Real-World Characteristics and Outcomes of Patients With Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma Treated With First-Line Bendamustine + Rituximab

J Clin Pathways. 2022;8(3):38-46. doi: 10.25270/jcp.2022.04.3
Received October 30, 2021; accepted March 4, 2022.

Abstract 

Objective: Bendamustine plus rituximab (B-R) was established as a preferred first-line therapy for indolent non-Hodgkin lymphoma (iNHL) and mantle cell lymphoma (MCL); however, only few reports on its performance on patients with advanced disease and co-morbidities are available to-date. We assessed the pattern of B-R administration, efficacy and safety in non-selected adult patients in the real-world setting. Materials and Methods: A retrospective single-center study of patients with iNHL and MCL who received first-line B-R at our institution from June 2013 to July 2021. Results: Two hundred twenty-one patients were evaluated (median age of 72 years at B-R initiation). Follicular lymphoma (50.3%) represented the most common subtype. Advanced disease (stage 4) and ECOG 3 performance status represented 68.6% and 11.3% of patients, respectively. Bendamustine dose was reduced in 33.8% of patients and administration was delayed in 49.2% of patients. Overall response rate was 94.5%, with 77.6% complete and 16.9% partial remissions.  At median follow-up (42 months), median event-free survival was 88 months. Eight percent relapsed, 7.5% developed secondary malignancies, and 7% had transformed lymphoma. Fifty-one patients (25.4%) died, including 17 from secondary malignancy/transformed B-cell lymphoma. Rates of grade 3-4 neutropenia was 22.4%, febrile neutropenia was 8.0%, grade 3-4 anemia was 8.0%, and grade 3-4 thrombocytopenia was 3.0%. G-CSF support received by 16.9% of patients. Conclusion:  Administration of B-R in a real-world setting was associated with a higher dose reductions and therapy delays as compared to the clinical trials. However, in older and higher risk patients with lower performance status, the efficacy and safety of B-R were comparable to those previously reported. No new adverse events were found.

Introduction

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoproliferative malignancies (LPM). NHL represents 2.8% of all new cancers and is the eighth most common cause of cancer-related death worldwide.¹ The incidence of NHL increases with age, with a median age at diagnosis of 67 years.² Indolent or low-grade NHL (iNHL) represent 40% of all subtypes of NHL, of which follicular lymphoma (FL) is the most frequent which accounts for about 20% of all lymphomas.^3,4 All other NHL subtypes have a frequency of less than 10%.⁵ MCL has traditionally been considered an aggressive lymphoma with poorer prognosis compared to other types of iNHL; however, more indolent variants are now well-recognized.³  

Rituximab is a genetically engineered chimeric antibody directed against CD20 antigen, one of the most common targets in B-Cell LPMs.⁵ The introduction of rituximab heralded an era of chemoimmunotherapy (CIT) in B-LPMs.^6,7 Bendamustine is a cytotoxic alkylating drug, with a favourable tolerability profile approved for more than 20 years in Germany; however, it only gained approval for the management of LPMs in the USA in 2008, and the European Union in 2010. Large scale clinical trials STiL and BRIGHT showed that a combination of bendamustine plus rituximab (B-R) significantly improved progression-free survival, increased rate of complete response and time to next lymphoma treatment, compared with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with iNHL, and particularly in MCL. B-R was also found to be less toxic than R-CHOP.^8,9 In 2013 Cancer Care Ontario (CCO) approved B-R as a first-line treatment for patients with indolent CD20 positive NHL and MCL. Therapy with B-R now constitutes a preferred first-line CIT regimen in iNHL and transplant ineligible MCL. Nevertheless, only few reports on efficacy and safety data of this combination in the real-world setting are available to-date. We therefore, reviewed the iNHL and MCL patients treated with B-R at our cancer center to assess the B-R administration pattern, efficacy, and safety in real-life, non-selected patients. 

Materials and Methods

Patients Population
We included all patients aged 18 years or older who received more than one cycle of B-R in our cancer center from June 2013 to July 2021. Patients (≥18 years) with a histologically confirmed diagnosis of iNHL, MCL, and CD20-positive subtypes - follicular (grade 1 and 2), lymphoplasmacytic (Waldenström’s Macroglobulinaemia), small lymphocytic, and marginal-zone lymphoma were included for analysis. There were no restrictions for ECOG performance status, World Health Organization (WHO) lymphoma staging or comorbidities. 

