Background and Aims

This study’s purpose was to evaluate the feasibility, safety, and efficacy trends of intratympanic sustained-exposure dexamethasone thermosensitive gel (OTO-104) for preventing cisplatin-induced hearing loss (CIHL).

Methods

This IRB-approved, randomized phase 2 trial was conducted at 8 centers in the United States (January-September 2017). Eligibility criteria were age 0.5-21 years; new diagnosis of neuroblastoma, hepatoblastoma, osteosarcoma, or extracranial germ cell tumor; planned cumulative cisplatin dose ≥ 200 mg/m²; normal baseline hearing and otoscopy. Participant ears were randomized for intratympanic injection of 0.2 ml OTO-104 6% in one and no treatment in the other. OTO-104 was administered through a 25-27 gauge needle by an otolaryngologist during other procedural sedation within 72 hours before cisplatin cycles (including multiday regimens). Feasibility was assessed by successful administration of intended OTO-104 doses. Adverse events (AEs) were monitored by physical examination, otoscopy, tympanometry, concurrent medications, and audiometry.

Results

Eighteen doses of OTO-104 were administered to 11 evaluable participants at 5 centers (median age 3 years, range 1-14; 6 female; 9 neuroblastoma, 2 osteosarcoma). Five participants received 1 dose, five received 2 doses, and one received 3 doses. OTO-104 was administered via intratympanic injection (9) or tympanostomy tubes (2). Sixteen injections were done during other procedural sedation; 2 were done awake. The median interval between OTO-104 and cisplatin was 14 hours (range 7-64). OTO-104 injection was successful in all 18 procedures. At end of study, clinically insignificant tympanic membrane scabs developed in 5 participants, but no pinna, external canal, or middle-ear changes were noted. No tympanogram shifts were noted. There were 5 otologic treatment-emergent AEs (2 transient mild-moderate otalgia [related] and 1 hypoacusis [unrelated]) and no related non-otologic treatment-emergent AEs. Sensorineural CIHL developed similarly in treated and untreated ears.

Conclusions

Intratympanic administration of OTO-104 to young children is feasible and safe. Further investigation using this route for preventing CIHL is warranted.

Background and Aims

Symptoms and associated distress in children diagnosed and treated for cancer is uniformly common, yet structured and systematic symptom monitoring is not yet commonplace. With increasing pressures on the healthcare workforce, improved systematic approaches to symptom management are required.

Methods

Following a review of relevant literature, the Sympotm Screening Pediatrics tool(SSPedi), a Patient-Reported Outcome Measure (PROM) validated for children with cancer (4-18 years) was selected as an appropriate measure to explore routine assessment of symptom burden. Medical, nursing and allied health oncology clinicians developed algorithms using consensus techniques to ascertain thresholds of concern for each symptom. Algorithm vetting and refinement were achieved through iterative interviews and consultation with clinicians. Self-management evidence-based recommendations for each symptom were also developed. Each algorithm uses a three-tiered ‘traffic light’ model to outline the appropriate management and resources to support clinical staff with evidence-based symptom management were also developed. The algorithms were incorporated into a smartphone application (app), and an iterative evaluation is planned to test safety, implementation, and efficacy of the app.

Results

Digital solutions provide alternative options for communication, information, and education and harness the best of community and hospital services. The RESPONSE system is a comprehensive approach to symptom management that includes a suite of tools and resources including a smartphone app that collects PROMs and delivers symptom management advice, as well as written resources for both the families of children with cancer and clinicians.

Conclusions

Children with cancer and their families have a distinct need for support, which includes information and education about managing the acute, and long-term impacts of cancer and cancer treatment. Incorporating technological and digital solutions offer new ways to consider how families and clinicians communicate and share information. We will evaluate effects on information exchange and symptom management for children and families, workflow processes for clinicians and organisational implications.

Background and Aims

Dexamethasone is a cornerstone of pediatric acute lymphoblastic leukemia (ALL) therapy, but it can induce serious neurobehavioral side effects. Our previous study suggests that children who suffer most from these side effects might benefit from addition of a physiological dose of hydrocortisone to dexamethasone treatment. Here we aimed to confirm this finding in pediatric patients with ALL who experience clinically relevant dexamethasone-induced neurobehavioral problems.

Methods

We performed a double-blind, randomized controlled trial (RCT) with cross-over design, including 52 children with ALL who experienced clinically relevant dexamethasone-induced neurobehavioral problems. A baseline measurement during one dexamethasone course was performed, the intervention was administered during the subsequent four dexamethasone courses. The intervention consisted of two courses hydrocortisone (10mg/m²/day) in a circadian rhythm, followed by two courses placebo, or vice versa. Neurobehavioral problems were measured with the parent-reported Strengths and Difficulties Questionnaire. Secondary endpoints were sleep problems, quality of life (QoL), hunger feeling and parental stress, measured with separate questionnaires. A generalized mixed model was estimated to study the effect of the intervention on all outcomes.

