CYTOMEGALOVIRUS RETINITIS AFTER TREATMENT WITH LENALIDOMIDE FOR MULTIPLE MYELOMA Hui Y. Lim, MBBS,* David Francis, MBBS,* Jonathan Yeoh, MBBS, FRANZCO,* Lyndell L. Lim, MBBS, FRANZCO*†
Purpose: To describe a case of cytomegalovirus retinitis in a patient after treatment with lenalidomide, a novel therapy in the treatment of multiple myeloma. Methods: Descriptive case report of a 67-year-old man on Lenalidomide maintenance therapy for multiple myeloma, who presented with unilateral painless blurring of vision because of retinitis. Results: Polymerase chain reaction of the vitreous sampling confirmed cytomegalovirus retinitis, although the patient’s serum polymerase chain reaction was negative for cytomegalovirus. The patient was treated with ganciclovir with good effect. Conclusion: Cytomegalovirus retinitis is rare in immunocompetent patients and not commonly reported in myeloma patients. Given the increasing use of novel therapies such as Lenalidomide, unusual infections such as cytomegalovirus retinitis should be considered in patients with visual symptoms, even if they are considered to be immune competent at presentation. RETINAL CASES & BRIEF REPORTS 7:172–175, 2013
with lenalidomide (Revlimid; Celgene, Summit, NJ), was otherwise immunocompetent at presentation.
From the *Department of Ophthalmology, Royal Melbourne Hospital, Parkville, Victoria, Australia; and †Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia.
Case Report
C
ytomegalovirus (CMV) retinitis is typically reported in immunocompromised patients, most frequently in HIV patients with CD4+ counts of ,50. Less frequently, CMV retinitis has been reported in transplant patients and those receiving immunosuppressive therapy.1,2 Patients may initially be asymptomatic or present with a variety of visual complaints. If left untreated, CMV retinitis may lead to profound visual loss from involvement of the macula or secondary retinal detachment.2 There are few cases of CMV retinitis in non-HIV patients and fewer reported in immunocompetent hosts.1,2 We present a case of CMV retinitis in a 67-year-old man with multiple myeloma, who, apart from recent treatment
A 67-year-old man with a medical history of multiple myeloma was referred to the ophthalmology department with a 3-day history of painless blurred vision in his left eye. At the time, he was being treated for recurrent myeloma in his left humerus with radiotherapy. Following the initial multiple myeloma diagnosis 20 months prior to presentation, the patient was placed on the LitVacc study, which involved the combination of lenalidomide and an autologous stem cell transplant composed of a tumor lysate prepared before chemotherapy and the patient’s dendritic cells.3 This was initially complicated with an episode of Pneumocystis jiroveci pneumonia that resolved with antibiotics 12 months before presentation. After the transplant, the patient was continued on a maintenance protocol. His most recent dose was 15 mg, ceased 4 weeks before. At presentation, initial investigations included an urgent computed tomography of the brain, followed by magnetic resonance imaging and lumbar puncture when the computed tomography was reported as normal. Blood testing revealed findings consistent with multiple myeloma, with increased serum paraproteins of 8 g/L with IgA kappa paraprotein, mildly decreased leukocyte count of 3.2 · 109/L (range, 4.0–11.0 · 109/L), normal neutrophil count of 2.0 · 109/L (range, 2.0– 8.0 · 109/L), reduced CD4 count of 0.14 L · 109/L (range, 0.35–2.63
None of the authors have any financial/conflicting interests to disclose. Reprint requests: Lyndell L. Lim, MBBS, FRANZCO, Centre for Eye Research Australia, University of Melbourne, 32 Gisborne Street, East Melbourne, Victoria 3002, Australia; e-mail: limllp@ unimelb.edu.au
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CMV RETINITIS AFTER LENALIDOMIDE TREATMENT L · 109/L), C-reactive protein 14 mg/L (range,5) and ESR 132 mm in 1 hour (range 2–14). Ophthalmic examination revealed a left visual acuity of 6/12 (right 6/6), normal pupillary responses, and anterior segment examination. Fundus examination revealed an area of hemorrhagic retinitis along the superotemporal arcade (Figure 1). There was no apparent vitritis or vasculitic change detected. Differential diagnosis included CMV retinitis, although no previous reports have been associated with lenalidomide use. Other possibilities were considered, such as syphilis, tuberculosis, atypical toxoplasmosis, and malignant infiltration. A vitreous sample was acquired, and at the same time, foscarnet (Foscavir; Astra Zeneca, North Ryde, NSW, Australia) 0.05 mL of 2,400 mg/0.1 