Research ArticleClinical Studies

Bendamustine Plus Rituximab for Mantle Cell Lymphoma: A Korean, Multicenter Retrospective Analysis

JUN HO YI, SEOK JIN KIM, JEONG-OK LEE, GYEONG-WON LEE, JAE-YONG KWAK, HYEON-SEOK EOM, JAE-CHEOL JO, YOON SEOK CHOI, SUNG YONG OH and WON SEOG KIM
Anticancer Research December 2022, 42 (12) 6083-6089; DOI: https://doi.org/10.21873/anticanres.16120

Abstract

Background/Aim: The combination of bendamustine and rituximab (BR) is highly effective in both treatment-naïve and relapsed or refractory mantle cell lymphoma (MCL). Due to the rarity of MCL and limited accessibility of BR, clinical outcome from BR in the routine clinical practice in Korean patients are limited. Patients and Methods: To evaluate the real-world outcomes of BR treatment for MCL in Korea, medical records from 37 patients were retrospectively analyzed. Results: Twenty-five patients received BR as first-line treatment, and ten, eight, and seven patients were classified as low-, intermediate-, and high-risk by MIPI-classification, respectively. With the follow-up duration of 24.3 months, the three-year progression-free survival (PFS) rate was 80.5%±11.8%. PFS significantly differed according to MIPI-classification (p=0.002) and TP53 status (p=0.042). The three-year overall survival (OS) rate was 92.0%±5.4%. In 12 patients who received BR as salvage treatment, the median age was 66. The median PFS was 12.8 months, and the three-year OS rate was 66.8%±16.2%. Conclusion: BR is an effective regimen for both newly-diagnosed and relapsed or refractory MCL patients in Korea, with favorable response rates and outcomes.

Key Words:

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin’s lymphoma (NHL) that arises from a naive pre-germinal center B-cell within the mantle zone surrounding the normal germinal center, which is characterized by t(11;14)(q13;q32) translocation and subsequent cyclin D1 over-expression (1). For many years, the combination of rituximab and combination chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or cytarabine, cisplatin, and dexamethasone (DHAP), has remained the standard first-line treatment for MCL. However, even after consolidating autologous stem cell transplantation (ASCT) (2) and maintenance treatment (3, 4), no treatment has achieved a survival plateau. Therefore, treatments that lead to prolonged remission while minimizing toxicity are needed.

Bendamustine is a bifunctional chemotherapeutic agent with anti-metabolite and alkylating properties. The combination of bendamustine and rituximab (BR) has demonstrated improved response rates and prolonged progression-free survival (PFS) as first-line (5, 6) and salvage treatment (7, 8) for MCL. Based on these studies, BR is the most commonly prescribed regimen for younger and elderly patients with MCL.

MCL comprises approximately 5-10% of all lymphomas in the Western world; however, it accounts for less than 3% of NHLs in Asia (9-11). Due to the paucity of the disease and lack of feasible novel treatment agents, the clinical outcomes for MCL patients treated with BR have been poorly defined in Asia. Thus, the aim of this study was to assess the efficacy of BR in MCL patients.

Patients and Methods

Patients. The inclusion criteria were as follows: 1) Patients with a primary diagnosis of MCL, confirmed immunophenotypically or cytogenetically; 2) patients who were treated with BR for the treatment of MCL; and 3) available medical records including clinicopathologic characteristics and clinical outcomes. Baseline demographics and disease characteristics were collected, including age, sex, Ann Arbor stage, pathology, and the presence of bulky disease (tumor ≥5 cm). Laboratory findings were collected, including complete blood count, serum lactate dehydrogenase (LDH), serum β2-microglobulin, prior treatment, and treatment outcomes. Each variable was collected at the time of diagnosis and the initiation of BR treatment.

Analysis. The aim of the present study was to evaluate the efficacy and safety of BR for MCL patients. PFS was calculated from the start date of BR treatment to the progression date or death. Overall survival (OS) was calculated from the start date of BR treatment to the date of death by any cause. PFS and OS were calculated using the Kaplan–Meier method, and subgroup comparisons were performed using a log-rank test. The response was assessed using imaging based on the Lugano criteria (12) and compared using Pearson’s λ2 tests. Data on dose reduction and treatment delay were collected. For all statistical analyses, p less than 0.05 was considered significant, and the analyses were performed using IBM SPSS Statistics for Windows, version 21.0 (IBM Corp., Armonk, NY, USA).

