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ABSTRACT

The treatment for metastatic melanoma has evolved signifi-cantly in the past few years. Ipilimumab, an immunotherapy,is now in mainstream oncology practice given that it hasshown improved overall survival in randomized clinical trials.Other immune modulating agents, such as programmeddeath receptor-1 and programmed death receptor ligand-1antibodies, are showing promise in early clinical trials. This

manuscript will review ipilimumab and its most common sideeffects. Immune-related adverse events (irAEs) are importanttorecognizeearly,andtheirpresentation, timingofonset,andgeneral recommendations for workup and management willbe reviewed. Assembling a multidisciplinary team, as well asthorough education of the patient, is recommended to opti-mize patient care. TheOncologist2013;18:733–743

Implications for Practice: Ipilimumab, an immunotherapy, has shown improved overall survival in randomized clinical trials andisnow inmainstreamoncologypractice. This study reviews ipilimumaband its commonsideeffects, emphasizing the importanceof early recognition of immune-related adverse events. Presentation, timing of onset, and recommendations for workup andmanagement of immune-related adverse events are discussed.

INTRODUCTION

Melanoma is currently the fifth and sixth most common can-cer inmenandwomen, respectively [1]. The incidence contin-ues to rise and it remains a leading disease in terms of loss ofexpected years of life [1]. Early stage disease is typically cur-able with surgical excision; however, the prognosis for ad-vanced, unresectable disease is poor, with an estimatedmedian survival of less than 1 year [2]. Traditionally, systemictherapies for advanced disease have had limited activity andbenefit [3]. Over the past 2 years, the therapeutic arsenal formetastatic melanoma has evolved dramatically. For the firsttime, two new agents have demonstrated a survival advan-tage in the treatment of advancedmelanoma. Ipilimumab, ananticytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody,withorwithout a gp100 vaccine, first demonstrated improved sur-vival compared with gp100 vaccine alone, leading to its ap-proval by the U.S. Food and Drug Administration (FDA) [4]. Inanother randomizedphase III trial, ipilimumab incombinationwithdacarbazine (DTIC)demonstrateda survival benefit com-paredwithDTIC alone [5]. Vemurafenib, a specific tyrosine ki-nase inhibitor of V600 mutated BRAF, demonstrated aresponse rate of approximately 50% and a significant de-crease in therelativeriskofdeathcomparedwithDTIC (hazardratio � 0.37) [6]. Vemurafenib is now FDA-approved, and inpatients with V600 mutated BRAF detected on mutationalanalysis, it is a standard of care treatment.

Ipilimumab is FDA-approved foruse in theUnitedStates inpatients with metastatic or unresectable stage III melanomaand in someother countries forpatientswhohaveprogressedon previous therapy. The approved schedule is ipilimumab 3mgperkilogramadministered intravenouslyevery3weeks forfour doses, aswasutilized in the randomizedphase III studyofipilimumab and gp100 [4]. Maintanence ipilimumab is onlybeing administered in clinical trials at this time. Given itsmechanismof action as an immune-modulating agent that af-fects T-cell function, its side effect profile is distinct from che-motherapiesandmolecular targeted therapiesaswell as fromother immunotherapies. Bristol-Myers Squibb sponsored aroundtable in November 2010with a panel ofmelanoma spe-cialists to discuss the clinical experience with ipilimumab, theevaluation, and management of immune-related adverseevents (irAEs), andpossiblematerials and information to facil-itate the education of community oncologists as well as pa-tients in light of impending FDA approval. This manuscript isthe result of the roundtable, and in it we will review the basicipilimumabprinciplesof use for the communityoncologist, in-cluding itsmechanismof action and side effect profile, aswellasprovidedataandexpertopinion regarding toxicitymanage-ment and patient selection. The U.S. FDA, in conjunctionwithBristol-Myers Squibb, initiated a risk evaluation and mitiga-tion strategy (REMS) optional educational program for ipili-

Correspondence: Leslie A. Fecher,M.D., Indiana UniversityMelvin and Bren Simon Cancer Center, 535 Barnhill Dr., Room 473, Indianapolis, In-diana 46202-5289, USA. Telephone: 317-948-7576; Fax: 317-944-3684; E-Mail: [email protected] Received December 28, 2012; accepted forpublication March 27, 2013; first published online in The Oncologist Express on June 17, 2013. ©AlphaMed Press 1083-7159/2013/$20.00/0http://dx.doi.org/10.1634/theoncologist.2012-0483

Ipilimumaband Its Toxicities:AMultidisciplinaryApproachLESLIE A. FECHER,a SANJIV S. AGARWALA,b F. STEPHEN HODI,c JEFFREY S.WEBERd

aUniversity of Pennsylvania Abramson Cancer Center, Philadelphia, Pennsylvania, USA; bSt. Luke’s Cancer Center, Bethlehem,Pennsylvania, USA; cDana-Farber Cancer Institute, Boston,Massachusetts, USA; dH. LeeMoffitt Cancer Center & Research Institute,Tampa, Florida, USADisclosures of potential conflicts of interestmay be found at the end of this article.

