High incidence of symptomatic cytomegalovirus infection in multiple myeloma patients undergoing autologous peripheral blood stem cell transplantation

Holmberg et al1 report on 268 cases of malignant diseases treated with autologous peripheral blood stem cell transplantation (APBSCT); an increased incidence of cytomegalovirus (CMV) disease was observed in patients who had autologous CD34⁺ selected cell infusion: 7 out of 31 cases (22.6%) developed CMV disease and 4 of them died. In univariate and multivariate analysis, only CD34 selection was significant for the development of CMV disease. Holmberg et al1 hypothesize that the delayed immune reconstitution observed after the infusion of CD34-selected cells increases susceptibility to CMV infection and disease.

In patients receiving allogeneic bone marrow transplantation the incidence of CMV infection, defined as either evidence of any level of quantitative PP65 antigenemia or a positive blood or mouth culture, ranges from 42% to 69%. The incidence of CMV disease was up to 23% in patients with concomitant GvHD2; posttransplant immunosuppression, concomitant GvHD, and immunosuppressive therapy to treat such complications may be partially responsible. Wingard et al3 reported a 45% incidence of CMV infection in a cohort of 143 autologous BMTs, which was similar to the infection rate observed in patients undergoing allogeneic transplant. Nevertheless, the incidence of CMV disease in autologous transplantation was only 2%. In a retrospective study of the EBMT group, the incidence of CMV pneumonia in autologous transplant was 0.8%.3 

The high incidence of CMV disease noticed by Holmberg et al1 had never been observed in previous series of patients undergoing autologous transplant; Holmberg et al indicate the CD34⁺ cell selection as the only predictive factor of CMV infection and disease; nevertheless, the incidence of CMV disease in multiple myeloma (MM) patients was 5 of 32 (15%): 4 of 5 had received selected cell transplant.

At our institution, 106 CMV seropositive patients affected with hematological malignancies received APBSCT after massive chemotherapy. They were affected with MM (33 cases), non-Hodgkin lymphomas (NHL) (42 cases), Hodgkin disease (HD) (18 cases), acute nonlymphoid leukemia (ANLL) (8 cases), and chronic granulocytic leukemia (CGL) (5 cases). The median age was 42 years (range, 18 to 61). Sixty patients were males, and 46, females. All patients received unselected peripheral blood stem cells mobilised with G-CSF and cyclophosphamide (CY) given at the dose of 4000 mg/m². Conditioning regimen was as follows: patients with MM received melphalan and thiotepa (14 cases) or a modified BEM regimen including carmustine 600 mg/m², etoposide 30 mg/kg, and melphalan 200 mg/m² (19 cases); patients with HD or NHL had carmustine, etoposide, and CY in association (BCV). Patients with ANLL or CGL had busulphan (BU) and CY at standard dose. The weekly screening of PP65 antigenemia was not routinely performed because the low incidence of CMV disease usual in patients undergoing autologous bone marrow transplantation. CMV antigenemia was effected only in patients with fever unresponsive to a wide spectrum of antibiotic therapy, joint pain, weakness or diarrhea, cough, or unexplained dyspnea or leucopenia. Patients with positive CMV antigenemia received prompt treatment with ganciclovir at the dose of 5 mg/kg every 12 hours over 3 weeks; in these selected patients, the weekly screening of antigenemia was thereafter performed.

One episode of CMV symptomatic infection was noticed in 8 patients (7.5%). The median time to CMV reactivation ranged from day +15 to day +374. The main characteristics of patients who developed CMV infection are reported in the Table.

Six out of 8 patients (75%) were affected with MM; the crude incidence of CMV infection in MM patients was 18%, and only 2 of 73 patients (2.7%) affected with NHL, HD, or ANLL had CMV complication (P = .011). In our experience, the diagnosis of MM seems to be predictive of CMV infection; we can hypothesize that the immunosuppressive status related to the underlying disease may have a role.

In previous studies, the incidence of CMV infection was never related to the diagnosis of MM probably because the low number of autologous bone marrow transplants performed before the use of peripheral blood stem cells become more general. Although many patients affected with MM receive APBSCT, there are not prospective studies exploring the incidence of CMV infection and disease in this subset of patients. We believe that, given the increased incidence of symptomatic CMV infection observed in our study, close monitoring and anti-CMV therapy are needed in patients with MM receiving autologous peripheral blood progenitor cell transplantation and particularly in those receiving CD34⁺ selected cell transplant.