Accepted Manuscript Rapid Onset of Retinal Toxicity from High-Dose Hydroxychloroquine Given for Cancer Therapy Loh-Shan B. Leung, Joel W. Neal, Heather A. Wakelee, Lecia V. Sequist, Michael F. Marmor PII:
S0002-9394(15)00419-5
DOI:
10.1016/j.ajo.2015.07.012
Reference:
AJOPHT 9402
To appear in:
American Journal of Ophthalmology
Received Date: 27 April 2015 Revised Date:
6 July 2015
Accepted Date: 10 July 2015
Please cite this article as: Leung L-SB, Neal JW, Wakelee HA, Sequist LV, Marmor MF, Rapid Onset of Retinal Toxicity from High-Dose Hydroxychloroquine Given for Cancer Therapy, American Journal of Ophthalmology (2015), doi: 10.1016/j.ajo.2015.07.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Rapid Hydroxychloroquine Toxicity in Cancer Therapy ABSTRACT: Purpose: To report rapid onset of retinal toxicity in a series of patients followed on high dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer.
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Design: Retrospective observational case series.
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Methods: Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The FDA-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing and multifocal electroretinography (mfERG). Results: Out of the seven patients having exposure of at least 6 months, two developed retinal toxicity at 11 and 17 months of exposure. Damage was identified by OCT imaging, mfERG testing, and in one case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss.
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Conclusions: These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high dose hydroxychloroquine to improve safety monitoring and preservation of vision.
ACCEPTED MANUSCRIPT Rapid Hydroxychloroquine Toxicity in Cancer Therapy
Rapid Onset of Retinal Toxicity from High-Dose Hydroxychloroquine Given for Cancer Therapy Short title: Rapid Hydroxychloroquine Toxicity in Cancer Therapy
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Loh-Shan B. Leung1, Joel W. Neal2, Heather A. Wakelee2, Lecia V. Sequist3, Michael F. Marmor1
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Correspondence: Loh-Shan B. Leung, Department of Ophthalmology, Byers Eye Institute, Stanford University Department of Ophthalmology. 2405 Watson Ct, Palo Alto, CA 94303. Phone: 650-721-6888 Fax: 650-565-8297 Email: [email protected]
Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California 2 Department of Medicine, Division of Oncology, Stanford University/Stanford Cancer Institute, Palo Alto, California 3
Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
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INTRODUCTION: Hydroxychloroquine has been a mainstay of treatment for rheumatologic conditions such as systemic lupus erythematosus and rheumatoid arthritis, and there are extensive risk and toxicity data for the typical range of doses. The risk of hydroxychloroquinemediated retinal toxicity is relatively low within the first 5-10 years of therapy when used at daily doses that do not exceed 5 mg/kg, typically 200-400 mg daily.1 Risk is clearly a balance between daily dose and duration of use, but there are little data available on the degree to which highly elevated doses can accelerate toxicity.
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Loading doses of up to 1200 mg hydroxychloroquine for starting therapy of rheumatologic conditions have been described, but have typically been given only for brief durations of less than 6 weeks.2,3 Hydroxychloroquine has recently been proposed as an adjunct chemotherapeutic agent for a number of types of cancer, after in vivo and in vitro studies showed potential efficacy in various tumor types. However, relatively high blood concentrations are required to achieve tumor inhibition in preclinical studies, with dose escalation studies showing that an excess of 600 mg daily may be necessary.4 These trials might in theory provide knowledge about the risk of high-dose hydroxychloroquine; however, FDA-mandated ocular screening is usually minimal by ophthalmologic standards, and patients are rarely followed for extended periods.
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Stanford was a study site for a phase II open-label, randomized multisite clinical trial investigating the efficacy of high-dose hydroxychloroquine (1000 mg daily) in addition to erlotinib vs. erlotinib alone for advanced lung cancer (Neal JW, et al. J Clin Oncol 2014;32:ASCO Abstract 8088). All patients in the hydroxychloroquine arm were referred for ongoing ophthalmic screening. The trial protocol only required visual acuity, color testing, Amsler grid testing and fundus examination (which are no longer considered sufficient for screening according to current recommendations).5 We added sensitive imaging modalities and functional testing to the follow-up of a number of these patients. We present ophthalmologic findings on those patients who had specialized retinal testing and maintained high-dose hydroxychloroquine for at least 6 months.
