Treatment of unilateral zone I cytomegalovirus retinitis in acute lymphoblastic leukemia with oral valganciclovir and intravitreal ganciclovir.

Cytomegalovirus retinitis (CMVR) is an opportunistic infection seen in immunocompromised patients, especially suffering from acquired immune deficiency syndrome. It is uncommonly seen in hematological malignancies and in patients on immunosuppressants. The authors present a 12-year-old girl with unilateral CMVR who was on maintenance phase therapy for mixed phenotype (B/myeloid) leukemia. Serology for human immunodeficiency virus was negative. The child was successfully treated with oral valganciclovir and repeated intravitreal ganciclovir injections. CMVR in pediatric population with leukemia can be successfully treated with oral valganciclovir and intravitreal ganciclovir injections.

Introduction

Cytomegalovirus (CMV), a type 5 herpesvirus, causes asymptomatic or minimally symptomatic illness in immunocompetent persons. However, it remains an important cause of opportunistic infection in severe immunocompromised states secondary to depression of cell-mediated immunity (with CD4 counts <50/μL) more commonly due to acquired immune deficiency syndrome (AIDS), followed by immunosuppressive drugs, blood transfusion and postallogeneic hematopoietic stem cell transplantation (HSCT), and lymphoma.[1] Recently, various case reports of CMV retinitis (CMVR) have been reported following intraocular or periocular corticosteroid administration and in children with leukemia, especially acute lymphoblastic leukemia (ALL).[23456] Herein, we report a case of unilateral CMVR in a child during maintenance phase therapy for ALL who was not treated with autologous or allogeneic HSCT before.

Case Report

A 12-year-old girl with mixed phenotype (B/myeloid) leukemia and chromosomal analysis showing t (9; 12) (p23; q13) was started on four-drug induction chemotherapy using prednisone, vincristine, daunorubicin, and L-asparaginase. She achieved complete remission. Thereafter, the patient was given consolidation therapy and was then on maintenance therapy with oral 6-mercaptopurine and methotrexate. The prophylactic drugs included Pneumocystis jirovecii prophylaxis with cotrimoxazole. During the 14th month of maintenance therapy, she presented with painless progressive loss of vision in the right eye for 5 days. At that time, her best-corrected visual acuity was hand movement close to face in the right eye and 20/20 in the left eye. The right eye showed a relative afferent pupillary defect. Examination of ocular adnexa and motility was unremarkable. Slit-lamp biomicroscopic examination of the anterior chamber and fundus of the left eye was normal. The right eye had retrolental cells and occasional anterior chamber cells. Optic disc edema with peripapillary hemorrhages, active retinitis lesions (cream-colored lesions associated with hemorrhages along superotemporal arcade till periphery), and perivascular cuffing were seen in the right fundus [Figure 1a]. Bone marrow aspiration and cerebrospinal fluid cytology were performed and were negative for any malignant cell. CD4 count was 79/μL. The diagnosis of zone 1 CMVR in the right eye was made, and the patient was started on oral valganciclovir 450 mg twice daily for 3 weeks. She also received intravitreal ganciclovir 2 mg twice weekly for 3 weeks. After 3 weeks, oral valganciclovir 450 mg once daily was started. She received another intravitreal ganciclovir injection at 4th week leading to complete resolution of retinitis. Serology for human immunodeficiency virus was negative at the beginning of the treatment and at 3 months of valganciclovir therapy.

Figure 1

(a) At presentation, the right eye showed swelling of the optic disc with surrounding intraretinal hemorrhages, and superotemporal whitened retina with intraretinal hemorrhages suggestive of active zone 1 cytomegalovirus retinitis. (b) At 3 months’ follow-up, the retinitis resolved leading to optic disc pallor, arteriolar attenuation, and mild pigmentary changes at the superotemporal fundus

At 3 months’ follow-up, the patient had achieved 20/60 vision in the right eye; there were pigmentary changes at the area of retinitis, mild arteriolar attenuation, and optic disc pallor ensued [Figure 1b]. The CD4 count improved to 409/μL at 7th month, and oral valganciclovir was stopped. At final follow-up of 18 months, there has been no recurrence in the right eye or involvement of the other eye.

