(P 406) LONG-TERM DENOSUMAB THERAPY IN GIANT CELL TUMOR PATIENTS MAY POTENTIALLY LEAD TO THE DEVELOPMENT OF OTHER PRIMARY TUMORS: AN INITIAL OBSERVATION

Objective: Giant cell tumor (GCT) is an intermediate locally aggressive primary bone tumor with metastatic potential, which overexpresses receptor activator of the nuclear factor kappa-B ligand (RANKL). Traditional treatment consists of surgical tumor resection, ranging from curettage with or without local adjuvants to en-bloc resection. Denosumab is a fully human monoclonal antibody that inhibits RANKL and was approved by the FDA as neoadjuvant drug therapy for advanced GCT. Although denosumab has shown promise in the treatment of GCT, it has also been associated with development of other primary tumors, including glioblastoma, as well as progression to malignant GCT, osteosarcoma, and undifferentiated pleomorphic sarcoma (UPS). In this case series of long-term patients treated with denosumab, we report our experience with the long-term use of denosumab in terms of developing another primary tumor as well as other complications.

Methods: Patients included in this study had been previously enrolled in one of two clinical trials for biopsy-proven GCT of bone treated with denosumab on a long-term basis. After local IRB approval, these patients were identified and their medical records were reviewed. Data on demographics, diagnosis, treatment duration, and major and minor events were collected. All patients had a biopsy-proven diagnosis of GCT of bone prior to enrollment in their treatment study. Before treatment initiation, patients were briefed on the treatment protocol, which included potential risks and benefits. During the treatment period, female patients were required to use two methods of contraception and all subjects received supplementary Calcium and Vitamin D. The denosumab injections were administered weekly for the initial four weeks and subsequently on a monthly basis. The outcomes were documented for future reference.

Results: 23 patients were included. The average age was 31.6 years (16 – 69). The primary location of GCT was the appendicular skeleton (74%). The most common reason for initiating denosumab treatment was tumor irresectability (35%). 14 patients (65%) had undergone prior surgical procedures and received treatment later due to local recurrence and/or pulmonary metastasis. The average length of treatment was 7.2 years (0.2 – 13). Out of the 23 patients, 5 patients (22%) developed a different primary malignant tumor including osteosarcoma (3), UPS (1), and abdominal pleomorphic rhabdomyosarcoma (1). In 4 of these patients, their secondary neoplasm occurred in their primary tumor or in the lungs. Adjudicated pathologic review by the study sponsor has suggested that atypia was present at the time of original diagnosis. The 5th patient developed a sclerotic lesion in a de-novo site (proximal femur) that presented with new onset of pain and was biopsy-proven as osteosarcoma. The average time between the start of treatment and diagnosis of the tumor was 52 months (3 -160). Other adverse effects included atypical fractures in 3 patients (13%), including 1 femur fracture requiring surgery and 2 metatarsal fractures treated conservatively.

Conclusion: While denosumab can be an effective treatment option for patients with irresectable, recurrent, and metastatic GCT, the long-term use of this drug may be associated with an increased risk of developing another primary tumor. Furthermore, atypical femur and metatarsal fractures are a known complication of denosumab treatment. Therefore, it is essential to exercise caution when considering denosumab as a treatment option and to have a detailed discussion with patients regarding the potential risks, benefits, and other available treatment alternatives before initiating therapy. This approach will ensure that patients receive appropriate and individualized treatment that is tailored to their specific needs and preferences while minimizing the potential risks and complications associated with the treatment. The role of denosumab in the treatment of GCT of bone continues to be defined and further study is needed.