European Journal of Haematology 96 (78–82)
ORIGINAL ARTICLE
Cytomegalovirus reactivation in patients with multiple myeloma Tetsuo Hasegawa, Yoshinobu Aisa, Kengo Shimazaki, Chisako Ito, Tomonori Nakazato Department of Hematology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan
Abstract The introduction of novel antimyeloma agents has improved the outcome of multiple myeloma (MM) dramatically. However, it has also led to an increasing incidence of Herpesviridae family virus infections, including a high incidence of post-transplant cytomegalovirus (CMV) reactivation after treatment with novel agents. We herein retrospectively assessed the CMV reactivation in all 120 newly diagnosed patients with MM consecutively seen and treated at our hospital. CMV antigenemia tests were ordered in 58 patients depending on the clinical context, and the incidence of CMV reactivation and proven/suspected CMV disease requiring antiviral therapy was 20% (24 of 120) and 11% (13 of 120) respectively, including those without stem cell transplantation (SCT). The clinical and laboratory characteristics of these patients were compared with those in 34 CMV antigenemia-negative (CMV-negative) patients. Patients with extramedullary disease or a low absolute lymphocyte count (ALC) had a higher risk of developing CMV reactivation. In addition, the median duration from the time of MM diagnosis to CMV reactivation was 5.0 months. These results suggest that, regardless of whether or not undergoing SCT, elderly patients with MM receiving novel agents should be monitored for CMV reactivation to allow for the timely diagnosis and treatment, especially for those with extramedullary disease. Key words cytomegalovirus; multiple myeloma; reactivation Correspondence Tomonori Nakazato, MD, Department of Hematology, Yokohama Municipal Citizen’s Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama 240-8555, Japan. Tel: +81 45 331 1961; Fax: +81 45 331 1960; e-mail: [email protected] Accepted for publication 19 February 2015
The outcome and survival of patients with MM have improved dramatically with the introduction of novel antimyeloma agents, such as bortezomib, thalidomide, and lenalidomide. However, it has been suggested that adverse events, including infections, are increased in patients treated with the combination of antimyeloma therapies and a steroid. MM itself is associated not only with impaired humoral immunity, but also with functional abnormalities of dendritic, T, and natural killer (NK) cells. In addition, the increased use of novel agents has led to a significantly increased incidence of infections caused by herpes simplex virus (HSV), varicella zoster virus (VZV), and CMV (1–4). Bortezomib was reported to lead to a four times higher risk of VZV reactivation and infections compared to patients with dexamethasone alone (5, 6), and a high incidence of post-transplant CMV reactivation in patients with MM after treatment with bortezomib-based regimens was recently reported (7). However, the incidence of CMV reactivation in the whole MM population
78
doi:10.1111/ejh.12551
in the era of novel agents, regardless of SCT, is not well known. The aims of this study were to establish the incidence of CMV reactivation and symptomatic CMV disease requiring treatment in the MM population and to compare the clinical and laboratory characteristics of patients with and without CMV reactivation. Patients and methods
Between 2005 and 2013, a total of 120 adult patients newly diagnosed with MM in our hospital were retrospectively analyzed. Patients were identified through an electronic database search of archived microbiology records. CMV antigenemia tests were ordered during times of acute illness in 58 patients, at the discretion of the attending physician and depending on the clinical context. At the time of MM diagnosis, the following clinical and demographic data were recorded: sex, age, the Eastern
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Hasegawa et al.