KeyWords. Ipilimumab • CTLA-4 • Antibody • Melanoma • Immune-mediated toxicity • immune-related adverse events • AEOSI

TheOncologist®

Melanoma and CutaneousMalignancies

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mumab with management guidelines [7]. The most commonipilimumab-related side effects, irAEs, will be reviewed, in-cluding their typical timing of onset as well as recommenda-tions for workup and management. Ipilimumab is generallywell-tolerated and irAEs typically are easily managed. Essen-tial to its use is a high level of awareness of potential toxicitiesas well as frequent and thorough elicitation of symptoms torecognize, diagnose, and manage toxicities promptly. Thetreating oncologistmust be knowledgeable andalert to possi-ble irAEs as well as assemble and collaborate with a team ofsubspecialists in their management. Subspecialists may in-clude gastroenterologists, hepatologists, endocrinologists,neurologists, ophthalmologists, dermatologists, rheumatolo-gists, infectious disease specialists, and possibly others. Goodcommunication between patient and health care providersalso contributes to successful and safe treatment with thisdrug. It isalsoadvisable tobeawareofmelanomaspecialists inand around your communitywhomay have expertisewith ip-ilimumab. This knowledge may be relevant and applicable toother immunomodulating agents under development.

CTLA-4CTLA-4 is a surfaceprotein expressedonactivatedand regula-tory T cells and is upregulated in malignancy [8–10]. It func-tions as a negative regulator of T-cell function, binding to B7.1and B7.2 on antigen-presenting cells and inducing cell-cyclearrest and T-cell anergy, or tolerance. Its counterpart on Tcells, surface protein CD28, is a positive regulator of T-cellfunctionandbindsB7with less affinity (Fig. 1) [11]. Thegoal ofCTLA-4blockade is tobreak immune tolerance toa cancer andmanifest a prolonged tumor-specific immune attack. How-ever, anti-CTLA-4 antibodies canalsobreak tolerance toother“normal” antigens, which leads to immune attack on normalparts of the body, such as the gastrointestinal (GI) track, theskin, or endocrine glands. Two CTLA-4 antibodies have been

developed and investigated in clinical trials, ipilimumab (Yer-voy, Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and tremelimumab (ticilimumab, CP-675,206, Pfizer,New York, NY [now MedImmune, http://www.pfizer.com]).This review will focus on ipilimumab, a fully human, IgG1monoclonal antagonist antibody to CTLA-4 that is FDA ap-proved and that has demonstrated a survival benefit in ran-domized clinical trials.

TOXICITYThe toxicities of ipilimumabarewell studied anddescribed in anextensiveclinicaltrialsexperience;however,ourknowledgecon-tinues to evolve as ipilimumab’s use increases. Treatment-re-lated adverse events are often mild to moderate, but occur inapproximately 70%–88% of patients [4, 12]. Toxicities directlycorrelate with ipilimumab dose [13]. Common treatment-re-latedadverseeventsatthetimeof infusions includefatigue,nau-sea, vomiting, diarrhea, fever, headache, dizziness, rash, andpruritus. Onset of these side effects can be during the infusion,within24–72hours, or later, and treatment is symptomaticwithdiphenhydramine,antipyretics, antipruritics, and intravenousororal fluidsasneeded.Temporaryhaltingandsubsequentslowingof the ipilimumab infusion is advised, but typically does not pre-vent continued treatment.Nonsteroidal premedicationsarenottypically administered but can be added in the event of an infu-sion reaction. Hypotension and tachycardia can be seen aroundthe timeof infusion, butnot commonly.

irAEs can occur at any point during treatment with ipili-mumab, but often present around the third or fourth dose.The presentations can be subtle, and other causes must beruled out. Establishing the correct diagnosis promptly, deter-mining severity based on common toxicity criteria grading[14], initiating treatmentwith steroids, if indicated, and hold-ing further anti-CTLA-4 treatment is essential. irAEs can be se-vere and life threatening, particularly if diagnosis is delayed.

T-cell

APC

T-cellactivation

TCR

MHCCD28

B7

CTLA-4

APC

T-cellinactivation

TCR

MHC B7

CTLA-4

T-cell

APC

T-cellproliferation

TCR

MHC

CTLA-4

lpilimumab

CD28 CD28

T-effector cell

B7

A B C

Figure 1. T-cell activation, inactivation, and proliferation. (A): T-cell activation occurs via costimulatory binding of B7 to CD28. (B):CTLA-4 is upregulated inmalignancy and binds B7, thus inhibiting T-cell activation. (C): Antagonism of CTLA-4 via ipilimumab promotesT-cell activation/proliferation. (Reprintedwith permission [11].)

Abbreviations:APC,antigenpresentingcell;CTLA-4,cytotoxicT-lymphocyteantigen-4;TCR,T-cellreceptor;MHC,majorhistocompatibilitycomplex.

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The incidence of grade 3 or higher irAEs is approximately 5%–25%and isdoserelated[4,12,13,15].ThemostcommonirAEsare dermatitis (pruritus, rash), enterocolitis, endocrinopa-thies (hypophysitis, thyroiditis), liver abnormalities (elevatedserum liver tests, hepatitis), and uveitis, and will be reviewedin detail. irAEs involving the nervous system also have beendescribed: central nervous system (CNS) or peripheral–sen-sory or motor deficits, as well as irAEs of the cardiovascularsystem, hematopoietic system, and others. The onset of irAEscan vary from insidious to sudden; severity can range frommild to life threatening, but they uncommonly result in signif-icantmorbidityordeath. irAEsoftenmimicotherknownauto-immune conditions, such as autoimmune hepatitis orinflammatory bowel disease. However, themechanism of ac-tion of the ipilimumab-induced irAEs may be distinct fromthose analogous autoimmune conditions. At this time, themechanisms of irAEs appear to be T-cell-mediated phenom-ena characterized by T-cell-rich inflammatory infiltrates withfew reports of circulating antibodies [16, 17].

