Case Report: Persistent cytomegalovirus (CMV) infection after haploidentical hematopoietic stem cell transplantation using in vivo alemtuzumab: emergence of resistant CMV due to mutations in the UL97 and UL54 genes
Kumi Oshima
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
Division of Hematology, Saitama Medical Center, Jichi Medical School, Saitama, Japan
Search for more papers by this authorYoshinobu Kanda
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
Division of Hematology, Saitama Medical Center, Jichi Medical School, Saitama, Japan
Search for more papers by this authorShinichi Kako
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Search for more papers by this authorYuki Asano-Mori1
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Division of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
Search for more papers by this authorTakuro Watanabe
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Search for more papers by this authorToru Motokura
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Search for more papers by this authorShigeru Chiba
Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
Search for more papers by this authorKimiyasu Shiraki
Department of Virology, Toyama University, Toyama, Japan
Search for more papers by this authorCorresponding Author
Mineo Kurokawa
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.===Search for more papers by this authorKumi Oshima
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
Division of Hematology, Saitama Medical Center, Jichi Medical School, Saitama, Japan
Search for more papers by this authorYoshinobu Kanda
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
Division of Hematology, Saitama Medical Center, Jichi Medical School, Saitama, Japan
Search for more papers by this authorShinichi Kako
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Search for more papers by this authorYuki Asano-Mori1
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Division of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan
Search for more papers by this authorTakuro Watanabe
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Search for more papers by this authorToru Motokura
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Search for more papers by this authorShigeru Chiba
Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
Search for more papers by this authorKimiyasu Shiraki
Department of Virology, Toyama University, Toyama, Japan
Search for more papers by this authorCorresponding Author
Mineo Kurokawa
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.===Search for more papers by this authorAbstract
Addition of in vivo alemtuzumab to the conditioning regimen enabled 2- or 3-locus-mismatched hematopoietic stem cell transplantation with an acceptable incidence of graft-versus-host-disease. However, the procedure was associated with a high incidence of cytomegalovirus (CMV) reactivation. Although preemptive therapy with ganciclovir prevented successfully severe CMV diseases and CMV-related mortality, a patient developed persistent positive CMV antigenemia for more than 1 year after transplantation and CMV disease, despite the use of ganciclovir and foscarnet. The in vitro susceptibility assay showed that the clinical isolate was resistant to foscarnet, moderately resistant to ganciclovir, but sensitive to cidofovir. Therefore, cidofovir was administered. CMV antigenemia became negative within 2 weeks and never developed again. Nucleotide sequence of the UL54 and UL97 of the clinical isolate showed 4 amino acid substitutions (V11L, Q578H, S655L, and G874R) in UL54 and 2 mutations (A140V and A594V) in UL97 compared with the Towne and AD169 strains. Ganciclovir resistance was suspected to be caused by both A594V of UL97 and Q578H of UL54, whereas foscarnet resistance was due mainly to Q578H of UL54. In conclusion, the in vitro susceptibility assay as well as nucleotide sequence of clinical isolate is important to choose appropriate antiviral agents for patients who have persistent CMV reactivation after stem cell transplantation. J. Med. Virol. 80:1769–1775, 2008. © 2008 Wiley-Liss, Inc.
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