Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children

Abstract

Background: Aurora Kinase A (AURKA) encodes a protein that regulates the formation and stability of the mitotic spindle and is highly active in atypical teratoid rhabdoid tumors (ATRT) through loss of the INI1 tumor suppressor gene. Alisertib (MLN8237) inhibits AURKA in vitro and in vivo. Given the strong preclinical data supporting the use of alisertib for ATRT patients, we sought and obtained permission to use alisertib in single patient treatment plans for 4 recurrent pediatric ATRT patients.

Methods: Patients with recurrent or progressive ATRT received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle. Disease evaluation (MRI of brain and spine and lumbar puncture) was done after 2 cycles of alisertib and every 2-3 cycles thereafter for as long as the patients remained free from tumor progression.

Results: Four patients with median age of 2.5 years (range, 1.39-4.87 y) at diagnosis received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle, and all 4 patients had disease stabilization and/or regression after 3 cycles of alisertib therapy. Two patients continued to have stable disease regression for 1 and 2 years, respectively, on therapy.

Conclusions: Single-agent alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology. Alisertib has moderate but manageable toxicities, and its chronic administration appears feasible in this pediatric population. These novel data support the incorporation of alisertib in future therapeutic trials for children with ATRT.

Keywords: ATRT; Aurora kinase A; brain tumor; pediatric; targeted therapy.

Fig. 1.

MRI of participant #4 from one week prior to initiating alisertib therapy (A) sagittal T1 with contrast, (B) axial T2 with contrast; (C) sagittal T1 with contrast one year on single-agent alisertib showing regression of tumor; (D) axial T2 with contrast one year on single-agent alisertib therapy showing regression of tumor that had persisted for 11.7 months.

Fig. 2.

ATRT tumors express aurora kinase A by immunohistochemistry. (A) Hematoxylin and eosin-stained section of ATRT demonstrated predominantly small cell morphology with only rare rhabdoid cells. (B) Loss of BAF47/INI1 immunoreactivity in tumor cells with retained staining in blood vessel walls. (C) The tumor cells demonstrated high frequency immunolabeling with Ki67 reflecting a high proliferative fraction. (D) The tumor demonstrated immunoreactivity with antibodies to Aurora Kinase A in a cytoplasmic and nuclear distribution. Scale bar represents 200 µM.