The primary treatment for most low-grade irAEs is sup-portive care; high-dose steroids and holding further ipili-mumab are indicated for higher grade irAEs. Not all irAEs willrequire permanent cessation of anti-CTLA-4 therapy. Typi-cally, themajoritywill respond to steroids, but a longer coursewith a slow taper over at least 1month is necessary. Too rapida taper can lead not only to recurrence of symptoms, but a re-bound with worsened severity. The optimal dose, schedule,and course of steroids are still uncertain. If symptoms persistdespite high-dose steroids or are refractory to steroid taper-ing, other immunosuppressive treatment may be necessary[18–20]. Importantly, patients can evolvemore than one irAEduring the course of their treatment orwhile on steroids [21].The development of irAEs appears to be associatedwith anti-tumor response in some studies [13, 22, 23]. Continued anti-

tumoractivity is seendespite steroid therapy in somepatientswith irAEs [21, 24, 25]. However, efficacy may be compro-misedmore so in patients on steroids at the time of initiationof ipilimumab [26]. The overriding principle remains: use ste-roids if needed, but avoid them if not.

Prior to each and every dose of ipilimumab, ensure thatlaboratory evaluations, including hepatic panel, basic meta-bolic panel, complete blood count with differential and thy-roid-stimulating hormone (TSH), and free thyroxine (T4) aredrawnandreviewed.Evaluationofamylaseand lipase levels isalso reasonable and recommended. Delayed irAE presenta-tions, weeks tomonths after treatment, are possible. It is un-known when the risk of irAEs from ipilimumab ends, thuscareful patient follow-up is recommended. Self-education aswell as the education of office staff and colleagues are key torecognizing and effectively managing the irAEs associatedwith ipilimumab. Prior to dosing ipilimumab, it is recom-mended to become familiar with available irAE treatment al-gorithms.Thealgorithmspresented in thismanuscript (Figs.2,4–6) are based on the roundtable discussion, as well as influ-encedbyother developedalgorithms, including thoseutilizedbyBMSin ipilimumabclinical trialprotocolsand inthepackageinsert [7, 27–29]. Educating patients and maintaining close

The development of irAEs appears to be associatedwith antitumor response in some studies. Continuedantitumor activity is seen despite steroid therapy insome patients with irAEs. However, efficacy may becompromised more so in patients on steroids at thetime of initiation of ipilimumab. The overriding prin-ciple remains: use steroids if needed, but avoid themif not.

Figure 2. Algorithm for skin irAEmanagement.

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communicationwith them is essential. Assembling amultidis-ciplinary team prior to treating patients with ipilimumab willfoster collaboration and facilitate their future care.

EDUCATION

PhysicianMedicine is a constantly evolving field and oncology currentlyhas some of the broadest and most rapid drug developmentpipelines. Molecularly targeted and immune-modulatingagents are now standards of care in addition to chemothera-pies. Ipilimumab possesses a unique mechanism of action aswell as a distinct toxicity profile and management strategycompared with other anticancer therapies. The treating on-cologist will need to direct and coordinate the overall care forthese patients. Review of the current literature, continuingmedical education lectures as well as consultation with col-leagues is essential. The FDA, in conjunction with Bristol-My-ers Squibb, initiated aREMSoptional educational program foripilimumab. Management guidelines are readily available aswell as patient educationmaterials, including awallet card, atwww.yervoy.com/hcp/rems.aspx [7]. There are hotlinesavailable for medical information as well as to report adverseevents. In theUnited States, when a physician places an orderfor ipilimumab, the company is notified and a representativecontacts the prescribing physician within 48 hours to provideand review relevant educationalmaterials and resources.

Patients and FamilyEarly recognition of symptoms and frequent monitoring iscentral to irAE management. Patients and families should becounseled concerning signs or symptoms. It is recommendedthat patients utilize symptom logs and carry wallet cards withdrugname, treatmentdates, and the treatingphysician’s con-tact information to facilitatecommunicationandpatient care.Inanemergencysetting, thepatientwillneedtobetheirownad-vocate. A unique issue for providers to consider when treatingpatients with metastatic melanoma is that they may not accu-ratelyreportsideeffectsforfearofbeingtakenofftreatment.Re-assuranceandeducationcanhelp.Themaximtocall earlyandtocall often to thephysicians’ office shouldbe reinforced.

MULTIDISCIPLINARYTEAM

Ancillary StaffOffice staff is the first lineof defense for recognizing andmon-itoring toxicities related to ipilimumab. Advanced care practi-tioners, nurses, and receptionists must be aware of warningsigns and symptoms so thatpatients are triagedappropriatelyand reassessed in a timely manner. Presentations as well ascase-based scenarios and posting of treatment algorithms inthe office can be beneficial.

