A Powerful Alliance for a New Era in Lymphoma Therapy: Bendamustine and Rituximab Redefine Treatment Paradigms

Sep 20, 2023 07:20 CST Updated Sep 19, 18:07

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Lymphoma is one of the common malignant tumors, with an incidence rate of approximately 6.68 per 100,000 in China, and there are about 100,000 new cases of lymphoma patients each year.¹Rituximab monotherapy or combination chemotherapy has significantly improved survival outcomes for lymphoma patients. Bendamustine, an important chemotherapeutic agent in lymphoma treatment, is widely used across various lymphoma subtypes. In recent years, multiple studies have confirmed the superior efficacy and safety of the rituximab plus bendamustine regimen (BR) in certain lymphoma subtypes. With the sequential approval and market entry of domestically produced bendamustine and rituximab in China, the accessibility of the BR regimen for Chinese lymphoma patients has greatly increased. This not only reduces the burden on patients but also holds promise to further improve the current state of lymphoma diagnosis and treatment in China. This article will focus on recommendations from authoritative guidelines both domestically and internationally, while integrating relevant research, to deeply explore the application prospects of the BR regimen in the field of lymphoma.

Synergistic Enhancement, Complementary Advantages: Rituximab and Bendamustine Reshape the Lymphoma Treatment Landscape

Rituximab is composed of human IgG1 and the variable region of murine CD20 antibody. It can specifically bind to CD20 on the surface of B cells, depleting CD20-positive B lymphocytes through two pathways: antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). It also increases cellular sensitivity to other chemotherapeutic drugs. Bendamustine, as a novel chemotherapeutic agent, possesses dual functionality of both alkylating and antimetabolite properties. It exerts its antitumor cytotoxic effects by alkylating DNA, causing cross-linking of single or double strands, thereby interfering with DNA synthesis and repair. In vitro studies have shown that bendamustine and rituximab have a synergistic effect, and their combination therapy demonstrates good efficacy and safety in certain subtypes of lymphoma.^2，3。

Guided by guidelines, multi-point layout,BR Regimen Earns Preferred Recommendation from Authoritative Guidelines Both in China and Abroad

Based on abundant evidence-based data and good clinical efficacy and safety profiles,BRThe regimen has been recommended by multiple guidelines for the treatment of various subtypes of lymphoma.

Indolent Lymphoma Chapter

Follicular Lymphoma (FL）

FL is one of the common types of non-Hodgkin lymphoma (NHL), accounting for 22% to 35% of NHL patients in Western countries. The proportion in China is slightly lower than in Western countries, accounting for 8.1% to 23.5% of NHL patients.⁴Multiple studies have confirmed the efficacy and safety of the BR regimen in the treatment of FL.

For treatment-naïve FL patients, the BRIGHT study validated the efficacy of the BR regimen. Study data showed that the 5-year progression-free survival (PFS) rates for first-line treatment of FL with the BR regimen and R-CHOP/R-CVP regimens were 65.6% and 55.8%, respectively (Figure 1). The BR regimen demonstrated superior long-term disease control compared to the R-CHOP/R-CVP regimens, with safety consistent with expectations and no new safety events reported during long-term follow-up.⁵。

Figure 1: 5-Year PFS Rates of the BR Regimen and R-CHOP/R-CVP Regimens in the BRIGHT Study

For patients with relapsed/refractory FL (R/R FL), a retrospective study showed that the PFS of the BR regimen was not reached, suggesting that the BR regimen can significantly improve patient PFS.⁶In addition, a Phase I/II study explored the efficacy of Temsirolimus combined with BV (BeRT) in R/R FL. 89% of patients achieved objective response, with a median follow-up of 2.7 years and a PFS of 1.6 years. The data indicate that the BeRT regimen is effective in treating R/R FL.⁷。

Based on the good efficacy and safety demonstrated by the BR regimen in previously untreated and R/R FL patients, the 2023 edition of the CSCO Lymphoma Guidelines recommends the BR regimen as a Level I treatment option for previously untreated and R/R FL patients. The 2023 V5 edition of the NCCN Guidelines recommends the BR regimen as the preferred treatment option (Category 2A) for previously untreated and R/R FL patients.

Mantle Cell Lymphoma (MCL）

MCL is a subclass of NHL originating from mature B cells, accounting for 6%~8% of NHL.⁸In the treatment of MCL, the BR regimen has also been extensively explored.

A retrospective study in Colombia explored the efficacy of BV in previously untreated MCL. The study showed that, compared with the R-CHOP regimen, the BR regimen significantly improved PFS in previously untreated MCL patients, with 3-year PFS rates of 66% and 51%, respectively.⁹(Figure 2). Additionally, results from a pooled analysis study indicate that autologous hematopoietic stem cell transplantation (ASCT) following induction therapy with BR combined with cytarabine (RB/RC) is well-tolerated and associated with high durable remission rates in newly diagnosed MCL patients.¹⁰。

Figure 2: Three-year PFS rates of the BR regimen and R-CHOP regimen in the Colombian retrospective study

In a single-center retrospective study, BR demonstrated good efficacy and tolerability in patients with relapsed/refractory MCL (R/R MCL), with an overall response rate (ORR) of 93%. Patients received a cumulative dose of bendamustine ≥720mg/m².²Patients experienced a significant extension in PFS and overall survival (OS).¹¹。

The excellent efficacy of the BR regimen in both frontline and R/R MCL has laid a solid foundation for its inclusion in guideline recommendations. The 2023 edition of the CSCO guidelines recommends the BR regimen as a Level II recommendation for frontline MCL and a Level I recommendation (previously unused, Category 2A) for R/R MCL. The 2023 V5 edition of the NCCN guidelines elevates the BR regimen from a preferred option (Category 2B) to a preferred option (Category 2A) for frontline MCL and includes it as a Category 2A recommendation for R/R MCL patients who have not previously received the BR regimen.

