Title: Medication related jaw osteonecrosis (MRONJ) late onset 3 years after IPILIMUMAB endovenous administration: a possible role of target therapy.

Authors: Agostino Guida (DMD, PhD, Consultant)¹, Francesco Perri (MD, Consultant) ², Franco Ionna¹ (MD, Head), Paolo A Ascierto³(MD, Head), Antonio M Grimaldi³ (MD, Consultant)

Affiliation: 1. Maxillo-facial and ENT Surgery Unit, INT – IRCCS “Fondazione G. Pascale”, Naples, Italy

Corresponding author: Francesco Perri, Head & Neck/Thyroid Medical Oncology Unit, INT – IRCCS “Fondazione G. Pascale”, Naples, Italy, INT – IRCCS “Fondazione G. Pascale”, via M. Semmola 53, 80131 Naples, Italy; ph./fax N.: +39815903464; e-mail address:f.perri@istitutotumori.na.it

Abstract

Background: The number of medication which may cause osteonecrosis of the jaws is increasing. Up until now, Ipilimumab has been associated to MRONJ only two times in literature.

Case presentation: A woman underwent endovenous chemotherapy with ipilimumab in 2015 for Metastatic Melanoma. In 2018, whilst she was undergoing target therapy (vemurafenib + cobimetinib), after wisdom tooth extraction, she developed MRONJ. She was successfully treated with medical therapy alone.

Conclusion: Ongoing target-therapy may have played a role in MRONJ late onset. Caution and vigilance in dental management of patients treated with novel MRONJ-related chemotherapy are needed. Multidisciplinary evaluation is advised.

Key words: Bisphosphonate-associated Osteonecrosis, Medically Compromised Patients, Medicament realated osteonecrosis of the jaw, Ipilimumab, Target-therapy, Vemurafenib, Cobimetinib, Osteonecrosis

Background

First reported cases of non-healing exposed bone in the maxillofacial region were recognized by oral and maxillofacial surgeons in patients treated with intravenous (IV) bisphosphonates (BP).¹During 2004, Novartis (Basel, Switzerland), manufacturer of pamidronate (Aredia) and zoledronic acid (Zometa) – two IV BPs- labelled this product as at risk for osteonecrosis of the jaws (ONJ).² Consequently, the subsequent year a warning followed for all BP drug class to be at risk for ONJ, which was re-named as bisphosphonate-realated ONJ (BRONJ).³

Since then, other BP and medications from other classes have been related to the development of ONJ, including denosumab (humanized monoclonal antibody blocking the activation of receptors for nuclear factor κβ ligand), bevacizumab (humanized monoclonal antibody), antiangiogenic medications - sunitinib (tyrosine kinase inhibitor).^4-10 Additionally, case reports have indicated possible association between ONJ and azacitidine, imatinib, everolimus, ziv-aflibercept and ipilimumab.^11-17 With the advent of these new classes of medications, the condition is now more aptly known as medication-related osteonecrosis of the jaw (MRONJ)¹. Both pathogenesis and associated risk factors not fully comprehended, especially for non-BP drugs related to ONJ, which may have very few cases reported in literature, such as ipilimumab.

Ipilimumab is a monoclonal antibody directed against the CTLA4 receptor, present on activated T lymphocytes. The resulting binding causes an increase of lymphocyte T activity directed against melanoma cell, which are therefore destructed. The antibody is administered intravenously at a dose of 3 mg / kg every 3 weeks, for 4 cycles. Approval of ipilimumab was based on a randomized three-arms phase III study which compared ipilimumab with a vaccine-therapy (gp100) and with the combination¹⁸, showing improved overall survival in patients undergoing ipilimumab. Ipilimumab is associated with the risk of immune-related side effects; sixty percent of immune-related adverse events were recorded in the study population. Approximately 15% of patients experienced grade 3 or 4 adverse events. Dermatitis was the most frequent immune-related event, and diarrhea the most dangerous (perforation risk if not promptly treated); severe cases should be treated with high-dose corticosteroids.

In present scientific literature, there are two reported cases of MRONJ onset in patients treated with ipilimumab alone and 1 in a patient treated with concomitant denosumab + ipilimumab.^12,17MRONJ onset in all cases during ipilimumab therapy or shortly after the conclusion of it.

In this case report, we describe the onset of MRONJ three years after the conclusion of treatment with ipilimumab.