PhysiciansA multidisciplinary group of physicians will be necessary foroptimal patient care. This teammay include a gastroenterolo-gist, hepatologist, endocrinologist, neurologist, ophthalmolo-gist, and dermatologist. Not all subspecialties may beimmediately accessible in smaller communities, thus physi-cians are encouraged to establish a consult network in ad-vance. Experience with ipilimumab may be limited and varyamong physicians; subspecialists may have no knowledge ofthe recommended treatment algorithms for irAEs. Presenta-

tions and discussions at tumor boards and staff meetings willfacilitate collaboration and patient care. Professional societ-ies andmeetings as well as personal interactions also provideopportunities for education. Including emergency depart-ment (ED) physicians in the network of physicians is encour-aged, as somepatientsmayneedevaluation inanEDduringorafter treatment. Emergency health care professionals oftenhave no experiencewith ipilimumab or in assessing andman-aging its associated toxicities. Patients should be able to pro-vide information (e.g., a wallet card) and insist upon directcommunication with the treating oncologist. The REMS pro-gram and online management guidelines may be helpful [7].The importance/need for any treating physicians to directlycontact the treating oncologist promptly cannot be empha-sized enough.

IMMUNE-RELATEDADVERSE EVENTSDermatologic ToxicitiesDermatologic toxicities are the most common ipilimumab-associated irAEs and are usually the first to manifest, afterdose1or 2. Themost common toxicities are amaculopapular,erythematous rash, orpruritus. The incidenceof rashandpru-ritus is approximately 40%–49% [4, 12] and most often mild.Providersshouldconsiderencouragingtheuseofmoisturizerspreventatively; other supportive measures such as antipru-ritic medications or topical steroids may be indicated (Fig. 2).Rare immediate hypersensitivity reactions, such as hives,havebeenobservedduringand just after infusionsbut arenotdiscussed in the literature.

It is uncommon to hold ipilimumab therapy for most der-matologicsideeffects.Persistentgrade2toxicitiesmayneces-sitate a course of oral steroids and prompt a dermatologyconsult. However, ipilimumab should be held for severe skinrashes (grade3or 4),whichmay require admission to thehos-

Adult 3.5 4.75 3.5

Age Half ofhead (A)

Half of onethigh (B)

Half of oneleg (C)

Lund Browder Chart

Figure 3. Lund Browder chart for estimating body surface areainvolved by rash. (Adapted from [30].)




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pital for management and workup in conjunction with a der-matologist as well as treatmentwith systemic steroids, eitherintravenous or oral. Blisters are rarely seen, and their pres-ence signals significant toxicity. Life-threatening dermato-logic complications such as Steven’s Johnson Syndrome ortoxic epidermal necrolysis havebeen seen in fewer than1%ofpatients andnecessitate emergent treatment andpermanentcessation of ipilimumab. It is important to accurately qualifyand quantify cutaneous toxicities. The Lund and Browderchart (Fig. 3) [30], for estimationofbody surfacearea involvedby burns, is used to assess the surface of involvement of rashforgrading.Dermatology referralmaybenecessary forpersis-tent moderate skin toxicities and is recommended for severeskin rashes. Vitiligo can also be seen and is considered a posi-tive prognostic sign in patients withmelanoma as it signals animmune attack on melanocytes. While permanent, this doesnot require any treatment or necessitate holding ipilimumab,although patients need to be aware that areas of vitiliginousskin are susceptible to severe sun damage.

EnterocolitisThe second most commonly reported irAE is diarrhea, withanygradediarrheareported inapproximately30%–35%ofpa-tientsandgrade3–5diarrheaorenterocolitis in5%–8%[4,12,13].Mild, intermittent changes inbowelmovementsare com-monly seen. In patients receiving ipilimumab, all diarrhea issuspect andmost likely related to ipilimumab. Patient educa-tion will ensure that all diarrhea is reported and managedpromptly. It can be self-limited; however, ipilimumab-relateddiarrhea is not typical of drug-induced or idiopathic diarrheaseenwithother cancer therapies. It oftenpresentsaround the

second dose of therapy, but its timing of onset can vary and isnot predictable. Symptoms canprogress rapidly topotentiallylife-threatening status, if untreated.

Algorithms for themanagementofdiarrheahavebeende-veloped and their use is recommended [7, 27–29] (Fig. 4). Ini-tialmanagement forgrade1diarrhea is symptomatic,withoutsteroids. Grade 2 diarrhea is managed symptomatically aswell, but if it persists orworsens, ipilimumab-induced entero-colitis is the most likely diagnosis and treatment with ipili-mumab should be held while a workup is pursued. Othercauses to be ruled out include gastroenteritis, other medica-tion-induced diarrhea, infectious diarrhea, such as bacterial(Clostridium difficile) or viral, or others. It is possible for pa-tients to have a superimposed infection in addition toipilimumab-induced diarrhea/colitis, and both require treat-ment. If a diagnosis of ipilimumab-induced colitis is estab-lished, treatment should be initiated with oral or intravenous(IV) steroids, depending on the grade of diarrhea. Once an in-tervention is initiated, reassessmentwithin 24hours in theof-fice or by telephone is necessary. Frequent reevaluation isrecommended as irAE symptoms and course can change rap-idly and response to interventions cannot be assumed. Refer-ral to a gastroenterologist for flexible sigmoidoscopy orcolonoscopy should be considered for persistent grade2diar-rhea, or any grade 3–4 diarrhea. Patients presenting withgrade 3–4 diarrheamay need hospital admission for workup,monitoring, IV hydration, bowel rest, and high-dose IV ste-roids. For patientswith refractory symptomsdespitemaximalmedical support and treatmentwithhighdose steroids for ap-proximately 5 days, a single dose of infliximab 5 mg/kg has

Figure 4. Algorithm for gastrointestinal irAEmanagement.




