ALBERT

Description: Purpose Previous studies have shown that children with silent inactivation of asparaginase had poorer outcomes as they were not switched to another asparaginase preparation that retained its activity. Recently, a case report was published that described the successful use of desensitization courses in a patient with severe hypersensitivity reaction to asparaginase. We analyzed whether continuation of asparaginase in case of silent inactivation may result in desensitization, disappearance of asparaginase antibodies (AAA) and recovery of asparaginase activity levels in children with newly diagnosed acute lymphoblastic leukemia (ALL). Patients and Methods Children who received intensified PEGasparaginase or Erwinia asparaginase for 30 weeks according to the intensification phase of the Dutch Childhood Oncology Group-ALL-10 medium-risk protocol were studied. All children had received native E.coli asparaginase in induction and all asparaginase preparations were administered intravenously in one hour. AAA against native E.coli asparaginase (Coli-AAA), PEGasparaginase (PEG-AAA), and Erwinia asparaginase (Erwinia-AAA) and PEGasparaginase and Erwiniaasparaginase activity levels were analyzed in serum. Results 7/89 patients had silent inactivation of PEGasparaginase. Two were detected by real-time asparaginase activity measurements and were switched to Erwinia asparaginase. Five patients continued PEGasparaginase because no real-time asparaginase measurements were available at the starting phase of our drug monitoring program. Those patients with silent inactivation were, therefore, not recognized in time. PEGasparaginase activity levels recovered in all 5 patients after 2-7 PEGasparaginase infusions. In all 5 patients, Coli-AAA were present at start of the intensification phase which declined over time coinciding with the rise of PEGasparaginase activity levels. PEG-AAA were absent at the start of intensification but also increased after 1-2 doses of PEGasparaginase, and declined thereafter also coinciding with recovery of the PEGasparaginase activity levels. 29% of the PEGasparaginase patients without an allergy and without silent inactivation were positive for Coli-AAA. Also in this group, the Coli-AAA gradually decreased to undetectable levels after 5 PEGasparaginase courses. In a different cohort of 59 patients treated with Erwinia asparaginase, there were no cases of silent inactivation and two developed allergic reactions. In 50% of the non-allergic patients, the Erwinia-AAA were absent at start of therapy, gradually increased and decreased to absent baseline values during 30 weeks of Erwiniaasparaginase therapy. Conclusion This unintended desensitization program applied in five patients with silent inactivation of PEGasparaginase leads to recovery of PEGasparaginase activity levels. However, this takes an unpredictable and sometimes long time period. Therefore, we do not advise such desensitization approaches, but recommend switching to Erwinia asparaginase. A significant proportion of patients treated for prolonged period with PEGasparaginase or Erwinia asparaginase develops antibodies without influencing asparaginase activity levels that disappear with continued use of the same asparaginase product. Disclosures: No relevant conflicts of interest to declare.

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: The high cumulative dose of dexamethasone, applied in the DCOG ALL9 protocol, prompted us to investigate the risk of osteoporosis, fractures and avascular necroses of bone (AVN) in children treated with acute lymphoblastic leukemia (ALL). Fracture risk and incidence of symptomatic AVN was assessed in 778 patients(482 boys, 297 girls), included in the ALL9 protocol since 1997. Total cumulative doses (TCD) of dexamethasone were 1370 mg/m2 and 1244 mg/m2 and of MTX 8.1g/m2 13.6g/m2 for NHR and HR patients respectively. No CNS-irradiation was applied. In children aged 〉3 years, lumbar spine bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DEXAscan), at diagnosis(T0), after 32 weeks(T1), at discontinuation of treatment at 109 weeks(T2), and one year after discontinuation of treatment(T3). Results were expressed as standard deviation scores (SDS). Symptomatic AVN was defined as on MRI confirmed AVN lesions in combination with non-vincristine related persistent pain in arms or legs. Fractures were reported in 82/778 (10.5%) patients. Most occurred after mild trauma. No difference was found in fracture incidence between boys and girls. BMD was measured in 387/427 (90.6%) eligible patients. Median BMD-SDS was significantly lower than zero at all times of evaluation, the lowest BMD values were found at T2 (−1.47 SDS). Fracture risk was 3.9 times higher as compared to healthy school children. Fracture incidence was correlated with BMD at T2 and T3(p=0.04 and p=0,04 respectively), but not at T0 and T1. A significant more rapid decline in BMD from T0 to T2 and to T3 was seen in patients with fractures as compared to patients without fractures. After discontinuation of therapy, BMD recovered faster in cases without fractures. Symptomatic AVN occurred in 33/778 (4.2%) of our patients (med age 14, range 6,5–18 years) showing irreversibility in 22 % of the cases. Differences found in the incidence between the centers may suggest underestimation of the risk of fractures and AVN in this prospective study. Children with ALL show a significantly increased fracture risk. Patients with a more severe reduction in BMD during treatment are more susceptible to fractures. The AVN incidence in this protocol did not exceed previous reports of prednisolone-based protocols.