Marginal Zone Lymphoma (MZL）

MZL is a common subtype of indolent non-Hodgkin lymphoma (iNHL) originating from the marginal zone of lymphoid follicles, which can occur in the spleen, lymph nodes, and mucosal lymphoid tissues. Multiple studies have validated the efficacy of the BR regimen in MZL patients.

An international analysis explored the BR frontline treatment regimen for MZL, enrolling 237 patients with an ORR of 93.2%, a complete response (CR) rate of 81%, and estimated 5-year PFS and OS rates of 80.5% and 89.6%, respectively (Figure 3). The study suggests that BR is an effective regimen for frontline treatment of MZL.¹²In addition, the results of a single-center retrospective study also validated the good efficacy of the BR regimen as a first-line treatment for MZL. Among the 65 patients included, the ORR reached 89.2%, and the safety profile was favorable with no treatment-related deaths occurring.¹³。

Figure 3 International Analysis BR Protocol 5-Year PFS Rate (A) and OS Rate (B)

The excellent efficacy and safety data of the BR regimen provide the basis for its inclusion in the guidelines, receiving a Level I recommendation (Category 2A) in both untreated and R/R MZL in the 2023 edition of the CSCO Lymphoma Diagnosis and Treatment Guidelines. The BR regimen is also recommended as the preferred option (Category 2B) and preferred option (Category 2A) for untreated and R/R MZL respectively in the 2023 V5 NCCN Guidelines.

Aggressive Lymphoma

Diffuse LargeB-cell Lymphoma (DLBCL)

Except for indolent lymphoma, the BR regimen has also been extensively explored in aggressive lymphomas. DLBCL is an aggressive tumor derived from mature B cells and is the most common subtype of iNHL, accounting for approximately 25% to 50% of all NHL cases.¹⁴. Numerous studies have confirmed the value of the BR regimen in R/R DLBCL patients.

A single-arm phase III study explored the efficacy and safety of the BR regimen in R/R DLBCL patients. A total of 38 patients received BR treatment, with an ORR and CR rate of 76.3% and 47.4%, respectively. After a median follow-up of 19.5 months, the median PFS was 11.9 months, and the median OS was 29.2 months.¹⁵(Figure 4). The study confirmed that the BR regimen has good efficacy and tolerability for R/R DLBCL patients. Additionally, a real-world study showed that both the BR regimen and the R-GemOx regimen have good efficacy and safety for patients ineligible for ASCT, with no statistical difference in 1-year OS rates, which were 50% and 60%, respectively.¹⁶。

Figure 4 Median OS (A) and Median PFS (B) in the Single-Arm Phase III Study BR Regimen

Based on the excellent efficacy data of the BR regimen, the BR regimen has also received a Level II recommendation in the 2023 edition of the CSCO Lymphoma Diagnosis and Treatment Guidelines for R/R DLBCL treatment.

Exploration knows no bounds, and the future is promising.China-Produced Medicines Boost BR Regimen, Creating New Opportunities for Lymphoma Treatment

In recent years, the BR regimen has continued to achieve new progress in the field of lymphoma, and the latest research consistently validates the efficacy of BR and its combination regimens in lymphoma. A network meta-analysis of BR+BTKi as first-line treatment for MCL showed that, compared with VR-CAP/R-CHOP regimens, BR+BTKi can prolong PFS in newly diagnosed MCL patients unsuitable for intensive treatment., inAmong the four first-line treatment regimens BR+BTKi, VR-CAP, R-CHOP, and BR, the BR+BTKi regimen has the highest probability of being the best intervention in PFS analysis, reaching up to 94.9%.¹⁷。

In addition, one Phase II clinical study also explored the efficacy of the R-BAC regimen in newly diagnosed MCL. In this study, all responding patients achieved CR. After a median follow-up of 86 months, the median OS and median PFS were not reached (Figure 5), with 7-year PFS and OS rates of 55% and 63%, respectively.¹⁸。

Figure 5 Median OS (A) and PFS (B) in the R-BAC regimen

Real-world study in Turkey explores the application of Pola+BR regimen in DLBCL, demonstrating significant efficacy with an ORR of 47.9%, a median follow-up of 5 months, and a median OS of 5 months.¹⁹。

In addition to efficacy, drug safety and accessibility are also key concerns in clinical practice. In terms of safety, real-world research data shows²⁰The common adverse events of the bendamustine-containing regimen are fever, pancytopenia, febrile neutropenia, etc.,The proportion of patients reporting adverse events was only 1.46%, with no adverse events such as hair loss.In terms of accessibility, drugs that have been approved for marketing in China and passed the consistency evaluation currently show high accessibility. They can provide patients with more flexible treatment options through various regimen combinations, offering better economic value and increasing patient benefits. Based on the excellent efficacy, safety, and outstanding accessibility of the BR regimen, it is believed that the BR regimen will play a greater role in the treatment of lymphoma, and it is expected that more patients will benefit significantly.

References:

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[13]Alice Morigi, et al. Hematol Oncol. 2020 Oct;38(4):487-492.

[14] National Health Commission of the People's Republic of China. Guidelines for the Diagnosis and Treatment of Diffuse Large B-Cell Lymphoma (2022 Edition)

[15]Kayoko Murayama, et al. Ann Hematol. 2022 May;101(5):979-989.

[16]Raluca Ionescu-Ittu, et al. J Comp Eff Res. 2019 Oct;8(13):1067-1075.

[17]Zhixin Sheng, et al. Eur J Haematol. 2023 Jun;110(6):602-607.

[18]Maria Chiara Tisi, et al. Blood Adv 2023; 7 (15): 3916–3924.

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