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METHODS The phase II trial evaluated EGFR-mutant advanced stage non-small cell lung cancer (NCT00977470), and was initiated at the Massachusetts General Hospital; Stanford participated as a subsite with approval by the Institutional Review Board of both institutions. Erlotinib was administered at standard oncologic doses, and hydroxychloroquine was started in patients randomized to the combination arm at 1000 mg daily, with dose reductions to 800mg, 600mg, 400mg or complete discontinuation allowed for toxicity. The protocol required examination pre-treatment and every 3 months for those patients in the hydroxychloroquine arm, but only with dilated fundus examination, visual acuity, color vision testing, and Amsler grid testing. Our purpose was not to study every patient, but to follow as many as possible of those who continued on hydroxychloroquine beyond 6 months, adding (as clinically indicated) automated 10-2 fields (Humphrey Field Analyzer, Zeiss-Meditec), spectral domain optical coherence tomography (SD-OCT)(Cirrus Model 4000, Zeiss-Meditec), fundus autofluorescence (FAF) (Heidelberg Engineering), and multifocal ERG (Diagnosys
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RESULTS: The Stanford site enrolled a total of 15 patients to the hydroxychloroquine plus erlotinib arm, of which seven had exposure beyond 6 months and underwent serial specialized diagnostic studies (mean exposure 16.5 months, range 7.5-25 months). Patient characteristics are shown in the table. The last follow up eye exam with retinal imaging studies ranged from 9 to 28 months after the start of therapy. Two patients developed definitive signs of toxicity without symptoms and are described below. Among those patients who did not develop signs of toxicity, one patient developed a retinal pigment epithelial detachment after discontinuing hydroxychloroquine, and an additional patient developed both a retinal pigment epithelial and serous neurosensory retinal detachment in one eye over the course of therapy, both of which resolved without recurrence. Neither event was believed to be associated with hydroxychloroquine.
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Case 1: A 66-year old Caucasian female was newly diagnosed with advanced lung adenocarcinoma. The patient had no other medical diseases, and renal function remained normal throughout her therapy. The patient was 1.59 m tall (ideal body weight: 53 kg6) and weighed about 50 kg (daily hydroxychloroquine dose: 20 mg/kg). Baseline examination showed visual acuity of 20/20 OD and 20/25 OS. The anterior and posterior segment exam was unremarkable, except for a subtle yellow spot in the fovea of the left eye associated with mild vitreomacular traction. SD-OCT (Figure 1) was otherwise normal with good visualization of the ellipsoid zone (EZ) and interdigitation zone (IZ). FAF was also normal. Baseline Humphrey 10-2 visual fields were unremarkable for any loss of central macular sensitivity (not shown).
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Follow up examinations with SD-OCT and FAF remained unchanged until the 11-month visit, although the SD-OCT showed very subtle intensity loss in the parafoveal EZ. There was no change in thickness on the subfield cube map, and the EZ alteration was not felt to be definitive enough to discontinue potentially effective anticancer therapy.
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The patient stopped hydroxychloroquine therapy at 13 months due to symptoms of dry mouth. When next examined at 15 months (Figure 1), she showed clear dropout of the parafoveal EZ (corresponding to the region of intensity loss at 11 months). There was also thinning of the overlying outer nuclear layer that averaged 30 microns in the parafoveal areas of the thickness map. FAF and ophthalmoscopic fundus examination were normal, but an mfERG showed widespread signal depression across the macula with the greatest loss in the parafoveal region (Figure 2). Follow up visual field testing was performed elsewhere and was not available. The patient did not report any symptoms of visual impairment. Case 2: A 65-year old Asian female with history of diabetes, hypertension and hyperlipidemia, was diagnosed with adenocarcinoma of the lung metastatic to the spine and brain. The
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patient was also 1.59 m tall (ideal body weight 53 kg) and weighed 78 kg (daily dose: 12.8 mg/kg). Baseline exam showed visual acuity of 20/30 OU, and no fundus abnormalities aside from minimal non-proliferative diabetic retinopathy. Visual fields (10-2) were unremarkable, as was the SD-OCT (Figure 2). SD-OCT, fundus autofluorescence imaging, and 10-2 visual fields were performed quarterly over the next 15 months without change.
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After 17 months, some patchiness of the inferior parafoveal IZ was noted, more prominently in the left eye, and by 19 months there was zone of diminished EZ brightness. But there was no thinning on the SD-OCT subfield maps, nor any diagnostic abnormality in FAF or visual field at this time or on subsequent follow up 3 months later. These changes were felt to be borderline and the decision was made to continue therapy.
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Evaluation at 25 months revealed clear loss of the inferior parafoveal EZ and IZ with visible thinning of the outer nuclear layer between about 2-6 degrees (Figure 3). These were the same areas showing borderline change at 17 months. The thickness map still remained within normal limits for age and FAF was unremarkable. An mfERG showed diffusely depressed signals throughout the macula with the greatest loss in the parafoveal region (Figure 4). Erlotinib was continued, but hydroxychloroquine was stopped because of the observed retinal toxicity.
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Examination three months after discontinuing hydroxychloroquine (Figure 2) showed further loss of the parafoveal EZ and IZ inferiorly, and now temporally as well. Parafoveal retinal thickness measured on SD-OCT was subnormal in the inferior subfields. Visual field testing showed a clear defect in the superior parafoveal region of both eyes, although FAF and fundus examination were unremarkable. The patient had no subjective symptoms of vision impairment.