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demonstrated rapid resolution of symptoms and durable effi-cacy and shouldbe considered [18, 19]. Infliximabmayalsobeconsidered for persistent grade 2 symptoms that do not re-solve despite treatment with steroids. Infliximab can be re-peated, but should not be used if there is concern forperforation or sepsis. Consider a surgical consult for patientswith severe diarrhea and/or ileus early in the treatmentcourse. If diarrhea persists despite maximal medical and sup-portivetherapy,includingtheuseoftotalparenteralnutrition, in-fliximab, and multiple tapering courses of steroids, then adiverting ileostomy or partial/complete colectomymay be indi-cated as a last resort. Rarely, colitis can progress to intestinalperforation (1%). Permanent cessation of ipilimumab is recom-mended for grade 3 or 4 colitis, hemorrhage, or perforation. Pa-tients subsequently treatedwithhigh-dose interleukin-2 appeartohavean increased riskof intestinal perforation [31].

At this time, it is not possible to predict who will developentercolitis. While metastatic disease involving the GI tract iscommonly seenwithmelanoma, this doesnot appear to influ-ence or predict ipilimumab-induced GI toxicity. Prophylacticoral budesonide failed to prevent the onset of GI irAEs in pa-tients treated with ipilimumab compared with placebo [24].Thirty-six percent (21/58) of patients in thebudesonide groupand35.1% (20/57) of patients in theplacebogroupdevelopedgrade �2 diarrhea and/or grade �2 colitis during the first 23weeks [32]. However, budesonide can be used in the treat-ment of lower grade enterocolitis.

Ipilimumab-induced enterocolitis has been likened to in-flammatory bowel disease or graft-versus-host disease(GVHD) given its presentation and response to immunosup-pressivemedications; however, its clinical and histologic find-ings are quite variable. In addition to inflammatory changesinvolving the colon, gastritis and small bowel enteritis also

have been described [18]. On endoscopy, edema, erythema,ulceration, and exudates may be seen. Endoscopic biopsieshavenotedmucosal erosion, T-cell rich lymphocytic infiltrateswithin the laminapropria,andepitheliumaccompaniedbyeo-sinophils and plasma cells, as well as neutrophilic infiltrateswith cryptitis and crypt abscesses [18, 32, 33]. Other serieshave reported rare granulomas [18] and prominent epithelialapoptosis andmucin depletion [33]. The phase II trial evaluat-ing prophylactic budesonide incorporated endoscopywith bi-opsy 1–2 weeks after the first dose of ipilimumab andendoscopy/biopsy ina fewpatientsafteronsetofgrade�2di-arrhea. Immune cell infiltration into themucosa after the firstdose of ipilimumabwas suggestive, but not predictive of lateronset diarrhea/colitis. Further, the microscopic appearanceand location of histologic changes observed after the onset ofdiarrhea/colitis were distinct from inflammatory bowel dis-ease (absenceofgranulomas, fissuringulcers) and fromGVHD(absence of prominent epithelial apoptosis). Interestingly,GVHDwas not induced orworsened in patients with relapsedmalignancies following allogeneic bone marrow transplantwhen treatedwith a single dose of ipilimumab [34].

HepatotoxicityLiver abnormalities are reported in approximately 2%–9% ofpatients and include elevation of serum liver transaminases,elevatedbilirubin, and inflammatoryhepatitis [4, 12, 13]. Ipili-mumab-induced hepatitis is rare but can be life threatening.Greater hepatotoxicity was seen when ipilimumab was com-bined with DTIC and was postulated to be related to hepatictoxicity associated with DTIC alone [5]. Typically, hepatic ab-normalities present around the second dose. Current guide-lines recommend evaluation of serum markers of hepaticfunction at baseline and, prior to each dose, and periodically

Figure 5. Algorithm for hepatic irAEmanagement.




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after completion of therapy. The presence of livermetastasescan confound interpretation of serum liver tests; liver metas-tases can present with either a cholestatic pattern and/ortransaminitis. Monitoring and/or minimizing intake of otherhepatotoxins such as alcohol or acetaminophen should bestressed to patients [35]. It is reasonable to check baseline vi-ral hepatitis serologies prior to dosing of ipilimumab. All ipili-mumab trials excluded patients with hepatitis B or C, and thepanel does not recommend treatmentwith ipilimumab in thesetting of active hepatitis B or C outside of a clinical trial.

