title: Cytomegalovirus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation is Associated with a Reduced Risk of Relapse in Patients with Acute Myeloid Leukemia Who Survived to Day 100 after Transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group.
abstract: Cytomegalovirus (CMV) infection is a major infectious complication after allogeneic hematopoietic cell transplantation (allo-HSCT). Recently, it was reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study was to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSCT in a large cohort of patients. The Japan Society for Hematopoietic Cell Transplantation's Transplantation-Related Complication Working Group retrospectively surveyed the database of the Transplant Registry Unified Management Program at the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (n = 1836), acute lymphoblastic leukemia (ALL, n = 911), chronic myeloid leukemia (CML, n = 223), and myelodysplastic syndrome (MDS, n = 569) who underwent their first allo-HSCT from HLA-matched related or unrelated donors between 2000 and 2009 and who survived without disease relapse until day 100 after transplantation were analyzed. Patients who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment, and the beginning of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, nonrelapse, and overall mortality. CMV reactivation and acute/chronic graft-versus-host disease (GVHD) were evaluated as time-dependent covariates. CMV reactivation was associated with a decreased incidence of relapse in patients with AML (20.3% versus 26.4%, P = .027), but not in patients with ALL, CML, or MDS. Among 1836 patients with AML, CMV reactivation occurred in 795 patients (43.3%) at a median of 42 days, and 436 patients (23.7%) relapsed at a median of 221 days after allo-HSCT. Acute GVHD grades II to IV developed in 630 patients (34.3%). By multivariate analysis considering competing risk factors, 3 factors were significantly associated with a decreased risk of AML relapse and 1 factor with an increased risk of AML relapse: CMV reactivation (hazard ratio [HR], .77; 95% confidence interval [CI], .59 to .99), unrelated donor compared with related donor (HR, .59; 95% CI, .42 to .84), development of chronic GVHD (HR, .77; 95% CI, .60 to .99), and pretransplantation advanced disease status compared with standard disease status (HR, 1.99; 95% CI, 1.56 to 2.52). However, CMV reactivation was associated with increased nonrelapse mortality (HR, 1.60; 95% CI, 1.18 to 2.17) and overall mortality (HR, 1.37; 95% CI, 1.11 to 1.69). A beneficial effect of CMV reactivation on subsequent risk of relapse was observed in patients with AML but not in those with other hematological malignancies. However, this benefit was nullified by the increased nonrelapse mortality. The underlying mechanism is unclear; however, immunological activation against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options, including vaccination and adoptive T cell transfer, may be useful to take advantage of the efficacy of CMV reactivation with minimal increase in nonrelapse mortality.
authors.affiliation: Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka, Japan. Electronic address: takenaka@intmed1.med.kyushu-u.ac.jp.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Takenaka
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Department of Hematology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Asano-Mori
authors.affiliation: Department of Hematology and Oncology, Hiroshima University Research Institute for Radiation Biology and Medicine, Hiroshima, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan.
authors.forename: Heiwa
authors.initials: H
authors.lastname: Kanamori
authors.affiliation: Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyamura
authors.affiliation: Department of Hematology, Meitetsu Hospital, Nagoya, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kato
authors.affiliation: Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Department of Hematology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Uchida
authors.affiliation: Department of Hematology, Osaka City University Hospital, Osaka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nakamae
authors.affiliation: Department of Hematology and Oncology, Hiroshima University Research Institute for Radiation Biology and Medicine, Hiroshima, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ichinohe
authors.affiliation: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Morishima
authors.affiliation: Department of Hematopoietic Stem Cell Transplantation Data Management and Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Ritsuro
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takuhiro
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Fukuda
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003587:Cytomegalovirus / Q000276:immunology; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000401:mortality / Q000628:therapy / Q000821:virology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007564:Japan; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000627:therapeutic use*; D009190:Myelodysplastic Syndromes / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D016016:Proportional Hazards Models; D012008:Recurrence; D012189:Retrospective Studies; D012955:Societies, Medical; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D061349:Unrelated Donors; D014775:Virus Activation / Q000276:immunology
chemical_list: D019653:Myeloablative Agonists
keywords: Allogeneic hematopoietic stem cell transplantation; Cytomegalovirus; Nonrelapse mortality; Risk of relapse