treatment (PEGasparaginase or Erwinia asparaginase) was investigated with the Fisher's exact tests. Finally, Spearman correlation coefficients were used to evaluate the relations between triglyceride, cholesterol, and asparaginase activity levels. Results In total, 89 patients were enrolled from two pediatric oncology centers. Triglyceride, cholesterol and ammonia levels increased rapidly in children with PEGasparaginase and remained temporary elevated, but normalized after the finishing the last asparaginase dose. Hypertriglyceridemia and hypercholesterolemia (grade 3/4) were found in 47% and in 25%, respectively, of the patients treated with PEGasparaginase. Studying the correlations between PEGasparaginase activity levels and triglyceride levels showed the strongest correlation at week 5 (Rs = 0.36, p=0.005). Children 〉= 10 years had higher triglyceride levels as compared to younger patients (〈 10 years) adjusted for asparaginase preparations: median levels of 4.9 mmol/L versus 1.6 mmol/L (p

Description: Abstract 3578 Purpose As survival rates for pediatric acute lymphoblastic leukemia (ALL) have significantly improved, awareness of side effects such as osteonecrosis becomes increasingly important. We studied incidence, risk factors, therapeutic strategies and outcome of symptomatic osteonecrosis in pediatric ALL patients. Methods Prospectively, the cumulative incidence of osteonecrosis was assessed in 694 patients treated with the dexamethasone-based protocol of the Dutch Childhood Oncology Group (DCOG)-ALL9. Osteonecrosis was defined by development of symptoms (NCI grade 2–4) during treatment or within the year after treatment discontinuation, confirmed by magnetic resonance imaging. Using logistic multivariate regression, we evaluated the following putative risk factors for osteonecrosis: age at diagnosis, gender, risk group of ALL treatment and BMI at diagnosis. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment, ≥1 year after osteonecrosis diagnosis. To evaluate whether the occurrence of osteonecrosis is related to the EFS, Cox-regression was used with osteonecrosis as time-dependent variable. Results The estimated cumulative incidence of symptomatic osteonecrosis at 3 years was 6.1%. In 35 patients osteonecrosis became apparent during treatment (1 during induction phase, 1 during intensification phase, and 33 during maintenance phase) and in 3 patients symptoms of osteonecrosis became apparent during the first year after stop of therapy. The mean time-interval between diagnosis of ALL and presentation of osteonecrosis was 1.2 years (range:1 month–2.7 years). In all 38 patients the weight-bearing joints of the lower limb were the primary location (hip (n=11), knee (n=25), ankle (n=2)). In the majority of patients (n=34) multifocal symptomatic involvement was reported. Logistic multivariate regression identified age (OR=1.47, P

Description: Abstract 2065 Background: Significant improvements in childhood cancer survival rates over recent decades have increased the importance of long-term treatment effects. Gonadal toxicity is a major complication in survivors of childhood cancer, which can especially occur in Hodgkin Lymphoma survivors, since they have been treated with alkylating agents. Inhibin B levels reflect gonadal function in men, and therefore this marker can be used to identify subgroups of childhood cancer survivors at risk for impaired gonadal function. Hitherto in male childhood cancer survivors, follow-up studies of gonadal function are lacking. Objective: To evaluate possible recovery of gonadal dysfunction over time in adult male survivors. Methods: In this retrospective study, adult male long-term childhood cancer survivors (n=201) of whom 24 (12%) were survivors of Hodgkin lymphoma were included. Serum inhibin B levels were used as a surrogate marker for gonadal function. Results: Median age at diagnosis was 6.0 years (range 0.0–17.5) and discontinuation of treatment was reached at a median age of 8.3 years (range 0.0–20.8). Inhibin B levels were first measured after a median follow-up time of 15.7 years (range 3.0–37.0). Median interval between the first (T1) and second measurement (T2) was 3.3 years (range 0.7–11.3). Median inhibin B level was 127 ng/L (range 5–366) at T1 and 156 ng/L (range 10–507) at T2. Survivors with an inhibin B level at first assessment≥105 ng/L have 50% chance to reach normal inhibin B levels, while this probability of recovery is negligible when the first inhibin B level is below 60 ng/L. The latter group consists of survivors of Hodgkin lymphoma treated with alkylating agents and survivors with an AAD score≥3. Conclusions: Our results suggest that recovery of gonadal function is possible even long after discontinuation of treatment. However, this recovery does not seem to occur in survivors who already reached critically low inhibin B levels after discontinuation of treatment, such as in survivors of a Hodgkin lymphoma treated with alkylating agents. Disclosures: No relevant conflicts of interest to declare.

