Faculty Bibliography

Pediatric leukemia is the single most common malignancy affecting children, representing up to 30% of all pediatric cancers. Dramatic improvements in survival for acute lymphoblastic leukemia (ALL) have taken place over the past 4 decades with outcomes approaching 90% in the latest studies. However, progress has been slower for myeloid leukemia and certain subgroups like infant ALL, adolescent/young adult ALL, and relapsed ALL. Recent advances include recognition of molecularly defined subgroups, which has ushered in precision medicine approaches. We discuss the current understanding of the biology of the various childhood leukemias, recent advances in research, and future challenges in this field.

PURPOSE: Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. METHODS: To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. RESULTS: Risk factors associated with pancreatitis included genetically defined Native American ancestry (P < .001), older age (P < .001), and higher cumulative dose of asparaginase (P < .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 x 10-9). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. CONCLUSION: Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.

A 1,2-dioxolane (FINO2) was identified as a lead compound from a screen of organic peroxides. FINO2 does not induce apoptosis, but instead initiates ferroptosis, an iron-dependent, oxidative cell death pathway. Few compounds are known to induce primarily ferroptosis. In contrast to the perceived instability of peroxides, FINO2 was found to be thermally stable to at least 150 degrees C. FINO2 was more potent in cancer cells than nonmalignant cells of the same type. One of the enantiomers was found to be more responsible for the observed activity.

BACKGROUND: The months immediately after the completion of treatment for childhood acute lymphoblastic leukemia (ALL) are often regarded as a stressful time for children and families. In this prospective, longitudinal study, the prevalence and predictors of anxiety and depressive symptoms after the completion of treatment were examined. METHODS: Participants included 160 children aged 2 to 9 years with standard-risk ALL who were enrolled on Children's Oncology Group protocol AALL0331. Parents completed standardized rating scales of their children's emotional-behavioral functioning and measures of coping and family functioning at approximately 1 month, 6 months, and 12 months after diagnosis and again 3 months after the completion of chemotherapy. RESULTS: At 3 months off therapy, approximately 24% of survivors had at-risk/clinically elevated anxiety scores and 28% had elevated depression scores, which are significantly higher than the expected 15% in the general population (P = .028 and .001, respectively). Patients with elevated anxiety 1 month after diagnosis were at greater risk of off-therapy anxiety (odds ratio, 4.1; 95% confidence interval, 1.31-12.73 [P = .022]) and those with elevated depressive symptoms 6 months after diagnosis were at greater risk of off-therapy depression (odds ratio, 7.88; 95% confidence interval, 2.61-23.81 [P = .0002]). In adjusted longitudinal analyses, unhealthy family functioning (P = .008) and less reliance on social support coping (P = .009) were found to be associated with risk of emotional distress. Children from Spanish-speaking families (P = .05) also were found to be at a greater risk of distress. CONCLUSIONS: A significant percentage of children experience emotional distress during and after therapy for ALL. These data provide a compelling rationale for targeted early screening and psychosocial interventions to support family functioning and coping skills. Cancer 2015. (c) 2015 American Cancer Society.

BACKGROUND: This prospective study describes the procedure-related anxiety, treatment-related anxiety, pain, and nausea experienced by children with standard-risk acute lymphoblastic leukemia (ALL) during the first year of treatment. METHODS: This study was undertaken at 31 Children's Oncology Group (COG) sites. Eligible children who were 2 to 9.99 years old were enrolled in a COG trial for patients with newly diagnosed standard-risk ALL from 2005 to 2009. Parents completed a demographic survey at the baseline and the Pediatric Quality of Life Inventory 3.0 Cancer Module (proxy version) and the General Functioning Scale of the Family Assessment Device 1, 6, and 12 months after the diagnosis. The association between patient-related (age, sex, ethnicity, and treatment), parent-related (marital status and education), and family-related factors (functioning, income, and size) and symptom scores was evaluated. RESULTS: The mean scores for procedure-related anxiety, treatment-related anxiety, and pain improved during the first year of treatment (P < .0389). The mean nausea score was poorer 6 months after the diagnosis in comparison with the other assessments (P = .0085). A younger age at diagnosis was associated with significantly worse procedure-related anxiety (P = .004). An older age (P = .0002) and assignment to the intensified consolidation study arm (P = .02) were associated with significantly worse nausea. CONCLUSIONS: Children with ALL experienced decreasing treatment-related anxiety, procedure-related anxiety, and pain during the first year of treatment. In comparison with scores at 1 and 12 months, nausea was worse 6 months after the diagnosis. Minimization of procedure-related anxiety in younger children and improved nausea control in older children and those receiving more intensified treatment should be prioritized. Cancer 2016. (c) 2016 American Cancer Society.

