Lorlatinib with or without chemotherapy in ALK-driven refractory/relapsed neuroblastoma: phase 1 trial results.

Neuroblastomas harbor ALK aberrations clinically resistant to crizotinib yet sensitive pre-clinically to the third-generation ALK inhibitor lorlatinib. We conducted a first-in-child study evaluating lorlatinib with and without chemotherapy in children and adults with relapsed or refractory ALK-driven neuroblastoma. The trial is ongoing, and we report here on three cohorts that have met pre-specified primary endpoints: lorlatinib as a single agent in children (12 months to <18 years); lorlatinib as a single agent in adults (≥18 years); and lorlatinib in combination with topotecan/cyclophosphamide in children (<18 years). Primary endpoints were safety, pharmacokinetics and recommended phase 2 dose (RP2D). Secondary endpoints were response rate and 123I-metaiodobenzylguanidine (MIBG) response. Lorlatinib was evaluated at 45-115 mg/m2/dose in children and 100-150 mg in adults. Common adverse events (AEs) were hypertriglyceridemia (90%), hypercholesterolemia (79%) and weight gain (87%). Neurobehavioral AEs occurred mainly in adults and resolved with dose hold/reduction. The RP2D of lorlatinib with and without chemotherapy in children was 115 mg/m2. The single-agent adult RP2D was 150 mg. The single-agent response rate (complete/partial/minor) for <18 years was 30%; for ≥18 years, 67%; and for chemotherapy combination in <18 years, 63%; and 13 of 27 (48%) responders achieved MIBG complete responses, supporting lorlatinib's rapid translation into active phase 3 trials for patients with newly diagnosed high-risk, ALK-driven neuroblastoma. ClinicalTrials.gov registration: NCT03107988 .

Neuropsychological surveillance model for survivors of pediatric cancer: A descriptive report of methodology and feasibility.

Objective: Neuropsychological late effects of pediatric cancer may not become apparent for years after therapy; therefore, serial monitoring is necessary for detecting changes to ensure timely intervention. Unfortunately, lack of access to neuropsychologists, increased patient volume, insurance authorization and reimbursement issues, time required for neuropsychological evaluation, and practice effects related to repeat testing present many challenges to provision of neuropsychological care for survivors of childhood cancer. Models involving surveillance and monitoring have been proposed, though minimal data exist related to the implementation and feasibility of such models. Method: In this descriptive feasibility study, the Neuropsychology Consult Clinic (NCC) at Children's Hospital Los Angeles is presented, outlining a methodology and algorithm for neuropsychological surveillance of survivors of non-CNS pediatric cancer and an account of the first three years of clinic implementation. Participants included 215 survivors (x̅ age = 5.6 years), including 75.3% Latinx patients. Results: The overall clinic implementation was found to be feasible, with approximately 75% of patients "passing" the screening and 25% "failing" the screening. Clinical judgment only conflicted with the algorithm 8.6% of the time. However, several limitations to feasibility were noted, including validity concerns and ability/time to complete parent-reported outcomes using Spanish forms, as well as access to bilingual examiners. Conclusions: These preliminary data support the feasibility of the NCC model with limitations as outlined above. This is the first phase in a multiphase plan to develop an appropriate screening clinic for survivors of pediatric cancer, with the next phase focusing on sensitivity/specificity of measures.

Neuropsychological outcomes on Head Start III: a prospective, multi-institutional clinical trial for young children diagnosed with malignant brain tumors.

BACKGROUND: Current pediatric brain tumor treatment focuses on titrating toxicity based on risk factors while simultaneously improving survivorship. The Head Start (HS) protocols I to IV (1991-present) use high-dose chemotherapy (HDCTx) with an aim of reducing or eliminating cranial irradiation in very young children, the most vulnerable to its effects. METHODS: We examined estimated Full Scale IQ, overall Adaptive Functioning, Working Memory, Processing Speed, and Verbal and Nonverbal Memory outcome data for 43 HS III patients diagnosed between ages 2 months and 7 years from 15 institutions in the United States and Canada. RESULTS: At a mean of 5.12 years postdiagnosis, the HS III patients performed within the average to low-average ranges across these variables; however, individual variability was noted with scores ranging from superior to impaired, and the sample as a whole performed lower than age expectations. Performance did not significantly differ by sex or ethnicity, diagnosis, or for those treated with an intravenous methotrexate dose of 400 mg/kg vs 270 mg/kg. Additionally, performance did not significantly differ by age at diagnosis or length of follow-up. CONCLUSIONS: The results, indicating overall average to low-average neurocognitive functioning, are encouraging, though significant individual variability was noted. Those who were younger at diagnosis, received more intensive methotrexate, and were further out from treatment were not at significantly increased risk of cognitive decline within our sample, suggesting a strategy of using HDCTx and autologous hematopoietic progenitor cell rescue to reduce or eliminate irradiation may allow for continued CNS development in young children treated for a brain tumor.