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DISCUSSION: We found that 2 of 7 patients followed with sensitive retinal exams for at least 6 months on high dose hydroxychloroquine developed characteristic EZ and IZ signs of hydroxychloroquine retinal toxicity. The earliest signs of toxicity (patchiness and loss of intensity of the parafoveal EZ and IZ) were detected at 11 and 17 months, and typical parafoveal thinning on OCT at 15 and 25 months in the first and second patient, respectively. These are the first cases of toxicity reported with daily doses of hydroxychloroquine in the range of 1000 mg. After the initial signs of toxicity were observed, damage progressed over the next 4-8 months (and at least for an additional 3 months after stopping the drug in one patient). As is typical with early toxicity, anatomic signs appeared before patients recognized any loss of vision. Even though the daily dose of hydroxychloroquine was high in our cases, the cumulative dose of hydroxychloroquine administered to each patient was well below the 1000 grams that has been considered high risk in some earlier studies.7 While the most recent recommendations by the American Academy of Ophthalmology suggest that ideal body weight be used to determine maximum hydroxychloroquine dosage (6.5
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mg/kg),5 a recent and comprehensive demographic study has shown that the risk of toxicity is reduced long-term by maintaining the daily dose under 5 mg/kg of real body weight.1 In the context of normal dosing, the detection of retinal toxicity in less than 5 years of exposure is extremely rare. Regardless of the method used to determine the maximum dosage, the patients in this study received substantially elevated doses (our patients were receiving 13-20 mg/kg of real body weight, and almost three times the dose based on 6.5 mg/kg of ideal body weight). Our results show that these dose levels can hasten the onset of recognizable maculopathy to as little as 11 months, even in the absence of risk factors such as renal disease, coincident use of other retinotoxic medications, or preexisting maculopathy. Although we cannot completely rule out a toxic synergy between erlotinib and hydroxychloroquine, we think this is highly unlikely. Erlotinib has been used as a chemotherapeutic agent for solid tumors for over a decade, with no retinal toxicity reported. The only reported drug synergy with hydroxychloroquine retinopathy is with the known retinotoxin, tamoxifen.1 However, the patients in our trial did develop ocular symptoms such as dysfunctional tearing, blepharitis, or trichomegaly which have been associated with erlotinib use.8
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High loading doses of hydroxychloroquine, up to 1200 mg daily, have been described in the rheumatologic literature, but typically only up to 6 weeks followed by standard dosing, and no vision loss or retinopathy has been reported for such therapy, although the ophthalmic screening methodology is poorly described.2,3 Previous phase I trials examining high doses of hydroxychloroquine in combination with a number of agents for the treatment of advanced solid tumors, glioblastoma multiforme, and melanoma, reported no dose-limiting toxicities reported for up to 1200 mg daily in some studies. However, the method of ocular screening for retinal toxicity was not uniform and probably suboptimal in many of these studies.4,9-11 Additionally, while these high doses were tolerated by a few patients in prior studies for up to 18 months, hydroxychloroquine dosing was commonly reduced after 3-4 months due to symptoms of fatigue, nausea, and vomiting or discontinued entirely when therapy was changed for disease progression.
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Our results suggest that clinical trials using high-dose hydroxychloroquine should monitor for ocular toxicity that may appear after the typical 3-4 month period studied in Phase I trials, and yet well before the 5-10 years of exposure required for hydroxychloroquine toxicity with standard doses. In clinical trials of anticancer therapy, of course, the risks of retinal damage must be balanced against the potential benefits of treatment for survival. However, once signs of hydroxychloroquine-related retinopathy are detected, the risk of symptomatic visual impairment becomes very significant if these high doses are continued. Use of sensitive early detection methods can help investigators and patients to make informed decisions about continuing therapy. We recommend that patients receiving elevated doses of hydroxychloroquine (well above 5 mg/kg of real body weight or 6.5 mg/kg of ideal body weight) should have exams approximately every 3 months that include at least SD-OCT and 10-2 visual fields (for non-Asian patients—wider 24-2 or 30-2 fields may be preferable in Asian patients, who often display early hydroxychloroquine damage in a more pericentral pattern12).
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ACCEPTED MANUSCRIPT Rapid Hydroxychloroquine Toxicity in Cancer Therapy Weaknesses of this study include the non-randomized study group as well as a small sample size, which precluded our ability to calculate risk or true incidence of hydroxychloroquine toxicity in the study population. However, the typical findings we have described at 11-17 months are the earliest reported for toxicity, and this implicates the extreme doses of the medication as the primary risk factor.
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In summary, high-dose hydroxychloroquine can result in accelerated retinal toxicity, within as little as 11 months of exposure. As the use of hydroxychloroquine is being explored for a variety of novel medical indications, investigators should be aware of the dose-duration relationship relative to hydroxychloroquine toxicity, and are encouraged to incorporate modern retinal screening techniques into the surveillance plan for trials using elevated doses.
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Acknowledgements/Disclosures: a. Funding/support: Genentech/Roche (South San Francisco, CA) provided funding for the trial and for ophthalmic screening exams b. Financial support: Loh-Shan Leung: No financial disclosures Joel Neal: Research funding from Genentech/Roche (South San Francisco, CA); Merck (Kenilworth, NJ); ArQule (Burlington, MA); Novartis (Basel, Switzerland); Exelixis (South San Francisco, CA); Boehringer Ingelheim (Ingelheim, Germany); Nektar (San Francisco, CA). All outside the submitted work with the exception of Genentech/Roche. Consulting/advisory: Clovis Oncology (Boulder, CO); CARET/Physicians Resource Management (Ann Arbor, MI). All outside the submitted work. Heather Wakelee: No financial disclosures Lecia Sequist: Consulting/advisory: Clovis Oncology; Novartis; AstraZeneca (London, UK); Genentech; Merrimack (Cambridge, MA); Boehringer Ingelheim; Taiho (Princeton, NJ). All uncompensated. Michael Marmor: No financial disclosures c. Other acknowledgements: Ryan Nelson
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References
Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132(12):1453-1460.
