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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.
Biol Blood Marrow Transplant. 2015 Nov; 21(11):2008-16.BB

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+Show Affiliations

Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka, Japan. Electronic address: takenaka@intmed1.med.kyushu-u.ac.jp.Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.Department of Hematology, Toranomon Hospital, Tokyo, Japan.Department of Hematology and Oncology, Hiroshima University Research Institute for Radiation Biology and Medicine, Hiroshima, Japan.Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan.Department of Hematology, Kanagawa Cancer Center, Yokohama, Japan.Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.Department of Hematology, Meitetsu Hospital, Nagoya, Japan.Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan.Department of Hematology, Toranomon Hospital, Tokyo, Japan.Department of Hematology, Osaka City University Hospital, Osaka, Japan.Department of Hematology and Oncology, Hiroshima University Research Institute for Radiation Biology and Medicine, Hiroshima, Japan.Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.Department of Hematopoietic Stem Cell Transplantation Data Management and Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan.Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan.Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26211985

Citation

Takenaka, Katsuto, et al. "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." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 21, no. 11, 2015, pp. 2008-16.
Takenaka K, Nishida T, Asano-Mori Y, et al. 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. Biol Blood Marrow Transplant. 2015;21(11):2008-16.
Takenaka, K., Nishida, T., Asano-Mori, Y., Oshima, K., Ohashi, K., Mori, T., Kanamori, H., Miyamura, K., Kato, C., Kobayashi, N., Uchida, N., Nakamae, H., Ichinohe, T., Morishima, Y., Suzuki, R., Yamaguchi, T., & Fukuda, T. (2015). 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. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 21(11), 2008-16. https://doi.org/10.1016/j.bbmt.2015.07.019
Takenaka K, et al. 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. Biol Blood Marrow Transplant. 2015;21(11):2008-16. PubMed PMID: 26211985.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Takenaka,Katsuto, AU - Nishida,Tetsuya, AU - Asano-Mori,Yuki, AU - Oshima,Kumi, AU - Ohashi,Kazuteru, AU - Mori,Takehiko, AU - Kanamori,Heiwa, AU - Miyamura,Koichi, AU - Kato,Chiaki, AU - Kobayashi,Naoki, AU - Uchida,Naoyuki, AU - Nakamae,Hirohisa, AU - Ichinohe,Tatsuo, AU - Morishima,Yasuo, AU - Suzuki,Ritsuro, AU - Yamaguchi,Takuhiro, AU - Fukuda,Takahiro, Y1 - 2015/07/26/ PY - 2015/05/11/received PY - 2015/07/20/accepted PY - 2015/7/28/entrez PY - 2015/7/28/pubmed PY - 2016/7/21/medline KW - Allogeneic hematopoietic stem cell transplantation KW - Cytomegalovirus KW - Nonrelapse mortality KW - Risk of relapse SP - 2008 EP - 16 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol Blood Marrow Transplant VL - 21 IS - 11 N2 - 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. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/26211985/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(15)00496-6 DB - PRIME DP - Unbound Medicine ER -