All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional committee. Institutional review boards approved the study protocols at the respective sites. This study was carried out by the Consortium for Improving Survival for Lymphoma in Korea.

Results

Patient characteristics and pathological features at the time of diagnosis. A total of 37 patients were included in the analysis. Their median age was 63 years (range=34-83 years), and 26 (70%) were male. Of the 32 cases in which cyclin D1 was evaluated, 31 cases (97%) were positive. The t(11;14) translocation was evaluated in 35 cases, and 32 cases (91%) were positive. SOX11 expression was positive in 14 out of 15 (93%) of the examined cases. Twelve patients were tested for the TP53 mutation, and five abnormalities (42%) were detected. The median value for Ki-67 levels was 35.0% (range=10.0-95.0%).

Twenty-five patients (68%) received BR as first-line treatment. The median age of these patients was 63 years (range=34-79), and 17 (68%) were male (Table I). A total of 21 patients (84%) were classified as Ann-Arbor stage III-IV, and the Eastern Cooperative Oncology Group performance scale (ECOG-PS) was 0-1 in 24 patients (96%) (Table I). Elevation in serum LDH levels was noted in eight patients (32%), and 16 patients (64%) had bone marrow involvement. Two or more cases of extranodal involvement were noted in 12 patients (48%). The median white blood cell count was 5,740/μl (range=1,990-13,280), and the median serum β2-microglobulin levels were 2.2 mg/dl (range=1.4-19.7 mg/dl) (Table I). Two patients had blastoid subtype MCL, and five out of ten (50%) evaluated patients carried a TP53 mutation. After classifying patients by the MCL International Prognostic Index (MIPI), ten (40%) patients were classified as low-risk, eight (32%) as intermediate-risk, and seven (28%) as high-risk (Table I).

View this table:
Table I.

Baseline characteristics and pathologic features of the 25 patients who had received bendamustine and rituximab (BR) as first-line treatment.

The remaining 12 patients (32%) included in this study received BR as salvage treatment. The median age was 66 years (range=60-79 years), and nine patients (75%) were male. BR was used as a second-, third-, fourth-, and fifth-line treatment in five (42%), three (25%), three (25%), and one patient (8%), respectively. For these patients, the first-line treatment was R-CHOP for nine patients (75%), and rituximab with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate-cytarabine (R-HyperCVAD/MA) for three patients (25%). Ibrutinib, bortezomib, and DHAP were used by nine (95%), two (17%), and two patients (17%), respectively. One patient received a prior ASCT. At the time of BR treatment, ECOG-PS was 0-1 in nine patients (75%), and the elevation in serum LDH levels was noted in eight patients (67%). The median white blood cell count was 7,270/μl (range=5,560-58,000). No patient had blastoid transformation. Of the two patients in whom TP53 status was examined, none had a mutation.

Outcomes of first-line BR treatment. Patients were treated with BR for a median of 6 cycles (range=1-6). The overall response rate (ORR), which includes complete responses (CR) and partial responses (PR), was 92% (23/25, 22 CR, 1 PR) with a median time to response of 2.3 months (95%CI=2.0-2.6). With the follow-up duration of 24.3 months (95%CI=17.4-31.2), the three-year PFS rate was 80.5%±11.8% (Figure 1A), which was significantly different between the low- or intermediate-risk MIPI group and high-risk group (100.0% vs. 71.4%±17.1%, p=0.002) (Figure 1B). The three-year PFS rate was also significantly different depending on the TP53 mutation status (100.0% for wild-type and 80.0%±17.9% for TP53 mutant, p=0.042) (Figure 1C). One of the two patients with blastoid variants showed immediate disease progression after the first cycle of BR treatment, while the other patient showed 39.4 months of remission. Although patients with higher a Ki-67 index (≥30%) showed inferior three-year PFS rates, this was not statistically significant (66.7%±27.2% vs. 100%, p=0.197). The presence of bulky disease (≥5 cm) did not impact the PFS (data not shown). Four patients could undergo ASCT after BR treatment. All these patients received four cycles of BR, which led to CR. After ASCT, no patient experienced disease progression at 12 months. Since only four patients experienced progressive disease after BR, their outcomes were not fully analyzed. The salvage treatments were ibrutinib in two patients and a high-dose cytarabine-based intensive treatment in one patient. The remaining patient with blastoid variant MCL could not receive further treatment due to rapid deterioration. The three-year OS rate of 25 patients was 92.0%±5.4% (Figure 2).