Chemoimmunotherapy
All patients received intravenous bendamustine (target dose 90 mg/m² given over 30–60 min on days 1 and 2 and rituximab 375 mg/m² on day 1 of each 4-week cycle) for up to six cycles. Patients who did not experience rituximab-associated infusion reaction were allowed to switch to subcutaneous rituximab formulation, given as 1,400 mg flat dose, starting cycle 2. All patients received standard antiemetic prophylaxis, but no prophylactic therapy with antibiotics, antiviral or anti-Pneumocystis Jiroveci Pneumonia were given. Prophylactic use of granulocyte-colony stimulating factors (G-CSF) was allowed, as per guidelines from the American Society of Clinical Oncology. If indicated, eligible patients proceeded with standard rituximab maintenance as per the CCO guidelines.¹⁰ 

Efficacy and Safety Assessment 
All patients underwent standard pre-treatment work-up, including a physical examination, complete blood count, serum chemistry, immunoelectrophoresis, immunoglobulin concentrations, computed tomography (CT) scan of the chest, abdomen, pelvis and neck, and bone marrow aspiration and biopsy. If clinically relevant, endoscopy of the gastrointestinal tract was performed. Tumour responses were assessed after cycles three and six, or at the end of treatment. Responses were classified as complete remission, partial remission, stable disease, or progressive disease using standard WHO response criteria. 

The WHO’s toxicity criteria were used to assess treatment related toxic effects. Blood counts, including differential counts, were done once per cycle or more frequently as needed. Duration of remission was assessed with clinical/laboratory assessment and CT scan or sonographic examination if relapse was clinically suspected.  

Statistics

We assessed the following parameters: 1) demographic and disease characteristics 2) doses and schedule of B-R 3) rates of overall and complete response, 4) event-free survival, defined as the time between first treatment and one of the following events: progressive disease, relapse after response, or death from any cause, 5) overall survival, 6) acute and late toxic effects, and 7) secondary malignancies.  On the cut-off date for this analysis (July 01, 2021), we censored data for patients who had no reported events at the most recent assessment. We used the Kaplan-Meier method to estimate survival curves and applied the log-rank test for the comparisons. Prism 9.1 software was used for statistical analysis. 

Results

Demographic and Disease Characteristics
A total of 201 patients received B-R as a first-line CIT. Patient demographics including baseline characteristics and numbers of patients in specific histology subgroups are presented in Table 1. Approximately one-half (50.3%) of the patients had follicular lymphoma (FL), 19.4% marginal zone lymphoma (MZL), 14.9% lymphoplasmacytic lymphoma (LPL) and 12.9% of patients had mantle-cell lymphoma. Stage 3 and 4 diseases represented 19.9% and 68.6% of patients, respectively. Extranodal disease was found in 38.6%. There were 56.2% males and 43.8% females. Median age was 68 years at diagnosis [range: 26-90] and 72 years [range: 34-94] at B-R initiation. Within the histological subgroups, the median age at B-R initiation was 68 years for those with FL, 76 years for those with MCL and 78 years for other iNHL. Of our 201 patients, previous history of secondary malignancy was presented in 46, (22.9%) patients. ECOG status of 3 had 11.4% of patients. Patients in the LPL and other iNHL groups had significantly lower baseline Hb values, compared to FL and MCL (P<0.0001 for both subgroups). There was no statistically significant difference in LDH values among histological subgroups.  In our cohort, 48.5% with FL had high risk disease (Follicular Lymphoma International Prognostic Index, FLIPI ≥3); 61.5% of LPL patients had a high International Prognostic Scoring System for Waldenstroem Macroglobulinemia (WMISS score ≥3), and 80.5% with MCL had high risk Mantle Cell Lymphoma International Prognostic Index (MIPI ≥6.2).^11-13 In patients with LPL, the median baseline total IgM level was 45 g/L [range: 6.5-95.4], and monoclonal (M) protein was 30 g/L [range: 4.0-54.1].  