2.
Furst DE, Lindsley H, Baethge B, et al. Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension. Arthritis Rheum 1999;42(2):357-365.
3.
Munster T, Gibbs JP, Shen D, et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum 2002;46(6):1460-1469.
4.
Rosenfeld MR, Ye X, Supko JG, et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 2014;10(8):1359-1368.
5.
Marmor MF, Kellner U, Lai TYY, Lyons JS, Mieler WF. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118(2):415-422.
6.
Robinson JD, Lupkiewicz SM, Palenik L, Lopez LM, Ariet M. Determination of ideal body weight for drug dosage calculations. Am J Hosp Pharm 1983;40(6):1016-1019.
7.
Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol 2007;143(5):801-809.
8.
Borkar DS, Lacouture ME, Basti S. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review. Support Care Cancer 2013;21(4):1167-1174.
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Mahalingam D, Mita M, Sarantopoulos J, et al. Combined autophagy and HDAC inhibition: A phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 2014;10(8):1403-1414.
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Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 2014;10(8):1391-1402.
Rangwala R, Leone R, Chang YC, et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 2014;10(8):1369-1379.
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Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology 2015;122(1):110-116.
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Figure Captions
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Figure 1. Development of hydroxychloroquine toxicity in Patient 1. Horizontal spectral domain OCT cross-sections and cube thickness diagrams from the left eye at baseline (Above) and after 15 months of hydroxychloroquine (Below). After 15 months the cube diagram shows parafoveal thinning 360 degrees, and the cross-sections show clear thinning of the outer nuclear layer and loss of ellipsoid zone and interdigitation zone bands (arrows). The fundus examination and fundus autofluorescence were normal (not shown).
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Figure 2. Multifocal electroretinogram showing hydroxychloroquine toxicity in Patient 1. The 103-hexagon trace array (Left), shows generalized weak signals throughout the macula. Normalized ring averages (Center and Right) should be in theory identical in all rings, as the stimulus pixel sizes are scaled to compensate for cone density, but here demonstrate amplitude loss in the parafoveal region (rings 2-4).
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Figure 3. Development of hydroxychloroquine toxicity in Patient 2. Vertical spectral domain OCT cross-sections and cube thickness diagrams from the right eye at baseline (Above) and after 28 months (Below). After 28 months, there is inferior parafoveal thinning evident in the cube diagram, as well as in the cross-section, which also shows focal loss of the inferior ellipsoid zone and bands (arrow). A 10-2 visual field pattern deviation plot from the right eye (inset) shows a corresponding superior parafoveal scotoma. The left eye also showed similar changes. The fundus examination and fundus autofluorescence were normal (not shown).
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Figure 4. Multifocal electroretinogram showing hydroxychloroquine toxicity in Patient 2. The 103-hexagon trace array (Left), shows generalized weak signals throughout the macula. Normalized ring averages (Center and Right) demonstrate amplitude loss in the parafoveal region (rings 2-4).
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Rapid Hydroxychloroquine Toxicity in Cancer Therapy
Sex Race
Weight (kg)
Dose/ kg
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68
M
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81
12
2 3
56 71
M M
A A
76 59
13 17/14
HCQ Duration of Cumulative Ophthalmic adverse events exposure follow up dose (g) (months)2 (months) 7.5 21.5 229 Retinal pigment epithelial detachment after discontinuation of hydroxychloroquine 10 10 298 19 19 539
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Age (y)
3
60 65 77 66
M F F F
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58 78 58 50
17 13 17 20
9 25 18 13
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Table 1: Characteristics of patients on high-dose hydroxychloroquine both with and without retinal toxicity
No patient had renal or liver disease Exposure at the last eye exam. HCQ: hydroxychloroquine 3 1000 mg/d for 11 months; 800 mg/d thereafter. 2
9 28 23 15
273 755 532 403
Retinal toxicity, trichomegaly Neurosensory retinal detachment left eye Retinal toxicity
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Loh-Shan B. Leung is studied medicine at the Johns Hopkins University School of Medicine. He subsequently completed postgraduate training in Ophthalmology at the Edward S. Harkness Eye Institute at Columbia Presbyterian Medical Center, and a fellowship in vitreoretinal surgery at the Byers Eye Institute at Stanford University. He is currently an affiliate Clinical Assistant Professor of Ophthalmology at Stanford University. His interests include retinal degenerations and dystrophies, retinal electrophysiology, and drug toxicity.