Figure 1.
Figure 1.

Progression-free survival (PFS) curves of patients who had received bendamustine and rituximab (BR) as first-line therapy. A) Progression-free survival (PFS) of all patients who received BR treatment as first-line therapy. B) PFS of patients who received BR treatment as first-line therapy classified according to the Mantle Cell Lymphoma International Prognostic Index. C) PFS of patients who received BR treatment as first-line therapy classified according to TP53 mutation status. The median follow-up was 24.3 months. The PFS rate is included as a percentage±standard deviation.

Figure 2.
Figure 2.

Overall survival (OS) curve of patients who had received bendamustine and rituximab BR as first-line therapy. The three-year OS rate of patients who received BR treatment as first-line therapy. The OS rate is included as a percentage±standard deviation.

The BR treatment was generally well-tolerated. Level 1 (90 mg/m2 → 70 mg/m2) dose reduction was required in three cases due to nausea, fatigue, and grade 3 neutropenia. There was a delay of treatment in five cases, which was mainly attributed to neutropenia (n=4) and fatigue (n=1). However, one patient could not complete the six planned treatment cycles due to prolonged neutropenia.

Outcomes of the salvage BR treatment. Patients were treated with BR for a median of four cycles (range=1-6). The CR and PR rates were 50.0% (6/12) and 33.3% (4/12), respectively, with a median time to response of 2.3 months (95%CI=1.7-2.9). The CR rates of patients who had received BR as the first or second and as the third or fourth salvage treatment were 62.5% (5/8) and 25.0% (1/4), respectively. The follow-up duration was 25.0 months (95%CI=17.0-33.0), and the median PFS was 12.8 months (95%CI=8.4-17.2) (Figure 3). The PFS of patients who had received BR as the first or second and as the third or fourth salvage treatment was 12.8 months and 3.7 months, respectively. The median OS was 22.7 months (95%CI=5.4-40.0) (Figure 3).

Figure 3.
Figure 3.

Progression-free survival (PFS) and overall survival (OS) of patients who had received bendamustine and rituximab as salvage therapy.

Discussion

MCL is a specific subtype of NHL with unfavorable characteristics of both aggressive and indolent lymphoma. To control its aggressive features, the standard of care for fit patients has included rituximab and a high-dose cytarabine-based induction therapy and consolidation with ASCT. To control its indolent features, long-term rituximab maintenance is required to achieve long-term survival (13). Despite these multimodal approaches, most patients eventually relapse. Thus, the optimal treatment for long-term remission of MCL should harbor a high response rate and favorable safety profiles.

The superiority of first-line BR was demonstrated by two large studies. In the German StiL NHL1-2003 trial, 94 elderly MCL patients received either BR or R-CHOP as first-line treatment (5). BR treatment resulted in better CR (40% vs. 30%, p=0.021) and prolonged PFS (35.4 months vs. 22.1 months, HR 0.49, p=0.0044) than R-CHOP (5). Similar results were found in the US BRIGHT trial in which 74 elderly MCL patients were randomly allocated to receive either BR or R-CHOP/CVP (14). The CR rate was significantly higher in the BR arm (50% vs. 27%, p=0.033). In addition, the long-term follow-up analysis showed that the survival benefit of BR was stronger for MCL patients compared to patients with other indolent lymphomas (6). Based on two large phase III trials, BR became the most prescribed first-line regimen for those who could tolerate ASCT. Also, recent real-world data showed similar results for BR, where the time-to-next treatment was 37.0 months (95%CI=32.9-40.6) (15). In our study, the CR rate for first-line BR treatment was 88%, and the three-year PFS rate exceeded 80%. Although the results seem to be better than those of other studies, they may be due to the small number of patients and the relatively short follow-up duration.

The promising outcomes in elderly patients led to trials with younger patients, which showed the role of BR as an induction treatment before ASCT. In the S1106 trial, 35 treatment-naïve MCL patients were treated with six cycles of BR before ASCT (16). The CR and PR rates were 40% and 43%, respectively, which resulted in successful ASCT in 23 patients (66%), a two-year PFS rate of 82%, and an OS rate of 87%. In a retrospective study from British Columbia, in which a total of 190 MCL patients were treated with BR as first-line therapy, 71 patients proceeded to ASCT (17). The three-year PFS and OS rates were 85.1% and 90.0%, respectively. In addition, BR treatment showed excellent outcomes when combined with alternating rituximab and a high dose of cytarabine (RC). In a study by Merryman et al., 88 patients received the combination of BR and RC, and the CR rate was 92%, and 84% of patients underwent planned consolidative ASCT (18). The three-year PFS and OS rates were 83% and 92%, respectively. In the current study, four patients underwent ASCT after treatment with BR, and the one-year PFS rate was 100%. The use of BR as first-line treatment before ASCT is becoming more common (19); however, further investigations are required.

