Mashayekhi, Arman

Shields, Carol L.

Shields, Jerry A.

Sioufi, Kareem

English

Name not available

Intravitreal Melphalan for Treatment of Primary Vitreoretinal Lymphoma: A New Indication for an Old Drug.

Jefferson Digital Commons

Thomas Jefferson UniversityJefferson Digital CommonsWills Eye Hospital Papers Wills Eye Hospital7-1-2017Intravitreal Melphalan for Treatment of PrimaryVitreoretinal Lymphoma: A New Indication for anOld Drug.Carol L. ShieldsThomas Jefferson University, carol.shields@shieldsoncology.comKareem SioufiThomas Jefferson UniversityArman MashayekhiThomas Jefferson University, Arman.Mashayekhi@jefferson.eduJerry A. ShieldsThomas Jefferson University, jerry.shields@shieldsoncology.comLet us know how access to this document benefits youFollow this and additional works at: https://jdc.jefferson.edu/willsfpPart of the Ophthalmology CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inWills Eye Hospital Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact:JeffersonDigitalCommons@jefferson.edu.Recommended CitationShields, Carol L.; Sioufi, Kareem; Mashayekhi, Arman; and Shields, Jerry A., "Intravitreal Melphalanfor Treatment of Primary Vitreoretinal Lymphoma: A New Indication for an Old Drug." (2017).Wills Eye Hospital Papers. Paper 69.https://jdc.jefferson.edu/willsfp/69Europe,thispracticeis lessconsistentlyusedintheUnitedStates.However, these studies do not constitute level I evidence, andthus, there is no worldwide consensus regarding endophthal-mitis prophylaxis with cataract surgery.6Limitations. This study is limitedby its retrospectivenatureandthe possibility of selection bias. The mechanism of this in-creasingnonsusceptibility to fluoroquinolones is not fullyun-derstood,but itmaybeassociatedwithwidespreaduseof fluo-roquinolones, use of antibiotics outside of the health caresector, and emergence of intrinsic genetic factors promotingresistance. Although this study involves only in vitro testing,the clinical implications of this laboratory data requires fur-ther investigations.Jack D. Stringham, MDNidhi Relhan, MDDarlene Miller, DHSc, CICHarry W. Flynn Jr, MDAuthor Affiliations: Bascom Palmer Eye Institute, Department ofOphthalmology, University of Miami Miller School of Medicine, Miami, Florida.Corresponding Author:HarryW. Flynn Jr, MD, Bascom Palmer Eye Institute,Department of Ophthalmology, University of Miami Miller School of Medicine,900 NW 17th St, Miami, FL 33136 (hflynn@med.miami.edu).Accepted for Publication: April 9, 2017.Published Online: June 15, 2017. doi:10.1001/jamaophthalmol.2017.1826Author Contributions:Drs Stringham and Flynn had full access to all of the datain the study and take responsibility for the integrity of the data and the accuracyof the data analysis.Concept and design: Stringham, Flynn.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Stringham.Critical revision of the manuscript for important intellectual content: All authors.Administrative, technical, or material support:Miller, Flynn.Supervision:Miller, Flynn.Conflict of Interest Disclosures: All authors have completed and submitted theICMJE Form for Disclosure of Potential Conflicts of Interest and none werereported.Funding/Support: This research work was supported in part by NationalInstitutes of Health Center Core grant P30EY014801 and a Research to PreventBlindness Unrestricted Grant.Role of the Funder/Sponsor: The funding organizations had no role in thedesign and conduct of the study; collection, management, analysis, andinterpretation of the data; preparation, review, or approval of themanuscript;and decision to submit themanuscript for publication.1. Schimel AM, Miller D, Flynn HW. Evolving fluoroquinolone resistance amongcoagulase-negative Staphylococcus isolates causing endophthalmitis. ArchOphthalmol. 