Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. e od:Bshshnt-soitdOtoerss eial opoie ains eiaetre- Osteonecrosis Cobimetinib, Medicament Vemurafenib, Target-therapy, Patients, Ipilimumab, Compromised , the Medically of Osteonecrosis, osteonecrosis vigilance alated -associated and Multidisci- Caution words: needed. Key are onset. chemotherapy late MRONJ-related MRONJ advised. novel with in is evaluation treated role patients plinary a alone. of played wisdom therapy management have dental after medical may in with cobimetinib), target-therapy treated + Ongoing successfully (vemurafenib was therapy Conclusion: She Metastatic target MRONJ. for undergoing developed 2015 was she in she extraction, until ipilimumab whilst tooth with Up 2018, chemotherapy literature. increasing. In endovenous underwent in is Melanoma. woman times two A the only presentation: of MRONJ Case osteonecrosis to cause associated may been 80131 which has 53, medication Ipilimumab now, of Semmola number M. The via Background: Pascale”, G. “Fondazione address: IRCCS Abstract e-mail – +39815903464; “Fon- IRCCS INT N.: – Italy, ph./fax INT Italy; Unit, Naples, Naples, Oncology Pascale”, Medical Neck/Thyroid G. & Head dazione 3. Perri, Francesco Italy author: Naples, “Fondazione Corresponding Pascale”, IRCCS G. – “Fondazione INT Italy IRCCS Department, Naples, Italy – Therapies Pascale”, Naples, INT Innovative G. Pascale”, Unit, and G. Immunotherapy Oncology “Fondazione Oncological Medical IRCCS Melanoma, Neck/Thyroid – & INT Head Unit, Surgery 2. ENT and Maxillo-facial 1. Affiliation: Ascierto A Consultant) endovenous Paolo PhD, IPILIMUMAB Head), (DMD, (MD, after Guida years Agostino 3 therapy. target Authors: onset of late role (MRONJ) possible osteonecrosis a jaw administration: related woman needed. Medication A is patients Title: successfully these literature. was of She in management 2018. dental times in in two MRONJ Vigilance developed only she alone. (MRONJ) and therapy 2015 osteonecrosis medical in with jaw Melanoma treated Metastatic related for medication ipilimumab with to therapy underwent associated been has Ipilimumab Abstract 2020 16, July 2 1 Grimaldi Guida Agostino of role therapy possible target a years administration: 3 endovenous onset IPILIMUMAB late after (MRONJ) osteonecrosis jaw related Medication siuoNzoaeTmr RC odzoePascale Fondazione Italy IRCCS Naples, Tumori Pascale”, Nazionale G. Istituto “Fondazione IRCCS – INT 1 1 rnec Perri Francesco , 3 M,Ha) noi Grimaldi M Antonio Head), (MD, 2 rnoIonna Franco , 1 1 rnec er M,Consultant) (MD, Perri Francesco , [email protected] 1 al Ascierto A Paolo , 3 M,Consultant) (MD, 1 n noi Maria Antonio and , 2 rnoIonna Franco , 1 Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. iue1 nroa npcinrvae h o-eln alveolus. non-healing the (figure revealed alveolus inspection mucosa the Intraoral swollen of 1: by walls Figure the surrounded and , until bottom non-suppurated clinical Intraorally, up the non-vascularized socket; tried abscess. of alveolar ongoing 1). treatment made of non-healed Every visible, nor a swelling clearly extraction. of of were sign presence the patient extra-oral the the before no that, Furthermore, confirmed had day referred She inspection alveolus. since She her unsuccessful. rinse been in contin- mouth had cycles. eugenol months, now 0.12% antibiotic oxide those Chlorexidine zinc the during used of cycle times among application had daily one-week three irrigation underwent mouthwash therapy with socket also 0.2% this sockets) daily she Chlorexidine four repeated dry occasionally, mouthwash and had since (AO, time, os) 0.2% she this cavity per Chlorexidine that During alveolar grams/day oral uing referred 0.75 an molar. She the + third for (2.25 in irrigation. right dentist Acid lower socket her pain Clavulanic the by + severe of treated Amoxicilline extraction experiencing of been the regular was after a had