Safety and Efficacy of Alendronate to Treat Osteopenia in Children During Therapy for Acute Lymphoblastic Leukemia: A Retrospective Cohort Study of Sequential Outcomes.

BACKGROUND: Low bone mineral density is encountered in children with acute lymphoblastic leukemia (ALL) before, during, and after treatment. Prior experience with alendronate, an oral bisphosphonate, demonstrated high tolerability and evident clinical efficacy. However, concerns have been expressed about the long-term safety and utility of such agents in children. PROCEDURE: Sixty-nine children with ALL received alendronate for a mean of 87 weeks after dual-energy radiograph absorptiometry. Dual-energy radiograph absorptiometry was repeated following the completion of alendronate, and 5 to 9 years later in a subgroup of 32 children. Lumbar spine areal bone mineral density (LS aBMD) Z scores were obtained. RESULTS: The mean LS aBMD Z score rose from -1.78 to-0.47 ( P <0.0001). There was a modest median loss of LS aBMD subsequently in the 32 subjects on long-term follow-up. Almost 80% (N=172) of the children remain in continuous complete remission at a mean of 14.5 years from diagnosis. Of those who received alendronate, which was almost uniformly well tolerated, 7/69 (10.3%) relapsed compared with 19/89 (21.3%) who did not receive the drug. DISCUSSION: Alendronate appears to be well tolerated and moderately effective in osteopenic children with ALL. Whether it offers protection against relapse of leukemia needs further study.

Relationships of Bone Mineral Density to Whole Body Mass, Fat Mass and Fat-free Mass in Long-term Survivors of Acute Lymphoblastic Leukemia in Childhood.

Body size influences bone mineral density (BMD) in health. Relationships of BMD with body mass index, fat mass (FM), fat-free mass, and appendicular lean mass were explored in acute lymphoblastic leukemia (ALL) survivors (n=75; 41 males; 45 standard risk ALL) >10 years from diagnosis. Dual energy radiograph absorptiometry performed body composition analysis. Relationships were assessed by regression analyses and Pearson correlation coefficients (r). Twenty subjects (26.3%) were osteopenic; lumbar spine (LS) BMD Z score <-1.00. Age at diagnosis, sex, ALL risk-category, type of post-induction steroid or cranial radiation did not correlate with LS or whole body (WB) BMD. Body mass index correlated significantly with LS BMD (r=0.333, P=0.004) and WB BMD (r=0.271, P=0.033). FM index (FM/height²) Z score showed no significant correlation with LS or WB BMD. Fat-free mass index Z score correlated strongly with LS BMD (r=0.386, P=0.013) and WB BMD (r=0.605, P<0.001) in males but not in females. The appendicular lean mass index, a surrogate for skeletal muscle mass, correlated significantly with LS BMD (r=0.367, P=0.018) and WB BMD (r=0.604, P<0.001) in males but not in females. Future studies to evaluate interventions to enhance BMD focused on improving body composition particularly skeletal muscle mass are warranted.

Body composition in long-term survivors of acute lymphoblastic leukemia diagnosed in childhood and adolescence: A focus on sarcopenic obesity.

BACKGROUND: The late effects of treatment for acute lymphoblastic leukemia (ALL) include disordered body composition, especially obesity. Less attention has been focused on the loss of skeletal muscle mass (SMM) and the combined morbidity of sarcopenic obesity. METHODS: A cross-sectional study of body composition was undertaken via dual-energy x-ray absorptiometry in 75 long-term survivors of ALL (more than 10 years after the diagnosis). Measures were obtained of the fat mass (FM), fat-free mass (equivalent to the lean body mass [LBM]), and whole-body bone mineral content. Health-related quality of life (HRQL) was measured with the Health Utilities Index. RESULTS: The sum of the FM, LBM, and whole-body bone mineral content matched the total body weight measured directly (r = 0.998). The appendicular lean mass (ALM) was derived from the LBM in all 4 limbs and accounted for approximately 75% of the SMM. According to the fat mass index (FMI; ie, FM/height2 ), 12% of females and 18% of males were frankly obese by World Health Organization criteria. The median FMI z score was + 0.40, whereas the median z score for the appendicular lean mass index (ALMI; ie, ALM/height2 ) was -0.40. Sarcopenic obesity, defined as a positive FMI z score with a negative ALMI z score, was present in 32 subjects (43%). There were statistically significant and clinically important differences in overall HRQL between subjects with and without sarcopenic obesity. CONCLUSIONS: Sarcopenic obesity is prevalent in long-term survivors of ALL, and this places them in double jeopardy from excess body fat and inadequate SMM (eg, a combination of metabolic and frailty syndromes). It is associated with an adverse impact on overall HRQL. Cancer 2018;124:1225-31. © 2017 American Cancer Society.

