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(MRONJ): Late Onset 3 Years After Ipilimumab Endovenous Administration with a Possible Role of Target Therapy

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(MRONJ): Late Onset 3 Years After Ipilimumab Endovenous Administration with a Possible Role of Target Therapy Received: 14 July 2020 | Revised: 28 September 2020 | Accepted: 4 October 2020 DOI: 10.1002/ccr3.3418 CASE REPORT New-generation anticancer drugs and medication-related osteonecrosis of the jaw (MRONJ): Late onset 3 years after ipilimumab endovenous administration with a possible role of target therapy Agostino Guida1 | Francesco Perri2 | Franco Ionna1 | Paolo A. Ascierto3 | Antonio M. Grimaldi3 1Maxillo-facial and ENT Surgery Unit, INT – IRCCS “Fondazione G. Pascale”, Abstract Naples, Italy Association of immunotherapy and/or chemotherapy and/or targeted therapy, in se- 2Head & Neck/Thyroid Medical Oncology quence or as single therapies, may induce osteonecrosis of the jaw. Multidisciplinary Unit, INT – IRCCS “Fondazione G. team management of these patients should be provided. Pascale”, Naples, Italy 3Melanoma, Oncological Immunotherapy KEYWORDS and Innovative Therapies Department, INT bisphosphonate-associated osteonecrosis, ipilimumab, medically compromised patients, – IRCCS “Fondazione G. Pascale”, Naples, Italy medication-related osteonecrosis of the jaw, target therapy Correspondence Francesco Perri, Head & Neck/Thyroid Medical Oncology Unit, INT – IRCCS “Fondazione G. Pascale,” via M. Semmola 53, 80131 Naples, Italy. Email: [email protected] 1 | INTRODUCTION First reported cases of nonhealing-exposed bone in the maxillofacial region were recognized by oral and maxillofa- The number of medication which may cause osteonecrosis of cial surgeons in patients treated with intravenous (IV) bis- the jaws is increasing. Up until now, Ipilimumab has been as- phosphonates (BP).1 During 2004, Novartis, manufacturer of sociated with MRONJ only two times in literature. A woman pamidronate (Aredia) and zoledronic acid (Zometa)—two IV underwent endovenous chemotherapy with ipilimumab in BPs—labeled this product as at risk for osteonecrosis of the 2015 for metastatic melanoma. In 2018, while she was un- jaws (ONJ).2 Consequently, the subsequent year a warning dergoing target therapy (vemurafenib + cobimetinib), after followed for all BP drug class to be at risk for ONJ, which wisdom tooth extraction, she developed MRONJ. She was was renamed as bisphosphonate-related ONJ (BRONJ).3 successfully treated with medical therapy alone. Ongoing Since then, other BPs and medications from other classes target therapy may have played a role in MRONJ late onset. have been related to the development of ONJ, including de- Caution and vigilance in dental management of patients nosumab (humanized monoclonal antibody blocking the acti- treated with novel MRONJ-related chemotherapy are needed. vation of receptors for nuclear factor κβ ligand), bevacizumab A multidisciplinary evaluation is advised. (humanized monoclonal antibody), and antiangiogenic This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. Clin Case Rep. 2021;9:61–66. wileyonlinelibrary.com/journal/ccr3 | 61 62 | GUIDA ET AL. medications—sunitinib (tyrosine kinase inhibitor).4-10 the lower right third molar. During this time, the patient had Additionally, case reports have indicated possible associ- been treated by her dentist for an alveolar osteitis (AO, dry ation between ONJ and azacitidine, imatinib, everolimus, sockets) with 1-week cycle of amoxicillin + clavulanic acid ziv-aflibercept, ipilimumab, and tocilizumab.11-18 With the (2.25 + 0.75 g/d per os) and chlorhexidine 0.2% mouthwash advent of these new classes of medications, the condition is daily socket irrigation. She referred that she had repeated this now more aptly known as medication-related osteonecrosis therapy three times during those months, continuing chlo- of the jaw (MRONJ).1 Both pathogenesis and associated risk rhexidine 0.2% mouthwash daily socket irrigation among factors not fully comprehended. This majorly reflects on its the antibiotic cycles. She referred that, occasionally, she also therapy as indications for surgery (sequestrectomy/curettage underwent application of zinc oxide eugenol in her alveolus. with possible reconstruction) vs antibiotic medical therapy Furthermore, the patient had used chlorhexidine 0.2% mouth (3 g amoxicillin + 1.5 metronidazole per os per day for at rinse since day before the extraction. Every treatment tried least 2 weeks) are still unclear and so great effort is also put up until now had been unsuccessful. She had no extra-oral in studying and developing complementary treatments, in- sign of swelling nor of ongoing abscess. Intraorally, clinical cluding application of platelet concentrates, ozone therapy, inspection