Anaplastic Lymphoma Kinase Inhibitors for Therapy of Neuroblastoma in Adults.

PURPOSE: Adult-onset neuroblastoma (AON) differs significantly in biology and clinical behavior from childhood-onset disease. AON poses therapeutic challenges since tolerance of intensive multimodality therapies that are standard of care for pediatric neuroblastoma (NB) is poor. AON is enriched for somatic mutations including anaplastic lymphoma kinase (ALK), deemed to be an oncogenic driver in NB. ALK inhibitors (ALKis), therefore, have the potential to be of therapeutic benefit. The purpose of this study is to report on their use in AON. METHODS: A single-center retrospective review of adults with NB receiving ALKi (2012-2022) was performed. Response was evaluated using International Neuroblastoma Response Criteria. RESULTS: Fifteen patients with ALK-mutated AON were treated with US Food and Drug Administration-approved ALKi starting at a median age of 34 (16-71) years. Initial ALKi was lorlatinib, crizotinib, and alectinib in seven, five, and three patients respectively; seven received multiple ALKis due to progressive disease/intolerability of one agent. All patients experienced ≥grade 2 adverse events (AEs): crizotinib and alectinib were associated primarily with gastrointestinal AEs, lorlatinib with neurologic AEs, weight gain, and hyperlipidemia resulting in dose reduction or discontinuation of ALKi in several patients. No responses were observed with crizotinib (n = 5 patients), ceritinib, alectinib, or brigatinib (n = 1 each). Of the 13 patients receiving lorlatinib, four, five, and four patients had a complete or partial response (major response rate 69%), and stable disease, respectively. Responses were noted in all disease compartments; complete metabolic response was seen in two L2 patients. Ten of 13 patients remain progression-free at a median of 19 (6-50) months on lorlatinib. Three (two receiving dose-reduced therapy) had progressive disease. Median survival from start of first ALKi was 43 ± 26 months. CONCLUSION: ALKis, particularly lorlatinib, are effective treatment options for AON. However, AEs necessitating dose reduction are common.

Multidisciplinary management of endocrinopathies and treatment-related toxicities in patients with Bloom syndrome and cancer.

The treatment of malignancy in cancer predisposition syndromes that also confer exquisite sensitivity to standard chemotherapy and radiation regimens remains a challenge. Bloom syndrome is one such disorder that is caused by a defect in DNA repair, predisposing to the development of early-onset age-related medical conditions and malignancies. We report on two patients with Bloom syndrome who responded well to chemotherapy despite significant alterations to standard protocols necessitated by hypersensitivity. Both patients experienced severe toxicities and exacerbation of endocrine comorbidities during chemotherapy. A multidisciplinary team of oncologists and endocrinologists is best suited to care for this patient population.