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S0002-9394(15)00419-5
DOI:
10.1016/j.ajo.2015.07.012
Reference:
AJOPHT 9402
To appear in:
American Journal of Ophthalmology
Received Date: 27 April 2015 Revised Date:
6 July 2015
Accepted Date: 10 July 2015
Please cite this article as: Leung L-SB, Neal JW, Wakelee HA, Sequist LV, Marmor MF, Rapid Onset of Retinal Toxicity from High-Dose Hydroxychloroquine Given for Cancer Therapy, American Journal of Ophthalmology (2015), doi: 10.1016/j.ajo.2015.07.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Rapid Hydroxychloroquine Toxicity in Cancer Therapy ABSTRACT: Purpose: To report rapid onset of retinal toxicity in a series of patients followed on high dose (1000 mg daily) hydroxychloroquine during an oncologic clinical trial studying hydroxychloroquine with erlotinib for non-small cell lung cancer.
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Design: Retrospective observational case series.
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Methods: Ophthalmic surveillance was performed on patients in a multicenter clinical trial testing high dose (1000 mg daily) hydroxychloroquine for advanced non-small cell lung cancer. The FDA-recommended screening protocol included only visual acuity testing, dilated fundus examination, Amsler grid testing, and color vision testing. In patients seen at Stanford, additional sensitive screening procedures were added at the discretion of the retinal physician: high-resolution spectral domain optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, Humphrey visual field (HVF) testing and multifocal electroretinography (mfERG). Results: Out of the seven patients having exposure of at least 6 months, two developed retinal toxicity at 11 and 17 months of exposure. Damage was identified by OCT imaging, mfERG testing, and in one case, visual field testing. Fundus autofluorescence imaging remained normal. Neither patient had symptomatic visual acuity loss.
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Conclusions: These cases show that high doses of hydroxychloroquine can initiate the development of retinal toxicity within 1-2 years. Although synergy with erlotinib is theoretically possible, there are no prior reports of erlotinib-associated retinal toxicity despite over a decade of use in oncology. These results also suggest that sensitive retinal screening tests should be added to ongoing and future clinical trials involving high dose hydroxychloroquine to improve safety monitoring and preservation of vision.
ACCEPTED MANUSCRIPT Rapid Hydroxychloroquine Toxicity in Cancer Therapy
Rapid Onset of Retinal Toxicity from High-Dose Hydroxychloroquine Given for Cancer Therapy Short title: Rapid Hydroxychloroquine Toxicity in Cancer Therapy
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Loh-Shan B. Leung1, Joel W. Neal2, Heather A. Wakelee2, Lecia V. Sequist3, Michael F. Marmor1
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Correspondence: Loh-Shan B. Leung, Department of Ophthalmology, Byers Eye Institute, Stanford University Department of Ophthalmology. 2405 Watson Ct, Palo Alto, CA 94303. Phone: 650-721-6888 Fax: 650-565-8297 Email: [email protected]
Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, California 2 Department of Medicine, Division of Oncology, Stanford University/Stanford Cancer Institute, Palo Alto, California 3
Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts
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INTRODUCTION: Hydroxychloroquine has been a mainstay of treatment for rheumatologic conditions such as systemic lupus erythematosus and rheumatoid arthritis, and there are extensive risk and toxicity data for the typical range of doses. The risk of hydroxychloroquinemediated retinal toxicity is relatively low within the first 5-10 years of therapy when used at daily doses that do not exceed 5 mg/kg, typically 200-400 mg daily.1 Risk is clearly a balance between daily dose and duration of use, but there are little data available on the degree to which highly elevated doses can accelerate toxicity.
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Loading doses of up to 1200 mg hydroxychloroquine for starting therapy of rheumatologic conditions have been described, but have typically been given only for brief durations of less than 6 weeks.2,3 Hydroxychloroquine has recently been proposed as an adjunct chemotherapeutic agent for a number of types of cancer, after in vivo and in vitro studies showed potential efficacy in various tumor types. However, relatively high blood concentrations are required to achieve tumor inhibition in preclinical studies, with dose escalation studies showing that an excess of 600 mg daily may be necessary.4 These trials might in theory provide knowledge about the risk of high-dose hydroxychloroquine; however, FDA-mandated ocular screening is usually minimal by ophthalmologic standards, and patients are rarely followed for extended periods.
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Stanford was a study site for a phase II open-label, randomized multisite clinical trial investigating the efficacy of high-dose hydroxychloroquine (1000 mg daily) in addition to erlotinib vs. erlotinib alone for advanced lung cancer (Neal JW, et al. J Clin Oncol 2014;32:ASCO Abstract 8088). All patients in the hydroxychloroquine arm were referred for ongoing ophthalmic screening. The trial protocol only required visual acuity, color testing, Amsler grid testing and fundus examination (which are no longer considered sufficient for screening according to current recommendations).5 We added sensitive imaging modalities and functional testing to the follow-up of a number of these patients. We present ophthalmologic findings on those patients who had specialized retinal testing and maintained high-dose hydroxychloroquine for at least 6 months.
