Cytomegalovirus reactivation is associated with increased mortality more than 100 days after allogeneic hematopoietic stem cell transplantation for adult T‐cell leukemia/lymphoma
Authors: Yasushi Sawayama, Hidehiro Itonaga, Takuya Fukushima, Nobuaki Nakano, Hiroshi Fujiwara, Atae Utsunomiya, Takahiro Fukuda, Toshihiro Miyamoto, Tetsuya Eto, Kaname Miyashita, Hirohisa Nakamae, Masao Ogata, Atsushi Yamanoha, Yasuhiko Miyazaki, Junya Kanda, Yoshiko Atsuta, Koji Kato
Journal: American Journal of Hematology (2019)

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-lymphocytic neoplasm with a poor prognosis, caused by human T-cell lymphotropic virus type I (HTLV-1).1 Multi-agent chemotherapy and novel drugs (eg, mogamulizumab and lenalidomide) are therapeutic options for aggressive ATL (ie, acute, lymphoma, and chronic type with unfavorable prognostic factors)1; however, allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers the only potential for cure along with graft-versus-ATL effects.2, 3 Cytomegalovirus (CMV) reactivation is one of the most frequent infectious complications after allo-HSCT. Several groups recently reported that CMV reactivation correlated with marked reductions in the risk of post-transplant relapse in patients with acute myeloid leukemia, but not in those with acute lymphoblastic leukemia, myelodysplastic syndrome, and malignant lymphoma.4, 5 Accordingly, the prognostic impact of CMV reactivation on the risk of post-transplant relapse may differ with the type of underlying disease. To gain further insight into this issue in post-transplant patients with ATL, we here conducted a retrospective study on a large cohort using our nationwide database. Data for ATL patients who fulfilled the following criteria were obtained from the Transplant Registry Unified Management Program database: (i) patients who received first allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation from related and unrelated donor between 1 January 2001, and 31 December 2014, and (ii) patients who had sustained engraftment. Since early death and disease relapse before day 100 after allo-HSCT were strongly affected by conditioning regimen-related toxicities and the pre-transplantation disease status, we limited the analysis to patients who survived without the relapse of ATL until day 100 after allo-HSCT (Supporting Information Figure 1). Patients underwent the surveillance of pp65 antigenemia from the time of neutrophil engraftment after allo-HSCT. CMV reactivation was defined as the diagnosis of CMV antigenemia and/or CMV disease. Preemptive therapy was generally initiated when at least two CMV pp65 antigen-positive cells per 50 000 white blood cells were identified. The primary endpoint was the probability of overall survival (OS) stratified by CMV reactivation. Secondary endpoints were TRM, ATL-associated mortality, and the incidence of CMV reactivation. Further details are provided in Supplementary Methods. The characteristics of 468 ATL patients who met these criteria and included in the present study are shown in Supporting Information Table S1. Median age at allo-HSCT was 56 years (range, 18-79 years). Among all patients, 342 developed any acute graft-versus-host disease (GVHD) at a median of 26 days after allo-HSCT (range, 4-95 days), while 255 developed any chronic GVHD at a median of 135 days (range, 100-1202 days). The median day of CMV reactivation was 40 days (range, 4-420 days), and the cumulative incidence rates of CMV reactivation on days 100 and 420 after allo-HSCT were 74.7% (95% confidence intervals [CIs], 70.3-78.5%) and 77.1% (95% CI, 72.8-80.7%), respectively (Figure 1A). CMV antigenemia only was observed in 310 patients (96.2%); CMV disease is shown in Supporting Information Table S2. Among 367 patients with CMV reactivation, CMV reactivation was documented in 194 (52.9%) without evidence of acute GVHD, and in 44 (12.0%) and 129 (35.1%) with grade I and grade II-IV acute GVHD, respectively. In the univariate and multivariate analyses, two factors correlated with an increased incidence of CMV reactivation: the use of unrelated BM/PBSC donor (hazard ratios [HRs], 2.17; 95% CI, 1.36-3.45; P = 0.001) and the development of acute GVHD grade II to IV (HR, 1.81; 95% CI, 1.45-2.28; P < 0.001); the combination with CMV seronegative-recipient and seronegative-donor was associated with a decreased incidence of CMV reactivation (HR, 0.45; 95% CI, 0.26-0.78; P = 0.005) (Supporting Information Table S3). Among patients who survived without relapse for more than 100 days after allo-HSCT, 3-year OS rates were 61.2% (95% CI, 55.7-66.3%) and 80.1% (95% CI, 69.6-87.2%) in those with and without an episode of CMV activation, respectively (P < 0.001) (Figure 1B). OS was significantly