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Introduction Due to bone fragility, children with acute lymphoblastic leukemia (ALL) have a 6-fold greater fracture risk during therapy compared to peers. Osteoporotic fractures are a concern, as they lead to adverse health outcomes including pain, loss of height due to vertebral deformity, and (transient) disability. In previous studies, lower lumbar spine bone mineral density (LS BMD) at ALL diagnosis was found to be prognostic for the occurrence of future fractures. However, routinely performing dual-energy X-ray absorptiometry (DXA) in each newly diagnosed child is not universally feasible. The aim of this study is to develop and validate an easy to use clinical risk prediction model for low lumbar spine bone mineral density (LS BMD Z-score ≤-2.0) at diagnosis, as an important indicator for fracture risk and further treatment-related BMD aggravation. Methods Children treated for ALL according to the Dutch Childhood Oncology Group (DCOG-ALL9; model development) protocol (n=249; median age: 7.6 years [range: 4.0-16.6 years]) and children from the Canadian STeroid-Associated Osteoporosis in the Pediatric Population (STOPP; model validation) cohort (n=99; median age: 7.3 years [range: 4.0-16.6 years]) were included in this study. Multivariable logistic regression analyses were used to develop the prediction model for low LS BMD at diagnosis, defined as a Z-score ≤-2.0 (evaluated with DXA). Candidate predictors included sex, age, height and weight Z-scores at diagnosis of ALL. The receiver operating characteristic area under the curve (AUC) was assessed for model performance. To confirm the association between low LS BMD at diagnosis and bone fragility during and shortly following ALL therapy, we performed multivariable logistic regression analyses. The dependent variables were: one or more symptomatic fractures from ALL diagnosis to 12 months following treatment cessation and low LS BMD at cessation of treatment. In addition, because of homogeneity in the intended glucocorticoid doses, we combined data from the DCOG-ALL9 and STOPP cohorts and performed multivariable pooled cohort analyses (meta-analysis). Potential associations between the six-month cumulative glucocorticoid dose and fractures that occurred in the first year of therapy, were explored. Furthermore, we assessed potential associations between the cumulative glucocorticoid dose at cessation of therapy, and the endpoints 'low LS BMD at therapy cessation' and 'fractures that occurred during treatment and within 12 months following treatment cessation'. Results The prediction model for low LS BMD at diagnosis included weight Z-scores (β = -0.70) and age (β = -0.10) at diagnosis. This model had an AUC of 0.71 (0.63 to 0.78) in the DCOG-ALL9 cohort, and resulted in correct identification of 71% of patients with low LS BMD at ALL diagnosis. Validation on the STOPP cohort showed an AUC of 0.74 (95% CI = 0.63 to 0.84). To calculate the probability of low LS BMD at ALL diagnosis for an individual patient, an online calculator is available at http://lsbmd-risk-calculator.azurewebsites.net/ We confirmed that low LS BMD at diagnosis is associated with LS BMD at treatment cessation (OR = 5.9; 95% CI = 3.2 to 10.9) and with symptomatic fractures (OR = 1.7; 95% CI = 1.3 to 2.4) that occurred from diagnosis until 12 months following treatment cessation. In pooled meta-analysis, lower LS BMD at diagnosis (OR = 1.6, 95% CI = 1.1 to 2.4) and six-month cumulative glucocorticoid dose (OR = 1.9, 95% CI = 1.1 to 3.3, for every gram increase) were associated with symptomatic fractures that occurred in the first year of therapy. Higher cumulative glucocorticoid dose at cessation of therapy (OR = 1.5, 95% CI = 1.2 to 2.0, for every gram increase), lower LS BMD Z-scores at diagnosis (OR = 7.9, 95% CI = 4.8 to 13.1) and higher age at diagnosis (OR = 1.6, 95% CI = 1.4 to 1.8), were associated with low LS BMD at cessation of therapy. Conclusion We developed and successfully validated a risk prediction model for low LSBMD at diagnosis in children aged 4-18 years with ALL. This is important because low LS BMD at diagnosis was strongly associated with bone fragility and fractures during and shortly following treatment for ALL. Our easy to use prediction model, can facilitate awareness and early identification of bone fragility in individual pediatric ALL patients, without performing DXA examination. Disclosures No relevant conflicts of interest to declare.