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METHODS The phase II trial evaluated EGFR-mutant advanced stage non-small cell lung cancer (NCT00977470), and was initiated at the Massachusetts General Hospital; Stanford participated as a subsite with approval by the Institutional Review Board of both institutions. Erlotinib was administered at standard oncologic doses, and hydroxychloroquine was started in patients randomized to the combination arm at 1000 mg daily, with dose reductions to 800mg, 600mg, 400mg or complete discontinuation allowed for toxicity. The protocol required examination pre-treatment and every 3 months for those patients in the hydroxychloroquine arm, but only with dilated fundus examination, visual acuity, color vision testing, and Amsler grid testing. Our purpose was not to study every patient, but to follow as many as possible of those who continued on hydroxychloroquine beyond 6 months, adding (as clinically indicated) automated 10-2 fields (Humphrey Field Analyzer, Zeiss-Meditec), spectral domain optical coherence tomography (SD-OCT)(Cirrus Model 4000, Zeiss-Meditec), fundus autofluorescence (FAF) (Heidelberg Engineering), and multifocal ERG (Diagnosys
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RESULTS: The Stanford site enrolled a total of 15 patients to the hydroxychloroquine plus erlotinib arm, of which seven had exposure beyond 6 months and underwent serial specialized diagnostic studies (mean exposure 16.5 months, range 7.5-25 months). Patient characteristics are shown in the table. The last follow up eye exam with retinal imaging studies ranged from 9 to 28 months after the start of therapy. Two patients developed definitive signs of toxicity without symptoms and are described below. Among those patients who did not develop signs of toxicity, one patient developed a retinal pigment epithelial detachment after discontinuing hydroxychloroquine, and an additional patient developed both a retinal pigment epithelial and serous neurosensory retinal detachment in one eye over the course of therapy, both of which resolved without recurrence. Neither event was believed to be associated with hydroxychloroquine.
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Case 1: A 66-year old Caucasian female was newly diagnosed with advanced lung adenocarcinoma. The patient had no other medical diseases, and renal function remained normal throughout her therapy. The patient was 1.59 m tall (ideal body weight: 53 kg6) and weighed about 50 kg (daily hydroxychloroquine dose: 20 mg/kg). Baseline examination showed visual acuity of 20/20 OD and 20/25 OS. The anterior and posterior segment exam was unremarkable, except for a subtle yellow spot in the fovea of the left eye associated with mild vitreomacular traction. SD-OCT (Figure 1) was otherwise normal with good visualization of the ellipsoid zone (EZ) and interdigitation zone (IZ). FAF was also normal. Baseline Humphrey 10-2 visual fields were unremarkable for any loss of central macular sensitivity (not shown).
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Follow up examinations with SD-OCT and FAF remained unchanged until the 11-month visit, although the SD-OCT showed very subtle intensity loss in the parafoveal EZ. There was no change in thickness on the subfield cube map, and the EZ alteration was not felt to be definitive enough to discontinue potentially effective anticancer therapy.
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The patient stopped hydroxychloroquine therapy at 13 months due to symptoms of dry mouth. When next examined at 15 months (Figure 1), she showed clear dropout of the parafoveal EZ (corresponding to the region of intensity loss at 11 months). There was also thinning of the overlying outer nuclear layer that averaged 30 microns in the parafoveal areas of the thickness map. FAF and ophthalmoscopic fundus examination were normal, but an mfERG showed widespread signal depression across the macula with the greatest loss in the parafoveal region (Figure 2). Follow up visual field testing was performed elsewhere and was not available. The patient did not report any symptoms of visual impairment. Case 2: A 65-year old Asian female with history of diabetes, hypertension and hyperlipidemia, was diagnosed with adenocarcinoma of the lung metastatic to the spine and brain. The
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patient was also 1.59 m tall (ideal body weight 53 kg) and weighed 78 kg (daily dose: 12.8 mg/kg). Baseline exam showed visual acuity of 20/30 OU, and no fundus abnormalities aside from minimal non-proliferative diabetic retinopathy. Visual fields (10-2) were unremarkable, as was the SD-OCT (Figure 2). SD-OCT, fundus autofluorescence imaging, and 10-2 visual fields were performed quarterly over the next 15 months without change.
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After 17 months, some patchiness of the inferior parafoveal IZ was noted, more prominently in the left eye, and by 19 months there was zone of diminished EZ brightness. But there was no thinning on the SD-OCT subfield maps, nor any diagnostic abnormality in FAF or visual field at this time or on subsequent follow up 3 months later. These changes were felt to be borderline and the decision was made to continue therapy.
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Evaluation at 25 months revealed clear loss of the inferior parafoveal EZ and IZ with visible thinning of the outer nuclear layer between about 2-6 degrees (Figure 3). These were the same areas showing borderline change at 17 months. The thickness map still remained within normal limits for age and FAF was unremarkable. An mfERG showed diffusely depressed signals throughout the macula with the greatest loss in the parafoveal region (Figure 4). Erlotinib was continued, but hydroxychloroquine was stopped because of the observed retinal toxicity.
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Examination three months after discontinuing hydroxychloroquine (Figure 2) showed further loss of the parafoveal EZ and IZ inferiorly, and now temporally as well. Parafoveal retinal thickness measured on SD-OCT was subnormal in the inferior subfields. Visual field testing showed a clear defect in the superior parafoveal region of both eyes, although FAF and fundus examination were unremarkable. The patient had no subjective symptoms of vision impairment.