worse in patients with than in those without an episode of CMV reactivation in the multivariate time-dependent analysis (HR, 2.54; 95% CI, 1.43-4.49; P = 0.001) (Supporting Information Table S4). Three-year ATL-associated mortality were 14.7% (95% CI, 11.1-18.7%) and 5.8% (95% CI, 2.1-12.3%) in patients with and without an episode of CMV activation, respectively (P = 0.024) (Figure 1C). Three-year TRM were 24.1% (95% CI, 19.6-28.8%) and 14.1% (95% CI, 7.6-22.6%) in patients with and without an episode of CMV activation, respectively (P = 0.008) (Figure 1D). In the multivariate analysis, an episode of CMV reactivation correlated with increased ATL-associated mortality (HR, 2.47; 95% CI, 1.03-5.89; P = 0.042) and TRM (HR, 2.14; 95% CI, 1.07-4.30; P = 0.032). No significant difference in ganciclovir or foscarvir administration period was observed in patients who were alive at the last follow-up (median interval, 20 days [range, 2-379 days]), those who died of ATL (median interval, 24 days [range, 1-124 days]), and those who died of transplantation-related toxicity (median interval, 18 days [range, 1-281 days]). The causes of death other than the relapse of ATL are summarized in Supporting Information Table S5. In patients with CMV reactivation, the most frequent cause of death was infectious complications (n = 31, 21.5%) followed by GVHD (n = 20, 13.9%). Among patients who died of infectious complications, one died of CMV pneumonia whereas the remaining patients died of mainly bacterial and/or fungal infections. The most important result of the present study was that OS was significantly worse in patients with than in those without an episode of CMV reactivation. This result was accounted for, at least in part, by increased ATL-associated mortality in ATL patients who developed CMV reactivation after allo-HSCT, which was not consistent with other hematological malignancies as above.4, 5 Considering the presence of graft-versus-ATL effect along with GVHD,3 CMV reactivation during the intensified GVHD treatment would imply the loss of clinically significant graft-versus-ATL effects. In the present study, CMV reactivation was an independent factor for ATL-associated mortality, while the occurrence of any grade acute GVHD was not. One possible reason for these results was that poor virus-specific immunity after allo-HSCT may be enhanced by residual ATL cells. Patients with ATL are more susceptible to active viral infections than those with other hematological malignancies.1 Based on post-transplant surveillance, our results suggest the use of CMV reactivation as a surrogate marker for the late-phase relapse of ATL, and this marker may contribute to risk stratifications for the optimal application of maintenance therapy using lenalidomide and mogamulizumab. Another interesting finding was that CMV reactivation also showed a negative impact on TRM as an independent variable, and the most frequent cause of transplant-related death was bacterial and/or fungal infections. Previous studies showed that CMV reactivation after allo-HSCT had a negative impact in patients with defective cellular immunity.6 Based on these findings, we speculated that persistent compromised cellular immunity after transplantation resulted in higher susceptibility to CMV reactivation and other life-threatening infections among ATL patients. In conclusion, we herein demonstrated the prognostic impact of post-transplant CMV reactivation on mortality more than 100 days after allo-HSCT in ATL patients. Further experimental and clinical investigations are necessary for the development of supportive care and reducing the risk of frank ATL relapse in the late phase. This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development, AMED. The authors would like to thank all the physicians and data managers at the various institutes who contributed valuable data on transplantation to the Japan Society for Hematopoietic Cell Transplantation (JSHCT) and all the members of the data management committees of JSHCT. The authors state that they have no conflicts of interest. Y.S., H.I., and T.F. designed the research and organized the project. Y.S. and H.I. analyzed the data and wrote the manuscript. Y.S., H.I., T.F., N.N., H.F., A.U., T.F., T.M., T.E., K.M., H.N., M.O., A.Y., Y.M., J.K., Y.A., and K.K. interpreted data and reviewed and approved the final manuscript. Supplemental Table 1 Patient characteristics Supplemental Table 2. CMV reactivation Supplemental Table 3. Risk factors for CMV reactivation Supplemental Table 4. Risk factors for mortality in ATL patients who survived without relapse for more than 100 days after allo-HSCT. Supplemental Table 5. Primary cause of death Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.