Maintenance therapy and risk of osteonecrosis in children and young adults with acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study.

PURPOSE: Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. METHODS: We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. RESULTS: After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. CONCLUSION: Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

Dyslipidemia at diagnosis of childhood acute lymphoblastic leukemia.

As survival of acute lymphoblastic leukemia (ALL) exceeds 90%, limiting therapy-related toxicity has become a key challenge. Cardio-metabolic dysfunction is a challenge during and after childhood ALL therapy. In a single center study, we measured triglycerides (TG), total cholesterol (TC), high (HDL) and low density lipoproteins (LDL) levels at diagnosis and assessed the association with BMI, early therapy response, on-therapy hyperlipidemia and the toxicities; thromboembolism, osteonecrosis and pancreatitis. We included 127 children (1.0-17.9 years) all treated according to the NOPHO ALL2008 protocol. Dyslipidemia was identified at ALL-diagnosis in 99% of the patients, dominated by reduced HDL levels (98%) and mild hypertriglyceridemia (61%). Hypertriglyceridemia was not associated with body mass index (P = 0.71). Five percent of patients had mild hypercholesterolemia, 14% had mild hypocholesterolemia, 13% had decreased and 1% elevated LDL-levels. Increased TG and TC levels at ALL-diagnosis were not associated with any on-therapy lipid levels. Lipid levels and BMI were not associated to MRD after induction therapy; However, BMI and hypercholesterolemia were associated with worse risk group stratification (P<0.045 for all). The cumulative incidence of thromboembolism was increased both for patients with hypo- (20.0%) and hypercholesterolemia (16.7%) compared to patients with normal TC levels (2.2%) at diagnosis (P = 0.0074). In conclusion, dyslipidemic changes were present prior to ALL-therapy in children with ALL but did not seem to affect dysmetabolic traits during therapy and were not predictive of on-therapy toxicities apart from an association between dyscholesterolemia at time of ALL-diagnosis and risk of thromboembolism. However, the latter should be interpreted with caution due to low number in the groups.

Comparing osteonecrosis clinical phenotype, timing, and risk factors in children and young adults treated for acute lymphoblastic leukemia.

BACKGROUND: Treatment-related osteonecrosis (ON) is a serious complication of treatment of acute lymphoblastic leukemia (ALL). PROCEDURE: This study included 1,489 patients with ALL, aged 1-45 years, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, using alternate-week dexamethasone during delayed intensification, with prospective registration of symptomatic ON. We aimed at comparing risk factors, timing, and clinical characteristics of ON in children and young adults. RESULTS: ON was diagnosed in 67 patients, yielding a 5-year cumulative incidence of 6.3%, but 28% in female adolescents. Median age at ALL diagnosis was 12.1 years and 14.9 years for females and males, respectively. At ON diagnosis, 59 patients had bone pain (91%) and 30 (46%) had multiple-joint involvement. The median interval between ALL and ON diagnosis was significantly shorter in children aged 1.0-9.9 years (0.7 years [range: 0.2-2.1]) compared with adolescents (1.8 years [range: 0.3-3.7, P < 0.001]) and adults (2.1 years [range: 0.4-5.3, P = 0.001]). Female sex was a risk factor in adolescent patients (hazard ratio [HR] = 2.1, 95% confidence interval [CI]: 1.1-4.2) but not in children aged 1.1-9.9 years (HR = 2.4, 95% CI: 0.9-6.2, P = 0.08) or adults aged 19-45 years (HR = 1.1, 95% CI: 0.3-4.0). Age above 10 years at ALL diagnosis (odds ratio [OR] = 3.7, P = 0.026) and multiple joints affected at ON diagnosis (OR = 3.4, P = 0.027) were risk factors for developing severe ON. CONCLUSION: We provide a detailed phenotype of patients with ALL with symptomatic ON, including description of risk factors and timing of ON across age groups. This awareness is essential in exploring measures to prevent development of ON.

Early presentation of osteonecrosis in acute lymphoblastic leukemia: Two children from the Nordic and Baltic cohort.