Systemic therapy was initiated between four and seven years after initial diagnosis. Treatment characteristics are summarized in Table 2. The most common indications for B-R initiation were bulky symptomatic lymphadenopathy (69.1%), cytopenia (36.8%), and constitutional symptoms (36.8%). Fifty-eight percent of patients had more than one indication for therapy. Median number of B-R cycles per patient delivered was 6 (range: 1-6). The median dose of bendamustine across all cycles was 90 mg/m² (range: 45-95 mg/m²). The mean dose was 86 mg/m² in cycle 1 and decreased to 77 mg/m² in cycle 6. Full doses of bendamustine were given in 66.2 % of patients and a reduced dose was given in 33.8%. The lowest dose of bendamustine (mean: 79.6 mg/m²) was recorded for the MZL group; the highest dose (mean: 84.1 mg/m²) in FL group. A total of 50.7% patients completed 6 cycles of B-R with no delays. In 49.2% of patients, therapy was delayed with a mean delay time of 1.8 weeks [range:1-10]. 

Efficacy
Overall response rate (ORR) was 94.5%, including 77.6% complete and 16.9% partial remissions (Figure 1). All subgroups responded well to B-R therapy. The lowest rate of complete response was found in the LPL group (11 patients, 37%), where most of the patients (60%) reached partial remission (PR) with persistence of M-protein after completion of 6 cycles of B-R. Median level of total IgM after B-R completion was 8.1 g/L [range: 0.2-94.5], and M-protein concentration was 5.3 g/L [range: 0-37.5], respectively (Figure 2). IgM and M-protein levels continued to decline with rituximab maintenance therapy, reaching 3.3 g/L [range 0.2-29.1] and 0 [range: 0-16.9], respectively. At the end of follow-up, no difference was observed in event free survival (EFS) between patients with measurable M-protein after B-R and those who had no M-protein.   

Median duration of follow-up was 42 months [range: 4-97]. Over the course of follow-up, we noted 60 (29.8%) events. Among them, 16 (8%) patients relapsed or had a progressive disease. The total population median EFS was 88.0 months.  Compared to other NHL, median EFS was the shortest for MCL (50 months); however, the difference did not reach statistical significance (P=0.099). There was no statistically significant difference in EFS among all other histological subtypes (Figure 4). Median overall survival (OS) was not reached in each histological group, including MCL (P=0.109), as shown in Figure 3. Fifty-one (25.4%) patients died, including 17 from secondary malignancy/transformed aggressive B-cell lymphoma. A total of 80.6% patients proceeded to rituximab maintenance. 

Safety
Rituximab-associated infusion reactions (IRs), fever, skin rash, nausea/vomiting, fatigue, and pain were the most common non-hematological AEs (Table 3). The highest number of AEs was recorded during cycle one (1.35 events-per patient), however decreased to 0.5 events-per-patient in cycle six. The IR rate was the highest in cycle one. There was a cumulative increase in fatigue during B-R induction from cycle one (6.2%) to cycle six (21.5%). No cases of Stevens-Johnson Syndrome or toxic epidermal necrolysis were observed. We noted Grade 3 and 4 anemia in 8.0% of patients, Grade 3 and 4 neutropenia in 22.4% of patients, and Grade 3 and 4 thrombocytopenia in 3.0% of patients (Table 4). Sixteen (8.0%) patients had febrile neutropenia, and six (3%) patients had severe infectious complications with a fatal outcome. Thirty-four (16.9%) patients required support with G-CSF for either febrile neutropenia or prolonged grade 3-4 neutropenia.  

Fourteen (7%) patients developed transformed aggressive B-cell lymphoma. In 15 (7.5%) patients new secondary malignancies, including two myelodysplastic syndromes (MDS) were recorded (Table 5). In most of them, secondary malignancies 

and transformed aggressive B-Cell lymphoma occurred after completion of B-R induction. Fifty-one (25.4%) patients died, including eight patients from aggressive lymphoma, two from MDS and seven patients from secondary malignancy. 

Discussion

Our experience with B-R in real-life setting in non-selected patients differs from a clinical trial setting. Compared to the StiL trial our patients were older. In the B-R arm of the StiL trial, only 23% of patients were over 70 years of age–this is compared to 56% in our cohort. Additionally, more than 10% of our patients had ECOG performance status 3, which was an exclusion criterion for the STiL trial. Our study showed that B-R can be delivered safely in elderly patients, including patients who are frail and with comorbidities. However, fewer patients in our cohort received the full dose of bendamustine: 66.2% vs. 95.9% in the STiL B-R arm. In our patient cohort the bendamustine dose was reduced due to lower tolerability and cytopenias. We showed that in the real-life setting dose reduction is expected in about 40% of patients, and therapy delays occur on an average of 1.8 weeks. The findings from this study are important for chemotherapy planning and patient counselling. 