Results

Both interventions, hydrocortisone and placebo, significantly decreased dexamethasone-induced neurobehavioral problems (estimated effect hydrocortisone -5.0 (95%-confidence interval (CI) -8.2 to -1.8, p=0.002), estimated effect placebo -7.2 (95%-CI -10.4 to -4.1, p<0.001). There was no benefit of hydrocortisone compared to placebo. Sleeping problems, hunger feeling and parental stress also decreased significantly during both interventions compared to no intervention.

Conclusions

Our results showed that clinically relevant dexamethasone-induced neurobehavioral problems significantly decreased after intervention with hydrocortisone or placebo in pediatric patients with ALL, but no additional beneficial effect of hydrocortisone compared to placebo was found. The next step is to find the best way to offer these effective interventions in an open-label way to children who experience clinically relevant side effects in clinical practice.

Background and Aims

To characterize glucarpidase efficacy and safety in compassionate use (CU) trials of patients undergoing high-dose methotrexate (MTX) therapy.

Methods

We performed post hoc analysis of Infants (aged ≥28 days-<2 years), Children (≥2-<12 years), Adolescents (≥12-<15 years), and Young Adults (YAs) (≥15-<25 years) from 4 multicentre, open-label, single-arm, glucarpidase CU trials. Patients had delayed MTX elimination secondary to renal dysfunction and received glucarpidase (50 U/kg). The primary endpoint was clinically important reduction in plasma MTX (CIR; MTX≤1 µmol/L at all post-glucarpidase measurements) based on high-performance liquid chromatography (HPLC).

Results

Eighty-six patients had ≥1 HPLC evaluation and were included in the efficacy analyses (patients without HPLC data were excluded). CIR was achieved by 12/15 patients (80.0%) with acute lymphoblastic leukaemia, 7/14 (50.0%) with non-Hodgkin lymphoma, 14/47 (29.8%) with osteosarcoma, 1/4 (25.0%) where tumour type was ‘other’, and 4/6 (66.7%) where tumour type was unknown. CIR was achieved by 0/1 Infants (0.0%), 5/16 Children (31.3%), 7/24 Adolescents (29.2%), and 26/45 YAs (57.8%). Median reduction in MTX was ≥98.7% in each age group 15 minutes post-glucarpidase. Patients with baseline central MTX<50 µmol/L (35/42; 83.3%) were more likely to achieve CIR than those with MTX≥50 µmol/L (1/37; 2.7%). The safety population comprised 271 paediatric/YA patients with ≥1 dose of glucarpidase or with evidence of follow-up after their first glucarpidase dose. The most common treatment-related adverse event (AE) was paraesthesia, occurring in 3 Adolescents (4.5%) and 6 YAs (5.2%). No other treatment-related AE occurred in ≥5% of any age group.

Conclusions

After accounting for baseline MTX, the efficacy of glucarpidase at inducing CIR in paediatric, adolescent, and YA patients with MTX<50 µmol/L (CIR: 83%) aligned with that previously reported in the overall (paediatric+adult) population (CIR: 59%),¹ demonstrating no dose adjustment is required in this setting.

1. Widemann et al. Pharmacotherapy 2014;34:427–39.

Background and Aims

Restriction of raw fruits and vegetables (neutropenic diet) is advised to patients receiving treatment for acute leukemia in low- and middle-income countries (LMIC) to reduce infections despite evidence to the contrary from high-income countries. We, therefore, conducted a randomized controlled trial (RCT) to ascertain the efficacy of the neutropenic diet in an LMIC setting.

Methods

Patients aged 1-60 years receiving induction chemotherapy for acute leukemia were randomized to a regular or neutropenic diet between Feb 2018- Mar 2020. Participants followed food safety guidelines in both arms. The study's primary objective was to compare the incidence of major infections (pneumonia, urinary tract infection, bacteremia, fungemia, meningitis, cellulitis, diarrhea, or any infection considered to be significant by the investigator) between patients receiving the two diets. The secondary objectives were to compare minor infections, stool microbial flora, and mortality rates.

Results

We randomized 200 patients, 98 patients to the regular diet arm and 102 to the neutropenic diet arm. The median age was 13-years. Major infections occurred in 32% of patients in the regular diet arm and 25% in the neutropenic diet arm (P=0.26). There were no statistically significant differences between patients receiving regular diet vs. neutropenic diet for blood culture positivity (n= 6 vs. 9), inotropic support (17 vs. 12), mechanical ventilation (8 vs. 5), third-line antibiotic use (28 vs. 20), minor infections (12 vs. 9), induction mortality (9 vs.4), and remission status (94% vs. 94%). The stool culture on day 15 of induction grew multi-drug-resistant bacteria in 37% of patients in the regular diet arm and 35% in the neutropenic diet arm (P=0.74). The three-year overall survival in the regular diet arm and neutropenic diet arm was 67.6% and 76.7% (P=0.13).

Conclusions

Neutropenic diet compared to regular diet did not prevent infections, reduce mortality, or change stool microbial flora in patients with acute leukemia