Im- alveolus, During she patient the non-healing the Clinic. that at a Outpatient reported to treated Oral due patient melanoma, our months the metastatic to referred BRAF-mutated visit, was with with follow-up Institute, treatment years-old-woman Our of of 58 Unit conclusion a munotherapy the 2018, November after years In three MRONJ of presentation onset Case the describe it. we of ipili- report, ipilimumab. ipilimumab. conclusion with case + the treated after this patients concomitant shortly In in or with onset therapy treated MRONJ ipilimumab patient of during a be cases cases in should all reported 1 cases two and severe are alone there treated); mumab literature, promptly immune-related scientific not frequent present if most In the risk was (perforation . Dermatitis dangerous high-dose events. with most Approximately adverse treated the 4 population. or diarrhea study 3 the and in grade ef- whichevent, recorded side experienced study immune-related were patients of events III of 3 risk adverse phase the 15% every immune-related with of three-arms kg associated percent randomized / is sixty Ipilimumab mg a combination fects; 3 the ipilimumab. cell, on undergoing with of based melanoma patients and dose was in against (gp100) survival a vaccine-therapy ipilimumab directed a at of activity with intravenously Approval ipilimumab T administered compared cycles. is lymphocyte 4 antibody lympho- of for T The increase activated weeks, destructed. an on present therefore causes receptor, are binding CTLA4 which ipilimumab. resulting the as against The related such directed literature, drugs antibody cytes. in non-BP monoclonal reported for a (MRONJ) cases especially is jaw few Ipilimumab comprehended, the very fully have of not may osteonecrosis which factors medication-related ONJ, risk as to known associated aptly and more pathogenesis now Both is condition the ipilimumab. ications, and in- ziv-aflibercept ONJ, everolimus, factor imatinib, of nuclear dine, development for the receptors to inhibitor). of related kinase activation been the have blocking classes antibody κβ other monoclonal from (humanized medications bisphosphonate-realated denosumab as and cluding re-named BP was other which then, ONJ, (ONJ). for Since BPs- risk jaws at IV the be two of to – class and osteonecrosis (BRONJ). drug (Zometa) ONJ for oral BP acid risk all by for zoledronic at recognized followed as and warning were (Aredia) product region this pamidronate maxillofacial of labelled the manufacturer (BP). in Switzerland), (IV) bone intravenous (Basel, with exposed treated patients non-healing in surgeons of maxillofacial cases reported First Background iad,bvczmb(uaie oolnlatbd) ninigncmdctos-sntnb(tyrosine sunitinib - medications antiangiogenic antibody), monoclonal (humanized bevacizumab ligand), 3 4-10 diinly aerprshv niae osbeascainbtenOJadazaciti- and ONJ between association possible indicated have reports case Additionally, 2 11-17 ihteavn fteenwcasso med- of classes new these of advent the With 2 osqety h usqetya a year subsequent the Consequently, 18 hwn mrvdoverall improved showing , 1 uig20,Novartis 2004, During 12,17 RN ne in onset MRONJ 1 . Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. srpre nltrtr,atrtedanss O,rgrls fteteay ed ormti eidof period a in remit to tends therapy, the of regardless of , injection of AO. AO topic for dentist diagnosis, treatment with the successful the even by most after months the prescribed literature, between 4 therapy in reported after antibiotic are observed reported which The was As eugenol, improvement oxide disease. no zinc “self-limiting” and and a useless, as resulted patient considered or the is with it socket, the alveolar all, after the above days within three clot and symptomatic one blood more between disintegrated time totally any in or halitosis”. at pain partially severity and without “postoperative a clinical in as with The