mL was injected intravitreally. Magnetic resonance imaging and lumbar puncture were normal with no evidence of central nervous system multiple myeloma recurrence. Syphilis and tuberculosis testing were negative. Varicella zoster IgG antibody, CMV IgG antibody, and herpes simplex virus IgG were detected in plasma, whereas toxoplasma IgG was not detected. The CMV IgM and polymerase chain reaction in the plasma were negative. Vitreous sampling was positive for CMV via multiplex polymerase chain reaction, so intravenous ganciclovir (Cymevene; Roche, Dee Why, NSW, Australia) was started (5 mg/kg once a day). Anterior chamber inflammation and posterior synechiae developed at Day 3 after foscarnet injection, so a cycloplegic, homatropine (Isopto Homatropine 2%; Alcon, Frenchs Forest, NSW, Australia) 3 times daily, and topical steroid, prednisolone–phenylephrine 1% to 0.12% (Prednefrin Forte; Allergan, Gordon, NSW, Australia), were started. Fundus examination 1 week after injection revealed 2 new macular intraretinal hemorrhages and a peripapillary hemorrhage (Figure 2). The areas of retinitis remained unchanged with no extension. A repeat intravitreal foscarnet injection was administered, and intravenous ganciclovir was continued for a further 2 weeks,
after which the patient was started on oral valganciclovir of 900 mg daily (Valcyte; Roche, Canada). Acuity improved to 6/9, and topical steroids were tapered. To date (9 months after presentation), there has been no recurrence (Figure 3).
Discussion Cytomegalovirus retinitis is believed to result from hematogenous spread from the systemic reactivation of a latent infection and therefore typically occurs in immunosuppressed individuals,1,2,4 with the most common manifestation being pulmonary disease.5–7 Although recurrent myeloma may cause impaired cell immunity, CMV retinitis has not been previously described to occur in newly diagnosed multiple myeloma or in recurrent disease.5,8 As our patient was not overtly neutropenic with an acceptable CD4+ count, despite the presence of recurrent myeloma, he was not considered to be severely immunocompromised. Lenalidomide is a new immunomodulatory drug that has multiple effects that include the induction of apoptosis, tumor necrosis factor a antagonism, and the inhibition of angiogenesis.5,7 Its side effects include myelosuppression and thromboembolism.6,7 Although it has been associated with Grade 3/4 bacterial infection, there have been very few cases of preventable Grade 3/4 viral and fungal infections.6
Fig. 1. Fundus photograph of the left eye showing hemorrhagic retinitis along the superotemporal arcade at presentation with no evidence of retinitis in the right eye.
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Fig. 2. Fundus photograph of the involved eye, 1 week after foscarnet injection, showing new macular intraretinal hemorrhages and peripapillary hemorrhage.
Fig. 3. Fundus photograph of the involved eye showing resolution of the retinitis (9 months after presentation).
RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 2
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CMV RETINITIS AFTER LENALIDOMIDE TREATMENT
In particular, there have been no cases of CMV retinitis reported, unlike in our patient. Grade 3 and 4 infections are defined as severe systemic infections requiring intravenous treatment or hospitalization and life-threatening sepsis (including septic shock), respectively, in accordance to National Cancer Institute’s Common Toxicity Criteria, version 2.0.9 Of note, the CMV retinitis in this patient occurred in the absence of detectable systemic CMV reactivation, as his serum CMV polymerase chain reaction was negative. Although the penetration of the blood–brain barrier by lenalidomide is still unknown, it has been reported to induce remission in the relapse of hematological malignancies within the orbit and central nervous system.10,11 Hence, it is possible that lenalidomide may have penetrated the blood–retinal barrier, allowing the reactivation of CMV in the eye. Novel therapies have transformed myeloma into a chronic condition, with multiple relapses and salvage therapies, all of which may result in cumulative immunosuppression and higher risk of opportunistic infections.8 In such a setting, the traditional HIV-based approach of reduced review frequency after sustained immune recovery with antiretrovirals may not apply. This case therefore underlines the importance of attention to the development of visual symptoms, with prompt ophthalmic review, of patients with multiple myeloma or those on novel therapies. Key words: cytomegalovirus retinitis, lenalidomide, multiple myeloma.