2012;130(12):1617-1618.2. Dave SB, Toma HS, Kim SJ. Ophthalmic antibiotic use andmultidrug-resistantstaphylococcus epidermidis: a controlled, longitudinal study.Ophthalmology.2011;118(10):2035-2040.3. Kim SJ, Toma HS. Antimicrobial resistance and ophthalmic antibiotics: 1-yearresults of a longitudinal controlled study of patients undergoing intravitrealinjections. Arch Ophthalmol. 2011;129(9):1180-1188.4. Chiquet C, Maurin M, Altayrac J, et al. Correlation between clinical data andantibiotic resistance in coagulase-negative Staphylococcus species isolatedfrom 68 patients with acute post-cataract endophthalmitis. Clin Microbiol Infect.2015;21(6):592.e1-592.e8.5. Haripriya A, Chang DF, Ravindran RD. Endophthalmitis reduction withintracameral moxifloxacin prophylaxis: analysis of 600000 surgeries.Ophthalmology. 2017;S0161-6420(16)30790-4.6. Grzybowski A, Schwartz SG, Matsuura K, et al. Endophthalmitis prophylaxisin cataract surgery: overview of current practice patterns around the world. CurrPharm Des. 2017;23(4):565-573.OBSERVATIONIntravitrealMelphalan for Treatment of PrimaryVitreoretinal Lymphoma: ANew Indicationfor anOld DrugPrimary vitreoretinal lymphoma (PVRL) is a malignant largeB-cell lymphoma affecting the eye and brain, with 5-yearcumulative survival rate of 35% in those with brain involve-ment (68% in those without).1 Ocular involvement mani-fests with aggregated tumor cells in the vitreous, retina,optic disc, and subretinal pigment epithelial space. Manage-ment involves treatment of both eyes and brain, and treat-ment options for the eye(s) include systemic chemotherapy,external radiotherapy, or intravitreal injection of chemo-therapy.Themostcommonlyused intravitrealmedication forPVRLis methotrexate.2,3 Others have investigated intravitrealrituximab.4 Herein, we report our experience with melpha-lan, a medication commonly used for treatment of vitreousseeding from retinoblastoma,5,6 in 3 eyes of 2 patients withPVRL. Bothmethotrexate andmelphalan have been used forretinoblastoma, andmethotrexate requires approximately 25injections/y, whereas melphalan needs fewer at 4 to 6 injec-tions/y, the latter achieving retinoblastoma seed control in upto 100% of cases.3,6Melphalan is a well-established alkylating agent, devel-oped in 1953 and used to treat several hematologic malig-nancies, including lymphoma, leukemia, and multiplemyeloma, as well as solid tumors including breast, ovarian,and neural cancers.5 When used in the vitreous for retino-blastoma, filtered preparation of 20 μg/0.1 mL is sufficientfor tumor control.6 Owing to its effect on lymphoma and ourexperience with this medication, we challenged PVRL withmelphalan.Methods | This retrospective investigation was approved bythe institutional review board of Wills Eye Hospital. Threeeyes of 2 patients with biopsy-confirmed PVRL were offeredstandard treatment or intravitreal melphalan (low dose [10μg/0.1 mL]). Following written consent, the medication wasinjected into the vitreous using sterile technique. Clinicalfeatures and outcomes were recorded.Results | Case 1. A92-year-oldwomanwith vitrectomy-provenbilateral PVRL (large B-cell lymphoma cytology) demon-strated severe vitreous tumor infiltration in the right eye andmild infiltration in the left eye, with subretinal pigment epi-thelial tumor in the left eye (Figure 1). Visual acuity was20/30 OD and 20/40 OS. She was treated with low-dose intra-vitreal melphalan (10 μg/0.1 mL) to both eyes. Following ini-tial injection, complete clearance of vitreous tumor in botheyes was noted within 3 weeks. During the 19-month follow-up, the right eye required 6 bimonthly injections for minorseed recurrence, and the left eye remained stable withoutrecurrence. There were no toxicities in either eye, but the lefteye showed stable focal subfoveal fluid, with mild macularedema at presentation and throughout her course. Finalvisual