increases defined which associated therapy. is any site, extraction, which start extraction disease of to the such history prior no around with account had compatible and into patients indeed MRONJ taken the was AO), as carefully appearance discarded was socket, radiographic AO be (dry to radiotherapy. osteitis possibility Neck and first alveolar & symptoms the between Head the was For was ORN case. diagnosis (ORN). this differential of MRONJ. and management the of the presentation, in chemotherapy cause encountered clinical we possible other ip- the issue as with –the first reported the treatment cobimetinib was agent been diagnosis the and never as Therefore, suspended have vemurafenib two patient- patient trametinib, MRONJ, the Our Dabrafenib, of by taken conclusion. cause drugs before. ipil- the possible years these, after a 3 Among shortly as ilimumab or list. cases denosumab. therapy drug clinical with ipilimumab MRONJ published association during of in three potential-cause one in and the reported therapy to been added has been imumab have medications healing. bone new complete Several showing follow-up, Conclusions months 4 and rinse). after Discussion mouth OPT 0.2% at chlorhexidine appearance Radiographic and metron- 4: os/die- + alveolus Figure per (amoxicilline the g therapy antibiotic/disinfectant 1.5 of of + weeks healing 4 -3 complete after patient idazole resolution showed the clinical OPT Complete and the new stopped 3: that, Figure was a after MRONJ months, and, the 4). evidenced 4 for prescribed and examination After Treatment 3 were clinical (figures defect. therapy monthly. The the of followed-up of weeks regularly follow-up disappeared. healing additional two-weeks was therefore complete Two the after had a During obtained symptoms healing. bone mm patient alveolar pain. her 5 of incomplete x that 10 case an but and a in of still therapy bone ejection prescribed mouth of the necrotic 0.2% was referred days chlorhexidine She of os) and 6 improvement. per os/die) evidence clinical showed per (1g patient clinical g the paracetamol 1.5 “no to visit, day; + showing related (3 a metronidazole MRONJ” symptoms” twice Radiotherapy. been + rinse 0 and Neck amoxicilline has with & “stage changes, which treatment a Head a radiographic one then starting os/die nor be findings, only weeks per smoking to clinical the three cobimetinib of evaluated was nonspecific for mg history was ipilimumab os/die 60 no it undergone, + per had mucosa, had vemurafenib mg She mg she 60 1440 medications extraction. MRONJ. taking cobimetinib: the tooth then os/die; her all the treatment was 1920 of by per Among She the (vemurafenib: moment experienced mg started cobimetinib (fever) the ongoing. 1440 toxicity + she still at then 3 vemurafenib mutation, pause), G. months, with week BRAF the replaced 3 1 to the patient was iv, for the Due and of mg os/die 2017 stopped os/die). presence in (3mg/kg per was up, per ipilimumab the follow treatment mg with the to the 2 treated During patient due + was disease. (300 so, she the dabrafenib+trametinib of disease, and remission with of progression complete progression with hepatic melanoma cycles) lung cutaneous had 4 for a for of 2015, weeks non- resection 3 in surgical every the a Then, revealing underwent patient 2009. visit, The in first harvested. carefully the was during anamnesis extraction. Her patient tooth after the months from 4 exhibited alveolus (OPT) healing Orthopantomography non-healed 2: a of Figure sign radiographic showed which 2). (OPT), (figure orthopantomography alveolus old three-days a exhibited She 12,17 tgn fteMOJwstu efre;bigteavou opeeysrone by surrounded completely alveolus the being performed; thus was MRONJ the of Staging 19 19,20 tl,a atro at otrcn eaaaye hwta Oteaysol be should therapy AO that show meta-analyses recent most fact, of matter a as Still, ahrta hrpui,a hr sn ulcmrhnino t ahgnssand, pathogenesis its of comprehension full no is there as therapeutic, than rather 12,18 3 sfra ieauerprs RN ne nalcases all in onset MRONJ reports, literature as far As 1 h a hstetdaccordingly, treated thus was She . 