Physical Activity in Long-term Survivors of Acute Lymphoblastic Leukemia in Childhood and Adolescence: A Cross-sectional Cohort Study.

Inadequate physical activity (PA) and elevated overweight/obesity (OW/OB) rates are common in survivors of cancer in childhood, especially acute lymphoblastic leukemia (ALL). Bony morbidity, including fractures, is also prevalent among survivors of ALL. This study examined the interrelationships of PA, measured in hours by the Habitual Activity Estimation Scale; OW/OG, defined by body mass index; and fractures (yes/no) in survivors of ALL (n=75) more than 10 years after diagnosis. All had been treated using protocols of the Dana Farber Cancer Institute Childhood ALL Consortium. The median age was 21.15 years and time from diagnosis 15.07 years, and 27 subjects had experienced fractures. More than 30% of the total sample were OW/OB. There was no correlation of body mass index with present PA. There were no significant differences between those with/without fractures in terms of age, sex, time from diagnosis, and the prevalence of OW/OB. Subjects with fractures during treatment reported more total activity on typical weekend days than those without fractures (mean 8.8 vs. 6.9 h, P<0.01). There was no significant difference on weekdays. Higher activity on weekends suggests that fractures may have occurred more commonly in those who had a more active lifestyle before, during, and after treatment.

Neurobehavioral side effects of corticosteroids during active treatment for acute lymphoblastic leukemia in children are age-dependent: report from Dana-Farber Cancer Institute ALL Consortium Protocol 00-01.

BACKGROUND: Although corticosteroids remain a mainstay of treatment for acute lymphoblastic leukemia (ALL), they can cause troublesome neurobehavioral changes during active treatment, especially in young children. We evaluated acute neurobehavioral side effects of corticosteroid therapy in preschool versus school-age children by obtaining structured reports weekly for 1 month. PROCEDURE: Parents of 62 children (2-17 years) treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 00-01 participated during the continuation phase of treatment. Patients received cyclical twice-daily 5-day courses of prednisone (PRED; 40 mg/m(2) /day) or dexamethasone (DEX; 6 mg/m(2) /day). Parents completed behavior rating scales about their child weekly during one steroid cycle [baseline (Day 0), active steroid (Day 7), post-steroid (Days 14 and 21)]. RESULTS: Behavioral side effects increased significantly (P < 0.001) during the steroid week for preschool children (<6 years) on measures of emotional control, mood, behavior regulation, and executive functions, returning to baseline during the two "off-steroid" weeks. In contrast, school-age children (≥ 6 years) did not demonstrate an increase in side effects during the steroid week. Steroid type (PRED vs. DEX) was not a significant predictor of neurobehavioral side effects. CONCLUSIONS: Preschool children are at greater risk for neurobehavioral side effects during active steroid treatment for ALL than school-age children and adolescents. DEX was not associated with more neurobehavioral side effects than PRED. Counseling of families about side-effects should be adapted according to age. The observed effects, moreover, were transient, reducing concerns about longer-term neurobehavioral toxicities.

Targeting synovial fibroblast proliferation in rheumatoid arthritis (TRAFIC): an open-label, dose-finding, phase 1b trial.

BACKGROUND: Current rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts-cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics. METHODS: Phase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR-European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (Cmax) and area under the plasma concentration time curve 0-6 h (AUC0-6) were measured. This study is registered with ISRCTN, ISRCTN36667085. FINDINGS: Between Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18-0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average Cmax and AUC0-6 were two-times higher in participants developing dose-limiting toxicities. INTERPRETATION: The maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial. FUNDING: UK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities.

Targeting the rheumatoid arthritis synovial fibroblast via cyclin dependent kinase inhibition: An early phase trial.