confirmed the presence of a nonhealed alveolar and laser treatment, in order both to prevent MRONJ and to socket; the bottom and the walls of the alveolus were clearly improve healing after surgical treatment of such lesions.19 visible, made of nonvascularized nonsuppurated bone, sur- Uncertainty increases both for diagnosis and treatment rounded by swollen mucosa (Figure 1). especially for non-BP drugs related to ONJ, which may have She exhibited a 3-day-old orthopantomography (OPT), very few cases reported in literature, such as ipilimumab. which showed radiographic sign of a nonhealed alveolus Ipilimumab is a monoclonal antibody directed against the (Figure 2). CTLA4 receptor, present on activated T lymphocytes. The Her anamnesis was carefully harvested. The patient un- resulting binding causes an increase of lymphocyte T activ- derwent a surgical resection of a cutaneous melanoma in ity directed against melanoma cells, which are therefore de- 2009. Then, in 2015, for lung progression of disease, she was structed. The antibody is administered intravenously at a dose treated with ipilimumab (3 mg/kg mg iv, every 3 weeks for of 3 mg/kg every 3 weeks, for 4 cycles. Approval of ipilim- 4 cycles) with complete remission of the disease. During the umab was based on a randomized three-arm phase III study follow-up, in 2017 the patient had hepatic progression, and which compared ipilimumab with a vaccine therapy (gp100) so, due to the presence of the BRAF mutation, she started and with their combination,20 showing improved overall sur- the treatment with dabrafenib + trametinib (300 + 2 mg per vival in patients undergoing Ipilimumab. Ipilimumab is as- os/die). Due to the G. 3 toxicity (fever) experienced by the sociated with the risk of immune-related side effects; sixty patient, the treatment was stopped and was replaced with percent of immune-related adverse events were recorded in vemurafenib + cobimetinib (vemurafenib: 1920 per os/die the study population. Approximately 15% of patients experi- for 3 months, then 1440 mg per os/die; cobimetinib: 60 mg enced grade 3 or 4 adverse events. Dermatitis was the most per os/die for 3 weeks then 1-week pause), still ongoing. She frequent immune-related event, and diarrhea, the most dan- was then taking 1440 mg vemurafenib + 60 mg cobimetinib gerous (perforation risk if not promptly treated); severe cases per os/die at the moment of her tooth extraction. She had no should be treated with high-dose corticosteroids. history of smoking nor head and neck radiotherapy. Among In present scientific literature, there are two reported cases all the medications she had undergone, ipilimumab was the of MRONJ onset in patients treated with ipilimumab alone only one that has been related to MRONJ.12,17 Staging of the and 1 in a patient treated with concomitant denosumab + ip- MRONJ was thus performed; it was evaluated to be a “stage ilimumab.12,17 MRONJ onset was in all cases during ipilim- 2 MRONJ” according to the AAOMS classification, showing umab therapy or shortly after the conclusion of it. “Exposed and necrotic bone(…) with evidence of infection, In this case report, we describe MRONJ occurred 3 years (…) symptomatic.”1 She was thus treated accordingly, start- after the conclusion of treatment with ipilimumab. ing a treatment with amoxicillin + metronidazole (3 + 1.5 g per os/die) and chlorhexidine 0.2% mouth rinse twice a day; paracetamol (1 g per os) was prescribed for pain control. 2 | CASE PRESENTATION During the 2-week follow-up visit, the patient showed clin- ical improvement. She referred the ejection of a 10 × 5 mm In November 2018, a 58 year-old-woman with BRAF-mutated bone sequestrum after 6 days of therapy and that her symp- metastatic melanoma, treated at the immunotherapy unit of toms had therefore disappeared. The clinical examination our institute, was referred to our oral pathology outpatient still highlighted an incomplete alveolar healing. Two addi- clinic. During a regular follow-up visit, the patient reported tional weeks of therapy were prescribed and, after that, the that she was experiencing severe pain in the oral cavity for patient obtained a complete healing of the defect (Figure 3). 4 months due to a nonhealing alveolus, after the extraction of Treatment for the MRONJ was stopped, and the patient was GUIDA ET AL. | 63 FIGURE 1 Intraoral inspection revealed the nonhealing alveolus FIGURE 3 Complete clinical resolution after 4 wks of antibiotic/ disinfectant therapy (amoxicillin + metronidazole −3 + 1.5 g per os/ die- and chlorhexidine 0.2% mouth rinse) FIGURE 2 Orthopantomography (OPT) exhibited from the patient during the first visit, revealing the nonhealing alveolus 4 mo after tooth extraction regularly followed up monthly. After 6 months, a new OPT showed complete healing
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