PURPOSE OF REVIEW: The prognosis for children with the most common childhood malignancy, acute lymphoblastic leukemia (ALL), has improved dramatically. However, the burden of therapy can be substantial, with long-term side-effects, and certain subgroups continue to have a poor outcome. RECENT FINDINGS: The recent discovery of new genetic alterations in high-risk subsets provides targets for precision medicine-based interventions using existing Food and Drug Administration approved agents. Novel immunotherapeutic approaches are being deployed in relapsed ALL, one of the leading causes of cancer cell death in children. Moreover, genomic analysis has charted the evolution of tumor subclones, and relapse-specific alterations now provide a mechanistic explanation for drug resistance, setting the stage for targeted therapy. There is greater recognition that host factors - genetic polymorphisms - influence cancer risk, response to therapy, and toxicity. In the future, it is anticipated that they will be integrated into clinical decision making to maximize cure and minimize side-effects. Recent efforts to limit prophylactic central nervous system irradiation have been successful, thereby sparing many children late neurocognitive impairments. SUMMARY: Integration of advances in precision medicine approaches and novel agents will continue to increase the cure rate and decrease the burden of therapy for childhood ALL.

Standard risk acute lymphoblastic leukemia (SR-ALL) has high cure rates, but requires 2-3 years of therapy. We aimed to (i) prospectively evaluate health-related quality of life (HRQOL) during and after SR-ALL therapy, and (ii) identify associated predictors. Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy. Mean PedsQL scores in physical, emotional and social functioning were impaired 1 month after diagnosis but steadily improved. Three months post-therapy, impaired physical and social functioning was observed in 27.8 and 25.8% of patients, respectively. In repeated-measures analysis, problematic family functioning predicted emotional (OR = 1.85, 95% CI 1.03-3.34) and social (OR = 1.99, 95% CI 1.21-3.27) impairment. Larger household size was associated with social impairment (OR = 1.21, 95% CI 1.02-1.45). Adverse neurological event(s) during therapy predicted post-therapy physical (OR = 5.17, 95% CI 1.61-16.63) and social (OR = 8.17, 95% CI 1.19-56.16) impairment. HRQOL 1 month after diagnosis was not predictive of HRQOL 3 months after therapy completion. In conclusion, children with SR-ALL experience considerable impairment in HRQOL at the end of induction, but rapidly improve. However, many still experience physical and social impairment 3 months post-therapy, suggesting a role for continued family and physical functioning support. Longer follow-up is needed to determine if post-therapy deficits change over time.

Primary neuroendocrine carcinomas (NEC) are rare tumors in children and young adults, resulting in a lack of standardized treatment approach. To refine the molecular taxonomy of these rare tumors, we performed whole exome sequencing in a pediatric patient with mediastinal NEC. We identified a somatic mutation in HRAS gene and LOH regions in NF2, MYO18B, and RUX3 genes. In addition, a germline heterozygous somatic variant in BRCA2 with LOH at that same position in the tumor tissue was also found. Our data provide valuable insight into the genomic landscape of this tumor, prompting further investigation of therapeutic targets.