INTRODUCTION: Targeted biologic therapies demonstrate similar efficacies in rheumatoid arthritis despite distinct mechanisms of action. They also exhibit a ceiling effect, with 10% to 20% of patients achieving remission in clinical trials. None of these therapies target synovial fibroblasts, which drive and maintain synovitis. Seliciclib (R-roscovitine) is an orally available cyclin-dependent kinase inhibitor that suppresses fibroblast proliferation, and is efficacious in preclinical arthritis models. We aim to determine the toxicity and preliminary efficacy of seliciclib in combination with biologic therapies, to inform its potential as an adjunctive therapy in rheumatoid arthritis. METHODS AND ANALYSIS: TRAFIC is a non-commercial, multi-center, rolling phase Ib/IIa trial investigating the safety, tolerability, and efficacy of seliciclib in patients with moderate to severe rheumatoid arthritis receiving biologic therapies. All participants receive seliciclib with no control arm. The primary objective of part 1 (phase Ib) is to determine the maximum tolerated dose and safety of seliciclib over 4 weeks of dosing. Part 1 uses a restricted 1-stage Bayesian continual reassessment method based on a target dose-limiting toxicity probability of 35%. Part 2 (phase IIa) assesses the potential efficacy of seliciclib, and is designed as a single arm, single stage early phase trial based on a Fleming-A'Hern design using the maximum tolerated dose recommended from part 1. The primary response outcome after 12 weeks of therapy is a composite of clinical, histological and magnetic resonance imaging scores. Secondary outcomes include adverse events, pharmacodynamic and pharmacokinetic parameters, autoantibodies, and fatigue. ETHICS AND DISSEMINATION: The study has been reviewed and approved by the North East - Tyne & Wear South Research Ethics Committee (reference 14/NE/1075) and the Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom. Results will be disseminated through publication in relevant peer-reviewed journals and presentation at national and international conferences. TRIALS REGISTRATION: ISRCTN, ISRCTN36667085. Registered on September 26, 2014; http://www.isrctn.com/ISRCTN36667085Current protocol version: Protocol version 11.0 (March 21, 2019).

Impact of short stature on health-related quality of life in long-term survivors of acute lymphoblastic leukemia in childhood and adolescence.

PURPOSE: Some survivors of acute lymphoblastic leukemia (ALL) in childhood and adolescence exhibit short stature, especially if their treatment included cranial irradiation. The impact of this outcome on health-related quality of life (HRQL) is uncertain and so formed the basis for the investigation reported here. METHODS: This study examined the association between self-reported HRQL and measured height in a cohort (n = 75) of survivors of ALL more than 10 years from diagnosis. HRQL was expressed as utility scores generated from a multi-attribute preference-based measure, the Health Utilities Index (HUI) which includes the complementary systems HUI2 and HUI3. For single attributes the range is from 1.00 (no limitations) to 0.00 (lowest level of function). For overall HRQL the range is 1.00 (perfect health) to 0.00 (equivalent to being dead). A negative score is associated with states of health worse than being dead. RESULTS: There were no statistically significant differences in overall HRQL between subjects <25th (n = 16, 21%), 15th (n = 11, 15%) and 10th (n = 10, 13%) centiles. A greater amount of emotional morbidity, focused on anger and depression, was manifest in those <25th and 15th centiles, with clinically important differences of 0.07 (p = 0.03) and 0.077 (p = 0.016) respectively, but not in the shortest group who were < 10th centile. CONCLUSIONS: Studies in large cohorts of young adults in the general population has reported an inconsistent relationship between height and HRQL. Results from the current study suggest that no such relationship exists in long-term survivors of ALL in childhood and adolescence.

Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial.

Importance: There are no medical interventions for the orphan disease CYLD cutaneous syndrome (CCS). Transcriptomic profiling of CCS skin tumors previously highlighted tropomyosin receptor kinases (TRKs) as candidate therapeutic targets. Objective: To investigate if topical targeting of TRK with an existing topical TRK inhibitor, pegcantratinib, 0.5% (wt/wt), is safe and efficacious in CCS. Design, Setting, and Participants: A phase 1b open-label safety study, followed by a phase 2a within-patient randomized (by tumor), double-blind, placebo-controlled trial (the Tropomyosin Receptor Antagonism in Cylindromatosis [TRAC] trial). The setting was a single-center trial based at a tertiary dermatogenetics referral center for CCS (Royal Victoria Infirmary, Newcastle, United Kingdom). Patients who had germline mutations in CYLD or who satisfied clinical diagnostic criteria for CCS were recruited between March 1, 2015, and July 1, 2016. Interventions: In phase 1b, patients with CCS applied pegcantratinib for 4 weeks to a single skin tumor. In phase 2a, allocation of tumors was to either receive active treatment on the right side and placebo on the left side (arm A) or active treatment on the left side and placebo on the right side (arm B). Patients were eligible if they had 10 small skin tumors, with 5 matched lesions on each body side; patients were randomized to receive active treatment (pegcantratinib) to one body side and placebo to the other side once daily for 12 weeks. Main Outcomes and Measures: The primary outcome measure was the number of tumors meeting the criteria for response in a prespecified critical number of pegcantratinib-treated tumors. Secondary clinical outcome measures included an assessment for safety of application, pain in early tumors, and compliance with the trial protocol. Results: In phase 1b, 8 female patients with a median age of 60 years (age range, 41-80 years) were recruited and completed the study. None of the participants experienced any adverse treatment site reactions. Three patients reported reduced pain in treated tumors. In phase 2a (15 patients [13 female; median age, 51 years], with 150 tumors), 2 tumors treated with pegcantratinib achieved the primary outcome measure of response compared with 6 tumors treated with placebo. The primary prespecified number of responses was not met. The incidence of adverse events was low. Conclusions and Relevance: In this study, pegcantratinib, 0.5% (wt/wt), applied once daily appeared to be well tolerated and to penetrate the tumor tissue; however, the low tumor drug concentrations demonstrated are likely to account for the lack of response. Dose-escalation studies to assess the maximal tolerated dose may be beneficial in future studies of CCS. Trial Registration: isrctn.org Identifier: ISRCTN75715723.