References 1. Kuo IC, Kempen JH, Dunn JP, et al. Clinical characteristics and outcomes of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am J Ophthalmol 2004;138:338–346. 2. Tajunisah I, Reddy SC, Tan LH. Acute retinal necrosis by cytomegalovirus in an immunocompetent adult: case report and review of the literature. Int Ophthalmol 2009;29:85–90. 3. Wood R. LitVacc trial seeking to help patients with multiple myeloma. Australas Biotechnol 2010;20:49–50. 4. Zhang M, Xin H, Atherton S. Murine cytomegalovirus (MCMV) spreads to and replicates in the retina after endotoxin-induced disruption of the blood-retinal barrier of immunosuppressed BALB/c mice. J Neurovirol 2005;11:365–375. 5. Nucci M, Anassie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis 2009;49:1211–1225. 6. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142. 7. Zeldis JB, Knight RD, Jacques C, et al. Lenalidomide in multiple myeloma: current role and future directions. Expert Opin Pharmacother 2010;11:829–842. 8. Schutt P, Brandhorst D, Stellberg W, et al. Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections. Leuk Lymphoma 2006;47:1570–1582. 9. National Cancer Institute. Common toxicity criteria v2.0 (CTC). Available at: http://ctep.cancer.gov/protocolDevelopment/ electronic_applications/docs/ctcv20_4-30-992.pdf. Accessed September 12, 2012. 10. Cox MC, Mannino G, Lionetto L, et al. Lenalidomide for aggressive B-cell lymphoma involving the central nervous system? Am J Hematol 2011;85:957. 11. Rubenstein JL, Treseler P, Stewart PJ. Regression of refractory intraocular large B-cell lymphoma with lenalidomide monotherapy. J Clin Oncol 2011;29:595–597.
Purpose: To describe a case of cytomegalovirus retinitis in a patient after treatment with lenalidomide, a novel therapy in the treatment of multiple myeloma. Methods: Descriptive case report of a 67-year-old man on Lenalidomide maintenance therapy for multiple myeloma, who presented with unilateral painless blurring of vision because of retinitis. Results: Polymerase chain reaction of the vitreous sampling confirmed cytomegalovirus retinitis, although the patient’s serum polymerase chain reaction was negative for cytomegalovirus. The patient was treated with ganciclovir with good effect. Conclusion: Cytomegalovirus retinitis is rare in immunocompetent patients and not commonly reported in myeloma patients. Given the increasing use of novel therapies such as Lenalidomide, unusual infections such as cytomegalovirus retinitis should be considered in patients with visual symptoms, even if they are considered to be immune competent at presentation. RETINAL CASES & BRIEF REPORTS 7:172–175, 2013
with lenalidomide (Revlimid; Celgene, Summit, NJ), was otherwise immunocompetent at presentation.
From the *Department of Ophthalmology, Royal Melbourne Hospital, Parkville, Victoria, Australia; and †Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia.