19,20 Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. e sde a earne nacrac ewe h ugo n h nooit ihtebs possible best the with Oncologist, the g and 1.5 side Surgeon + unpredictable the 3 cause between metronidazole; may accordance + which in (amoxicilline arranged drugs, protocol recent be antibiotic for ensuring may relatively prophylactic interest, os/die) risk of the patient’s other per management of at the few in administration the be decision The in the to best the effects. result vigilance to the and reported taking possible Oncologist strict addition in drugs, the best help and in chemotherapy between the may event– novel cooperation caution Surgeon advised; Maxillofacial single with recommend strongly & treated a authors Dentist/Oral thus patients is of the evaluation of MRONJ, reports Multidisciplinary management MRONJ. ipilimumab paper dental fully- of this the not literature if in pharmacodynamics in Even their new-generation several reported being to now. mechanisms, cases reaction unexpected until adverse have up major may a comprehended drugs be This may in ipilimumab. MRONJ drugs. time with medications, anti- well-known treatment of to on window addition was a In patient into the patient when cells to the T similarly MRONJ, of have Conclusions for cytotoxicity may risk and clones Moreover, at reactivity T-CELL was ipilimumab. the of she empowered enhances which effect such therapy the of anti-BRAF re-stimulating by re-activation spreading, that modulated tumor-antigen The demonstrated and a increased been induced have been has may had it therapy response target whose The the activity lead by + cytokines. T-CELL tumor can and immunosuppressive (vemurafenib the melanoma molecules decreasing to therapy BRAF-mutant stimulatory and damage immune in target We populations, cell of inhibitors ongoing cell expression MEK immunosuppressive circumstances. enhancing the and reducing by certain by BRAF cytokines, microenvironment under of co-caused stimulatory immune effect effect been anti-cancer an The side have to the patient. late may term like the a long onset of just also This MRONJ cobimetinib) Still, be the completion. long-term may that treatment the inhibitors. MRONJ after suggest years. in checkpoint years many endocrinopathies, is by for 10 and drug induced last and the hepatitis, can immune-responses 7 of effects 5, advantage the side at real to effects, alive the itself, due patients seen, mend is of have to efficacy we 20% As about bone with vulnerable before. efficacy years this half-life 3 blood on treatment day 14.7 demand Ipilimumab a have the to known increase is Ipilimumab could . extraction) bone CTLA4 localized tooth in presence. loss. resulting T-cells ignite (e.g. bone activated may in T-cells surgery systemic activated involved shortly resulting as of oral been ligand, osteonecrosis, or number have with osteoprotegerin during may associated the via be Ipilimumab empowering occurred to osteoclastogenesis that by shown ONJ metastatic that been necrosis have against suggested -related T-cells bone vaccination activated authors ipilimumab deficient of of The of therapy. process kind cases of systemic the a the reported in inducing responses melanoma of years, are antitumor metastatic end many there the with the for after literature patients improve persist In can in to therapy) survival able melanoma. of incremented months is significant 2 CTLA-4 a (about the is of result ipilimumab. undergoing block The therefore and The cells T-cells. presenting antigen activated to responses. binding cells, expressed T-cell T-regulatory is suppressor diminishing CTLA-4 in and (CTLA-4). T-cells for activated antigen-4 immunotherapy in T-lymphocyte-associated