Effect of cytomegalovirus reactivation with or without acute graft-versus-host disease on the risk of nonrelapse mortality.

BACKGROUND Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied. METHODS We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a pre-emptive strategy for CMVR between 2008 and 2017. RESULTS The cumulative incidences of grade II-IV acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD-/CMVR-, G24GVHD-/CMVR+, G24GVHD+/CMVR-, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (HR [hazard ratio], 1.59, 95% CI, 1.24-2.05, P < 0.001) and with G24GVHD (HR, 1.34, 95% CI, 1.06-1.70, P = 0.014), but the interaction between G24GVHD and CMVR was not significant (P = 0.326). Subgroup analyses suggested that the joint effect of acute GVHD and CMVR might vary according to the baseline characteristics. CONCLUSIONS These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.

[1]  H. Einsele,et al.  How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation. , 2020, Blood.

[2]  J. Kanda,et al.  Heterogeneous impact of cytomegalovirus reactivation on nonrelapse mortality in hematopoietic stem cell transplantation. , 2020, Blood advances.

[3]  S. Kako,et al.  Impact of graft‐versus‐host disease and graft‐versus‐leukemia effect based on minimal residual disease in Philadelphia chromosome‐positive acute lymphoblastic leukemia , 2020, British journal of haematology.

[4]  H. Einsele,et al.  Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). , 2019, The Lancet. Infectious diseases.

[5]  R. Leavitt,et al.  A Mortality Analysis of Letermovir Prophylaxis for Cytomegalovirus (CMV) in CMV-seropositive Recipients of Allogeneic Hematopoietic Cell Transplantation , 2019, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  Mei-Jie Zhang,et al.  Direct adjusted survival and cumulative incidence curves for observational studies , 2019, Bone Marrow Transplantation.

[7]  J. P. Martins,et al.  Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation , 2019, Science.

[8]  H. Einsele,et al.  Antiviral prophylaxis for cytomegalovirus infection in allogeneic hematopoietic cell transplantation. , 2018, Blood advances.

[9]  Michael Boeckh,et al.  Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic‐Cell Transplantation , 2017, The New England journal of medicine.

[10]  S. Nierkens,et al.  Strategies before, during, and after hematopoietic cell transplantation to improve T-cell immune reconstitution. , 2016, Blood.

[11]  R. Chemaly,et al.  How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. , 2016, Blood.

[12]  M. Norkin,et al.  Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. , 2016, Blood.

[13]  M. Sorror,et al.  CMV Viral Load and Mortality after Hematopoietic Cell Transplantation: A Cohort Study in the Era of Preemptive Therapy , 2016, The Lancet. Haematology.

[14]  K. Takenaka,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 C , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[15]  Bruce R. Blazar,et al.  CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire. , 2015, Blood.

[16]  H. Einsele,et al.  Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation. , 2014, The New England journal of medicine.

[17]  G. Papanicolaou,et al.  CMX001 to prevent cytomegalovirus disease in hematopoietic-cell transplantation. , 2013, The New England journal of medicine.

[18]  B. Sandmaier,et al.  CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. , 2013, Blood.

[19]  H. Nakasone,et al.  Clinical factors predicting the response of acute graft-versus-host disease to corticosteroid therapy: an analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[20]  Y. Kanda,et al.  Investigation of the freely available easy-to-use software ‘EZR' for medical statistics , 2012, Bone Marrow Transplantation.

[21]  H. Einsele,et al.  Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. , 2011, The Lancet. Infectious diseases.

[22]  M. Boeckh,et al.  Cytomegalovirus in hematopoietic stem cell transplant recipients. , 2011, Hematology/oncology clinics of North America.

[23]  A. Gratwohl,et al.  Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease. , 2010, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[24]  K. Akashi,et al.  A randomized controlled trial of plasma real-time PCR and antigenemia assay for monitoring CMV infection after unrelated BMT , 2010, Bone Marrow Transplantation.

[25]  A. Toubert,et al.  Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation. , 2009, Blood.

[26]  Stephen W Lagakos,et al.  Statistics in medicine--reporting of subgroup analyses in clinical trials. , 2007, The New England journal of medicine.

[27]  M. Boeckh,et al.  Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. , 1996, Blood.

[28]  P. Grambsch,et al.  Proportional hazards tests and diagnostics based on weighted residuals , 1994 .

[29]  E. Holler,et al.  Graft-versus-host disease , 2009, The Lancet.

[30]  V. Miller,et al.  Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  J. Kanda.  Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation , 2015, International Journal of Hematology.

[32]  Y. Atsuta.  Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data) , 2015, International Journal of Hematology.

[33]  Mei-Jie Zhang,et al.  SAS macros for estimation of direct adjusted cumulative incidence curves under proportional subdistribution hazards models , 2011, Comput. Methods Programs Biomed..

[34]  P. Ljungman,et al.  Risk factors for the development of cytomegalovirus disease after allogeneic stem cell transplantation. , 2006, Haematologica.