Case Report
C
ytomegalovirus (CMV) retinitis is typically reported in immunocompromised patients, most frequently in HIV patients with CD4+ counts of ,50. Less frequently, CMV retinitis has been reported in transplant patients and those receiving immunosuppressive therapy.1,2 Patients may initially be asymptomatic or present with a variety of visual complaints. If left untreated, CMV retinitis may lead to profound visual loss from involvement of the macula or secondary retinal detachment.2 There are few cases of CMV retinitis in non-HIV patients and fewer reported in immunocompetent hosts.1,2 We present a case of CMV retinitis in a 67-year-old man with multiple myeloma, who, apart from recent treatment
A 67-year-old man with a medical history of multiple myeloma was referred to the ophthalmology department with a 3-day history of painless blurred vision in his left eye. At the time, he was being treated for recurrent myeloma in his left humerus with radiotherapy. Following the initial multiple myeloma diagnosis 20 months prior to presentation, the patient was placed on the LitVacc study, which involved the combination of lenalidomide and an autologous stem cell transplant composed of a tumor lysate prepared before chemotherapy and the patient’s dendritic cells.3 This was initially complicated with an episode of Pneumocystis jiroveci pneumonia that resolved with antibiotics 12 months before presentation. After the transplant, the patient was continued on a maintenance protocol. His most recent dose was 15 mg, ceased 4 weeks before. At presentation, initial investigations included an urgent computed tomography of the brain, followed by magnetic resonance imaging and lumbar puncture when the computed tomography was reported as normal. Blood testing revealed findings consistent with multiple myeloma, with increased serum paraproteins of 8 g/L with IgA kappa paraprotein, mildly decreased leukocyte count of 3.2 · 109/L (range, 4.0–11.0 · 109/L), normal neutrophil count of 2.0 · 109/L (range, 2.0– 8.0 · 109/L), reduced CD4 count of 0.14 L · 109/L (range, 0.35–2.63
None of the authors have any financial/conflicting interests to disclose. Reprint requests: Lyndell L. Lim, MBBS, FRANZCO, Centre for Eye Research Australia, University of Melbourne, 32 Gisborne Street, East Melbourne, Victoria 3002, Australia; e-mail: limllp@ unimelb.edu.au
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CMV RETINITIS AFTER LENALIDOMIDE TREATMENT L · 109/L), C-reactive protein 14 mg/L (range,5) and ESR 132 mm in 1 hour (range 2–14). Ophthalmic examination revealed a left visual acuity of 6/12 (right 6/6), normal pupillary responses, and anterior segment examination. Fundus examination revealed an area of hemorrhagic retinitis along the superotemporal arcade (Figure 1). There was no apparent vitritis or vasculitic change detected. Differential diagnosis included CMV retinitis, although no previous reports have been associated with lenalidomide use. Other possibilities were considered, such as syphilis, tuberculosis, atypical toxoplasmosis, and malignant infiltration. A vitreous sample was acquired, and at the same time, foscarnet (Foscavir; Astra Zeneca, North Ryde, NSW, Australia) 0.05 mL of 2,400 mg/0.1 mL was injected intravitreally. Magnetic resonance imaging and lumbar puncture were normal with no evidence of central nervous system multiple myeloma recurrence. Syphilis and tuberculosis testing were negative. Varicella zoster IgG antibody, CMV IgG antibody, and herpes simplex virus IgG were detected in plasma, whereas toxoplasma IgG was not detected. The CMV IgM and polymerase chain reaction in the plasma were negative. Vitreous sampling was positive for CMV via multiplex polymerase chain reaction, so intravenous ganciclovir (Cymevene; Roche, Dee Why, NSW, Australia) was started (5 mg/kg once a day). Anterior chamber inflammation and posterior synechiae developed at Day 3 after foscarnet injection, so a cycloplegic, homatropine (Isopto Homatropine 2%; Alcon, Frenchs Forest, NSW, Australia) 3 times daily, and topical steroid, prednisolone–phenylephrine 1% to 0.12% (Prednefrin Forte; Allergan, Gordon, NSW, Australia), were started. Fundus examination 1 week after injection revealed 2 new macular intraretinal hemorrhages and a peripapillary hemorrhage (Figure 2). The areas of retinitis remained unchanged with no extension. A repeat intravitreal foscarnet injection was administered, and intravenous ganciclovir was continued for a further 2 weeks,
after which the patient was started on oral valganciclovir of 900 mg daily (Valcyte; Roche, Canada). Acuity improved to 6/9, and topical steroids were tapered. To date (9 months after presentation), there has been no recurrence (Figure 3).