One of the major challenges of the management of MCL patients is the high-risk features represented by MIPI, Ki-67, blastoid variant, or TP53 mutation. Conventional treatment including high-dose cytarabine-based induction followed by ASCT or ibrutinib, failed to improve the outcomes in MCL patients, especially those with a TP53 mutation (20, 21). Unfortunately, treatment with BR also failed to improve the outcomes of high-risk patients. In the retrospective study from British Columbia in which 190 MCL patients were treated with BR, patients with a high-risk MIPI classification, Ki-67 greater than or equal to 50%, or blastoid or pleomorphic variants had an increased likelihood of not responding to BR and had significantly lower PFS and OS rates (17). In addition, the combination of lenalidomide (22) or ibrutinib (23) with BR did not improve prognosis. In this study, we identified seven patients with high-risk MIPI and five patients with a TP53 mutation whose three-year PFS rates were significantly lower than their counterparts. Currently, alternative consolidation strategies, including allogeneic stem cell transplantation or chimeric antigen receptor T-cell therapy, are recommended for patients with a TP53 mutation (24).

As expected, the outcomes of salvage treatment with BR were not as good as first-line treatment. The CR rate was 50.0% which was significantly lower than that of the first-line treatment (88%, p=0.012). The CR rate continued to decrease (62.5% for the first- and second-line salvage treatment and 25.0% for the third- and fourth-line salvage treatment). Similarly, while the three-year PFS rate of the first-line treatment was 80.5%, the median PFS of the first- and second-line was 12.8 months, and the third- and fourth-line salvage treatment was 3.7 months. Considering the favorable efficacy, BR should be considered as a primary regimen for the first-line treatment of MCL.

Despite the favorable efficacy of BR treatment, prolonged immune suppression is a substantial problem. BR was less frequently associated with neutropenia, a problem with conventional therapies, such as R-CHOP; however, prolonged lymphopenia accompanied by various opportunistic infections occurred more frequently (25). Infectious events attributed to bendamustine treatment were more prominent in elderly patients (26), and there was an emerging consensus to delay bendamustine treatment during the SARS-CoV-2 pandemic era (27). This study did not notice significant infectious complications due to the relatively younger age of the patients and short follow-up duration. As the efficacy exceeds the harm from the bendamustine-based treatment even in the elderly patients (28, 29), proper prophylactic strategy, as well as tailored approaches, should be provided.

This study had some limitations, including its retrospective nature and relatively short-term follow-up. Also, only a small number of patients were included in the analysis as BR is not reimbursed by the Korean Health Insurance system, limiting the accessibility for many MCL patients. Furthermore, several biological indices were not completely collected, including TP53 mutation, immunohistochemistry status, Ki67, or serum β2-microglobulin. Lastly, the prophylactic strategies for the patients were not analyzed and cannot be used to guide future BR use.

In conclusion, the clinical outcomes of BR therapy for Korean MCL patients were comparable with those from previous data. The efficacy and safety shown in this study provide additional evidence to support the use of BR in MCL patients, especially as first-line treatment.

Footnotes

  • Authors’ Contributions

    JHY and WSK designed the analysis and wrote the manuscript. SJK, JOL, GWL, JYK, HSE, and JCJ collected and interpreted the data. JHY, SJK, and YSC performed the statistical analysis. All Authors reviewed and approved the final version of the manuscript.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received October 6, 2022.
  • Revision received October 11, 2022.
  • Accepted October 12, 2022.

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Bendamustine Plus Rituximab for Mantle Cell Lymphoma: A Korean, Multicenter Retrospective Analysis
JUN HO YI, SEOK JIN KIM, JEONG-OK LEE, GYEONG-WON LEE, JAE-YONG KWAK, HYEON-SEOK EOM, JAE-CHEOL JO, YOON SEOK CHOI, SUNG YONG OH, WON SEOG KIM
Anticancer Research Dec 2022, 42 (12) 6083-6089; DOI: 10.21873/anticanres.16120
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