Serumliver test levels canrapidly increase, fluctuate,andoc-casionally resolve without intervention. Management algo-rithms have been developed and are recommended [7, 27, 28](Fig. 5). If abnormal values for aspartate aminotransferase, ala-nine transaminase,or total bilirubingreater thanorequal to twotimes the baseline are detected, monitoring should increasewith labs repeated every 1–3 days, and workup forautoimmunity should be considered, including serum antinu-clearantibody, smoothmuscleantibody,antimitochondrialanti-bodies, antisoluble liver antigen/liver pancreas antibodies,anti-liver–kidneymicrosomal-1antibodies,andothersasappro-priate.Consider imaging toassess fornonautoimmunecausesofliver abnormalities. Consultation with a gastroenterologist orhepatologist is reasonable,anda liverbiopsymaybeconsidered.Therearelimitedpathologicdataregardingchangesseenwithip-ilimumab-induced hepatitis. A few case reports have demon-strated inflammation, necrosis, and rare, if any, fibrosis. Thesefindings more closely resemble those seen with drug-inducedacutehepatitis rather thanclassic autoimmunehepatitis; clinicalcorrelation is essential [36]. An increased frequencyof labmoni-toring should continue until the liver labs have stabilized or im-proved then continue with weekly monitoring. Rebound hasbeen described with elevated liver tests as well as with otherirAEs. For example, transaminases are abnormal on a follow-upappointment and the ipilimumabdose is skipped. The liver teststhennormalizeandipilimumabisresumedwiththenextplanneddose and the liver tests subsequently elevate again. These casesareoftendifficulttogaugeandmanageandconsiderationofcon-sultation with a hepatology specialist is advised. If serum livertests are greater than eight times the upper limit of normal, fur-ther ipilimumab should be held and labs repeated within 24hours. If no improvement and an irAE is suspected, hospital ad-mission and initiation of high-dose IV steroids and hepatologyconsult is advised. If there is an inadequate response to high-dose steroids, additional immunosuppressive therapymaybeneeded [35]. Gastroenterologists will be readily available inmost settings, but dedicated hepatologists may not be. Per-manent cessation of ipilimumab is indicated for ipilimumab-induced hepatitis that requires treatmentwith steroids.

EndocrinopathiesEndocrinopathies, other than thyroid dysfunction, are uncom-mondiagnosesinoncology.Hypothyroidismcanbeseenwithim-munotherapies and some molecular therapies and typicallyfollow a subacute presentation. In contrast, the most commonendocrinopathy seen with ipilimumab is hypophysitis. Autoim-mune hypophysitis, or lymphocytic hypophysitis, is quite rareand often presents in women late in pregnancy or postpartumand is accompanied by altered pituitary function, most com-monly of corticotrophin (ACTH) [37]. Hypophysitis related totreatmentwith ipilimumabtypicallypresentsatorafter thethird

infusion, with an incidence of approximately 1.5% (range: 0%–17%) [4, 15, 38]. The presenting symptoms of ipilimumab-in-duced hypophysitis can be quite vague and require vigilance.Symptoms can include fatigue, headaches, myalgias, loss of ap-petite,ornauseaandvomiting.Patientsmayalsocomplainofeyepain, diplopia, or other visual changes. Visual changes and/orheadaches in patients with metastatic melanoma should alsoprompt concern for possible CNS or orbital metastases andshouldbeevaluatedwithacontrastedbrainmagneticresonanceimaging (MRI). Hypophysitis typically manifests as diffuse en-largement of the pituitary, with or without areas of necrosis, onbrainMRIbutmayalsohavenormal findings [39,40]. Laboratoryevaluations include TSH, free T4, total and free triiodothyronine(T3),cortisol,ACTH,luteinizinghormone,follicle-stimulatinghor-mone, and testosterone (in men). Low levels of ACTH, TSH, andgonadotropins lead to low free T4, cortisol, and testosterone,andestablishthediagnosisofhypophysitiswithhypopituitarism.Ipilimumab-induced hypophysitis typically involves the anteriorpituitary, impacting the thyroid andadrenal axes [40]. Less com-mon presentations include hyponatremia due to the syndromeof inappropriate anti-diuretic hormone (SIADH) secretionordia-betes insipidus [41].

Hypophysitis with associated adrenal insufficiency/crisis is apotentially life-threateningmatterandrequiresurgentattention(Fig. 6). The hallmarks of adrenal insufficiency are hypotension,dehydration, and electrolyte abnormalities, such as hyponatre-miaandhyperkalemia. IVhigh-dose steroidswithmineralocorti-coid activity such asmethylprednisolone should be started afterlaboratory tests are drawn andwhile waiting for results and en-docrineconsult, thendiscontinuedlater ifanothercauseisdeter-mined.Patientsshouldbeevaluatedfor infectionsand/orsepsis.If noevidenceofadrenal crisis, it is reasonable towait for labora-toryresultsprior tostartingsteroids.Allpatientswithhypophysi-tis require corticosteroids and likely thyroid hormonereplacement, aswell as testosterone replacement inmen. Pred-nisone1mg/kg/day,ortheequivalent, istypicallyrecommendedas a starting dose, if clinically stable. Steroids can be slowly ta-peredtoalowerphysiologicdoseoncesymptomsarecontrolled.The need for steroids is likely to be permanent in endocrinopa-thies, as opposed to other irAEs, as this functions as both hor-mone replacement and immunosuppression. MRI findings ofpituitary enlargement and inhomogeneity typically resolvewithtreatment; thyroid hormone and/or testosterone replacementtherapymaynotbepermanent [40].