Discussion Cytomegalovirus retinitis is believed to result from hematogenous spread from the systemic reactivation of a latent infection and therefore typically occurs in immunosuppressed individuals,1,2,4 with the most common manifestation being pulmonary disease.5–7 Although recurrent myeloma may cause impaired cell immunity, CMV retinitis has not been previously described to occur in newly diagnosed multiple myeloma or in recurrent disease.5,8 As our patient was not overtly neutropenic with an acceptable CD4+ count, despite the presence of recurrent myeloma, he was not considered to be severely immunocompromised. Lenalidomide is a new immunomodulatory drug that has multiple effects that include the induction of apoptosis, tumor necrosis factor a antagonism, and the inhibition of angiogenesis.5,7 Its side effects include myelosuppression and thromboembolism.6,7 Although it has been associated with Grade 3/4 bacterial infection, there have been very few cases of preventable Grade 3/4 viral and fungal infections.6
Fig. 1. Fundus photograph of the left eye showing hemorrhagic retinitis along the superotemporal arcade at presentation with no evidence of retinitis in the right eye.
174
Fig. 2. Fundus photograph of the involved eye, 1 week after foscarnet injection, showing new macular intraretinal hemorrhages and peripapillary hemorrhage.
Fig. 3. Fundus photograph of the involved eye showing resolution of the retinitis (9 months after presentation).
RETINAL CASES & BRIEF REPORTS´ 2013 VOLUME 7 NUMBER 2
175
CMV RETINITIS AFTER LENALIDOMIDE TREATMENT
In particular, there have been no cases of CMV retinitis reported, unlike in our patient. Grade 3 and 4 infections are defined as severe systemic infections requiring intravenous treatment or hospitalization and life-threatening sepsis (including septic shock), respectively, in accordance to National Cancer Institute’s Common Toxicity Criteria, version 2.0.9 Of note, the CMV retinitis in this patient occurred in the absence of detectable systemic CMV reactivation, as his serum CMV polymerase chain reaction was negative. Although the penetration of the blood–brain barrier by lenalidomide is still unknown, it has been reported to induce remission in the relapse of hematological malignancies within the orbit and central nervous system.10,11 Hence, it is possible that lenalidomide may have penetrated the blood–retinal barrier, allowing the reactivation of CMV in the eye. Novel therapies have transformed myeloma into a chronic condition, with multiple relapses and salvage therapies, all of which may result in cumulative immunosuppression and higher risk of opportunistic infections.8 In such a setting, the traditional HIV-based approach of reduced review frequency after sustained immune recovery with antiretrovirals may not apply. This case therefore underlines the importance of attention to the development of visual symptoms, with prompt ophthalmic review, of patients with multiple myeloma or those on novel therapies. Key words: cytomegalovirus retinitis, lenalidomide, multiple myeloma.
References 1. Kuo IC, Kempen JH, Dunn JP, et al. Clinical characteristics and outcomes of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am J Ophthalmol 2004;138:338–346. 2. Tajunisah I, Reddy SC, Tan LH. Acute retinal necrosis by cytomegalovirus in an immunocompetent adult: case report and review of the literature. Int Ophthalmol 2009;29:85–90. 3. Wood R. LitVacc trial seeking to help patients with multiple myeloma. Australas Biotechnol 2010;20:49–50. 4. Zhang M, Xin H, Atherton S. Murine cytomegalovirus (MCMV) spreads to and replicates in the retina after endotoxin-induced disruption of the blood-retinal barrier of immunosuppressed BALB/c mice. J Neurovirol 2005;11:365–375. 5. Nucci M, Anassie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis 2009;49:1211–1225. 6. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007;357:2133–2142. 7. Zeldis JB, Knight RD, Jacques C, et al. Lenalidomide in multiple myeloma: current role and future directions. Expert Opin Pharmacother 2010;11:829–842. 8. Schutt P, Brandhorst D, Stellberg W, et al. Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections. Leuk Lymphoma 2006;47:1570–1582. 9. National Cancer Institute. Common toxicity criteria v2.0 (CTC). Available at: http://ctep.cancer.gov/protocolDevelopment/ electronic_applications/docs/ctcv20_4-30-992.pdf. Accessed September 12, 2012. 10. Cox MC, Mannino G, Lionetto L, et al. Lenalidomide for aggressive B-cell lymphoma involving the central nervous system? Am J Hematol 2011;85:957. 11. Rubenstein JL, Treseler P, Stewart PJ. Regression of refractory intraocular large B-cell lymphoma with lenalidomide monotherapy. J Clin Oncol 2011;29:595–597.