Item does not contain fulltext PURPOSE: To elucidate incidence and risk factors of bone mineral density and fracture risk in children with Acute Lymphoblastic Leukemia (ALL). METHODS: Prospectively, cumulative fracture incidence, calculated from diagnosis until one year after cessation of treatment, was assessed in 672 patients. This fracture incidence was compared between subgroups of treatment stratification and age subgroups (Log-Rank test). Serial measurements of bone mineral density of the lumbar spine (BMDLS) were performed in 399 ALL patients using dual energy X-ray absorptiometry. We evaluated risk factors for a low BMD (multivariate regression analysis). Osteoporosis was defined as a BMDLS

Abstract 5215 Introduction. Currently, the 5-year survival for childhood NHL is ∼80%. Because of this high survival rate and since treatment is administered in a growing and developing individual, long-term side effects are an important issue. Studies on endocrine long-term effects in survivors of childhood non-Hodgkin lymphoma (NHL) are scarce and often limited by small sample sizes, or by the fact that data of NHL survivors have been combined with that of survivors of other malignancies. Aim of this study was to investigate the long-term endocrine effects of treatment for childhood NHL. Methods. A single centre cohort of 84 survivors (22 females) was included in this retrospective study. Median age was 21 yrs (9–40 yrs) and time after cessation of therapy 12 yrs (4–30 yrs). Height, weight, percentage fat, lean body mass (LBM), bone mineral content (BMC), bone mineral density of total body (BMDTB) and lumbar spine (BMDLS) were measured. Bone mineral apparent density of the lumbar spine (BMADLS) was calculated to correct for bone size. Thyroid stimulating hormone (TSH), free thyroxin (fT4), insulin-like growth factor-1 (IGF-1), Inhibin-B and anti-müllerian hormone (AMH) levels were measured. Results were compared with Dutch controls. Results. Height was lower in survivors at follow-up (mean SDS −0.36, P=0.002), but further analysis showed that shorter stature was already present at diagnosis (mean SDS −0.28, P=0.023). BMI, percentage fat, BMC, BMDTB, BMDLS and BMADLS were not different from controls. LBM was lower in survivors (mean SDS −0.47, P=0.008). TSH, fT4 and IGF-1 were normal in all survivors. Three out of 20 adult females had low AMH levels and 55% (23/42) of adult males had low Inhibin-B levels. Conclusion. Twelve years after cessation of therapy, survivors of NHL did not develope adiposity, osteopenia or osteoporosis or thyroid disease. Male NHL survivors seem to be at risk for infertility. Disclosures: No relevant conflicts of interest to declare.

