ALK inhibitors for treatment of adult-onset neuroblastoma.

Abstract

2001 Background: Neuroblastoma (NB), a rare malignancy of the sympathetic nervous system, is a tumor of early childhood with > 90% of cases diagnosed before 5 years of age. Adult-onset NB (AON) is extremely rare and differs significantly from childhood disease. AON, while more indolent, is usually metastatic at diagnosis, generally chemotherapy-resistant, and almost invariably lethal. Additionally, standard therapies for NB such as dose-intensive chemotherapy and anti-GD2 antibody are poorly tolerated by adults. Prior studies have shown AON is enriched for genomic aberrations especially ALK (Suzuki et al 2018). Although ALK inhibitors (ALKi) are effective for therapy of lymphoma and non-small cell lung cancer, their use in AON has not previously been reported. Methods: Retrospective review of patients > 18 years old at diagnosis seen at Memorial Sloan Kettering Cancer Center (MSKCC) was performed after IRB approval. Response to ALKi was evaluated using International Neuroblastoma Response Criteria; objective responses were also noted. Progression-free (PFS) and overall survival (OS) was calculated using Kaplan-Meier methods. Results: Since 1979, 52 patients with AON were seen at MSKCC. Of 23 patients evaluated, 14 (61%), harbored somatic ALK mutations. Seven were treated with FDA-approved ALKi. One patient initially diagnosed at 12 years of age was treated with ALKi following a relapse 15 years later. Overall, all ALKi were well-tolerated; reported adverse events included grade 1-2 nausea and vomiting (n = 6), and neurologic symptoms including hallucinations, drowsiness, and dizziness (n = 1 patient each) which resolved after stopping ALKi. Four patients received > 1 ALKi either due to progressive disease or intolerance. Most patients responded to the first ALKi with objective though partial response (n = 5) while one had progressive disease (PD). Median time to progression for initial ALKi was 15.5 months (10-45). One patient with no evaluable disease after four prior relapses was treated with alectinib for 36 months without PD. Of the patients treated with a second ALKi (n = 4), 1 had CR and 2 had PR after not having progressed previously, while the other had stable disease. Median OS from beginning treatment with first ALKi was 46.5 (17-74) months. Conclusions: AON is a rare disease which is a therapeutic challenge. Enrichment of ALK mutations permits consideration of targeted therapy. ALKi were well tolerated, often associated with significant responses, and treatment with serial ALKi led to ongoing benefit. Given this, ALKi should be considered for treatment in future AON cases.

Neuroblastoma in Adults: A Scoping Review of Presentations, Genetics and Therapies

“…The total number of adult neuroblastoma cases was 679. Five articles included overlapping patients [8–10,39,40], but were still included as they provided different information. For cohort studies, male proportion ranged between 44% [6] to 59% [2].…”

“…Treatment toxicities included thrombocytopenia in 69% (20/29; 4 patients grade 3, 16 patients grade 4) [A43]; neutropenia in 69% (20/29; 7 patients grade 3; 13 patients grade 4); need for granulocyte colony- stimulating factor support in 45% (13/29); need for autologous hematopoietic stem cell support in 25% (7/28); 13% (2/15) late-onset grade 2 thyroid abnormalities; 6% (1/16) had second hematologic malignancies. Stiefel and colleagues [10] reported 14 adult neuroblastoma patients with somatic ALK mutations, 7 of whom were treated with FDA-approved ALK inhibitors.…”

“…4q, 11p, 11p; 12q, 19p; 6p). Mazzocco 2015 [36] Double color FISH on interphase nuclei using MYCN/LAF probe for chromosomes 2p24 and 2q11; ALK assessed in exons 20 to 28 of the ALK gene; ATRX assessed in five exons (10,16,19,30,32) and five portions of exon 9 and flanking splice junctions of ATRX 0/3 tumor MYCN amplification. 0/3 ALK mutations.…”