P0892 - NTRK Fusion-Positive Congenital Spinal Glioblastoma treated with Carboplatin, Etoposide, and Larotrectinib

Introduction
Primary spinal glioblastoma multiforme (GBM) is a rare central nervous system tumor accounting for less than 3% of pediatric central nervous system tumors. The congenital form of this malignancy is even more unusual. Here we present a case of a newborn diagnosed at birth with an advanced spinal cord congenital glioblastoma and successfully treated with etoposide/carboplatin chemotherapy and Larotrectinib.

Case Description
The patient was born full term via induced vaginal delivery due to decreased fetal movement. She was noted to have decreased tone in the delivery room, with a postured right arm; MRI of the brain and spine revealed an infiltrative mass in the lower brainstem, cervical spine, and upper thoracic spine. The patient underwent biopsy and subtotal resection. Samples were sent for genomic analysis. Chemotherapy treatment with carboplatin/etoposide was initiated quickly due to her deteriorating clinical status. The tumor was then found to have a MEF2D-NTRK1 gene fusion, making the use of a targeted inhibitor possible. After completion of chemotherapy cycle #1, the tumor demonstrated a positive clinical response; the patient stabilized and the tumor reduced in size. Larotrectinib was then added and continued daily as a maintenance therapy. Subsequent brain and spine imaging demonstrated a decrease in volume of the tumor, as well as a lack of supratentorial involvement or leptomeningeal spread. As of this writing, 6 cycles of carboplatin and etoposide have been completed, with ongoing Larotrectinib maintenance therapy; the patient’s cervical tumor remains stable in size. The patient has reached 8 months of age and is doing well clinically.

Discussion
The outcome of pediatric primary spinal GBM is uncertain, but thought to be poor, even with resection, radiotherapy, and chemotherapy. One systematic review found a median survival time of only 10 months. However, genomic studies have found that pediatric GBMs are distinct from adult GBMs. Recent advances in targeted chemotherapy, including the development of a targeted NTRK fusion inhibitor, Larotrectinib, may change the outcome of this challenging malignancy. Larotrectinib has been used successfully in the treatment of NTRK fusion-positive infantile fibrosarcoma, but shows promise in treating NTRK fusion-positive malignancies regardless of histology type.

Conclusion
Existing literature, and our experience with this case, suggest that targeted therapy for NTRK-driven high-grade pediatric CNS tumors may make long-term survival possible. Screening for such gene fusions is potentially life-saving and should be standard in this population.