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DISCUSSION: We found that 2 of 7 patients followed with sensitive retinal exams for at least 6 months on high dose hydroxychloroquine developed characteristic EZ and IZ signs of hydroxychloroquine retinal toxicity. The earliest signs of toxicity (patchiness and loss of intensity of the parafoveal EZ and IZ) were detected at 11 and 17 months, and typical parafoveal thinning on OCT at 15 and 25 months in the first and second patient, respectively. These are the first cases of toxicity reported with daily doses of hydroxychloroquine in the range of 1000 mg. After the initial signs of toxicity were observed, damage progressed over the next 4-8 months (and at least for an additional 3 months after stopping the drug in one patient). As is typical with early toxicity, anatomic signs appeared before patients recognized any loss of vision. Even though the daily dose of hydroxychloroquine was high in our cases, the cumulative dose of hydroxychloroquine administered to each patient was well below the 1000 grams that has been considered high risk in some earlier studies.7 While the most recent recommendations by the American Academy of Ophthalmology suggest that ideal body weight be used to determine maximum hydroxychloroquine dosage (6.5
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mg/kg),5 a recent and comprehensive demographic study has shown that the risk of toxicity is reduced long-term by maintaining the daily dose under 5 mg/kg of real body weight.1 In the context of normal dosing, the detection of retinal toxicity in less than 5 years of exposure is extremely rare. Regardless of the method used to determine the maximum dosage, the patients in this study received substantially elevated doses (our patients were receiving 13-20 mg/kg of real body weight, and almost three times the dose based on 6.5 mg/kg of ideal body weight). Our results show that these dose levels can hasten the onset of recognizable maculopathy to as little as 11 months, even in the absence of risk factors such as renal disease, coincident use of other retinotoxic medications, or preexisting maculopathy. Although we cannot completely rule out a toxic synergy between erlotinib and hydroxychloroquine, we think this is highly unlikely. Erlotinib has been used as a chemotherapeutic agent for solid tumors for over a decade, with no retinal toxicity reported. The only reported drug synergy with hydroxychloroquine retinopathy is with the known retinotoxin, tamoxifen.1 However, the patients in our trial did develop ocular symptoms such as dysfunctional tearing, blepharitis, or trichomegaly which have been associated with erlotinib use.8
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High loading doses of hydroxychloroquine, up to 1200 mg daily, have been described in the rheumatologic literature, but typically only up to 6 weeks followed by standard dosing, and no vision loss or retinopathy has been reported for such therapy, although the ophthalmic screening methodology is poorly described.2,3 Previous phase I trials examining high doses of hydroxychloroquine in combination with a number of agents for the treatment of advanced solid tumors, glioblastoma multiforme, and melanoma, reported no dose-limiting toxicities reported for up to 1200 mg daily in some studies. However, the method of ocular screening for retinal toxicity was not uniform and probably suboptimal in many of these studies.4,9-11 Additionally, while these high doses were tolerated by a few patients in prior studies for up to 18 months, hydroxychloroquine dosing was commonly reduced after 3-4 months due to symptoms of fatigue, nausea, and vomiting or discontinued entirely when therapy was changed for disease progression.
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Our results suggest that clinical trials using high-dose hydroxychloroquine should monitor for ocular toxicity that may appear after the typical 3-4 month period studied in Phase I trials, and yet well before the 5-10 years of exposure required for hydroxychloroquine toxicity with standard doses. In clinical trials of anticancer therapy, of course, the risks of retinal damage must be balanced against the potential benefits of treatment for survival. However, once signs of hydroxychloroquine-related retinopathy are detected, the risk of symptomatic visual impairment becomes very significant if these high doses are continued. Use of sensitive early detection methods can help investigators and patients to make informed decisions about continuing therapy. We recommend that patients receiving elevated doses of hydroxychloroquine (well above 5 mg/kg of real body weight or 6.5 mg/kg of ideal body weight) should have exams approximately every 3 months that include at least SD-OCT and 10-2 visual fields (for non-Asian patients—wider 24-2 or 30-2 fields may be preferable in Asian patients, who often display early hydroxychloroquine damage in a more pericentral pattern12).
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In summary, high-dose hydroxychloroquine can result in accelerated retinal toxicity, within as little as 11 months of exposure. As the use of hydroxychloroquine is being explored for a variety of novel medical indications, investigators should be aware of the dose-duration relationship relative to hydroxychloroquine toxicity, and are encouraged to incorporate modern retinal screening techniques into the surveillance plan for trials using elevated doses.
