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.
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.
Oshima
Kumi
K
Department of Hematology and Oncology, University of Tokyo, Tokyo, Japan.
Kanda
Yoshinobu
Y
Kako
Shinichi
S
Asano-Mori
Yuki
Y
Watanabe
Takuro
T
Motokura
Toru
T
Chiba
Shigeru
S
Shiraki
Kimiyasu
K
Kurokawa
Mineo
M
D000074323:Alemtuzumab; D000754:Anemia, Refractory, with Excess of Blasts / Q000601:surgery*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000009:adverse effects*; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D017726:Cytomegalovirus Retinitis / Q000188:drug therapy / Q000209:etiology* / Q000517:prevention & control / Q000821:virology*; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D017245:Foscarnet / Q000494:pharmacology / Q000627:therapeutic use; D015774:Ganciclovir / Q000494:pharmacology / Q000627:therapeutic use; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008969:Molecular Sequence Data; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D017354:Point Mutation / Q000187:drug effects; D014764:Viral Proteins / Q000235:genetics; D014775:Virus Activation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D063065:Organophosphonates; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; D017245:Foscarnet; D000074323:Alemtuzumab; D003596:Cytosine; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D004259:DNA-Directed DNA Polymerase; D000077404:Cidofovir; D015774:Ganciclovir