Introduction: High-dose methotrexate (MTX) is used in the treatment of proliferative diseases such as acute lymphoblastic leukemia. Therapeutic drug monitoring of plasma MTX is important to monitor efficacy and adverse events. The authors aimed to develop a liquid chromatography, electrospray ionization, tandem mass spectrometry (LC-ESI-MS/MS)-based method to determine MTX in plasma for therapeutic drug monitoring and pharmacokinetic studies. Methods: Samples were analyzed using a Waters Acquity UPLC and Quattro Premier XE. A Waters Acquity UPLC BEH C18 column (2.1 mm · 100 mm, 1.7 mm) was used running an isocratic mobile phase of 21% methanol and 10 mM ammonium bicarbonate. The electrospray was operated in the positive ionization mode monitoring the following mass transitions: m/z 455.2 . 308.2 for MTX and m/z 458.2 . 311.2 for MTXd3. The analysis combined straightforward sample preparation, consisting of dilution and protein precipitation, with a 3-minute run time. Results: The method was linear up to 50 m M( r 2 . 0.99), and the coefficient of variation was ,6% for intraday and ,10% for interday precision. Average recovery was 99%. There were no significant matrix effects. The lower limit of quantitation, defined as the lowest concentration at which the coefficient of variation ,20% and S/N . 1:10, was 5 nM. Method comparison with the Abbott TDx fluorescent polarization immunoassay (FPIA) showed excellent agreement, and a small but significant negative constant bias was detected (LCMS/MS = 0.98 · FPIA 2 7.3). Conlusions: The authors developed a specific and sensitive stable isotope dilution LC–ESI–MS/MS method to monitor MTX concentrations in plasma within the clinically relevant range. The method can be easily applied in clinical laboratories because it combines straightforward sample pretreatment with LC-MS/MS.

Purpose We studied cumulative incidence, risk factors, therapeutic strategies, and outcome of symptomatic osteonecrosis in pediatric patients with acute lymphoblastic leukemia (ALL). Patients and Methods Cumulative incidence of osteonecrosis was assessed prospectively in 694 patients treated with the dexamethasone-based Dutch Child Oncology Group–ALL9 protocol. Osteonecrosis was defined by development of symptoms (National Cancer Institute grade 2 to 4) during treatment or within 1 year after treatment discontinuation, confirmed by magnetic resonance imaging. We evaluated risk factors for osteonecrosis using logistic multivariate regression. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment 1 year or more after osteonecrosis diagnosis. Results Cumulative incidence of osteonecrosis at 3 years was 6.1%. After adjustment for treatment center, logistic multivariate regression identified age (odds ratio [OR], 1.47; P < .01) and female sex (OR, 2.23; P = .04) as independent risk factors. Median age at diagnosis of ALL in patients with osteonecrosis was 13.5 years, compared with 4.7 years in those without. In 21 (55%) of 38 patients with osteonecrosis, chemotherapy was adjusted. Seven patients (18%) underwent surgery: five joint-preserving procedures and two total-hip arthroplasties. Clinical follow-up of 35 patients was evaluated; median follow-up was 4.9 years. In 14 patients (40%), symptoms completely resolved; 14 (40%) had symptoms interfering with function but not with activities of daily living (ADLs; grade 2); seven (20%) had symptoms interfering with ADLs (grade 3). In 24 patients, radiologic follow-up was available; in six (25%), lesions improved/disappeared; in 13 (54%), lesions remained stable; five (21%) had progressive lesions. Conclusion Six percent of pediatric patients with ALL developed symptomatic osteonecrosis during or shortly after treatment. Older age and female sex were risk factors. After a median follow-up of 5 years, 60% of patients had persistent symptoms.

Body mass index and change in body mass index during treatment may influence treatment outcome of pediatric patients with acute lymphoblastic leukemia. However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. We prospectively collected data on body composition from a cohort of newly diagnosed Dutch pediatric patients with acute lymphoblastic leukemia (n=762, age 2-17 years). Patients were treated from 1997-2004 and the median follow-up was 9 years (range, 0-10). Body mass index at diagnosis was expressed as age-and gender-matched standard deviation scores and on the basis of these scores the patients were categorized as being underweight, of normal weight or overweight. Multivariate analyses showed that patients who were underweight (8%) had a higher risk of relapse [hazard ratio: 1.88, 95% confidence interval (1.13-3.13)], but similar overall survival and event-free survival as patients who had a normal weight or who were overweight. Patients with loss of body mass index during the first 32 weeks of treatment had a similar risk of relapse and event-free survival, but decreased overall survival [hazard ratio: 2.10, 95% confidence interval (1.14-3.87)] compared to patients without a loss of body mass index. In addition, dual X-ray absorptiometry scans were performed in a nested, single-center cohort. Data from these scans revealed that a loss of body mass consisted mainly of a loss of lean body mass, while there was a gain in the percentage of fat. In conclusion, being underweight at diagnosis is a risk factor for relapse, and a decrease in body mass index early during treatment is associated with decreased survival. In addition, loss of body mass during treatment seems to consist mainly of a loss of lean body mass. This study was approved by the Medical Ethical Committee in 1996 (trial number NTR460/SNWLK-ALL-9).

Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age- and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, P

There is no consensus regarding how to manage osteonecrosis in pediatric acute lymphoblastic leukemia patients. Therefore, we performed a quality assessment of the literature with the result of a search strategy using the MESH terms osteonecrosis, children, childhood cancer, surgery, bisphosphonates, 6 hydroxymethyl-glutaryl CoA reductase inhibitors, anticoagulants and hyperbaric oxygen, and terms related to these MESH terms. A randomized controlled trial showed that osteonecrosis can be prevented by intermittent, instead of continuous, corticosteroid administration. The studies on interventions after onset of osteonecrosis were of low-quality evidence. Seven pediatric acute lymphoblastic leukemia studies described non-surgical interventions; bisphosphonates (n=5), hyperbaric oxygen therapy (n=1), or prostacyclin analogs (n=1). Safety and efficacy studies are lacking. Five studies focused on surgical interventions; none was of sufficient quality to draw definite conclusions. In conclusion, preventing osteonecrosis is feasible in a proportion of the pediatric acute lymphoblastic leukemia patients by discontinuous, instead of continuous, steroid scheduling. The questions as to how to treat childhood acute lymphoblastic leukemia patients with osteonecrosis cannot be answered as good-quality studies are lacking.

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 Conclusion This is the first study investigating the influence of genetic variation of the VDR, COLIA1, ESR1 and GR on body composition, BMD and fracture risk in pediatric ALL. We found the VDR 5'-end (Cdx-2/GATA) haplotype 3 as a protective factor for excessive fat gain during therapy. Moreover, this haplotype 3 of the VDR 5'-promoter was determined as risk factor for a lower BM(A)D-LS at diagnosis that remained during ALL treatment. Carriage of ESR1 (PvuII/XbaI) haplotype 3 negatively influenced recovery of lean body mass after treatment discontinuation. Disclosures No relevant conflicts of interest to declare.

Coagulation alterations may be involved in osteonecrosis in childhood acute lymphoblastic leukemia. Retrospectively, we evaluated the available coagulation parameters at diagnosis and during induction treatment of 161 acute lymphoblastic leukemia patients: 24 with symptomatic osteonecrosis (median age: 13.8 years, range 4.0-17.2) and 137 without osteonecrosis (median age: 4.9 years, range 1.0-16.7). Coagulation parameters of both groups were similar at diagnosis. After four weeks of treatment including dexamethasone, levels of antithrombin and protein S were significantly less in osteonecrosis-positive than in osteonecrosis-negative patients. Subsequently, after four doses of asparaginase and tapering dexamethasone, these coagulation parameters equally decreased in both groups. Consequently, nadirs of antithrombin and protein S were significantly lower in osteonecrosis-positive than in osteonecrosis-negative patients, even reaching levels below lower normal limits in the osteonecrosis-positive group. A reduced dexamethasone related increase of antithrombin and protein S, and subsequent decline below normal levels after introduction of asparaginase, may result in a hypercoagulable state, contributing to development of symptomatic osteonecrosis.

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 Conclusion: We conclude that symptomatic ON and low BMD during antileukemic treatment co-occur in pediatric ALL patients. BMD status at ALL diagnosis does not seem to precede ON. However, the development of ON seems to aggravate BMD decline during antileukemic treatment, most likely due to bone destruction and the advised physical immobilization. Disclosures No relevant conflicts of interest to declare.