an both patients. cytotoxic as melanoma 2011 against metastatic) March antibody or in monoclonal (unresectable Administration advanced Drug of and management Food AO. US the MRONJ. than the to rather by ipilimumab related approved visit) patient, was be first the Ipilimumab could our to which administered during agents drug evaluated therapies we only anticancer as the various was 0, the amongst stage (which before, MRONJ a visible with reported than compatible not As rather more socket, event 1 an post-extraction stage is non-healing therapy, a antibiotic a during possibly to ejected was related but inspection sequestrum first bone the a at process. of diagnosis presence differential the the Furthermore, in discarded thus was AO months. commonly most weeks, or days 18,21 h muersos nue yiiiua ihol ylso treatment of cycles 4 only with ipilimumab by induced response immune The 20 hltteei orpr nsinicltrtr fA essigfrseveral for persisting AO of literature scientific in report no is there whilst , 12 12 ti ocial ht iial opuiu,dare,vitiligo, diarrhea, pruritus, to similarly that, conceivable is It 23 4 hl h ain ecie norcs a completed had case our in described patient the while 22 ruafo eua rlatvt or activity oral regular from Trauma 12 plmmbi humanized a is Ipilimumab 24,25 . Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. References super- applicable. scientific Not performed PAA and FI manuscript. Acknowledgements the revised FP manuscript. the vision. crafted AMG and AG corporate or private institutional, contributions any Authors’ by support/grants financial nor source entity. funding no received Authors interests competing no Funding have they that declare authors The upon author corresponding the from interests available Competing are study current the during request. analysed reasonable and used datasets The materials and data of Availability applicable. Not publication for Consent applicable. Not participate to (BRONJ); consent and ONJ approval Ethics bisphosphonate-realated (ONJ); (OPT); Declariations orthopantomography jaws (AO); osteitis the alveolar (MRONJ); (ORN). jaw of osteoradionecrosis the and of osteonecrosis osteonecrosis ipilimumab medication-related between (BP); relation the Bisphosphonates understand studies Further fully adverse to pain. abbreviation of order and of discomfort target-therapy. in occurrence List patient’s of cases, the interference in of reduce possible result number the may may large and paper, cooperation MRONJ, a our Such on in shown needed condition. have are we systemic as and which, oral events both of evaluation SoekA,Lpo ,Bd J ta.Dnsmbcmae ihzldoi cdfrtetreatment the for acid zoledronic with compared Denosumab al. denosumab et of JJ, study Body II A, Lipton phase AT, activecontrolled Stopeck Randomized 5. al. et J, Figueroa GG, Steger A, Lipton 4. Uie ttsFo n rgAmnsrto,Oc fDu aey otaktn aeyreview. safety Postmarketing Safety: Drug of Office Administration, Drug NJ, and Hanover, Food East States Zometa. United and LabelofAredia 3. the PrecautionsAddedto Surgeons Maxillofacial DearDoctor. and JA. Oral Hohnecker of 2. Association American al. et J, Fantasia TB, Dodson SL, Ruggiero 1. fbn eatssi ainswt dacdbes acr admzd obebidsuy Clin J study. double-blind randomized, a cancer: breast advanced 28:5132-5139. with 2010; patients Oncol in metastases 25:4431- 2007; bone Oncol of Clin J metastases. bone cancer-related breast with 4437. patients in safety and efficacy 2019 09, October Accessed 04-FDA-Tab3.pdf. ipopoae.Aalbea:http://www.fda.gov/ohrms/dockets/ac/05/briefing/20054095B2 at: Available Bisphosphonates. 