Cooperative Oncology Group (ECOG) PS, type of myeloma, Durie–Salmon stage, the International Staging System (ISS) stage, extramedullary disease and cytogenetics (Gbanding). In addition, the median duration from the time of diagnosis, the prior treatment, the number of treatment regimens, the use of a bortezomib regimen, and the absolute lymphocyte count (ALC) were recorded at the time CMV antigenemia was tested in 58 patients. The clinical characteristics and treatment of 24 CMV antigenemia-positive (CMV-positive) patients were also abstracted from the electronic medical records. The clinical and laboratory characteristics of the CMV-positive group were identified and compared with those of the CMV-negative group using Fisher’s exact test and the Mann–Whitney U-test. Statistical significance was set at a value of P < 0.05. All statistical analyses were performed using the EZR software program (version 1.26, Saitama Medical Center, Jichi Medical University, Japan). CMV infection was defined as CMV antigenemia (detection of CMV pp65 in leukocytes) regardless of the symptoms or signs (8). CMV disease was defined as evidence of CMV infection with attributable symptoms and histopathological findings (8) in the absence of bacterial, viral, or fungal infections. Suspected CMV disease was defined by the presence of clinical and imaging features of CMV disease with CMV antigenemia in the absence of histopathological findings, because biopsies could not be performed due to the patients’ poor general conditions. The blood CMV pp65 antigen test was based on a monoclonal antibody against the virus and immunofluorescence. When the test results were positive, the number of positive cells per 106 white blood cells was measured. Although CMV antigenemia was tested on clinical suspicion of reactivation, no routine surveillance for CMV antigenemia had been conducted. According to the clinical context, we started specific antiviral therapy in the presence of CMV antigenemia with standard symptoms of CMV disease, such as gastritis, enteritis, and pneumonia. The conduct of the trial adhered to the Declaration of Helsinki, and this study was approved by our Institutional Ethical Committee. Results
During the 8-yr period studied, the baseline characteristics of 120 patients at the time of MM diagnosis are summarized in Table 1. The median age of the patients was 69 yr old (range 36–88), 61 (51%) were male and 27 (23%) underwent auto-SCT. CMV antigenemia was tested on clinical suspicion during treatment in 58 patients (48%), and the incidence of CMV reactivation during MM treatment was at least 20% (24 of 120). Five of these patients had undergone auto-SCT, while 19 had not.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
CMV reactivation in myeloma patients
Table 1 Clinical characteristics of the 120 assessable patients Characteristics Sex Male Female Age, years Median (range) ECOG PS 0–2 3–4 Type of myeloma IgG IgA IgD BJP Non-secretory Durie–Salmon stage I II/III A/B ISS stage I II III Extramedullary disease (+) ( ) Cytogenetics (G-banding) Normal karyotype Del 13 Others
n (%)
61 (51) 59 (49) 69 (36–88) 68 (57) 52 (43) 68 23 5 22 2
(57) (19) (4) (18) (2)
11 (9) 109 (91) 104 (87)/16 (13) 20 (17) 41 (34) 59 (49) 31 (26) 89 (74) 90 (75) 5 (4) 25 (21)
The clinical characteristics of the 58 assessable patients are shown in Tables 2 and 3. The median age, sex, ECOG PS, type of myeloma, Durie–Salmon stage, and ISS stage did not show significant differences between the CMV-positive and CMV-negative groups. However, in the CMV-positive group, the number of patients with extramedullary disease was significantly higher than that in the CMV-negative group (46% vs. 18%, P = 0.039). At the time CMV antigenemia was tested, the CMV-positive group had a significantly shorter median duration from the time of diagnosis (5.0 vs. 20 months, P = 0.025) and a lower median ALC (0.22 vs. 0.51 9 109/L, P = 0.019). No significant differences were detected in the prior treatment or number of treatment regimens. The clinical findings, laboratory features, treatment, and outcome of patients with CMV antigenemia are described in Table 4. Among the 24 patients diagnosed with CMV reactivation, 19 (80%) had undergone treatment with a bortezomib-combined regimen. Thirteen patients had developed proven/suspected CMV disease, including six patients with enterocolitis, five patients with gastritis, and two patients with pneumonia. All 13 patients received specific antiviral therapy and 11 (85%) improved.