Background: Body mass index (BMI: kg/m2) and change in BMI during treatment might influence treatment outcome of pediatric patients with acute lymphoblastic leukemia (ALL). However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. Therefore, we studiedthe influence of (change in) BMI on treatment outcome in pediatric ALL patients who were treated according to a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). Patients and Methods: Data on body composition were prospectively collected from a cohort of newly diagnosed Dutch pediatric ALL patients (N=762, age 2-17 years), treated from 1997-2004. BMI at diagnosis was expressed as standard deviation scores (SDS) and categorized into underweight (≤–1.8SDS), or normal weight and overweight (>–1.8SDS). BMI loss was defined after 32 weeks of treatment. Dual X-ray absorptiometry scans were performed in a nested single center cohort (n=106) to assess the contribution of %fat and lean body mass to BMI. Multivariate analyses were corrected for age at diagnosis and risk treatment grpup. Results: Multivariate analyses showed that patients with underweight (8%) had an increased risk of relapse (Hazard Ratio (HR) 1.79, 95% CI: [1.04-3.10], and a similar overall survival (HR 1.10 [0.57-2.10]). BMI loss during the first 32 weeks of treatment was associated with a decreased overall survival (HR 2.10 [1.14-3.87]), and a similar risk of relapse (HR 1.27 [0.70-2.30]) compared to patients without BMI loss. Dual X-ray absorptiometry revealed that BMI loss mainly consisted of a loss of lean body mass and gain in %fat. Conclusion: Underweight at diagnosis is associated with an increased risk of relapse and a BMI loss early during treatment is associated with an increased mortality. This suggests that these patients might benefit from exercise interventions and a high-quality nutrient diet during therapy. Disclosures No relevant conflicts of interest to declare.

Introduction: Methotrexate (MTX) is an important and effective chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). However MTX can induce toxicity, which can lead to amendments of treatment and subsequent impaired survival. The aim of this study was to identify metabolic and genetic determinants of MTX toxicity. Patients and Methods: In this prospective study, 134 Dutch pediatric ALL patients were treated with four high dosages MTX (HD-MTX: 5 g/m2) every other week according to the DCOG-ALL10 protocol. Toxicity was prospectively scored and a National Cancer Institute (NCI) grade ≥3 was considered clinically relevant toxicity. Plasma MTX levels were measured at 24 and 48 hours after each HD-MTX infusion. Erythrocyte folate, plasma folate and plasma homocysteine levels were determined at the start of protocol M. Seventeen single nucleotide polymorphisms (SNPs) in 7 candidate genes in the MTX pathway were analyzed. Results: Grade ≥3 mucositis occurred in 20% of the patients, skin toxicity in 7%, diarrhea in 3%, and neurotoxicity in 3%. Mucositis occurred especially after the first course compared to the other courses (p=0.006). Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher baseline levels of erythrocyte folate (median 1.2 μmol/L vs. 1.4 μmol/L, p Conclusion: Mucositis is the most frequent occurring toxicity during the HD-MTX phase in pediatric ALL treatment, and occurs especially after the first MTX course. Only a higher baseline erythrocyte folate, which reflects the accumulation of MTX polyglutamates in mucosal cells, and the wild-type variant of rs7317112 SNP in ABCC4 were determinants of mucositis in pediatric ALL during MTX-HD treatment. Disclosures No relevant conflicts of interest to declare.