Intrinsic thyroid dysfunction can also be seen with ipili-mumab and most often presents as autoimmune thyroiditis[16,21].Minetal.alsoreportedacaseofGraves’ophthalmop-athy presenting with eye pain, conjunctivitis, proptosis, andperiorbital edema with elevated antithyroid peroxidase andantithyroglobulin antibodies [16]. After an initial response tosteroids, the patient relapsedwhile on a steroid taper and re-quired resumption of IV high-dose steroids. Symptoms andabnormal lab findings persisted for several months. In thiscase, the patient was treated with a burst of methylpred-nisolone1000mgIVdaily for3–5days followedby lowerdosesof IV/oral steroids. A burst of high-dose steroids is reasonabletoconsider inpatientswithpotentially severeor life-threaten-ing irAEs. Current recommendations includebaseline TSHandfree T4 and monitoring of this every 3 weeks during ipili-mumab treatment and every 2–3 months following comple-




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tion. Baseline early morning cortisol levels during treatmentmay be considered, but are not required [42]. Ipilimumabshouldbepermanently discontinued in cases of adrenal crisis.However, if a patient is clinically stable at the time of presen-tation with an endocrinopathy that is controlled with hor-mone replacement, it may be reasonable to resumeipilimumab. Endocrinologists are a very subspecialized groupandmaynotbereadilyavailable inall locales.Establishingcon-tact ahead of time with an endocrinologist, and possibly a pi-tuitary specialist, is recommended.

Neurologic ToxicitiesAs previously discussed, irAEs can be transient and presentwithvague symptoms. Neuropathies associated with ipilimumab of-ten fall into this category and have been difficult to assess. Pa-tientswithpreexistingneuropathiesdonotappearatgreaterriskfor ipilimumab-induced neuropathy; however, the presence ofdiabetesmellitusorchemotherapy-associatedneuropathiescanconfounddiagnosis andmanagement. Thepanel felt that a neu-rologyconsult foranysymptommoreseverethangeneral,vagueneuropathy should be considered as well as anMRI to evaluateforadisease-relatedcause.Whileextremelyrareat less than1%,life-threatening neuropathies, such as Guillain-Barre syndrome,severe motor neuropathy, or myasthenia gravis have been re-ported[43].Numbnessandtinglingofthehandsandfeetcanrap-idly progress to loss of sensory and motor function within 48hours.Onepatient respondedwithin48hours to treatmentwithhigh-dose methylprednisolone, after infectious etiologies wereruled out, with significant recovery by 4 weeks. Despite treat-mentwithhighdosesteroids, thepatientdidevidenceantitumorbenefit. Other presentations of neurotoxicity have included en-teric neuropathywith severe refractory constipation, inflamma-tory myopathy, aseptic meningitis, and optic neuritis [18, 44–

46]. Any CNS or severe motor or sensory neuropathynecessitatespermanent cessationofCTLA-4 therapy.

Other ToxicitiesAs previously stated, ipilimumab may prompt a T-cell–medi-ated immune attack on any part of the body. Ophthalmic tox-icities are important to recognize, with uveitis being themostcommon [47]. While rare (1% or less), patients with visualchangesneed tobeseenandevaluatedbyanophthalmologistpromptly and may require treatment with steroid eye dropsand/or systemic steroids if an irAE is confirmed or highly sus-pect. Again, evaluation for CNS or orbital metastases shouldbe considered. There may be an association between ipili-mumab-induced enterocolitis and uveitis [47]. Case reportshave described glomerulonephritis presenting with protein-uria and positive anti-double stranded DNA antibodies [48]:pneumonitis [34], temporal arteritis [40], as well as sarcoid-osis [49, 50]. Additionally, hematologic toxicities including neu-tropenia [51], thrombocytopenia [52], red cell aplasia [53], andclotting dysfunction [17] have been described. Vigilance and ahighlevelofsuspicionforpossibleirAEsonthepartofthetreatingoncologist areessential to theuseof ipilimumab.

TOXICITIES OF IMMUNOSUPPRESSIONHigh-dose steroids are indispensable for the treatment of mod-erate to severe irAEs. However, with high doses and prolongedcourses aswell as the possibility for additional immunosuppres-siveagents, thesemedications carry toxicitiesaswell.Direct sideeffects of steroids include activation, depression, insomnia, psy-chosis (rarely), appetite stimulation,myopathy, andhyperglyce-mia, as well as other issues. Deconditioning can be exacerbatedwith frequent hospitalizations and erratic oral intake. Further,prolonged steroids and other immunosuppressives carry an in-

Figure 6. Algorithm for endocrine irAEmanagement.




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creasedriskof infection.Commonbacterial infectionscanoccur;however, viral and fungal infections as well as opportunistic in-fections, lesscommonlyseen in thesolidoncologyrealm,are im-portant to recognize. Consideration should be given toprophylactic antimicrobials against pneumocystis jiroveci pneu-monia (formerlypneumocystis carinii),herpessimplexvirus,andfungalorganisms in somepatients [20]. Tuberculosis (TB) testingtoevaluate for latentTB is recommendedprior to initiationof in-fliximab or other anti-tumor necrosis factor alpha antagonists[54].Aninfectiousdiseasespecialistmayneedtobeamemberofanoncologist’smultidisciplinary team.