Description: Purpose A prospective drug monitoring study was performed to analyse the efficacy of very prolonged use of PEGasparaginase and Erwiniaasparaginase by assessing asparaginase activity, asparagine, glutamine levels and asparaginase antibodies in children with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Children received 15 PEGasparaginase infusions (2,500 IU/m2 every other week) according to the Dutch Childhood Oncology Group (DCOG)-ALL-10 medium risk intensification protocol after having received native E.coli asparaginase (5,000 IU/m2 every 3 days, 8 doses in total) in the induction course. In case of an allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20,000 IU/m22x-3x per week) was given. All asparaginase preparations were administered intravenously in one hour. Serum asparaginase activity, asparagine, glutamine levels and asparaginase antibodies were measured. Results 89 patients were enrolled in two centers to monitor the PEGasparaginase courses. 62/89 (70%) patients without clinical allergy to and without silent inactivation of PEGasparaginase had serum mean trough activity levels of 899 U/L which were much higher than requested. 20/89 (22%) of the patients showed an allergy and 7/89 (8%) silent inactivation in intensification. All 20 allergic patients (grade 1-4 Common Terminology Criteria Adverse Events) showed PEGasparaginase activity levels of zero. This was not due to the fact that the PEGasparaginase infusion was stopped, as 18 patients showed their allergic reactions at the second dose whereas the serum asparaginase activity level after the first full dose already appeared to be zero in all 18 cases. Moreover, in 4 patients with grade 1 allergy, the second full PEGasparaginase dose was given with pre-treatment of clemastine and hydrocortisone, also resulting in unmeasurable serum activity levels of PEGasparaginase. 59 children from 7 centers with allergy to or silent inactivation of PEGasparaginase who were switched to Erwinia asparaginase were enrolled to monitor the Erwiniaasparaginase courses. Only 2/59 (3%) of the patients developed an allergy to Erwinia asparaginase. No patients with silent inactivation of Erwinia asparaginase were seen. Of the non-allergic Erwinia asparaginase patients, 55/57 (96%) had at least one serum Erwinia asparaginase trough activity level ≥ 100 U/L and 57/57 (100%) ≥ 50 U/L. In 65% and 85% of all samples had serum trough activity levels ≥ 100 U/L and ≥ 50 U/L, respectively. In 33% of patients, the administration frequency could be reduced from 3 times to 2 times per week based upon serum Erwinia asparaginase activity levels ≥ 100 U/L at 72 hours. Serum asparagine level was strongly depleted, but not always completely depleted in Erwinia asparaginase treated patients in contrast to PEGasparaginase. Serum glutamine level was slightly lowered by Erwiniaasparaginase, but no glutamine depletion was observed with both compounds. The presence of serum asparaginase antibodies is related to allergy to and silent inactivation of asparaginase, but predicting asparaginase allergy or silent inactivation is clinically not applicable because of the low specificity, 64% (95%-CI: 43%-82%). Conclusion The use of native E.coli asparaginase in induction leads to 22% allergy and 8% silent inactivation rates of PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront already in the induction course instead of native E.coli asparaginase. The dose of PEGasparaginase of 2,500 IU/m2 can be lowered. Switching to Erwinia asparaginase in case of allergy to or silent inactivation of PEGasparaginase leads to effective asparaginase activity levels in the majority of patients. Measuring serum asparaginase activity levels to monitor efficacy of asparaginase is preferred over serum asparagine levels and serum asparaginase antibodies. Therapeutic drug monitoring has now been implemented to individualize PEGasparaginase and Erwinia asparaginase dose and to detect silent inactivation in the current DCOG-ALL-11 protocol. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1505 Asparaginase is an essential component of combination chemotherapy of acute lymphoblastic leukemia (ALL). Asparaginase breaks down asparagine into aspartic acid and ammonia. Because asparagine is necessary for protein synthesis, its depletion leads to cell death. Recently, it has been suggested that mesenchymal cells in the bone marrow may produce asparagine and form ‘protective niches’ for leukemic cells. In vitro, this led to high levels of asparagine and asparaginase resistance of the ALL cells (Iwamoto et al. (J Clin Invest. 2007)). However, it is unknown if this holds true for the clinical in vivo situation. The aim of our study is to analyse whether mesenchymal cells or other cells in the bone marrow indeed produce significant amounts of asparagine in vivo that may lead to clinical asparaginase resistance. Ten de novo ALL patients were enrolled in this study. All children received induction chemotherapy according to protocol 1-A and 1-B of the Dutch Childhood Oncology Group (DCOG) ALL-10 protocol. Asparaginase levels and amino acid levels (asparagine, aspartic acid, glutamine and glutamic acid) were measured in bone marrow (BM) and peripheral blood at diagnosis (day 1), days 15, 33 and 79. On days that asparaginase was administered (days 15 and 33) it was ensured that study material was obtained before the E-coli L-asparaginase infusions. Changes over time of asparaginase trough levels in BM and peripheral blood were evaluated using Mixed models ANOVA. The amino acids levels in 0.5 ml BM, 3 ml BM and peripheral blood at days 15 and 33 were also compared using Mixed models ANOVA. All these analyses were done after log transformation of measured values to get approximate normal distributions. A two-sided p-value 〈 0.05 was considered statistically significant. The asparaginase levels were all below detection limit (〈 5 IU/L) in BM and peripheral blood at days 1 and 79. In both compartments, the median asparaginase trough levels were not significantly different at days 15 and 33. At diagnosis, no significant difference in asparagine level between 3 ml BM and peripheral blood was found (median: 44.5 μM (range 20.6–59.6 μM) and 43.9 μM (range 18.4 –58.5 μM), respectively). However, the median level of aspartic acid at diagnosis in 3 ml BM (19.2 μM; range 6.2–52.6 μM) was significantly higher as compared to median level of peripheral blood (5.7 μM; range 2.4–10.1 μM) (p=0.002). The aspartic acid levels were also higher in BM compared to peripheral blood at days 15 and 33 (both p=0.001) and at day 79 (p=0.002). Aspartic acid levels were significantly higher in 0.5 ml versus 3 ml BM (p=0.001) and this difference was also found when comparing 0.5 ml BM versus peripheral blood (p

Description: Chnages in hemostasis are often seen in children with ALL. Although increased thrombin generation is already present at diagnosis, thromboembolism is reported only after start of therapy, indicating a relationship between disease and treatment. We present results of a prospective study on coagulation and fibrinolysis in 64 children with newly diagnosed ALL. The DCOG ALL-9 remission induction protocol consists of weekly vincristine IV and oral dexamethasone 6 mg/m2 during 4 weeks. From day 29, dexamethasone is tapered and Asparaginase Paronal® is introduced, twice weekly at 6000 IU/m2 IV for 2 weeks. Results from the introduction of Paronal are given as medians (25th – 75th perc): Day 29 Paronal 1 Day 33 Paronal 2 Day 36 Paronal 3 Day 40 Paronal 4 Day 43 *1 p