acuity was 20/50 OU.Lettersjamaophthalmology.com (Reprinted) JAMAOphthalmology July 2017 Volume 135, Number 7 815© 2017 American Medical Association. All rights reserved.Downloaded From: http://jamanetwork.com/ by a Thomas Jefferson University User  on 08/01/2017Case2. A65-year-oldmanwithchronicuveitis inbotheyesandvitrectomy-proven PVRL (large B-cell lymphoma cytology)demonstratedmoderatevitreous tumor inbotheyes (Figure2).At treatment, visual acuitywas20/150ODand20/400OS.Theright eye was treatedwith intravitreal melphalan and the lefteye with intravitreal methotrexate. The right eye demon-strated rapid improvement of visual acuitywithin 2 days (perpatient observation) andmeasured 20/50 at 1 month, requir-ing no further melphalan injections over 16 months follow-up, whereas the left eye showed slower response and a totalof 19 injectionsofmethotrexateover 11months follow-up.Botheyes showed intermittent cystoid macular edema from uve-itis, and final visual acuity was 20/50 OD and 20/70 OS.A summary of the 3 eyes with PVRL revealed rapid re-sponse to low-dose intravitrealmelphalan,with complete vit-reous tumor clearance in 2 cases following a single injectionand tumor control following multiple injections in one case.There was no retinal toxicity.Figure 1. Case 1: A 92-Year-OldWomanBaseline fundus photograph, right eyeABaseline optical coherence tomography, right eyeC1-mo Follow-up, right eyeE13-mo Follow-up, right eyeGBaseline fundus photograph, left eyeBBaseline optical coherence tomography, left eyeD1-mo Follow-up, left eyeF13-mo Follow-up, left eyeHA 92-year-old womanwith visualacuity of 20/30 OD and 20/40 OSand biopsy-proven posteriorvitreoretinal lymphoma showeddense vitreous infiltrate in the righteye (A) andmild vitreous infiltrate inthe left eye (B) with peripheralmultifocal retinal pigment epithelialinfiltrates. Optical coherencetomography showed hazy view of thefovea in the right eye from vitreousopacification and intraretinal edemawith shallow subretinal fluid in theleft eye (C and D). Following 1injection of intravitreal melphalan toeach eye, complete clearance ofvitreous cells was documented inboth eyes (E and F) at 1 month.Optical coherence tomographyshowed a normal right fovea (G) andunchanged edema and subretinalfluid in the left eye (H). Final visualacuity was 20/50 OU at 16months’follow-up.Letters816 JAMAOphthalmology July 2017 Volume 135, Number 7 (Reprinted) jamaophthalmology.com© 2017 American Medical Association. All rights reserved.Downloaded From: http://jamanetwork.com/ by a Thomas Jefferson University User  on 08/01/2017Discussion |These 3 eyeswith PVRLdemonstrate that intravit-real melphalan, currently used for vitreous seeds fromretinoblastoma,6 can result invitreous lymphomacontrolwithfew injections. Given the limited number of cases and rela-tively short follow-up, further investigation seems war-ranted to determine efficacy, safety, and appropriate treat-ment regimen.Carol L. Shields, MDKareem Sioufi, MDArmanMashayekhi, MDJerry A. Shields, MDAuthor Affiliations:Ocular Oncology Service, Wills Eye Hospital, ThomasJefferson University, Philadelphia, Pennsylvania.Figure 2. Case 2: A 65-Year-OldManBaseline fundus photograph, right eyeABaseline optical coherence tomography, right eyeCFundus photograph following melphalan injection,right eyeE13-mo Follow-up, right eyeGBaseline fundus photograph, left eyeBBaseline optical coherence tomography, left eyeDFundus photograph following 13 methotrexate injections,left eyeF13-mo Follow-up, left eyeHA 65-year-old man with visual acuityof 20/150 OD and 20/400OSwithchronic posterior uveitis andbiopsy-proven posterior vitreoretinallymphoma showedmoderatevitreous infiltrate in both eyes at thetime of treatment (A and B). Opticalcoherence tomography showed tracemacular edema in the right eye (C)and shallow