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Table 2 Clinical characteristics of the 58 assessable patients CMV positive (N = 24) Sex Male 11 (46%) Female 13 (54%) Median age, 69 (56–85) years (range) ECOG PS 0–2 9 (37%) 3–4 15 (63%) Type of myeloma IgG 11 (46%) IgA 4 (17%) IgD 0 (0%) BJP 8 (33%) Non-secretory 1 (4%) Durie–Salmon stage I 2 (8%) A/B 19 (79%)/5 (21%) International Staging System, N (%) I 4 (17%) II 9 (38%) III 11 (45%) Extramedullary disease (+) 11 (46%) ( ) 13 (54%)
CMV negative (N = 34)
20 (59%) 14 (41%) 69 (36–86)
Table 3 Clinical characteristics of the 58 assessable patients P-value
0.425 0.602
21 (62%) 13 (38%)
0.109
18 7 3 6 0
0.308
(53%) (21%) (9%) (17%) (0%)
3 (9%) 30 (88%)/4 (12%)
1 0.467
5 (15%) 9 (26%) 20 (59%)
0.623
6 (18%) 28 (82%)
0.039
Bold values of
ORIGINAL ARTICLE
Cytomegalovirus reactivation in patients with multiple myeloma Tetsuo Hasegawa, Yoshinobu Aisa, Kengo Shimazaki, Chisako Ito, Tomonori Nakazato Department of Hematology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan
Abstract The introduction of novel antimyeloma agents has improved the outcome of multiple myeloma (MM) dramatically. However, it has also led to an increasing incidence of Herpesviridae family virus infections, including a high incidence of post-transplant cytomegalovirus (CMV) reactivation after treatment with novel agents. We herein retrospectively assessed the CMV reactivation in all 120 newly diagnosed patients with MM consecutively seen and treated at our hospital. CMV antigenemia tests were ordered in 58 patients depending on the clinical context, and the incidence of CMV reactivation and proven/suspected CMV disease requiring antiviral therapy was 20% (24 of 120) and 11% (13 of 120) respectively, including those without stem cell transplantation (SCT). The clinical and laboratory characteristics of these patients were compared with those in 34 CMV antigenemia-negative (CMV-negative) patients. Patients with extramedullary disease or a low absolute lymphocyte count (ALC) had a higher risk of developing CMV reactivation. In addition, the median duration from the time of MM diagnosis to CMV reactivation was 5.0 months. These results suggest that, regardless of whether or not undergoing SCT, elderly patients with MM receiving novel agents should be monitored for CMV reactivation to allow for the timely diagnosis and treatment, especially for those with extramedullary disease. Key words cytomegalovirus; multiple myeloma; reactivation Correspondence Tomonori Nakazato, MD, Department of Hematology, Yokohama Municipal Citizen’s Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama 240-8555, Japan. Tel: +81 45 331 1961; Fax: +81 45 331 1960; e-mail: [email protected] Accepted for publication 19 February 2015
The outcome and survival of patients with MM have improved dramatically with the introduction of novel antimyeloma agents, such as bortezomib, thalidomide, and lenalidomide. However, it has been suggested that adverse events, including infections, are increased in patients treated with the combination of antimyeloma therapies and a steroid. MM itself is associated not only with impaired humoral immunity, but also with functional abnormalities of dendritic, T, and natural killer (NK) cells. In addition, the increased use of novel agents has led to a significantly increased incidence of infections caused by herpes simplex virus (HSV), varicella zoster virus (VZV), and CMV (1–4). Bortezomib was reported to lead to a four times higher risk of VZV reactivation and infections compared to patients with dexamethasone alone (5, 6), and a high incidence of post-transplant CMV reactivation in patients with MM after treatment with bortezomib-based regimens was recently reported (7). However, the incidence of CMV reactivation in the whole MM population
78
doi:10.1111/ejh.12551
in the era of novel agents, regardless of SCT, is not well known. The aims of this study were to establish the incidence of CMV reactivation and symptomatic CMV disease requiring treatment in the MM population and to compare the clinical and laboratory characteristics of patients with and without CMV reactivation. Patients and methods
Between 2005 and 2013, a total of 120 adult patients newly diagnosed with MM in our hospital were retrospectively analyzed. Patients were identified through an electronic database search of archived microbiology records. CMV antigenemia tests were ordered during times of acute illness in 58 patients, at the discretion of the attending physician and depending on the clinical context. At the time of MM diagnosis, the following clinical and demographic data were recorded: sex, age, the Eastern
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Hasegawa et al.
