Aggravated bone density decline following symptomatic osteonecrosis in children with acute lymphoblastic leukemia.

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<0.01 and with osteonecrosis: -1.73 versus without osteonecrosis: -0.57, P<0.01). Multivariate linear models showed that patients with osteonecrosis had steeper BMDLS and BMDTB declines during follow-up than patients without osteonecrosis (interaction group time, P<0.01 and P<0.01). We conclude that bone density status at the diagnosis of acute lymphoblastic leukemia does not seem to influence the occurrence of symptomatic osteonecrosis. Bone density declines from the time that osteonecrosis is diagnosed; this suggests that the already existing decrease in bone density during acute lymphoblastic leukemia therapy is further aggravated by factors such as restriction of weight-bearing activities and destruction of bone architecture due to osteonecrosis. Osteonecrosis can, therefore, be considered a risk factor for low bone density in children with acute lymphoblastic leukemia.

The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia.

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).

Bone mineral density at diagnosis determines fracture rate in children with acute lymphoblastic leukemia treated according to the DCOG-ALL9 protocol.

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≤-2 SDS combined with clinical significant fractures. RESULTS: The 3-year cumulative fracture incidence was 17.8%. At diagnosis, mean BMDLS of ALL patients was lower than of healthy peers (mean BMDLS=-1.10 SDS, P<0.001), and remained lower during/after treatment (8months: BMDLS=-1.10 SDS, P<0.001; 24months: BMDLS=-1.27 SDS, P<0.001; 36months: BMDLS=-0.95 SDS, P<0.001). Younger age, lower weight and B-cell-immunophenotype were associated with a lower BMDLS at diagnosis. After correction for weight, height, gender and immunophenotype, stratification to the high risk (HR)-protocol arm and older age lead to a larger decline of BMDLS (HR group: ß=-0.52, P<0.01; age: ß=-0.16, P<0.001). Cumulative fracture incidences were not different between ALL risk groups and age groups. Patients with fractures had a lower BMDLS during treatment than those without fractures. Treatment-related bone loss was similar in patients with and without fractures (respectively: ΔBMDLS=-0.36 SDS and ΔBMDLS=-0.12 SDS; interaction group time, P=0.30). Twenty of the 399 patients (5%) met the criteria of osteoporosis. CONCLUSION: Low values of BMDLS at diagnosis and during treatment, rather than the treatment-related decline of BMDLS, determine the increased fracture risk of 17.8% in children with ALL.

Prospective study on incidence, risk factors, and long-term outcome of osteonecrosis in pediatric acute lymphoblastic leukemia.

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.

Pegfilgrastim in pediatric cancer patients.

Chemotherapy-induced neutropenia is a major dose-limiting side effect of intensive chemotherapy in cancer patients. Recently, pegfilgrastim (a product with a long half-life, resulting in once-per-cycle dosage) was introduced to prevent neutropenia in adults. The authors report 32 episodes of pegfilgrastim use in seven pediatric cancer patients to diminish chemotherapy-induced neutropenia. Feasibility was assessed by adherence to treatment protocol and safety was assessed by adverse effects. There were only two treatment delays (6%) due to neutropenia. No short-term adverse effects were recorded. The use of pegfilgrastim is feasible in pediatric cancer patients, without short-term adverse effects or major treatment delay due to neutropenia.

Bone histomorphometry in children with newly diagnosed acute lymphoblastic leukemia.

The objective of this study was to obtain insight into bone formation and resorption in children with newly diagnosed untreated acute lymphoblastic leukemia (ALL). In 23 consecutive children with ALL, a bone biopsy was taken from the crista iliaca posterior under ketamine anesthesia, together with the diagnostic marrow aspiration, before any treatment was given. Histomorphometric assessment was done of bone volume, bone area, trabecular thickness, osteoid volume, osteoid area, osteoid width, number of osteoblasts, erosion area, and number of osteoclasts. Data were analyzed in age groups under and over 10 y and compared with biopsies from 15 children, obtained during the work-up for other malignancies (only patients without bone marrow involvement were included). In ALL patients, bone volume and trabecular thickness were decreased in children <10 y. In patients >10 y, these parameters were not significantly different from the controls; bone densitometry showed no significant loss of bone in patients >10 y as well. Numbers of osteoblasts and osteoid surface occupied with osteoblasts were reduced in both age groups, as was the number of resorbing osteoclasts. No indications of osteomalacia were found. Childhood ALL results in a reduced number of both osteoblasts and osteoclasts, with a subsequent reduced osteoid formation and reduced bone resorption. This leads to a reduced bone volume and trabecular thickness, especially in younger children. In adolescents, the disturbance of bone (re)modeling is less serious, probably because of the strong stimulus on bone formation of sex hormones. The skeletal impairment at diagnosis is potentially reversible.