Patient characteristics

The clinical background information of all patients with ML is shown in Table 1. The median age of the study participants was 69 years, and 53% (126/236) of the patients were men. Most patients had a good Eastern Cooperative Oncology Group performance status (73%; 173/236), B symptoms (30%; 71/236), and advanced-stage disease (62%; 146/236). B cell lymphomas (83%; 195/236), including diffuse large B cell lymphomas (n = 128) and follicular lymphomas (n = 47), comprised the largest subcategory of MLs, followed by T/NK cell lymphomas (11%; 25/236) and HLs (7%; 16/236). Most patients were treated with rituximab (76%; 180/236); this included R-CHOP (like) regimens (69%; 163/236). Moreover, 9% (21/236) of the patients received treatment with bendamustine or fludarabine. In addition, 14% (32/236) of the patients received steroid pretreatment before primary therapy (PT) for ML. Radiation therapy was administered to 39% (92/236) of the patients, who had received a median of 1 therapeutic regimen (range: 0–7). Furthermore, 23% (55/236) of the patients received a dose reduction in PT for ML.

Table 1 Clinical background of patients with ML Characteristics of patients with CMVI

The characteristics of patients with CMVI are shown in Table 1. CMVI developed in 5.5% (13/236) of patients with ML; this group included 8 (62%) men, featured 8 (62%) cases of B cell ML and 5 (38%) of T cell ML, and had a median age of 64 (range: 42–85) years. Approximately half (54%; 7/13) of these patients had received steroid pretreatment before PT for ML, and 62% (8/13) had received > 2 therapeutic regimens for ML. Twelve (92%) patients had received anti-CMV treatments. The median number of CMV antigen-positive cells per 5 × 104 leukocytes at the initial development of CMVI was 3 (range: 1–636). Most patients (92%; 12/13) with CMVI received ganciclovir or valganciclovir, and 2 (15%) were intubated because of pneumonitis. The majority (85%; 11/13) of patients with CMVI eventually died from lymphoma progression (n = 9) or pneumonitis (n = 2). The putative affected organs by CMV were the liver (hepatitis) in seven and the lung (pneumonitis) in five, whereas four patients had fever only. The median duration of treatment for CMV was 15.5 (range: 0–35) days. Regarding the response to treatment for CMV, 7 out of 13 patients recovered, but the rest did not recover from CMVI. Regarding the treatment of lymphoma after CMVI, of the five patients who developed CMVI during the first-line treatment, two received no treatment, and each of the remaining three patients received CHASE, consisting of cyclophosphamide, cytosine arabinoside, etoposide, and dexamethasone, ESHAP, consisting of etoposide, methylprednisolone, cytarabine, and cisplatin, or oral etoposide. Both patients who developed CMVI during the second-line treatment received oral etoposide, but one died without recovering from CMVI. Of the six patients who developed CMVI after the third-line treatment, four patients died without recovering from CMVI during the final treatment regimen for lymphoma (methylprednisolone, rituximab, CHASE, or EPOCH, consisting of etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, respectively). However, the remaining two patients recovered from CMVI; then, FCM, consisting of fludarabine, cyclophosphamide, and mitoxantrone, or radiotherapy was performed.

In addition, patients with CMVI had a higher C-reactive protein (CRP) level (5.659 vs. 1.913 mg/dL; p = 0.0002) and lower hemoglobin (10.862 vs. 12.039 g/dL; p = 0.0493) and serum albumin levels (3.1 vs. 3.7 g/dL; p = 0.0005) at diagnosis than those without CMVI (Table 2).

Table 2 Laboratory data of patients with and without CMV infection at the time of malignant lymphoma diagnosis OS and RFs in patients with CMVI and cumulative incidence of CMVI during follow-up period

A comparison of OS between patients with and without CMVI revealed significantly worse OS in the former (3-year OS: 10% vs. 76%, p < 0.0001 by log-rank test; Fig. 1). To identify the RFs associated with CMVI, the clinical characteristics and background data were compared between patients with and without CMVI in a univariate analysis (Table 3). A significantly higher incidence of CMVI development was observed in patients with B symptoms [odds ratio (OR): 5.79 (95% confidence interval [CI]: 1.55–26.7); p = 0.00321)], T cell lymphoma [OR: 6.26 (95% CI: 1.47–24.2); p = 0.006406], steroid pretreatment before PT for ML [OR: 9.08 (95% CI: 2.40–35.6); p = 0.0004262], > 2 therapeutic regimens for ML [OR: 11.4 (95% CI: 3.04–47.8); p = 0.0000818], achievement of first remission [OR: 0.26 (95% CI: 0.07–0.98); p = 0.02311], serum albumin level < 3.5 g/dL [OR: 8.02 (95% CI: 1.98–46.8); p = 0.0007837], and CRP level of more than the upper limit of normal [OR: infinity (95% CI: 2.57–infinity); p = 0.0006962]. The use of rituximab was not a significant RF for CMVI [OR: 0.34 (95% CI: 0.09–1.28); p = 0.08545]. These independent seven parameters were subsequently included in a multivariate analysis to determine the independent RFs for CMVI development, which identified steroid pretreatment before PT for ML [OR: 4.71 (95% CI: 1.06–21.0); p = 0.0419] and > 2 therapeutic regimens for ML [OR: 9.25 (95% CI: 2.33–36.8); p = 0.00159] (Table 3). A cumulative incidence of CMVI during follow-up in the total cohort was 5.5%. In addition, each cumulative incidence of CMVI in patients pretreated with steroid before PT for ML or received > 2 therapeutic regimens for ML was 21.9% (7/32) or 22.9% (8/35), respectively.

Fig. 1

OS of patients with malignant lymphoma, with or without CMV infection. The OS of patients (n = 13) with malignant lymphoma who developed CMVI (a) was significantly worse (p < 0.0001, log-rank test) than that of patients (n = 223) without CMVI (b). The estimated 3-year OS rates of patients with and without CMVI were 10 and 76%, respectively. CMVI, cytomegalovirus infection; OS, overall survival

Table 3 Univariate and multivariate analysis of risk factors for CMV infectionCMVI in patients with ML according to the literature

Several investigators had previously reported retrospective studies of CMVI in patients with ML, as shown in Table 4 [6,7,8,9]. The reported incidence rate of CMVI ranged from 3.9 to 16% in those studies, which were not limited to patients with ML who had not received HSCT. Although our study included only patients with ML who had not received HSCT, the incidence (5.5%) of CMVI was within the range reported in those earlier studies. In addition, 2 of the 4 previous studies reported RFs of CMVI or CMV disease, such as the use of rituximab-containing regimens [7, 9] or hyper-CVAD (cyclophosphamide, vincristine, adriamycin, and dexamethasone) [9]. However, the authors did not identify the use of steroid pretreatment or number of therapeutic regimens for ML as RFs for CMVI. Two studies have reported the use of rituximab as an RF of CMVI development in patients with ML [7, 9], and CMVI-related fatalities have been reported among patients with ML who were treated with rituximab [1]. Although the use of rituximab-containing regimens was not identified as an RF for CMVI in our study, further investigations are required to clarify whether rituximab use is an RF for CMVI development in patients with ML. In addition, the disadvantages in survival prognosis in patients with ML with CMVI were not obviously reported, except in our study.

Table 4 CMVI in patients with ML according to the literature