Osteonecrosis (ON) is usually considered treatment related in patients with acute lymphoblastic leukemia (ALL). We report two patients with presentation of ON at the time of ALL diagnosis. Both were females and diagnosed with ALL at age 8 and 14 years. In the latter, some symptoms and radiologically verified ON in both knees were still present after the end of ALL therapy. No pediatric patients have previously been reported with ON presenting before initiation of ALL therapy.

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy.

During chemotherapy for childhood acute lymphoblastic leukemia, all organs can be affected by severe acute side effects, the most common being opportunistic infections, mucositis, central or peripheral neuropathy (or both), bone toxicities (including osteonecrosis), thromboembolism, sinusoidal obstruction syndrome, endocrinopathies (especially steroid-induced adrenal insufficiency and hyperglycemia), high-dose methotrexate-induced nephrotoxicity, asparaginase-associated hypersensitivity, pancreatitis, and hyperlipidemia. Few of the non-infectious acute toxicities are associated with clinically useful risk factors, and across study groups there has been wide diversity in toxicity definitions, capture strategies, and reporting, thus hampering meaningful comparisons of toxicity incidences for different leukemia protocols. Since treatment of acute lymphoblastic leukemia now yields 5-year overall survival rates above 90%, there is a need for strategies for assessing the burden of toxicities in the overall evaluation of anti-leukemic therapy programs.

Endocrine evaluation of reproductive function in girls during infancy, childhood and adolescence.

Puberty is characterized by a series a hormonal events leading to the attainment of adult reproductive capacity. Clinical manifestations of the pubertal processes include breast development, pubic hair development, menarche and regular menstrual bleedings. Abnormal pubertal development includes a spectrum of disorders such as premature thelarche, premature adrenarche, central and peripheral precocious puberty, adolescent polycystic ovarian syndrome, functional ovarian hyperandrogenism, late-onset congenital adrenal hyperplasia, primary and secondary amenorrhea, and premature ovarian insufficiency. Diagnosis of these reproductive disorders includes biochemical as well as clinical evaluation. The biochemical evaluation of reproductive function includes measurement of basal reproductive hormone levels and dynamic pituitary or adrenal hormone testing. Correct interpretation of such test results requires detailed knowledge on the normal maturational changes in the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes. Changes in basal reproductive hormone levels in infancy, childhood and adolescence as well as the GnRH and ACTH test procedures in girls and adolescents are described in this chapter.

Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty.

The decline in age at puberty in the general population has been paralleled by an increase in the number of girls referred for evaluation of precocious puberty (PP). In 1999, The Lawson Wilkins Pediatric Endocrine Society recommended a lowering of the age limit for evaluation of PP in girls. However, the limited evidence on which these recommendations were based led many experts to question these new suggestions. The emergence of new European pubertal timing data evaluated by robust clinical as well as biochemical markers has broadened our insight on how to interpret the recent pubertal changes. The recent pubertal trends have resulted in a concomitant lowering of the lower limit of normality of the pubertal onset. However, evidence suggests that age at the gonadotropin and sex steroid surges have not changed. Thus, it looks as if an increasing proportion of contemporary early pubertal girls may experience isolated gonadotropin-independent thelarche rather than central PP, which may not be discernible on pubertal examination alone. Thus, the population-based limits of normality should not be directly translated into revision of age limits for evaluation of PP due to the risk of misdiagnosing rapid progressive PP as well as intracranial and other underlying pathology.

Pathological and incidental findings on brain MRI in a single-center study of 229 consecutive girls with early or precocious puberty.

UNLABELLED: Central precocious puberty may result from organic brain lesions, but is most frequently of idiopathic origin. Clinical or biochemical factors which could predict a pathological brain MRI in girls with CPP have been searched for. With the recent decline in age at pubertal onset among US and European girls, it has been suggested that only girls with CPP below 6 years of age should have brain MRI performed. OBJECTIVE: To evaluate the outcome of brain MRI in girls referred with early signs of puberty in relation to age at presentation as well as clinical and biochemical parameters. METHOD: A single-center study of 229 consecutive girls with early or precocious puberty who had brain imaging performed. We evaluated medical history, clinical and biochemical factors, and four groups were defined based on the outcome of their MRI. RESULTS: Thirteen out of 208 (6.3%) girls with precocious puberty, but no other sign of CNS symptoms, had a pathological brain MRI. Importantly, all 13 girls were above 6 years of age, and 6 girls were even 8-9 years old. Twenty girls (9.6%) had incidental findings on brain MRI. Furthermore, 21 girls had known CNS pathology at time of evaluation. Basal LH was significantly higher in girls with newly diagnosed CNS pathology compared to girls with a non-pathological MRI (p = 0.025); no cut of value was found as values overlapped. CONCLUSION: A high frequency of 6-8 year old girls with precocious puberty in our study had a pathological brain MRI, which could not be predicted from any clinical nor biochemical parameters. Thus, we believe that girls with precocious pubertal development of central origin before 8 years of age should continue to be examined by a brain MRI.