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: Background: Osteonecrosis (ON) and decline of bone mineral density (BMD) are serious side effects during and after treatment of childhood acute lymphoblastic leukemia (ALL). It is unknown whether ON and low BMD co-occur in the same patients, and whether these two osteogenic side effects can influence each other’s development during pediatric ALL treatment. Methods: BMD and the incidence of symptomatic ON were prospectively assessed in 466 patients with ALL (4-18 years of age) treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Symptomatic ON was defined as persistent pain in arms or legs not caused by vincristine administration, and confirmed by magnetic resonance imaging. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) were measured by dual X-ray absorptiometry at ALL diagnosis, after 32 weeks of treatment, at cessation of treatment (109 weeks) and 1 year after cessation of treatment. BMD was expressed as age-matched and gender-matched standard deviation scores (SDS; Z-score). Multivariate linear mixed models were adjusted for age at diagnosis. Results: Thirty patients (6.4%) suffered from ON. At cessation of treatment, mean BMDLS was -1.28 SDS (SD: 1.27, n=332; p

Description: Abstract 4227 Asparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia (ALL). Due to increasing costs of treatment of childhood ALL more insight in costs of asparaginase preparations is desired. In order to compare pharmacoeconomic aspects of PEGasparaginase, Erwinia asparaginase and native E.coli asparaginase, we performed a cost-effectiveness analysis in Dutch Childhood Oncology Group (DCOG) ALL-10 medium risk group (MRG) intensification protocol. Between April 2005 and October 2009, MRG patients were included in this multi-center study. Treatment costs were calculated based on patient level data of 84 subjects (33 female), and were related to allergy to asparaginase. We have used 3 treatment scenarios for asparaginase of which 2 scenarios were hypothetical: PEGasparaginase as first line preparation and Erwinia asparaginase as second line used as scenario 1 (similar to the actual ALL-10 treatment schedule); native E.coli asparaginase as first line preparation and Erwinia asparaginase as second line used as hypothetical scenario 2; or native E.coli asparaginase as first line preparation, PEGasparaginase as second line and Erwinia asparaginase as third line preparation used as hypothetical scenario 3. Medical technology assessments techniques were used for this cost-effectiveness analysis. Decision tree analysis was used to compare costs of PEGasparaginase or Erwinia asparaginase to native E.coli asparaginase, while taking into account the incidence of allergy to asparaginase and the different associated costs. Sensitivity analyses (one-way and two-way) were conducted to account for uncertainty in the used prices and calculated costs. The total costs of the ALL-10 MRG intensification course of 30 weeks were $71,147 per patient. Subgroup analysis revealed that the costs were $57,893 in patients without PEGasparaginase allergy (N=64). The costs were significantly higher ($113,558) in case of PEGasparaginase allergy (N=20) necessitating a switch to Erwinia asparaginase. The total costs were also calculated based on two weeks of asparaginase exposure; in case of PEGasparaginase the costs were $ 1,930 and for Erwinia asparaginase $ 3,785 per two weeks of treatment. Decision tree analysis showed that the treatment costs were $ 70,402 when using native E.coli asparaginase as first line preparation in intensification (scenario 3) and $ 71,809 when using PEGasparaginase as first line preparation (scenario 1). Treatment costs using native E.coli asparaginase as first line followed by Erwinia asparaginase as second line (scenario 2) the costs would be significantly higher ($ 103,474). One-way sensitivity analysis showed that the subgroup with allergy to native E.coli asparaginase (scenario 2) had the largest range in treatment costs. When treatment costs were calculated with the new European price of Erwinia asparaginase (the price has been doubled in March 2011), both treatments with PEGasparaginase as first line preparation (scenario 1) or native E.coli asparaginase as first line preparation (scenario 3) would be less expensive ($ 100,199 or $ 103,089, respectively) compared to the native E.coli asparaginase scenario 2 ($ 190,284). Two-way sensitivity analysis revealed that treatment with PEGasparaginase (scenario 1) is less expensive than treatment with native E.coli asparaginase (scenarios 2) for allergy probabilities of PEGasparaginase ranging from zero to 0.8 with a fixed allergy rate of 0.65 (Veerman et al. (Lancet Oncol. 