Discussion

CMVR remains the leading cause of blindness in patients with AIDS even in the current era of highly active antiretroviral therapy (HAART). Till date, there are only a few reports of CMVR in children with ALL on maintenance phase chemotherapy.[23456] Maintenance therapy in ALL can cause severe immunosuppression leading to opportunistic infections including CMVR. Immunosuppression occurs due to low total leukocyte count, decreased total lymphocyte count, decreased CD4 count, reduced functional CD4 cells in the presence of normal absolute CD4 count,[1] and reduced immunoglobulin levels.[25] During maintenance therapy, the recovery of T-helper and T-suppressor cells is delayed although the reconstitution of B cells and natural killer cells occurs early.[7] A recent review of CMV disease (CMVD) in ALL showed that most commonly CMVD occurred during maintenance phase after at least 6 months, with a median age of 10 years and no gender predilection.[2] The chemotherapeutic agents most commonly prescribed during the maintenance phase when CMVD occurred were methotrexate, 6-mercaptopurine, vincristine, and steroids.[2] Our diagnosis of CMVR was a clinical one based on the classical features of retinitis at the posterior pole along the arcade vessels, lack of vitritis, extensive intraretinal hemorrhage, immunosuppression due to leukemia on maintenance therapy, and reduced CD4 counts. CMVR is usually unilateral, aggressive, and may lead to retinal detachment in up to 50% cases. In AIDS, the anti-CMV therapy can be stopped if the patient is on HAART, CMVR is inactive for more than 4 months, and the CD4 remains better than 100/μL on two occasions 3 months apart.[8] Involvement of the other eye can occur rapidly. Therefore, prompt treatment with systemic antivirals [oral valganciclovir, intravenous (IV) ganciclovir, foscarnet, fomivirsen, and cidofovir] to prevent the involvement of the other eye along with local antiviral administration (intravitreal ganciclovir, fomivirsen, or cidofovir) for rapid regression of disease is an effective option for treating such disease.

Intravitreal antiviral injection alone does not prevent involvement of the other eye, systemic/visceral disease, and mortality, though it provides a good vitreous concentration of the antiviral agent.[8] Intravitreal ganciclovir is effective in controlling intraocular infection though concerns include endophthalmitis, increased intraocular pressure, and retinal detachment. The authors added intravitreal ganciclovir along with oral valganciclovir as the optic disc was involved and there was severe vision loss. The intravitreal ganciclovir implant (Vitrasert®; Bausch and Lomb Inc., CA, USA), the preferable intravitreal therapy for zone I CMVR,[9] is not presently available in India.

Typical regimen of CMVR starts with 2–3 weeks of induction phase followed by long-term maintenance phase as there is a risk of relapse in up to 50% cases[8] as the anti-CMV drugs are virustatic. However, the optimal therapy, route, and drug for CMVR in children have not yet been defined. Oral valganciclovir has good bioavailability, does not need IV access, is well tolerated, and has similar efficacy compared to IV ganciclovir.[10] Although oral valganciclovir has been used prophylactically in pediatric patients to prevent CMV infection in various immunosuppressive therapies and as maintenance therapy for CMVR in ALL,[4] induction and maintenance therapy of CMVR by valganciclovir with intravitreal ganciclovir in pediatric ALL patients have not been described before. Contraindication of oral valganciclovir includes hemoglobin <8 g/dL, absolute neutrophil count <500 cells/μL, and platelet count <25,000/μL. The limitation of our report includes single case, and as both oral and intravitreal antivirals were used, clinical efficacy of each modality alone cannot be commented. Oral valganciclovir along with multiple intravitreal ganciclovir injections may aid in early recovery and help these patients to maintain vision. Larger randomized control trials are required to establish the preferred mode of therapy for CMVR in pediatric population with hematological malignancies.

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Conflicts of interest

There are no conflicts of interest.