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Acknowledgements/Disclosures: a. Funding/support: Genentech/Roche (South San Francisco, CA) provided funding for the trial and for ophthalmic screening exams b. Financial support: Loh-Shan Leung: No financial disclosures Joel Neal: Research funding from Genentech/Roche (South San Francisco, CA); Merck (Kenilworth, NJ); ArQule (Burlington, MA); Novartis (Basel, Switzerland); Exelixis (South San Francisco, CA); Boehringer Ingelheim (Ingelheim, Germany); Nektar (San Francisco, CA). All outside the submitted work with the exception of Genentech/Roche. Consulting/advisory: Clovis Oncology (Boulder, CO); CARET/Physicians Resource Management (Ann Arbor, MI). All outside the submitted work. Heather Wakelee: No financial disclosures Lecia Sequist: Consulting/advisory: Clovis Oncology; Novartis; AstraZeneca (London, UK); Genentech; Merrimack (Cambridge, MA); Boehringer Ingelheim; Taiho (Princeton, NJ). All uncompensated. Michael Marmor: No financial disclosures c. Other acknowledgements: Ryan Nelson
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References
Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132(12):1453-1460.
2.
Furst DE, Lindsley H, Baethge B, et al. Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension. Arthritis Rheum 1999;42(2):357-365.
3.
Munster T, Gibbs JP, Shen D, et al. Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis. Arthritis Rheum 2002;46(6):1460-1469.
4.
Rosenfeld MR, Ye X, Supko JG, et al. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 2014;10(8):1359-1368.
5.
Marmor MF, Kellner U, Lai TYY, Lyons JS, Mieler WF. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118(2):415-422.
6.
Robinson JD, Lupkiewicz SM, Palenik L, Lopez LM, Ariet M. Determination of ideal body weight for drug dosage calculations. Am J Hosp Pharm 1983;40(6):1016-1019.
7.
Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol 2007;143(5):801-809.
8.
Borkar DS, Lacouture ME, Basti S. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: a five-year review. Support Care Cancer 2013;21(4):1167-1174.
9.
Mahalingam D, Mita M, Sarantopoulos J, et al. Combined autophagy and HDAC inhibition: A phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 2014;10(8):1403-1414.
11.
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10.
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1.
Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. Autophagy 2014;10(8):1391-1402.
Rangwala R, Leone R, Chang YC, et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 2014;10(8):1369-1379.
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Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology 2015;122(1):110-116.
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Figure Captions
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Figure 1. Development of hydroxychloroquine toxicity in Patient 1. Horizontal spectral domain OCT cross-sections and cube thickness diagrams from the left eye at baseline (Above) and after 15 months of hydroxychloroquine (Below). After 15 months the cube diagram shows parafoveal thinning 360 degrees, and the cross-sections show clear thinning of the outer nuclear layer and loss of ellipsoid zone and interdigitation zone bands (arrows). The fundus examination and fundus autofluorescence were normal (not shown).
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Figure 2. Multifocal electroretinogram showing hydroxychloroquine toxicity in Patient 1. The 103-hexagon trace array (Left), shows generalized weak signals throughout the macula. Normalized ring averages (Center and Right) should be in theory identical in all rings, as the stimulus pixel sizes are scaled to compensate for cone density, but here demonstrate amplitude loss in the parafoveal region (rings 2-4).
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Figure 3. Development of hydroxychloroquine toxicity in Patient 2. Vertical spectral domain OCT cross-sections and cube thickness diagrams from the right eye at baseline (Above) and after 28 months (Below). After 28 months, there is inferior parafoveal thinning evident in the cube diagram, as well as in the cross-section, which also shows focal loss of the inferior ellipsoid zone and bands (arrow). A 10-2 visual field pattern deviation plot from the right eye (inset) shows a corresponding superior parafoveal scotoma. The left eye also showed similar changes. The fundus examination and fundus autofluorescence were normal (not shown).
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Figure 4. Multifocal electroretinogram showing hydroxychloroquine toxicity in Patient 2. The 103-hexagon trace array (Left), shows generalized weak signals throughout the macula. Normalized ring averages (Center and Right) demonstrate amplitude loss in the parafoveal region (rings 2-4).
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Sex Race
Weight (kg)
Dose/ kg
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68
M
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81
12
2 3
56 71
M M
A A
76 59
13 17/14
HCQ Duration of Cumulative Ophthalmic adverse events exposure follow up dose (g) (months)2 (months) 7.5 21.5 229 Retinal pigment epithelial detachment after discontinuation of hydroxychloroquine 10 10 298 19 19 539
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Age (y)
3
60 65 77 66
M F F F
A A A C
58 78 58 50
17 13 17 20
9 25 18 13
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Table 1: Characteristics of patients on high-dose hydroxychloroquine both with and without retinal toxicity
No patient had renal or liver disease Exposure at the last eye exam. HCQ: hydroxychloroquine 3 1000 mg/d for 11 months; 800 mg/d thereafter. 2
9 28 23 15
273 755 532 403
Retinal toxicity, trichomegaly Neurosensory retinal detachment left eye Retinal toxicity
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Loh-Shan B. Leung is studied medicine at the Johns Hopkins University School of Medicine. He subsequently completed postgraduate training in Ophthalmology at the Edward S. Harkness Eye Institute at Columbia Presbyterian Medical Center, and a fellowship in vitreoretinal surgery at the Byers Eye Institute at Stanford University. He is currently an affiliate Clinical Assistant Professor of Ophthalmology at Stanford University. His interests include retinal degenerations and dystrophies, retinal electrophysiology, and drug toxicity.
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