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
2. Head & Neck/Thyroid Medical Oncology Unit, INT – IRCCS “Fondazione
G. Pascale”, Naples, Italy
3. Melanoma, Oncological Immunotherapy and Innovative Therapies
Department, 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.