subretinal debris in theleft eye (D). Following a singlemelphalan injection in the right eye(E), complete clearance of vitreouscells was documented and persisteduntil last examination. Following 13injections of methotrexate in the lefteye (F), vitreous clearance was noted.At last examination, opticalcoherence tomography documentedtrace foveal edema in the right eye(G) andmoderate macular edema inthe left eye (H). At 13 months, finalvisual acuity was 20/50 OD and20/70 OS.Lettersjamaophthalmology.com (Reprinted) JAMAOphthalmology July 2017 Volume 135, Number 7 817© 2017 American Medical Association. All rights reserved.Downloaded From: http://jamanetwork.com/ by a Thomas Jefferson University User  on 08/01/2017Corresponding Author: Carol L. Shields, MD, Ocular Oncology Service, WillsEye Hospital, Thomas Jefferson University, 840Walnut St, Ste 1440,Philadelphia, PA 19107 (carolshields@gmail.com).Published Online: June 15, 2017. doi:10.1001/jamaophthalmol.2017.1810Conflict of Interest Disclosures: All authors have completed and submitted theICMJE Form for Disclosure of Potential Conflicts of Interest and none werereported.Funding/Support: Support provided by Eye Tumor Research Foundation,Philadelphia, Pennsylvania (Dr Carol L. Shields).Role of the Funder/Sponsor: The funder had no role in the design and conductof the study; collection, management, analysis, and interpretation of the data;preparation, review, or approval of themanuscript; and decision to submit themanuscript for publication.Additional Contributions:We thank Emil A. Say, MD, Oncology Service, WillisEye Hospital, Philadelphia, Pennsylvania, for his contribution to patient care. Nocompensation was received from a funding sponsor for such contributions.1. Riemens A, Bromberg J, Touitou V, et al. Treatment strategies in primaryvitreoretinal lymphoma: a 17-center European collaborative study. JAMAOphthalmol. 2015;133(2):191-197.2. Levasseur SD, Wittenberg LA, White VA. Vitreoretinal lymphoma: a 20-yearreview of incidence, clinical and cytologic features, treatment, and outcomes.JAMA Ophthalmol. 2013;131(1):50-55.3. Frenkel S, Hendler K, Siegal T, Shalom E, Pe’er J. Intravitreal methotrexate fortreating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol.2008;92(3):383-388.4. Larkin KL, Saboo US, Comer GM, et al. Use of intravitreal rituximab fortreatment of vitreoretinal lymphoma. Br J Ophthalmol. 2014;98(1):99-103.5. Bayraktar UD, Bashir Q, QazilbashM, Champlin RE, Ciurea SO. Fifty years ofmelphalan use in hematopoietic stem cell transplantation. Biol Blood MarrowTransplant. 2013;19(3):344-356.6. Shields CL, Douglass AM, BeggacheM, Say EA, Shields JA. Intravitreouschemotherapy for active vitreous seeding from retinoblastoma: outcomes after192 consecutive injections: the 2015 Howard Naquin Lecture. Retina. 2016;36(6):1184-1190.COMMENT&RESPONSEPatient CoauthoredHistory Could ImproveHealth Record AccuracyTo the EditorThe article byValikodath et al1 showcases a prob-lemwithmodern health records: documentation does not al-waysmatch thepatient’s concerns. The authors conclude thatelectronicmedical recorddatamaynot provide a comprehen-sive resource for clinical practice or “big data” research.I agree that a solution may come from patient-generatedinformation. In a previous report,2 patients were invited tocomplete a replica of a history as defined by the Centers forMedicare andMedicaid Services. Patients completed a 3-pageprehistory form with approximately 30 questions in a struc-tured format that includedchief complaint(s), a historyofpre-sent illness, the status of chronic condition(s), a reviewof sys-tems, and a past family social history.3A total of 263 patients whowere aged 14 to 94 years com-pleted the form in preparation for a family physician visit. Onarriving to theoffice, theprehistory formwas scanned into theelectronic health record as a document and the content wastranscribed by a staff member into the history component ofthe encounter note. The prehistory was recognized as a writ-ten request to amend the health record per the Health Insur-ancePortability andAccountabilityAct PrivacyRule (45C.F.R.