2 p 2004. Oncology, Novartis Surg Maxillofac Oral J Update. Jaw—2014 the 72:1938-1956. of 2014; Osteonecrosis Medication-Related on Paper Position 5 03 - Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. Bn ,CgilA,Dn ,e l eetv RF60 niiinehne -elrcgiinof recognition T-cell enhances inhibition BRAFV600E Selective al. et P, immune the Dang AP, by Cogdill recognition tumor A, improves Boni inhibition 25. BRAF al. et 2016;17(11):e481 F, Oncol Nicoletti Lancet adjuvant P, melanoma. in Fagone advanced destruction M, in joint survival and Donia loss prolongs bone 24. Ipilimumab regulate TK. cells Burki T Activated 177 23. al. of et follow-up I, long-term Sarosi ipilimumab: U, Feige with YY, blockade Kong CTLA-4 al. 22. et RM, Sherry JC, Yang PA, with Prieto Con- patients 21. and Concepts in of ipilimumab Review S´anchez-Garc´es Comprehensive with M, A survival Taberner-Vallverd´u Nazir M Osteitis: M, Improved Alveolar 20. M. Miloro al. E, Olech et A, on DF, Kolokythas update McDermott 19. An SJ, jaw: O’Day the FS, of osteonecrosis Hodi Medication-related 18. the al. of et AZ, Osteonecrosis Sax S. STY, Labropoulos Liang F, AA, Owosho Tzerbos E, 17. Vardas acute with D, patient Galiti a in E, jaw Razis the of O, ziv-aflibercept. Osteonecrosis with Nicolatou-Galitis al. associated 16. et and jaw M, irinotecan the Moschogianni to of D, aflibercept, Galiti Osteonecrosis related with O, al. complication Nicolatou-Galitis associated et new 15. osteonecrosis N, Jaw a McCleary P, jaw Enzinger al. the H, et Mawardi of R, 14. Osteonecrosis Spadi F, al. Pinta report. et A, case a Ponzetti SK, everolimus: Yom 13. to M, related jaw Scordo the of AA, Osteonecrosis Owosho HD. patients 12. Jung in HS, necrosis Park bone YS, Jung jaw DW, and Kim bleeding Gingival 11. al. et A, Psyrri M, Migkou O, Nicolatou-Galitis 10. Etl L one ,FroiA ta.Otoersso h a eae obvczmb lnOncol Clin J bevacizumab. to related jaw Oral the Surg of Oral Osteonecrosis report. al. case et a A, Farooki jaw: M, of Fornier osteonecrosis CL, Estilo related Sunitinib 9. H. denosumab Lehman with E, treated Regev patients Y, in and Fleissig jaw pharmacology the 8. of denosumab Osteonecrosis of al. relationship et L, The Levi OR. A, Blanchard Beirne AA, Owosho E, Naumann 7. K, Ettinger J, Malan 6. eaoawtotaetn ypoyefnto.Cne e 2010;70(13):5213-9. Res Cancer function. lymphocyte affecting without melanoma T-cell adoptive involving 1(9):1476-1483. melanoma 2012; against Oncoimmunology therapies transfer. combinatorial for implications Potential system: 1999;402:304–9. Nature 2012;18:2039–47. ligand. Res osteoprotegerin Cancer Assoc through Am arthritis J Off Res: Cancer 2015;20(5):e633-9. Clinical Bucal melanoma. metastatic Cir with Oral patients Patol Oral Med review. systematic A management: socket 2010;2010:249073. Dent J 711–23. Int 363: troversies. 2010; Med J Engl 2018;125:440–445 N Radiol evaluation melanoma. Oral dental metastatic Pathol premedication Oral of Med role clinical Oral the Surg and with Oral experience report center prevention. case cancer in kettering a sloan memorial imatinib: the receiving leukemia 2013;4:29-33. myelogenous Oncol chronic Clin with Forum patient implications. a 2016;2:220-223. in Treat. jaw Metasta Cancer J azacitidine. received who leukemia, myeloid 7:E81-E87. 2016; Oncol Gastrointest J 2016;102. Tumori district. oral to attention fluorouracil: e100-e101. 2015;51: Oncol Oral Ipilimumab. 2013;51:e302-e304. implications. Surg clinical Maxillofac with Oral cases J 2012;113:234-238. 2 Br Radiol of Oral report Pathol Oral sunitinib: Med receiving Oral carcinoma Surg Oral cell renal metastatic with 2008;26:4037-4038. 2012;113:e1-e3. Radiol 44:265- Oral 2016; Pathol Surg Oral Craniomaxillofac J Med patients. thirteen of series a 2012;114:671-676. bone: Radiol the 270. Oral to Pathol tumors Oral metastatic Med for Oral Surg Oral jaws. the of osteonecrosis 6 ,e l ffiayo ieetmtosue o dry for used methods different of Efficacy al. et A, ´ Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. 7 Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. 8 Posted on Authorea 16 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159493267.78873525 — This a preprint and has not been peer reviewed. Data may be preliminary. 9