Cooperative Oncology Group (ECOG) PS, type of myeloma, Durie–Salmon stage, the International Staging System (ISS) stage, extramedullary disease and cytogenetics (Gbanding). In addition, the median duration from the time of diagnosis, the prior treatment, the number of treatment regimens, the use of a bortezomib regimen, and the absolute lymphocyte count (ALC) were recorded at the time CMV antigenemia was tested in 58 patients. The clinical characteristics and treatment of 24 CMV antigenemia-positive (CMV-positive) patients were also abstracted from the electronic medical records. The clinical and laboratory characteristics of the CMV-positive group were identified and compared with those of the CMV-negative group using Fisher’s exact test and the Mann–Whitney U-test. Statistical significance was set at a value of P < 0.05. All statistical analyses were performed using the EZR software program (version 1.26, Saitama Medical Center, Jichi Medical University, Japan). CMV infection was defined as CMV antigenemia (detection of CMV pp65 in leukocytes) regardless of the symptoms or signs (8). CMV disease was defined as evidence of CMV infection with attributable symptoms and histopathological findings (8) in the absence of bacterial, viral, or fungal infections. Suspected CMV disease was defined by the presence of clinical and imaging features of CMV disease with CMV antigenemia in the absence of histopathological findings, because biopsies could not be performed due to the patients’ poor general conditions. The blood CMV pp65 antigen test was based on a monoclonal antibody against the virus and immunofluorescence. When the test results were positive, the number of positive cells per 106 white blood cells was measured. Although CMV antigenemia was tested on clinical suspicion of reactivation, no routine surveillance for CMV antigenemia had been conducted. According to the clinical context, we started specific antiviral therapy in the presence of CMV antigenemia with standard symptoms of CMV disease, such as gastritis, enteritis, and pneumonia. The conduct of the trial adhered to the Declaration of Helsinki, and this study was approved by our Institutional Ethical Committee. Results
During the 8-yr period studied, the baseline characteristics of 120 patients at the time of MM diagnosis are summarized in Table 1. The median age of the patients was 69 yr old (range 36–88), 61 (51%) were male and 27 (23%) underwent auto-SCT. CMV antigenemia was tested on clinical suspicion during treatment in 58 patients (48%), and the incidence of CMV reactivation during MM treatment was at least 20% (24 of 120). Five of these patients had undergone auto-SCT, while 19 had not.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
CMV reactivation in myeloma patients
Table 1 Clinical characteristics of the 120 assessable patients Characteristics Sex Male Female Age, years Median (range) ECOG PS 0–2 3–4 Type of myeloma IgG IgA IgD BJP Non-secretory Durie–Salmon stage I II/III A/B ISS stage I II III Extramedullary disease (+) ( ) Cytogenetics (G-banding) Normal karyotype Del 13 Others
n (%)
61 (51) 59 (49) 69 (36–88) 68 (57) 52 (43) 68 23 5 22 2
(57) (19) (4) (18) (2)
11 (9) 109 (91) 104 (87)/16 (13) 20 (17) 41 (34) 59 (49) 31 (26) 89 (74) 90 (75) 5 (4) 25 (21)
The clinical characteristics of the 58 assessable patients are shown in Tables 2 and 3. The median age, sex, ECOG PS, type of myeloma, Durie–Salmon stage, and ISS stage did not show significant differences between the CMV-positive and CMV-negative groups. However, in the CMV-positive group, the number of patients with extramedullary disease was significantly higher than that in the CMV-negative group (46% vs. 18%, P = 0.039). At the time CMV antigenemia was tested, the CMV-positive group had a significantly shorter median duration from the time of diagnosis (5.0 vs. 20 months, P = 0.025) and a lower median ALC (0.22 vs. 0.51 9 109/L, P = 0.019). No significant differences were detected in the prior treatment or number of treatment regimens. The clinical findings, laboratory features, treatment, and outcome of patients with CMV antigenemia are described in Table 4. Among the 24 patients diagnosed with CMV reactivation, 19 (80%) had undergone treatment with a bortezomib-combined regimen. Thirteen patients had developed proven/suspected CMV disease, including six patients with enterocolitis, five patients with gastritis, and two patients with pneumonia. All 13 patients received specific antiviral therapy and 11 (85%) improved.
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CMV reactivation in myeloma patients
Hasegawa et al.
Table 2 Clinical characteristics of the 58 assessable patients CMV positive (N = 24) Sex Male 11 (46%) Female 13 (54%) Median age, 69 (56–85) years (range) ECOG PS 0–2 9 (37%) 3–4 15 (63%) Type of myeloma IgG 11 (46%) IgA 4 (17%) IgD 0 (0%) BJP 8 (33%) Non-secretory 1 (4%) Durie–Salmon stage I 2 (8%) A/B 19 (79%)/5 (21%) International Staging System, N (%) I 4 (17%) II 9 (38%) III 11 (45%) Extramedullary disease (+) 11 (46%) ( ) 13 (54%)
CMV negative (N = 34)
20 (59%) 14 (41%) 69 (36–86)
Table 3 Clinical characteristics of the 58 assessable patients P-value
0.425 0.602
21 (62%) 13 (38%)
0.109
18 7 3 6 0
0.308
(53%) (21%) (9%) (17%) (0%)
3 (9%) 30 (88%)/4 (12%)
1 0.467
5 (15%) 9 (26%) 20 (59%)
0.623
6 (18%) 28 (82%)
0.039
Bold values of
