Outcomes of Patients with Indolent Lymphoma Treated with Bendamustine Plus Rituximab Compared to Rituximab Plus CVP or CHOP Chemoimmunotherapy in Ontario

Background For patients with symptomatic advanced stage indolent lymphoma, rituximab (R) was traditionally used alongside cyclophosphamide, vincristine, prednisone (CVP), or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Bendamustine plus rituximab (BR) has been found to increase progression-free survival compared to R-CVP/CHOP, albeit with possible increased toxicity. Since 2013, bendamustine has been approved for public reimbursement for treatment of indolent lymphomas in Ontario, Canada, and has become the preferred regimen. We aimed to assess survival and toxicity of patients with indolent lymphoma treated with BR compared with R-CVP/CHOP in Ontario. Methods We conducted a retrospective cohort population-based study using administrative healthcare databases from Ontario, Canada. Patients were included if they had a diagnosis of indolent lymphoma and were treated with R-CVP/CHOP from 2005-2012, or with BR from 2013-2018. Patients with mantle cell lymphoma were excluded. Treatment groups were propensity score matched based on lymphoma subtype, age, sex, prior cancer diagnosis, time since diagnosis and rural or urban residence. The primary outcome of the study was overall survival (OS) from time of first treatment to death or end of study period. Secondary outcomes included toxicities during the first nine months of treatment, such as infections and secondary malignancies, associated resource utilization, and outcomes of patients treated with rituximab maintenance therapy. Cox regression models were used to assess factors associated with mortality. Results A propensity-matched cohort of 2032 patients treated with BR and 2032 treated with R-CVP/CHOP (1473 patients treated with R-CVP, 559 patients treated with R-CHOP) were included. The median age of patients was 65 years and 48% were female. A majority of patients had a diagnosis of follicular lymphoma (58.9% of patients treated with BR, 59.7% of patients treated with R-CVP/CHOP, p=0.59). Median follow-up time was 41 and 87 months for patients treated with BR and R-CVP/CHOP, respectively. BR was associated with significantly lower mortality compared to R-CVP/CHOP (HR 0.77, 95% CI 0.67-0.89, p<0.01). Five-year OS was 80% and 75% for patients treated with BR and R-CVP/CHOP, respectively (Figure 1). A total of 969 patients died during a follow-up period of seven years - 331 (16.3%) treated with BR and 638 (31.4%) treated with R-CVP/CHOP. Causes of death were available in 861 patients (88.9%), shown in Table 1. Most patients in both groups died from lymphoma (66.9% treated with BR, 66.4% treated with R-CVP/CHOP, p=0.88). A Charlson comorbidity index greater than or equal to 2 was associated with increased mortality (HR 3.04, 95% CI 2.45-3.77). Treatment toxicities are listed in Table 2.Over a nine-month period after treatment initiation (induction), patients treated with BR had a mean of 0.85 emergency department visits compared to a mean of 1.01 for patients treated with R-CVP/CHOP (p<0.01). Admissions for febrile neutropenia were more common in patients treated with R-CVP/CHOP compared to BR (4.9% vs. 2.2%, p<0.01), whereas infections resulting in hospitalization were more common in patients treated with BR. (21.9% vs. 17.3%, p<0.01). A majority of patients in both cohorts received maintenance therapy (81% of patients treated with BR, 64.1% of patients treated with R-CVP/CHOP). The use of maintenance therapy with either regimen was associated with less mortality (HR 0.16, 95% CI 0.14-0.19). Among patients who received maintenance therapy, patients previously treated with BR had more hospital admissions for fever (21.5% vs. 18.3%, p=0.03) and infections (37.9% vs. 31.5%, p<0.01) over a three-year period. Conclusion In these well-matched cohorts of patients with indolent lymphoma, improved OS was seen with BR compared to R-CVP/CHOP. Patients treated with BR had more infectious complications, although more episodes of febrile neutropenia were seen in patients treated with R-CVP/CHOP. The use of maintenance therapy was associated with less mortality, although patients who received maintenance therapy may have been a more fit and selected population. Higher infectious toxicities were seen for patients who received maintenance rituximab after BR. This study supports BR as the standard of care, and future prospective studies should evaluate the survival and toxicity impact of rituximab maintenance. Figure 1 Figure 1. Disclosures Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

Epigenetics of Indolent Lymphoma and How It Drives Novel Therapeutic Approaches—Focus on EZH2-Targeted Drugs

Purpose of Review Epigenetic modifier gene mutations are common in patients with follicular lymphoma. Here we review the pathogenesis of these mutations and how they are targeted by epigenetic drugs including EZH2 inhibitors in both mutated and wild-type disease. Recent Findings The use of EZH2 inhibitor tazematostat in early phase clinical trials has proved encouraging in the treatment of follicular lymphoma harbouring an EZH2 mutation; however, responses are also seen in patients with wild-type disease which is partially explained by the off target effects of EZH2 inhibition on immune cells within the tumour microenvironment. Summary Further studies incorporating prospective molecular profiling are needed to allow stratification of patients at both diagnosis and relapse to further our understanding of how epigenetic modifier mutations evolve over time. The use of tazematostat in combination or upfront in patients with an EZH2 mutation remains unanswered; however, given durable responses, ease of oral administration, and tolerability, it is certainly an attractive option.

Assessment of naive indolent lymphoma using whole-body diffusion-weighted imaging and T2-weighted MRI: results of a prospective study in 30 patients

Background We prospectively evaluated the diagnostic utility of whole-body diffusion-weighted imaging with background body signal suppression and T2-weighted short-tau inversion recovery MRI (WB-DWIBS/STIR) for the pretherapeutic staging of indolent lymphoma in 30 patients. Methods This prospective study included 30 treatment-naive patients with indolent lymphomas who underwent WB-DWIBS/STIR and conventional imaging workup plus biopsy. The pretherapeutic staging agreement, sensitivity, and specificity of WB-DWIBS/STIR were investigated with reference to the multimodality and multidisciplinary consensus review for nodal and extranodal lesions excluding bone marrow. Results In the pretherapeutic staging, WB-DWIBS/STIR showed very good agreement (κ = 0.96; confidence interval [CI], 0.88–1.00), high sensitivity (93.4–95.1%), and high specificity (99.0–99.4%) for the whole-body regions. These results were similar to those of 18F-FDG-PET/CT, except for the sensitivity for extranodal lesions. For extranodal lesions, WB-DWIBS/STIR showed higher sensitivity compared to 18F-FDG-PET/CT for the whole-body regions (94.9–96.8% vs. 79.6–86.3%, P = 0.058). Conclusion WB-DWIBS/STIR is an effective modality for the pretherapeutic staging of indolent lymphoma, and it has benefits when evaluating extranodal lesions, compared with 18F-FDG-PET/CT.