Bendamustine has a potent immunosuppressive effect because it causes T-cell
lymphopenia, which might lead to a second primary
malignancy (SPM) and would increase the risk of
infection. Using the Medical Data Vision administrative claims database, we compared the cumulative incidence of SPM,
infections within 6 months, and overall survival (OS) among untreated patients with indolent
B-cell lymphomas (iBCL) who received
rituximab-based
chemotherapy between 2009 and 2020. Patients with grade 3b
follicular lymphoma or a previous history of
malignancy were excluded. Eligible 5234 patients were assigned to three cohorts:
rituximab monotherapy (N = 780), RCHOP/RCVP/RTHPCOP (
doxorubicin replaced with
pirarubicin) (N = 2298), or
bendamustine/
rituximab (BR) (N = 2156). There were 589 recorded SPMs, of which
myelodysplastic syndromes were the most common (1.7%). The cumulative incidence of SPM was significantly higher in patients treated with BR than in those treated with
rituximab monotherapy (p < 0.01) or RCHOP/RCVP/RTHPCOP (p < 0.0001): the 5-year cumulative incidence function was 18.1%, 12.5%, and 12.9%, respectively. In the Fine-Gray subdistribution hazards model, BR showed a significantly higher cumulative incidence of SPM than RCHOP/RCVP/RTHPCOP (subhazard ratio, 1.33; 95% confidence interval [CI], 1.10-1.61). Furthermore, in sensitivity analysis, a nested case-control study using an entire cohort showed consistent results: the SPM odds ratios (95% CI) of first-line
bendamustine,
bendamustine after first-line, and any-line
bendamustine were 1.43 (1.14-1.78), 1.26 (0.96-1.64), and 1.33 (1.09-1.62), respectively. Regarding
infections, adjusted odds ratios (95% CI) of BR compared to RCHOP/RCVP/RTHPCOP were as follows:
cytomegalovirus infection, 13.7 (4.88-38.4);
bacterial pneumonia, 0.63 (0.50-0.78); and
pneumocystis pneumonia, 0.24 (0.11-0.53). There was no significant difference in OS between RCHOP/RCVP/RTHPCOP and BR in patients with follicular, mantle cell, marginal zone, or lymphoplasmacytic
lymphomas. In conclusion, treatment strategies that consider the risk of SPM and
infections after
chemotherapy are warranted in patients with iBCL.