Cytomegalovirus Infection in Patients with Lymphoma Treated With Bendamustine Are Underdiagnosed, Require Awareness

In a study with results published in Annals of Hematology, the investigators determined multiple risk factors for clinically significant-cytomegalovirus (CS-CMVi) and found that co-occurrence in patients with lymphoma treated with bendamustine (Bendeka; Teva) increases mortality and poor health outcomes.¹

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“Physicians should be aware of the underdiagnosed and potentially fatal injection,” the study authors cautioned.¹

The combination of bendamustine and rituximab (Rituxan; Genentech, Biogen) in effective in controlling disease with a lack of adverse effects compared with other regimens. However, there is greater attention being paid recently to opportunistic infections in patients treated with bendamustine-containing regimens, as more reports have been published.¹

One such study found that bendamustine treatment prior to CAR T-cell therapy results in poorer outcomes in patients with refractory large B-cell lymphoma (LBCL). Patients had a shorter progression-free survival and overall response rate compared to those who had not previously received bendamustine.²

Investigators aimed to flesh out the risks of CS-CMVi in patients with lymphoma receiving bendamustine, given that CMV infections have been found to increase mortality and morbidity significantly in allogeneic hematopoietic stem cell transplantation (HSCTs).¹

Lymphoma patients receiving treatment at Taipei Veterans General Hospital in Taiwan between September 2010 and April 2022 were evaluated for their inclusion. In total, 211 patients with lymphoma who were treated with bendamustine-containing regimens were included in the study, of which 27 (12.8%) had CS-CMVi. A large portion of the patients had either aggressive lymphoma (39.8%) or indolent lymphoma (60.2%).¹

According to a univariate analysis, risk factors associated with CS-CMVi were having 1 or more previous lines of therapy before bendamustine, serum albumin <3.5 g/dL, serum IgG <700 mg/dL, and liver disease. Additionally, in the backward multivariate analysis, these risk factors were further seen as significant risk factors.¹

Cumulative incidence of CS-CMVi was 10.1 events per 100 person-years during the 3-year follow-up period of the trial, with 92.6% of incidents occurring within the first year following the first cycle of bendamustine-containing treatments.¹

Further analysis focused on the overall survival of patients with lymphoma treated with bendamustine. Multiple risk factors were identified, including age of 70 or greater (HR 2.82), aggressive lymphoma (HR 3.77), and poor ECOG performance (HR 3.42). Ultimately, the 3-year mortality rate was 51.8%.¹

The investigators discussed that, to the best of their knowledge, this study was the only one to exist that predicts CS-CMVi n lymphoma patients through a comprehensive review of laboratory data, comorbidities, and baseline patient characteristics.¹

In a previously conducted real-world study, relapse or refractory lymphoma, and being treated with bendamustine as a result, was determined to be a risk factor of CMV. Throughout the large cohort of 167 patients with non-Hodgkin lymphoma, 41 (25%) experienced reactivations of CMV with a median time to reactivation of 54 days.³

The results of the current study align with this data, but importantly, this study evaluates the previously unexplored relationship between liver disease and CMV infection in bendamustine-treated lymphoma patients.¹

Aggressive lymphoma and poor ECOG performance were determined to be “straightforward mortality risk factors” for bendamustine-treated patients with lymphoma, as aggressive lymphoma displays faster progression of disease. Furthermore, several previously conducted studies have established CMV infection increasing mortality risk.¹

Some limitations of the study were noted. Firstly, it was not until 2014 that bendamustine-containing regimens became the frontline therapy of less aggressive lymphomas – other immunomodulatory agents might have interfered with the results garnered. In addition, routine CMV testing was not conducted in non-transplantation patients with lymphoma.¹

REFERENCES

1. Huang JP, Yeh CM, Gong YW, et al. Risk and impact of cytomegalovirus infection in lymphoma patients treated with bendamustine. Ann Hematol. 2024. doi:10.1007/s00277-024-05839-0

2. McGovern G. Bendamustine treatment before CAR T-cell therapy results in poorer outcomes in patients with LBCL. Pharmacy Times. Published January 3, 2024. Accessed August 22, 2024. https://www.pharmacytimes.com/view/bendamustine-treatment-before-car-t-cell-therapy-results-in-poorer-outcomes-in-patients-with-lbcl

3. Pezzullo L, Giudice V, Serio B, et al. Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens. Open Medicine. 2021;16(1):672-682. doi:10.1515/med-2021-0274