Disseminated cytomegalovirus disease after bendamustine: a case report and analysis of circulating B- and T-cell subsets

Abstract

BackgroundBendamustine, used for the treatment of indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, is known to cause prolonged myelosuppression and lymphocytopenia and has been associated with the risk of developing serious and fatal infections. While reports of localized CMV infections in asymptomatic patients exist, disseminated CMV disease has not been described.Case presentationWe report the first case of disseminated CMV infection in a 75-year-old male diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with massive bone marrow infiltration. Despite 6-cycle R-bendamustine chemotherapy resulted in a good partial response, the patient developed persistent fever and severe weight loss. Analysis of cerebrospinal fluid and peripheral blood revealed the presence of CMV-DNA, while the fundus oculi examination revealed bilateral CMV retinitis. Treatment with induction and maintenance drugs was complicated by neutropenia and deterioration of renal function with electrolyte imbalance. From an immunological standpoint, we observed a profound imbalances in phenotype and function of B- and T-cell subsets, with a high proportion of circulating total, activated CD69+ and CD80+ B-cells, a low γ/δ T-cell frequency with a high proportion of CD69- and CD38-expressing cells, and hyperactivated/exhausted CD4+ and CD8+ T-cell phenotypes unable to face CMV challenge.ConclusionsWe hereby describe a severe form of disseminated CMV disease after R-bendamustine treatment. Our observations strongly support the careful clinical monitoring of CMV reactivation/infection in oncologic patients undergoing this therapeutic regimen.

Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens

“…Clinical manifestations and severity of CMV reactivation vary among patients treated with bendamustine, from no symptoms to severe CMV disease and death [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ], as also described in our cohort. In symptomatic patients, various antiviral agents are employed, such as ganciclovir and VGCV at 900 or 1,800 mg/daily [ 46 ].…”

“…CMV reactivation develops early in bendamustine administration usually after the third cycle of therapy, as documented in several case reports [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]; however, no significant differences in long-term cumulative incidence of reactivation were registered in our cohort between patients who received less than three courses of bendamustine and subjects who had more than three cycles of therapy, while in multivariate analysis the number of cycles of bendamustine increased the risk of CMV reactivation in treatment-naïve patients who received bendamustine as first-line therapy. This augmented susceptibility to viral reactivation might be caused by an impairment in T cell immunity, such as decreased circulating levels of CMV-specific CD8 + cytotoxic lymphocytes and CD4 + T cells [ 19 , 28 , 31 , 34 , 42 , 43 ]. In our study, patient with CMV reactivation had a significant depression of CD4 + T cell count between the second and third cycle of bendamustine compared to those subjects without CMV reactivation, in contrast with Isono et al who documented a CD4 + cell decreased after the sixth course of bendamustine [ 26 , 43 ].…”

“…CMV reactivation in NHL patients has been anecdotically reported after bendamustine exposure often in older subjects with iNHL including FL, MCL, or MALT [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Most of those cases are refractory or relapsed iNHL, and they usually received bendamustine with or without rituximab as second or above line of therapy developing CMV disease after the third cycle of treatment.…”

“…In NHL, CMV reactivation is a frequent cause of mortality, and prophylaxis might be warranted in patients at risk, such as patients with high antigenemia burden, recurrent CMV reactivation, and antiviral-associated toxicities [ 24 ]. In older iNHL (FL, MZL, and Waldenström macroglobulinemia) treated with bendamustine-containing regimens, the risk of CMV reactivation is increased (HR, 3.98; 95% CI, 1.40–11.26) compared to patients treated without bendamustine [ 18 ]; in particular, CMV reactivation is frequent in patients treated with bendamustine as third line or above therapy and exposed to corticosteroids [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Similarly, in our cohort, incidence of CMV reactivation was higher in patients aged >60 years; however, similar rates of reactivation were documented between indolent and aggressive diseases, or between bendamustine course as first-line therapy and second-line or above treatment (26 vs 11% respectively; P = 0.1361).…”

“…Therefore, CD4 + T cell depression during bendamustine treatment might affect the CMV-specific CD4 + T cell pool, thus increasing susceptibility to CMV reactivation in NHL patients. We also documented a significant decrease in circulating anti-CMV IgG at the nadir of reactivation which likely mirrors hyperactivation and/or exhaustion in both B and T cell immune responses [ 28 ].…”