Clinical and neuropsychological outcome of pediatric non-midline central nervous system germinoma treated with chemotherapy and reduced dose/volume irradiation: The Children's Hospital Los Angeles experience.

BACKGROUND: Germ cell tumors (GCT) arising from non-midline structures (basal ganglia, thalamus, and posterior fossa) are rare. Although patients with midline (pineal and suprasellar) germinoma have excellent survival with chemotherapy and whole ventricular irradiation (WVI), germinoma in non-midline locations have traditionally been treated with craniospinal irradiation (CSI) or whole brain irradiation (WBI) to achieve similar outcomes. However, CSI and WBI are associated with significant long-term neuropsychological sequelae. METHODS: We describe the clinical and neuropsychological outcomes of patients with non-midline germinoma treated at the Children's Hospital Los Angeles between 1990 and 2015. RESULTS: Nine patients had basal ganglia/thalamic germinoma and one patient had a cerebellar primary. Eight patients received chemotherapy followed by reduced dose/volume irradiation, whereas two patients received chemotherapy alone as upfront therapy. One patient in the chemotherapy alone group relapsed after 4.3 years and was salvaged with CSI plus boost. The overall survival for the entire cohort was 100% at a median follow-up of 8.5 years. Neuropsychological data were available for six patients at a median of five months (baseline) and 4.2 years (follow-up) post-diagnosis. At four-year follow-up, data available revealed intact overall cognitive ability, verbal memory, and executive functioning, but persistent deficits in fine motor function. Comparison of baseline to follow-up suggests a downward trend in working memory, planning/problem-solving, verbal memory, and visuospatial integration. CONCLUSION: Chemotherapy followed by reduced dose/volume of irradiation is an effective strategy resulting in long-term survival in patients with non-midline germinoma. Neuropsychological data suggest relatively minimal morbidity over time.

Cognitive outcomes among Latino survivors of childhood acute lymphoblastic leukemia and lymphoma: A cross-sectional cohort study using culturally competent, performance-based assessment.

BACKGROUND: This study sought to characterize cognitive outcomes among Latino survivors of childhood acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). PROCEDURE: In this cross-sectional cohort study, Latino survivors of ALL (n = 57) and LL (n = 5) aged 6-16 years were pooled and evaluated using validated measures of cognitive, academic, and behavioral function and English language proficiency. Performance was compared with norms using single-sample t-tests. RESULTS: In this cohort (n = 62, 50% male), mean ages at diagnosis and testing were 4.5 and 10.8 years, respectively; mean time off treatment was 44.7 months. All participants spoke English and over half (57%) identified Spanish as the primary language in the home. Forty-two families (68%) placed in the two lowest Hollingshead socioeconomic status categories. Participants were below average for working memory (P < 0.001). Overall, participants were in the average range, but significantly lower than published norms on domain-specific measures of verbal comprehension (P < 0.001); perceptual reasoning (P = 0.033); processing speed (P = 0.003); visual memory (P < 0.001); visuomotor attention, scanning, and sequencing (P = 0.005); and reading comprehension (P = 0.001). Parents reported concerns with working memory (P < 0.001) and metacognition (P = 0.014). CONCLUSIONS: Similar to other childhood ALL/LL survivors, overall cognitive function in this Latino sample was relatively preserved but selected deficits were observed. Routine cognitive screening is indicated in this population.

Effect of Sensorineural Hearing Loss on Neurocognitive Functioning in Pediatric Brain Tumor Survivors.

BACKGROUND: Intensified therapy with platinum-based regimens for pediatric brain tumors has dramatically increased the number of pediatric brain tumor survivors (PBTS) but frequently causes permanent sensorineural hearing loss (SNHL). Although neurocognitive decline in PBTS is known to be associated with radiation therapy (RT), SNHL represents a potential additional contributor whose long-term impact has yet to be fully determined. METHODS: The neurocognitive impact of significant SNHL (Chang scale ≥ 2b) in PBTS was assessed through a retrospective cohort study of audiograms and neurocognitive testing. Scores for neurocognitive domains and subtest task performance were analyzed to identify specific strengths and weakness for PBTS with SNHL. RESULTS: In a cohort of PBTS (n = 58) treated with platinum therapy, significant SNHL was identified in more than half (55%, n = 32/58), of which the majority required hearing aids (72%, 23/32). RT exposure was approximately evenly divided between those with and without SNHL. PBTS were 6.7 ± 0.6 and 11.3 ± 0.7 years old at diagnosis and neurocognitive testing, respectively. In multivariate analyses adjusted for RT dose, SNHL was independently associated with deficits in intelligence, executive function, and verbal reasoning skills. Subtests revealed PBTS with SNHL to have poor learning efficiency but intact memory and information acquisition. CONCLUSIONS: SNHL in PBTS increases the risk for severe therapy-related intellectual and neurocognitive deficits. Additional prospective investigation in malignant brain tumors is necessary to validate these findings through integration of audiology and neurocognitive assessments and to identify appropriate strategies for neurocognitive screening and rehabilitation specific to PBTS with and without SNHL.