Even with dose reduction, however, B-R retains its efficacy with high ORR and EFS that are comparable to those reported in the STiL trial.  We found that ORR (94.5%) did not differ from that of the STiL trial (93%); however, rate of CR was higher in our study (77.6% vs. 40%).⁸ Our results are comparable to the ones reported in a retrospective analysis performed at seven European centers, which showed 94% ORR with 63% CR.¹⁴ Like previous reports, patients with LPL have a higher rate of PR with persisting M-protein after completion of B-R. In 235 patients with Waldenstroem’s macroglobulinemia (WM) treated with B-R induction, 89.9% of patients achieved a PR.¹⁵ The rate of PR was lower in our patients (37%); however, over the course of Rituximab maintenance therapy, the amount of M-protein continued to decline. Whether this decline was due to the effect of maintenance therapy or a delayed response to B-R remains unknown. However, the same study with WM patients showed no difference in progression free survival or overall survival after two years of rituximab maintenance, when compared with observation alone after B-R induction.15 Based on our results the presence of M-protein (PR) after completion of B-R induction may not be indicative of an inferior clinical outcome in LPL/WM patients. 

We observed a high ORR in patients with MCL, with a higher rate of CR as compared to a recent report from British Columbia Cancer Agency. In that study with 90 patients, the ORR to B-R was 88%, including 54% CR. However, EFS in the MCL cohort in our study was comparable with PFS reported by Villa et al.¹⁶ Overall, compared to other histological subgroups, patients with MCL had the lowest EFS in our study. In contrast, ORR in our patients with MZL was 100%, similar to the recently reported rate between 89.3 to 100%.¹⁷ The median EFS in our patient cohort was higher than reported in the STiL trial (88.0 vs. 69.5 months); however, this difference may be due to a shorter follow-up time reported in STiL trial (42 vs 45 months) or perhaps is influenced by the addition of maintenance therapy with rituximab in most of our patients.

Neurotoxic effects, specifically peripheral neuropathy, were not common and the rate did not differ from the ones reported in the STiL and BRIGHT trials. G-CSF use was significantly higher in the B-R arm than in the STiL trial: 16.9% vs. 4%. This observation may be due to a higher proportion of elderly patients with comorbidities and higher ECOG performance status, or differences in clinical practice among the institutions. Importantly, we did not identify any new adverse events that have not been previously reported. The rate and spectrum of secondary malignancies (7%) were similar to the ones reported in B-R arm of STiL trial (7.66%) but less than those reported in the BRIGHT 5-year follow-up study (9.9%). The incidence of transformed aggressive lymphoma in our cohort (7%) was higher than previously reported in BRIGHT study (2.2%).⁹  Two of our patients (0.99%) developed MDS compared to one patient each in STiL (0.76%) and BRIGHT (0.45%) trials. It is unknown whether this was due to older age, higher ECOG status, and/or more advanced disease stage in our patients.  

Our study reported a significantly lower rate of rituximab-associated IRs than those previously reported. Since 2018, our cancer center introduced an enhanced premedication with montelukast and rupatadine.¹⁸ The incidence of rituximab IRs in the first cycle was reported only in 34% of patients in our study. Review of IRs over the time of our study confirmed a significant decrease in rituximab-associated IRs after the implementation of enhanced premedications with montelukast and rupatadine at our institution since 2018. 

In conclusion, administration of B-R in a real-world setting was associated with a higher dose reductions and therapy delays as compared to a clinical trial setting. However, in patients with higher risk disease, lower performance status and older patients, the efficacy and safety of B-R was comparable to that previously reported in clinical trials. No new adverse events were found. 

Author Information

Authors: Rouslan Kotchetkov, MD, PhD¹; David Susman², Erica DiMaria, MD¹; Lauren Gerard, MD¹;
Derek Nay, MD¹ 

Affiliations: ¹ Simcoe Muskoka Regional Cancer Program, Royal Victoria Regional Health Centre, Barrie, ON L4M 6M2, Canada ²University of Western Ontario, 1151 Richmond St, London, Ontario, Canada N6A 3K7

Disclosures: The authors have no disclosures to report.

Address correspondence to:

Rouslan Kotchetkov 
Simcoe Muskoka Regional Cancer Program, Royal Victoria Regional Health Centre
Barrie, Ontario, Canada L4M 6M2
Phone:+1-705-728-9090
Fax: +1-705-739-5630
Email: KotchetkovR@rvh.on.ca

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