Anthropometry in Long-Term Survivors of Acute Lymphoblastic Leukemia in Childhood and Adolescence.

PURPOSE: Body mass index (BMI) is an inadequate measure of nutritional status in children and adolescents with cancer as it does not distinguish muscle from adipose tissue. However, arm anthropometry offers simple assessments of fat mass and lean body mass; especially valuable in low- and middle-income countries where the great majority of young people with cancer live and access to sophisticated expensive measures of body composition is markedly limited. METHODS: The nutritional status of 75 long-term survivors of acute lymphoblastic leukemia was assessed by arm anthropometry, in addition to BMI, in a cross-sectional cohort study. Normal ranges for triceps skin fold thickness (TSFT, a surrogate for fat mass) and mid-upper arm circumference (MUAC, a surrogate for lean body mass) were between the 15th and 85th percentiles for age and sex. Overweight/obesity was classified as a TSFT >85th percentile and sarcopenia as an MUAC <15th percentile. Height normalized indices for TSFT and MUAC were also calculated. RESULTS: Overweight/obesity was identified in 1/3 of subjects by a BMI >25 and by TSFT; and 20% of the subjects had a TSFT >95th percentile. Only two subjects were sarcopenic. None met the combined criteria for sarcopenic obesity. TSFT and MUAC/height indices did not add sensitivity to identification of sarcopenia or obesity. CONCLUSIONS: TSFT is a useful measure of overweight/obesity in this population, but MUAC does not identify a notable proportion with sarcopenia. Further resolution may be provided by more sophisticated measures of body composition.

Tropomyosin Receptor Antagonism in Cylindromatosis (TRAC), an early phase trial of a topical tropomyosin kinase inhibitor as a treatment for inherited CYLD defective skin tumours: study protocol for a randomised controlled trial.

BACKGROUND: Patients with germline mutations in a tumour suppressor gene called CYLD develop multiple, disfiguring, hair follicle tumours on the head and neck. The prognosis is poor, with up to one in four mutation carriers requiring complete surgical removal of the scalp. There are no effective medical alternatives to treat this condition. Whole genome molecular profiling experiments led to the discovery of an attractive molecular target in these skin tumour cells, named tropomyosin receptor kinase (TRK), upon which these cells demonstrate an oncogenic dependency in preclinical studies. Recently, the development of an ointment containing a TRK inhibitor (pegcantratinib - previously CT327 - from Creabilis SA) allowed for the assessment of TRK inhibition in tumours from patients with inherited CYLD mutations. METHODS/DESIGN: Tropomysin Receptor Antagonism in Cylindromatosis (TRAC) is a two-part, exploratory, early phase, single-centre trial. Cohort 1 is a phase 1b open-labelled trial, and cohort 2 is a phase 2a randomised double-blinded exploratory placebo-controlled trial. Cohort 1 will determine the safety and acceptability of applying pegcantratinib for 4 weeks to a single tumour on a CYLD mutation carrier that is scheduled for a routine lesion excision (n = 8 patients). Cohort 2 will investigate if CYLD defective tumours respond following 12 weeks of treatment with pegcantratinib. As patients have multiple tumours, we intend to treat 10 tumours in each patient, 5 with active treatment and 5 with placebo. Patients will be allocated both active and placebo treatments to be applied randomly to tumours on the left or right side. The target is to treat 150 tumours in a maximum of 20 patients. Tumour volume will be measured at baseline and at 4 and 12 weeks. The primary outcome measure is the proportion of tumours responding to treatment by 12 weeks, based on change in tumour volume, with secondary measures based on adverse event profile, treatment compliance and acceptability, changes in tumour volume and surface area, patient quality of life and pain. DISCUSSION: Interventions for rare genetic skin diseases are often difficult to assess in an unbiased way due to small patient numbers and the challenges of incorporating adequate controls into trial design. Here we present a single-centre, randomised, placebo-controlled trial design that leverages the multiplicity of tumours seen in an inherited skin tumour syndrome that may inform the design of other studies in similar genetic diseases. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number Registry, ISRCTN75715723 . Registered on 22 October 2014.