Abstract 4296 Background Aim of this study was to investigate status and longitudinal evolvement of BMD in long-term adult survivors. Patients and methods A single-center cohort of 410 adult long-term survivors (171 females) was included in this retrospective study. Age at diagnosis was 6.6 years (0.0–16.8 yrs), and at follow up 24.5 years (18.0–49.3 yrs). Median follow-up time was 15.2 years (5.1–39.8 yrs). BMD of the lumbar spine (BMDLS) and total body (BMDTB) were measured. Results were compared with healthy age matched controls. Results Overall BMDTB and BMDLS were low in long-term survivors (median standard deviation score (SDS) −0.60, P < 0.001 and median SDS −0.40, P < 0.001 respectively). In ALL survivors both BMDTB (median SDS −0.65, P < 0.001) and BMDLS (median SDS −0.48, P < 0.001) were low. Backwards elimination of the multivariate linear regression analysis showed that both cranial irradiated and/or total body irradiated survivors were at significant risk for low BMDTB. BM(A)DLS was not different between survivors and controls and no risk factors were identified for low BM(A)DLS. In general, a slight but significant improvement of BMDTB and BMDLS was found in our sequential measurement. This BMD improvement was not found for ALL survivors alone. Conclusions Our study shows low BMD in childhood cancer survivors treated with cranial or total body irradiation. However, sequential DXA analysis shows ongoing recovery of bone mass, which suggests a potential for reaching peak bone mass later in life. Disclosures: No relevant conflicts of interest to declare.

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 Conclusion This large prospective study shows that the low value of BMDLS both at diagnosis and during treatment, rather than the treatment-related decline of BMDLS, determines the markedly increased fracture risk of 17.8%. Disclosures: No relevant conflicts of interest to declare.

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 Conclusion 6% of pediatric ALL patients developed symptomatic osteonecrosis during/shortly after treatment. Older age and female gender were risk factors after adjustment for treatment center. After a median follow-up of five years, 60% of the survivors with osteonecrosis had persistent symptoms. Disclosures: No relevant conflicts of interest to declare.

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.

Osteonecrosis (ON) is a serious complication of chemotherapy for pediatric acute lymphoblastic leukemia (ALL). Impairment of microcirculation seems to be involved in the pathogenesis of ON. We hypothesized that variation in hypercoagulability plays a role in the etiology of ON during treatment of ALL. Dexamethasone (dexa) and asparaginase (asp) are important drugs in the induction treatment of pediatric ALL that may influence the coagulation system. In the current study differences in coagulation parameters between pediatric ALL patients with and without ON were evaluated. Blood samples were taken at diagnosis and at several time-points during induction of the DCOG-ALL9 treatment schedule. Procoagulant factors (fibrinogen, factor II,V,VII,IX,X), anticoagulant factors (antithrombin (AT), protein C and protein S), parameters of thrombin generation (prothrombin fragment 1+2 (F1+2), thrombin antithrombin (TAT) complex) and of fibrinolysis (α2-antiplasmin (a2AP), plasminogen, plasmin-α2AP (PAP) complex, D-dimers) were determined. In total 137 patients without ON and 24 patients with ON were evaluated. In addition plasminogen activator inhibitor type 1 (PAI-1) activity and tissue plasminogen activator antigen (tPA-ag) concentration were studied in 25 patients, 15 without ON and 10 with ON. At diagnosis no significant differences in any of the coagulation parameters were found between patients with and without ON. After 4 weeks dexa treatment (day 29), AT, protein-C activity and protein-S total (anticoagulants) were significantly less upregulated in ON positive patients as compared to ON negative patients (respectively p=0.043, p=0.029, p=0.023). During tapering of dexa and administration of 4 doses asp at day 29, 33, 36 and 40 these parameters significantly decreased in both ON positive and negative patients. However, the nadir of these anticoagulant proteins reached lower levels in the ON positive patients as compared to ON negative patients and in ON positive patients levels even reached below lower limits of normal reference ranges. No other dexa or asp induced differences in any of the other coagulation parameters were found between ON negative and positive patients. These results indicate that development of ON in pediatric ALL patients seems to be associated with less upregulation of AT, protein C and protein S after 4 weeks treatment with dexa (day 29). ON positive patients subsequently declined below the lower limit of normal reference range during tapering of dexa and administration of asp in contrast to ON negative patients. This may suggest a therapy induced hypercoagulable state contributing to the development of ON.