Subsequent Primary Malignancies in Patients with Indolent B Cell Non-Hodgkin Lymphoma Receiving Frontline Bendamustine Rituximab Therapy
Authors: Davies Gwynivere A , Prica Anca , Ante Zharmaine , Liu Ning , Pond Gregory R , Balitsky Amaris K , Mozessohn Lee 
Published: December 2024

Introduction:
Bendamustine is used in combination with rituximab (BR) for frontline treatment of indolent non-Hodgkin lymphoma (iNHL). BR was publicly funded in Ontario, Canada in 2013. Though patients often experience prolonged treatment free survival after therapy, patient burden can result from infections and toxicities including subsequent primary malignancy (SPM).
Reported cumulative incidence of SPM ranges from 3-18% over 3-9 years, usually in mixed cohorts receiving BR frontline or at relapse, with an unclear dose dependent association. The impact of covariates on SPM development and effects on survival in this setting are unknown. We examined the relationship between frontline BR treatment and the development of SPM among iNHL patients in Ontario.
Methods:
We conducted a population-based retrospective cohort study using linked healthcare databases in Ontario, Canada including all provincial residents ≥18 years diagnosed with iNHL (excluding CLL/SLL and hairy cell leukemia) who received BR as first systemic therapy from Jan 1, 2013 to Dec 31, 2022. Patients receiving ≥7 cycles were excluded. Follow up occurred from first bendamustine dose until the earliest of end of observation (Dec 31, 2023), death or loss of provincial coverage. Baseline variables including age, sex, rurality, marginalization (quintiles), comorbidity burden measured by Aggregated Diagnosis Groups (ADG), and lymphoma subtype were collected, along with treatment data including timing of initiation post diagnosis, number of cycles, maintenance (RM) usage and subsequent therapies.
Primary outcome was time to a SPM, identified with ICD codes and excluding cases of diffuse large B cell lymphoma and iNHL. Cumulative incidence of developing SPM was estimated using cumulative incidence function accounting for the competing risk of death prior to SPM for the entire cohort and in patients receiving 1-4 vs. 5-6 cycles. Cause-specific hazard models examined the association between baseline characteristics and SPM, considering the competing event of death and adjusting for covariates. Cumulative incidence of all-cause death was estimated using the Kaplan Meier method. A Cox regression model examined the association between baseline characteristics and all-cause death with SPM modeled as a time-varying covariate.
Results:
6284 patients were identified; mean age 66.9 years and 43.7% female. 14.4% lived rurally, 23.6% in the most marginalized quintile and 36.3% had a high ADG score. Median time from iNHL diagnosis to treatment was 4 months(Q1-3 2-34). Common histologies included follicular (51.0%), marginal zone (13.0%) and mantle cell lymphoma (10.6%). 17.8% developed an alternate cancer after iNHL diagnosis but prior to BR. Most received 5-6 cycles (83.7%) of BR. Overall, 69.5% received RM with a difference between patients receiving 1-4 vs. 5-6 cycles(25.2% vs. 78.1%, p&lt;0.0001). Subsequent usage of radiation, autologous and allogeneic stem cell transplant did not differ by group. Median follow up was 4 years after initiating therapy.
The cumulative incidence of developing SPM during follow up was 14.6%(95%CI 13.3-16.1). Median time to diagnosis was 2.36 years(Q1-3 0.98-4.32). Most commonly these were cancers of the respiratory tract and thorax (17.4% of SPM), digestive system (16.7%) and hematopoietic neoplasms (12.4%). 31.8% patients died during follow up. The probability of SPM at 5 years was 9.5%(95%CI 8.6-10.4%) for 5-6 vs. 7.5%(95%CI 5.9-9.4%) for 1-4 cycles(p=0.05). Male sex, age, marginalization, ADG category and lymphoma subtype were associated with development of SPM.
Conversely, the probability of death prior to a SPM was much higher for those with truncated therapy with a 5 year cumulative incidence of 20.3%(95%CI 19.1-21.5%) for 5-6 vs. 56.2%(95%CI 52.8-59.4%) for 1-4 cycles. The majority of deaths within the latter group occurred within the first year of therapy (35.4%). Sex, age, marginalization, ADG category and subtype were also associated with risk of death. Cumulative incidence of death during follow up was 47.9%.
Conclusions:
Patients with iNHL had a 9.2% risk of developing SPM 5 years after frontline BR. Examination by cycle number suggests dose dependency; consideration could be given to trials examining risk adapted protocols especially given effective salvage therapies. Next steps include review of hematopoietic SPM histology and evaluating the impact of subsequent therapies on SPM.