2009)). This also holds true if a fixed allergy rate for native E.coli asparaginase of 0.4 is used, which is frequently found in studies using less native E.coli asparaginase in intensification after native E.coli asparaginase in induction (Nachman et al. (JCO 1997) and Willer et al. (Blood 2011)). In conclusion, treatment with native E.coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy carried similar overall costs compared to the treatment with PEGasparaginase as first line drug (followed by Erwinia asparaginase in case of allergy). However, PEGasparaginase is preferred, because it is administered less frequently, with less outpatient care visits and is less immunogenic compared to native E.coli asparaginase. The costs with PEGasparaginase are much lower compared to Erwinia asparaginase. Disclosures: No relevant conflicts of interest to declare.

Description: Purpose Vincristine (VCR) is a commonly used drug in the treatment of several pediatric cancers. Unfortunately, children suffer from dose-limiting vincristine-induced peripheral neuropathy (VIPN). We aimed to assess whether the administration of VCR by means of one-hour infusions, resulting in lower peak levels, leads to less VIPN than bolus injections in children having completed the induction phase of their treatment for acute lymphoblastic leukemia (ALL) or Hodgkin's lymphoma (HL). Methods The study is part of the VINCA trial, an international randomized controlled trial studying the effect of administration method of VCR on the development and severity of VIPN during treatment of several types of childhood cancer. Participants were measured 3-6 times (depending on the number of VCR administrations and the total treatment period) and one final measurement 6 months after cessation of therapy. VIPN was assessed using the pediatric modified total neuropathy scale (ped-mTNS) and four items of the common toxicity criteria of adverse events (CTCAE version 4.03) items: constipation, peripheral sensory neuropathy, peripheral motor neuropathy and neuralgia. For the current analysis two measurements were taken into account. The first measurement was performed before onset of VCR therapy and the second after induction at day 33 (after 4 VCR administrations) in case of ALL or in week 7 (after 6 VCR administrations) in case of HL. VIPN was defined as a CTCAE sum score of ≥ 2 and/or a total ped-mTNS score of ≥ 5, whereas severe PNP was defined as an individual CTCAE item score of ≥ 3 or a total ped-mTNS score of ≥ 10. Analysis were done using logistic regression or cox-regression. Results were corrected for age, gender and ethnicity. Results In total, 91 children participated in the study, 58 (64%) of whom were treated for ALL and 18 (20%) for HL. 15 (20%) dropped out of the trial or could not be included in the current analysis due to insufficient data (n=6 drop-out or no measurements available after induction, n=9 time between measurement was larger than 64 days). Of the remaining 61, 35 (57%) were randomized in the bolus group and 26 (43%) in the one-hour group. Overall, there was a mean increase of 2.77 for the CTCAE sum score and 7.81 for the ped-mTNS sum score in the bolus group, compared to 2.12 and 6.38, respectively, in the one-hour group (CTCAE: β=-0.71, CI: -1.7-0.44, ped-mTNS: β=-0.84, CI=-3.65-1.97). 27 (77%) children developed neuropathy in the bolus group and 19 (73%) in the one-hour group. Children in the bolus group had a slightly increased, but not significant, risk of developing VIPN compared to children in the one-hour group (hazard ratio=1.21; 95% CI: 0.66 - 2.20). The proportion of children with severe neuropathy was equal in both groups (42%). Conclusions Children treated for ALL or HL who receive VCR by means of one-hour infusions or bolus injections seem to be at equal or diminished risk of developing VIPN during induction therapy. Results of longer follow-up that includes the total treatment period should demonstrate whether VIPN occurs less frequently and/or is less severe in case VCR is administered through one-hour infusions compared to administrations by bolus injections. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Description: Key Points Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Switching to Erwinia asparaginase leads to effective asparaginase activity levels in most patients who experienced an allergy to PEGasparaginase.

