Cytomegalovirus retinitis during maintenance therapy for T-cell acute lymphoblastic leukemia.

To the Editor: Children with acute lymphoblastic leukemia (ALL) may accompany with viral infection or reactivation such as cytomegalovirus (CMV) under stem cell transplantation (SCT). However, hemophagocytic lymphohistiocytosis (HLH) or retinitis due to CMV infection under chemotherapy has been rarely reported.1,2 Furthermore, primary CMV infection tended to occur in infancy in the Japanese pediatric population, but now tends to occur later in childhood.3 Here, we describe a first ALL patient with retinitis and HLH due to CMV infection that occurred during maintenance therapy for T-cell ALL. The patient was a 7-year-old boy diagnosed with T-cell ALL at 5 years of age. He had no increased susceptibility to various infections on his past history and had no hypogammaglobulinemia at presentation. He was treated under Tokyo Children’s Cancer Study Group L04-16 HEX/BFM95 protocols followed by consolidation therapy for 10 months.4 He responded well to the induction therapy and obtained complete remission. After consolidation therapy for 10 months, maintenance therapy consisting 6-mercaptopurine (6MP) and methotrexate (MTX) was started.4 At the 7 months of maintenance therapy, the dosages of 6MP and MTX were reduced because of occurrence of leukocytopenia. The leukocytopenia (<2 10/mL) gradually worsened and other symptoms such as fever, and hepatosplenomegaly appeared. On the first day of hospitalization, his clinical data were as follows: leukocyte count, 1000/mL (normal range, 3500 to 9000/mL); platelet count, 7.6 10/mL (normal range, 15 to 30 10/mL); hemoglobin concentration, 10.0 g/dL (normal range, 13.0 to 18.0 g/dL), and C-reactive protein level, 1.7mg/dL (normal range, <0.3mg/dL). A significant decrease in CD4-positive cells was also seen (33 cells/mL). Ectopic enzymes, alanine aminotransferase, lactate dehydrogenase, and g-glutamyl transpeptidase were 55 IU/L(normal range, 4 to 44 IU/L), 475 IU/L(normal range, 106 to 211 IU/ L), and 74 IU/mL(normal range, 16 to 73 IU/L), respectively. Serum ferritin concentration was very high (10,385 ng/mL; normal range, 30 to 310ng/mL). A bone marrow smear revealed phagocytosis but no leukemic cells. According to the diagnostic guideline for HLH,5 he was diagnosed with HLH from these clinical data, such as fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, and phagocytosis. Cells containing inclusion bodies were found in urinary sediments (5 to 10 cells/field by microscopy). CMV genomes were found to be positive in white blood cells and serum by polymerase chain reaction (PCR) or real-time PCR, as previously reported.6 Enzyme-linked immunosorbent assay showed significant elevation of serum immunoglobulin M against CMV, although this was not detected in a serum sample before onset of fever. In addition, there was an increase in CMV p66 antigen (C7-HRP)-expressing leukocytes (12 of 47,000 cells). However, Varicella-zoster virus and Epstein-Barr virus genomes were not detected in serum and leukocytes (<10 copies/mg of purified DNA). From these clinical data, the patient was diagnosed with HLH due to primary CMV infection and treated with a steroid (dexamethasone 10mg/m/d) and g-globulin (250mg/kg/d 3d). When the serum ferritin level decreased and the platelet count recovered, 6MP and MTX treatment was restarted. Although CMV antigenemia persisted, he had no treatment for CMV infection because of no clinical symptoms of CMV infection. Thereafter, retinitis (left eye) was observed by fundoscopy (Fig. 1A). Ganciclovir was administered (10mg/ kg/d 7d), followed by oral administration of valganciclovir (900mg/ d 21d, followed by 450mg/d), resulting in negative CMV antigenemia and improvement of retinitis (Fig. 1B). In the present case, we considered that the causative agent of HLH and retinitis was the primary CMV infection during maintenance chemotherapy. There are many reports suggesting that reactivation of CMV infection results in pneumonia, enterocolitis, and retinitis after allogeneic SCT.6 To our best knowledge, there are no other reports of CMV-associated HLH and retinitis in ALL under maintenance chemotherapy. CMV retinitis is reported in 15% to 36% of human immunodeficiency virus–infected patients and 0.2% to 8% of patients who receive allogeneic SCT.7 Thus, both diseases might be associated with extremely low levels of CD4-positive cells during maintenance therapy. Indeed, a decrease in CD4-positive cells due to infections such as human immunodeficiency virus may frequently be accompanied by retinitis due to CMV.6 Furthermore, there remains the possibility that steroid therapy for HLH sustained CMV antigenemia and caused retinitis. Therefore, anti-CMV drugs might be required at an earlier phase. In conclusion, CMV infection should be considered not only during allogeneic SCT, but also during chemotherapy. It has been reported that primary CMV infection tended to occur in infancy in the Japanese pediatric population, but nowadays tends to occur later in childhood.3 Thus, the number of pediatric ALL patients with primary CMV infection during chemotherapy is expected to increase in the future.