Pediatric Precision Medicine at the National Cancer Center Japan: Prospective Genomic Study of Pediatric Patients with Cancer as Part of the TOP-GEAR Project.

PURPOSE: This single-center, prospective molecular profiling study characterizes genomic alterations and identifies therapeutic targets in advanced pediatric solid tumors. METHODS: As part of the TOP-GEAR (Trial of Onco-Panel for Gene profiling to Estimate both Adverse events and Response by cancer treatment) project at the National Cancer Center (NCC), Japan, we enrolled pediatric patients with a refractory or recurrent disease during August 2016-December 2021 and performed genomic analysis of matched tumors and blood using originally developed cancer gene panels, NCC Oncopanel (ver. 4.0) and NCC Oncopanel Ped (ver. 1.0). RESULTS: Of 142 patients (age, 1-28 years) enrolled, 128 (90%) were evaluable for genomic analysis; 76 (59%) patients harbored at least one reportable somatic or germline alteration. The tumor samples were collected during the initial diagnosis in 65 (51%) patients, after treatment initiation in 11 (9%) patients, and upon either disease progression or relapse in 52 (41%) patients. The leading altered gene was TP53, followed by MYCN, MYC, CDKN2A, and CDK4. The commonly affected molecular processes were transcription, cell-cycle regulation, epigenetic modifiers, and RAS/mitogen-activated protein kinase signaling. Twelve (9%) patients carried pathogenic germline variants in cancer-predisposing genes. Potentially actionable findings were identified in 40 (31%) patients; to date, 13 (10%) patients have received the recommended therapy on the basis of their genomic profiles. Although four patients had access to targeted therapy through clinical trials, the agents were used in nine patients in an off-label setting. CONCLUSION: The implementation of genomic medicine has furthered our understanding of tumor biology and provided new therapeutic strategies. However, the paucity of proposed agents limits the full potential of actionability, emphasizing the significance of facilitating access to targeted cancer therapies.

Safety and efficacy of multiple tyrosine kinase inhibitors in pediatric/adolescent and young adult patients with relapsed or refractory osteosarcomas: A single-institution retrospective analysis.

BACKGROUND: The prognosis of relapsed or refractory osteosarcoma remains poor. Recent reports have stated that molecular targeting agents, including multiple tyrosine kinase inhibitors (MTKIs), are effective against adult osteosarcoma. To determine the safety and efficacy of MTKI therapy in children, adolescents and young adults (AYAs), we conducted a retrospective study on adverse events and treatment outcomes. METHODS: We retrospectively reviewed the medical records of patients with relapsed or refractory osteosarcoma who received MTKI therapy at the Department of Pediatric Oncology, National Cancer Center Hospital, from December 2013 to May 2021. RESULTS: The study included 31 patients (15 males and 16 females) who received MTKIs, including sorafenib monotherapy (seven patients), sorafenib and everolimus (14 patients), and regorafenib monotherapy (10 patients). Their median age was 17 years (range: 11-22 years). The incidence of treatment-related grade 3 nonhematological adverse events was 14.3% in the sorafenib monotherapy group, 21.4% in the sorafenib with everolimus group, and 20.0% in the regorafenib monotherapy group. No grade 4 nonhematological adverse events were observed. The median progression-free survival (PFS) was 51 days in the sorafenib monotherapy group, 101 days in the sorafenib with everolimus group, and 167 days in the regorafenib monotherapy group. CONCLUSION: The safety profile of MTKI therapies in pediatric and AYA patients was comparable to that in adult patients. MTKI therapies, particularly regorafenib, against pediatric relapsed osteosarcoma can suppress tumor growth and prolong PFS with tolerable adverse events.

Nelarabine-induced myelopathy in patients undergoing allogeneic hematopoietic cell transplantation: a report of three cases.

Nelarabine is an effective treatment for T-cell acute lymphoblastic leukemia/lymphoma. Myelopathy is a rare but serious adverse event associated with this drug. Three patients who received nelarabine at the National Cancer Center Hospital from December 2014 to March 2021 developed myelopathy 20 days before, 12 days after, and 29 days after allogeneic hematopoietic cell transplantation (allo-HCT), respectively. Magnetic resonance imaging showed that two of the patients had lesions in the dorsal column or medulla oblongata, and one had no abnormalities in the head or spine. Despite treatment with intravenous immunoglobulin and methylprednisolone, all patients became unable to walk. One patient died on day 101 after allo-HCT due to progressive neurotoxicity. The other two patients showed spontaneous improvement in neurological symptoms, but one died of mucormycosis on day 476. Autopsy revealed spongiosis in the posterior funiculus in both patients who died, and also in the medulla oblongata in one patient. In the surviving patient, positron emission tomography on day 84 showed abnormal accumulation, suggesting continued inflammation. These cases demonstrated pathophysiological features of nelarabine-induced myelopathy and indicate that allo-HCT may worsen the condition. It is necessary to elucidate the underlying mechanism and establish diagnostic methods and therapies.

Evaluation of aprepitant and fosaprepitant in pediatric patients.

BACKGROUND: Single-dose i.v. fosaprepitant has been approved as an alternative to 3 day oral aprepitant, a neurokinin-1 receptor antagonist, and improves prevention of chemotherapy-induced nausea and vomiting (CINV). Because fosaprepitant has shown similar efficacy to aprepitant in adult patients only, this study compared the efficacy and safety of aprepitant and fosaprepitant in pediatric patients. METHODS: Children younger than 18 years who received aprepitant or fosaprepitant to manage CINV between January 2015 and March 2018 at the National Cancer Center Hospital (Tokyo) were recruited to this study. The primary endpoint was complete response (CR; no vomiting/rescue medication) between 0 and 120 h after the start of chemotherapy. Secondary endpoints were safety based on the frequency of severe adverse events, and evaluation of patient characteristics as risk factors (effect of age and sex). RESULTS: A total of 125 chemotherapy cycles were evaluated. In the aprepitant group, CR was observed in 36 of 80 treatment cycles (45.0%), whereas in the fosaprepitant group, it was observed in 19 of 45 cycles (42.2%; P = 0.852). No treatment-related severe adverse events were observed in either group. The number of non-CR was greater than that of CR in patients aged 6-14 years. The difference in CR rate between male and female patients was not statistically significant (47.1% vs 40.0%, respectively; P = 0.471). CONCLUSIONS: Aprepitant and fosaprepitant were safely used and may be equally useful for pediatric patients receiving highly emetogenic chemotherapy. CR rate may be associated with patient age.

A case of recurrent histiocytic sarcoma with MAP2K1 pathogenic variant treated with the MEK inhibitor trametinib.

Histiocytic sarcoma in advanced clinical stages is typically an aggressive neoplasm, with poor response to conventional chemotherapy. An 18-year-old male with refractory histiocytic sarcoma that had transformed from Rosai-Dorfman disease was admitted to our hospital. A pathogenic variant of MAP2K1 was detected by next-generation sequencing of tumor specimens. Affected regions showed excellent responses to the MEK inhibitor trametinib. It has been reported that RAS/MEK/ERK pathway is activated in many cases of histiocytic sarcoma. MEK inhibition may represent a useful treatment option in histiocytic sarcoma.