§ 164.526).I was the physician who conducted the medical encoun-ters for patients with a prehistory and I can attest to the im-provement inmedical record accuracy. I was able to enter theexamination room, greet the patient, and then read the pa-tient’s narrative, all ofwhichwas documented in the record. Ifinished the history with specific questions and then per-formed a pertinent examination. Any medical decision mak-ing occurring readily transformed to shared decision makingbecause the patientswere engaged and Iwas relieved of cleri-cal burdens.After seeing the physician, each patient was given a pa-per copy of the encounter note at the checkout window. Pa-tientswere instructed to gohome, read their record, and scoreit with an anonymous survey. Patients who completed a pre-history form in preparation for amedical encounter reportedfeeling better heard and understood.Medical record inaccuracy could adversely affect patientsafety anddata analytics. These comments suggest that a pre-history form potentially may be ameans of improving healthrecord accuracy.Michael JohnWarner, DOAuthor Affiliation: Patient Advocacy Initiatives, Johnstown, Pennsylvania.Corresponding Author:Michael JohnWarner, DO, Patient Advocacy Initiatives,130 Jennie Ln, Johnstown, PA 15904 (drmichaelwarner@patientadvocacyinitiatives.org).Published Online: June 8, 2017. doi:10.1001/jamaophthalmol.2017.1637Conflict of Interest Disclosures: The author has completed and submitted theICMJE Form for Disclosure of Potential Conflicts of Interest and none werereported.Editorial Note: This letter was shown to the corresponding author of theoriginal article, who declined to reply on behalf of the authors.1. Valikodath NG, Newman-Casey PA, Lee PP, Musch DC, Niziol LM,WoodwardMA. Agreement of ocular symptom reporting between patient-reportedoutcomes andmedical records. JAMA Ophthalmol. 2017;135(3):225-231, 231.2. Warner MJ, Simunich TJ, Warner MK, Dado J. Use of patient-authoredprehistory to improve patient experiences and accommodate federal law. J AmOsteopath Assoc. 2017;117(2):78-84.3. Patient Advocacy Initiatives. PreHistory forms available for free at non-profit:http://www.PatientAdvocacyInitiatives.org. Accessed February 16, 2017.Incorporating Clinical, Histological,and Genetic Parameters for ChoroidalMelanomaPrognosticationWalter et al1 recently reported that tumor diameter measure-ment enhances thepredictionofmetastatic disease fromclass2uvealmelanoma(UM),asclassifiedwithgeneexpressionpro-filing. They advocate combining these 2 predictors when es-timating prognoses.Weagreewith this recommendation. Since 2007,wehavepublishedseveral articles emphasizing the importanceof com-biningclinical,histologic, andgenetic survivalpredictorswhenestimating a prognosis for UMposttreatment.2We developedan online prognostic tool predicting survival usingmultivari-able analyses, also accounting for age and sex.2 Walter et al1have not cited these articles, so their Discussion does not in-terpret their results by taking into consideration all other rel-evant evidence in the literature.Letters818 JAMAOphthalmology July 2017 Volume 135, Number 7 (Reprinted) jamaophthalmology.com© 2017 American Medical Association. All rights reserved.Downloaded From: http://jamanetwork.com/ by a Thomas Jefferson University User  on 08/01/2017

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Intravitreal Melphalan for Treatment of Primary Vitreoretinal Lymphoma: A New Indication for an Old Drug.

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