SELECTION OF PATIENTSIpilimumab therapy is not right for every melanoma patient,yet selection criteria for ipilimumab are still uncertain andthere remain significant gaps in knowledge. Currently, nopre-dictive markers are available to guide which patients will gettherapeuticbenefit fromipilimumab.One factor toconsider isthepaceof apatient’smelanoma. Inpatientswith rapidlypro-gressive disease, they may not be able to survive the timeneeded tomanifest a response to immunotherapy [55]. Treat-ment with an agent with a shorter time to possible responsemay be preferable. Thus, patient selection for ipilimumabpresently centers on factors that may predict unacceptabletoxicity. Age does not appear to impact tolerance or efficacy

and ipilimumab has been administered safely to patients intheir80s.Whilenocontraindications to treatmentare listed inthe FDA-approvedpackage insert, it is crucial to elicit a historyof any prior autoimmune diseases, such as Crohn’s disease,systemic lupus erythematosus, rheumatoid arthritis,multiplesclerosis, etc. All clinical trials with ipilimumab excluded sub-jectswith prior autoimmunedisease given the concern for ex-acerbation that could lead to significant morbidity ormortality. The panel did not recommend ipilimumab therapyin patients with systemic autoimmune conditions such as theones previously listed outside of a clinical trial. However, it isunclear if patients with type I diabetes, severe psoriasis, orother conditions can be safely treated with ipilimumab, andno consensus on these conditions was reached. In the settingof autoimmune hypothyroidism or vitiligo that can be easilymanaged and are not considered life threatening, treatmentwith ipilimumab is reasonable. Patientswith conditions of un-clear etiology that may have an autoimmune component,such as sarcoidosis, are also challenging. There are very lim-ited, if any, data regarding ipilimumab in these patient sub-sets, and there is no consensus regarding such patients at thistime.Others excluded fromclinical trialswith CTLA-4blockingagents included patients with hepatitis B or C, human immu-

nodeficiency virus, or those on chronic immunosuppression,including organ transplant patients. Over time, case reportsand anecdotal data are becoming available [56, W.H. Sharf-man, personal communication].

Prior to treatment with ipilimumab, there should be ananalysisof thepossiblebenefitsandrisksandadiscussionwiththe patient and family. The current status of any underlyingautoimmune (or other immune-mediated) condition, possi-bilityofexacerbation (whichmaybepersistent), andpotentialfor response to treatment (if exacerbated) must be consideredanddiscussed. Inmetastaticmelanoma,nosystemic treatmentsareconsideredcurativeandthatmustbeweighedagainstpoten-tialtoxicities,whichcouldleadtosignificantmorbidityordeath. Ifthe decision is made to treat with ipilimumab, closemonitoringandaggressiveeducation forancillary staff aswell as forpatientsand their families is recommended.

CONCLUSIONIpilimumab is a definite advance in the treatment of metastaticmelanoma, demonstrating improved survival and durability ofresponse in randomized trials. Continued investigations will in-form us about its optimal schedule and dose. Often well toler-ated,includingintheelderly, ipilimumab-inducedirAEscanoccurand are not typical of other anticancer agents. irAEsmay followanunpredictable course and, if untreated, canbe severe and lifethreatening. Vigilance and suspicion are needed in treating pa-tients with ipilimumab so that an irAE, if manifest, can be diag-nosed and managed promptly. Most are controlled with high-dose steroids followedbya slowtaper. In somecases, additionalimmunosuppression may be necessary. Steroids should beavoided if not needed; however, if an irAEdevelops, they shouldbeusedwithouthesitation,as theydonot impairantitumorben-efitsof ipilimumab.Assemblingandeducatingamultidisciplinaryteam of physicians and ancillary staff will facilitate the care andmanagementof thesepatients.

ACKNOWLEDGMENTSTheauthors take full responsibility for the content of this pub-lication and confirm that it reflects their viewpoint andmedi-cal expertise. The authors also wish to acknowledge JenniferWietzke, Ph.D., and Rebecca Goldstein, Ph.D., from StemSci-entific, fundedbyBristol-MyersSquibb, forprovidingeditorialsupport. Neither Bristol-Myers Squibb nor StemScientific in-fluenced the content of the manuscript, nor did the authorsreceive financial compensation for authoring themanuscript.

AUTHOR CONTRIBUTIONSConception and Design: Leslie A. Fecher, Sanjiv S. Agarwala, F. Stephen Hodi,Jeffrey S.Weber

Collectionand/orAssemblyofData:LeslieA.Fecher,SanjivS.Agarwala,F.Ste-phenHodi, Jeffrey S.Weber

Data Analysis and Interpretation: Leslie A. Fecher, Sanjiv S. Agarwala, F. Ste-phenHodi, Jeffrey S.Weber

ManuscriptWriting: Leslie A. Fecher, F. StephenHodi, Jeffrey S.WeberFinal Approval of Manuscript: Leslie A. Fecher, Sanjiv S. Agarwala, F. StephenHodi, Jeffrey S.Weber

DISCLOSURESLeslie Fecher:Genentech-Roche,Bristol-Myers Squibb (C/A); ImedexLLC,DavaOncology, First Consult LLC (H);Genentech-Roche, sanofi-aventis, Bristol-Myers Squibb (RF);Sanjiv S.Agarwala:Bristol-MyersSquibb,Roche (C/A,H);F. StephenHodi:Bristol-Myers Squibb (C/A,RF); JeffreyS.Weber:Bristol-Myers Squibb (RF,H).(C/A)Consulting/advisory relationship; (RF)Research funding; (E) Employment; (H)Honorariareceived; (OI)Ownership interests; (IP) Intellectual property rights/inventor/patentholder; (SAB)Scientific advisoryboard

Currently, no predictive markers are available toguidewhichpatientswill get therapeuticbenefit fromipilimumab.One factor to consider is thepaceofapa-tient’s melanoma. In patients with rapidly progres-sive disease, theymay not be able to survive the timeneeded to manifest a response to immunotherapy.Treatmentwith an agentwith a shorter time topossi-ble responsemay be preferable.




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