Increased severity of respiratory infections associated with elevated anti-LPS IgG2 which inhibits serum bactericidal killing.

Although specific antibody induced by pathogens or vaccines is a key component of protection against infectious threats, some viruses, such as dengue, induce antibody that enhances the development of infection. In contrast, antibody-dependent enhancement of bacterial infection is largely unrecognized. Here, we demonstrate that in a significant portion of patients with bronchiectasis and Pseudomonas aeruginosa lung infection, antibody can protect the bacterium from complement-mediated killing. Strains that resist antibody-induced, complement-mediated killing produce lipopolysaccharide containing O-antigen. The inhibition of antibody-mediated killing is caused by excess production of O-antigen-specific IgG2 antibodies. Depletion of IgG2 to O-antigen restores the ability of sera to kill strains with long-chain O-antigen. Patients with impaired serum-mediated killing of P. aeruginosa by IgG2 have poorer respiratory function than infected patients who do not produce inhibitory antibody. We suggest that excessive binding of IgG2 to O-antigen shields the bacterium from other antibodies that can induce complement-mediated killing of bacteria. As there is significant sharing of O-antigen structure between different Gram-negative bacteria, this IgG2-mediated impairment of killing may operate in other Gram-negative infections. These findings have marked implications for our understanding of protection generated by natural infection and for the design of vaccines, which should avoid inducing such blocking antibodies.

The immediate effect of triceps surae myofascial trigger point therapy on restricted active ankle joint dorsiflexion in recreational runners: a crossover randomised controlled trial.

OBJECTIVES: To investigate the immediate effect on restricted active ankle joint dorsiflexion range of motion (ROM), after a single intervention of myofascial trigger point (MTrP) therapy on latent triceps surae MTrPs in recreational runners. DESIGN: A crossover randomised controlled trial. PARTICIPANTS: Twenty-two recreational runners (11 men and 11 women; mean age 24.57; ±8.7 years) with a restricted active ankle joint dorsiflexion and presence of latent MTrPs. INTERVENTION: Participants were screened for a restriction in active ankle dorsiflexion in either knee flexion (soleus) or knee extension (gastrocnemius) and the presence of latent MTrPs. Participants were randomly allocated a week apart to both the intervention (combined pressure release and 10 s passive stretch) and the control condition. RESULTS: A clinically meaningful (large effect size) and statistically significant increase in ankle ROM in the intervention compared to the control group was achieved, for the soleus (p = 0.004) and the gastrocnemius (p = 0.026). CONCLUSION: Apart from the statistical significance (p < 0.05), these results are clinically relevant due to the immediate increase in ankle dorsiflexion. These results must be viewed in caution due to the carry-over effect in the RCT crossover design and the combined MTrP therapy approach.

Health status and health-related quality of life in adolescent survivors of cancer in childhood.

PURPOSE: Adolescent survivors of cancer in childhood face particular challenges due to their maturational trajectory, including psychosocial adjustments, self-help skills, intellectual functioning and socialization. To better understand these, we assessed the health status and health-related quality of life (HRQL) in a 20-year cohort of such survivors in a single institution. METHODS: Health status and HRQL were measured with a self-complete questionnaire from the Health Utilities Index (HUI) family of multi-attribute, preference-based instruments that provide utility scores for single attributes and overall HRQL. RESULTS: Eighty-four (42 males, 42 females) of 129 eligible subjects (65%) participated. More than 80% of the respondents reported some form of morbidity. Overall HRQL utility scores were lower for both the males and females than for corresponding members of the Canadian general population. Female survivors self-reported a significantly greater burden of morbidity (mean overall HUI2/HUI3 scores: .83/.73 vs. .90/.84 for males, p < .02), which was most evident in the attributes of emotion and cognition. CONCLUSIONS: The majority of adolescent survivors of cancer in childhood carry a morbidity burden into their teen and young adult years. These findings may guide the support required by this population.