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: Purpose Vincristine (VCR) is frequently used for the treatment of pediatric cancer. However, it can lead to dose-limiting vincristine-induced peripheral neuropathy (VIPN). This study aimed to investigate if prolonging the duration of VCR administration (1-hour infusions instead of push injections) reduces VIPN in children with cancer during the first year of treatment. Methods The VINCA trial is an international multicenter randomized controlled trial. Participants were randomized to receive all VCR administrations through push injections or 1-hour infusions. Dose of VCR was 1.5-2 mg/m2 with a maximum of 2 mg. VIPN measurements were performed at baseline and 1-3 times during treatment, depending on the number of VCR administrations and the total treatment time, using 4 items of the common toxicity criteria of adverse events (CTCAE version 4.03): constipation, peripheral sensory neuropathy, peripheral motor neuropathy and neuralgia. Individual item scores range from zero (no complaints) to five (death). The primary outcome of this trial was total sum CTCAE score during first year of treatment. For the current analysis, patients treated for acute lymphoblastic leukemia (ALL) or Hodgkin's lymphoma were included. All included patients were analyzed according to the intention-to-treat principle. Besides VIPN measurements, data on all relevant co-medication during treatment were collected, including data of concurrent azole therapy (as azole treatment is known to interact with VCR treatment). Descriptive data were analyzed using either chi-square tests or t-tests. Longitudinal data were analyzed using repeated measures mixed model analysis for continuous outcomes (total CTCAE sum score) and generalized estimating equations for dichotomous outcomes (having VIPN yes or no, with VIPN defined as a CTCAE score of ≥ 2 on any of the 4 CTCAE items). Patients were considered to have been treated with concurrent azole therapy when azoles were used during the week before or following VCR administration and if ≥ 50% of VCR administrations between two succeeding measurements were given with concurrent azole therapy. Results were corrected for concurrent azole therapy, cumulative VCR dose, disease, age, gender, ethnicity and time since diagnosis. Results In total 90 children (n=45 one hour infusions group, n=45 push injections group) participated in the study, 58 (64%) with ALL and 18 (20%) with HL. Participants in the two randomization groups did not significantly differ regarding gender, age, ethnicity, diagnosis, or cumulative VCR dose. Overall results showed no effect of randomization on total CTCAE score (β=0.07, 95% confidence interval (CI) -0.42-0.56, p=0.78). However, concurrent azole treatment appeared to be an effect modifier in this analysis and therefore results are reported separately for measurements with (n=24) and without concurrent azole therapy (n=226). Among patients who received concurrent azole therapy, total CTCAE sum score was significantly higher in the push group compared to the 1-hour group (β=1.95, 95% CI 0.49-3.41, p=0.01), while among those without concurrent azole therapy, these CTCAE sum scores did not differ between the two randomization groups (β=-0.17, 95% CI: -0.67-0.34, p=0.52). The risk of developing VIPN (no/yes) did not significantly differ between both randomization groups, irrespective whether concurrent azole treatment was given or not (with azole: OR (95% CI)=4.92 (0.60-40.37), p=0.14; without azole: OR (95% CI)=0.97 (0.51-1.82, p=0.92). Conclusions Overall, administration method of VCR given as push injection or 1-hour infusion did not seem to affect the risk of developing VIPN in children treated for ALL or HL when using the current dosing regimen. However, when concurrent azole treatment is given, total CTCAE scores are significantly lower in children in the 1-hour infusion group compared to the push injection group, demonstrating less VIPN. These results indicate that for children treated with VCR and concurrent azole therapy for the prevention or treatment of fungal infections, administration of VCR by 1-hour infusions instead of push injections is recommended. Figure Disclosures Kaspers: Helsinn Healthcare: Consultancy; Boehringer Ingelheim Pharma: Other: Member of a DSMC. van der Sluis:medac: Consultancy; jazz farmaceuticals: Consultancy.