Diagnostic work-up of 449 consecutive girls who were referred to be evaluated for precocious puberty.

OBJECTIVE: A decrease in age at pubertal onset has been observed internationally. The aim of this study was to describe a large cohort of Caucasian girls referred with signs of early puberty according to etiology and compare biochemical characteristics. METHODS: In this single-center study, we included 449 consecutive Caucasian girls who were referred with signs of early puberty during the years 1993-2009. We evaluated pubertal stage, height, weight, and bone age. FSH, LH, estradiol, and inhibin B were determined, and a standard GnRH test was performed. Brain magnetic resonance imaging was performed to rule out pathologies. RESULTS: During the period from 1993-2008, we found an increase in the number of girls in most diagnostic groups. Of 449 girls, 88 had central precocious puberty (CPP), and 12 of these had an organic origin. A total of 129 had early-normal variant (8-9 yr), 69 had premature thelarche, and 49 premature adrenarche. Receiver operating characteristic analyses revealed that basal LH was superior in predicting the maximal LH level during GnRH testing in comparison with FSH, estradiol, and inhibin B levels. Basal LH levels were above the age-related 2 sd in 26.2, 19.6, 65.1, and 75.0% of girls with, respectively, early-normal variant, premature thelarche, idiopathic CPP, and organic CPP, but LH levels below the detection limit were also seen among girls with a pubertal GnRH test. CONCLUSION: We observed an increasing number of girls referred because of early pubertal signs. An elevated basal LH was highly predictive of a pubertal GnRH test result, whereas a low LH did not exclude central pubertal activation.

Insulin sensitivity and lipid profiles in girls with central precocious puberty before and during gonadal suppression.

CONTEXT: Early menarche is associated with increased risk of cardiovascular disease in adulthood. It is unknown whether metabolic risk factors are adversely affected in girls with central precocious puberty (CPP) already at time of diagnosis. OBJECTIVE: The objective of the study was to evaluate metabolic profiles in girls with early normal puberty (EP) and CPP. DESIGN AND SETTING: This was a combined cross-sectional and longitudinal study at a tertiary center of pediatric endocrinology. PATIENTS AND INTERVENTION: Twenty-three girls with EP or CPP and 115 controls with normal pubertal timing were evaluated by oral glucose tolerance test, dual-energy x-ray absorptiometry scan, and fasting blood samples. Fifteen girls (13 CPP) were treated with GnRH agonists (GnRHa) and reevaluated after 12 and 52 wk of treatment. MAIN OUTCOME MEASURES: Insulin and glucose levels during oral glucose tolerance test and fasting lipid levels were measured. RESULTS: At the time of diagnosis, girls with CPP had higher fasting insulin, triglyceride, and low-density lipoprotein-cholesterol levels as well as lower insulin sensitivity and high-density lipoprotein/total cholesterol ratios (all P<0.05) compared with controls after adjustment for pubertal stage and body fat percentage. Age at pubertal onset positively predicted insulin sensitivity for a given pubertal stage (P=0.04) in girls with EP and CPP. Insulin sensitivity decreased significantly during 1 yr of GnRHa treatment (P=0.04). CONCLUSIONS: Girls with CPP had adverse metabolic profiles at the time of diagnosis compared with puberty-matched controls. In addition, those with the earliest onset of puberty had the most adverse metabolic profiles. Surprisingly, metabolic profiles deteriorated even further after withdrawal of sex steroids by GnRHa treatment.