Secondary primary malignancies in indolent non-Hodgkin lymphoma patients receiving frontline bendamustine-rituximab

Background — Bendamustine-rituximab (BR) is common frontline therapy for indolent B-cell non-Hodgkin lymphomas (iBCL), but its association with secondary primary malignancies (SPM) is unclear.

Methods — The authors conducted a population-based study using linked Ontario health care databases. Patients ≥18 years old with untreated iBCL receiving BR (2013–2022) were compared to a historical cohort receiving cyclophosphamide-based regimens (rituximab, cyclophosphamide, vincristine, prednisone/rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CVP/CHOP], 2006–2012). Five-year SPM incidence was assessed using cumulative incidence function and competing risk models. Landmark analysis was conducted at 6 months after index date.

Results — A total of 6878 patients (BR, 4611; R-CVP/CHOP, 2267) were identified; BR recipients were older (65.6 vs. 62.8 years, p < .001). The 5-year cumulative incidence of SPM was higher with BR versus R-CVP/CHOP (8.9% vs. 7.2%, p = .019) as was the SPM rate at 6.4 versus 4.9 per 100,000 person-days (p = .006), with higher rates of respiratory tract, male genitourinary, and skin cancers. Myelodysplastic syndrome/acute myeloid leukemia cases were similar accounting for group size (n = 23 vs. 11, p = .20). Multivariable analysis showed no significant difference in SPM risk (hazard ratio [HR], 1.13; 95% CI, 0.93–1.36, p = .22); full versus abbreviated BR was associated with borderline higher SPM risk (cumulative incidence function, 10.7% vs. 7.2%; HR, 1.51, p = .06). No difference was seen by cycles for R-CVP/CHOP. Development of SPM shortened survival (HR, 3.67; 95% CI, 3.15–4.29, p < .001).

Conclusions — Although BR patients demonstrated a higher SPM risk at 5 years in univariate models, this finding was not present on multivariable analysis. An increased number of BR cycles was associated with borderline increased SPM risk. These findings require prospective validation and studies examining risk-adapted abbreviation of chemotherapy.