A Phase II Study of Bendamustine Plus Rituximab in Patients with Relapsed or Progressive Marginal Zone Lymphoma: KCSG LY14-09

Jeong-Ok Lee; Jinny Park; Hye Jin Kang; Shin Young Hyun; Gyeong-Won Lee; Ho-Young Yhim; Hyo Jung Kim; Jong Seok Lee; Dae Seog Heo; Tae Min Kim

doi:10.4143/crt.2025.815

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Original Article A Phase II Study of Bendamustine Plus Rituximab in Patients with Relapsed or Progressive Marginal Zone Lymphoma: KCSG LY14-09: Jeong-Ok Lee¹, Jinny Park^2,a), Hye Jin Kang³, Shin Young Hyun^4,b), Gyeong-Won Lee⁵, Ho-Young Yhim⁶, Hyo Jung Kim⁷, Jong Seok Lee¹, Dae Seog Heo⁸, Tae Min Kim⁸; DOI: https://doi.org/10.4143/crt.2025.815
Published online: December 3, 2025

¹Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

²Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea

³Department of Internal Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

⁴Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea

⁵Division of Hematology and Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju, Korea

⁶Department of Internal Medicine, Jeonbuk National University Medical School, Jeonju, Korea

⁷Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea

⁸Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

Correspondence: Tae Min Kim, Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: 82-2-2072-2228 E-mail: gabriel9@snu.ac.kr

^a)Present address: Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Korea
^b)Present address: Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

• Received: August 1, 2025 • Accepted: December 2, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
This multicenter, phase II study examined the efficacy and safety of bendamustine plus rituximab in patients with relapsed or progressive marginal zone lymphoma (MZL).
Materials and Methods
Patients received six cycles of bendamustine 90 mg/m² intravenously on day 1 and 2, rituximab 375 mg/m² intravenously in cycle 1, and 1,400 mg subcutaneously in cycles 2-8 on day 1 every 4 weeks. Bendamustine dose reduction to 60 mg/m² (level –1) and 40 mg/m² (level –2) was allowed based on prespecified toxicity criteria. The primary endpoint was overall response rate (ORR) and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.
Results
Among the 26 evaluable patients, 81.8% achieved an ORR, while 40.7% had a complete response. The median PFS was 46.06 months, and the estimated 3-year OS rate was 92.3%. Hematological toxicities, primarily neutropenia (grade 3/4, 48.1%), were the most common adverse events, resulting in both reduction and interruption of bendamustine doses, accounting for 18 of 24 dose-reduced cycles (75.0%) and 7 of 17 missed cycles (41.2%), respectively. Nonhematologic toxicities were generally mild, with nausea and fatigue identified as the most frequently reported toxicities. The mean relative dose intensities were 76.9% (range, 31.5 to 100) for bendamustine and 91.3% (range, 72.7 to 100) for rituximab.
Conclusion
Bendamustine plus rituximab is a highly effective and tolerable treatment for patients with relapsed or progressive MZL, providing durable disease control.
Key words: Marginal zone lymphoma, Rituximab, Bendamustine hydrochloride

Introduction

Marginal zone lymphomas (MZLs) are a heterogeneous group of indolent lymphomas classified according to their site of origin into extranodal MZL (EMZL), splenic MZL, and nodal MZL (NMZL). MZL is the second most common subtype of non-Hodgkin lymphoma in Korea [1]. Although generally indolent, MZL frequently relapses, and advanced or transformed cases remain incurable, requiring treatment strategies that minimize toxicity while maintaining long-term disease control.

Clinical research for MZL has been limited owing to the rarity of the disease and challenges associated with nonmeasurable mucosal lesions. To date, IELSG-19 remains the only phase 3 trial dedicated to MZL, demonstrating improved event-free survival with rituximab plus chlorambucil over monotherapy, although no overall survival benefit was observed [2,3].

Bendamustine plus rituximab (BR) has become one of the most widely used frontline regimens for indolent lymphomas based on the BRIGHT and StiL trials [4,5]. Although MZL accounted for only 10%-13% of enrolled patients and the progression-free survival (PFS) advantage of BR over R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) was marginal in this subgroup, BR is frequently adopted as initial therapy for advanced MZL in many regions. In Korea, R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) is commonly used as the first-line treatment for advanced-stage MZL because, although BR has been available for indolent lymphoma since late 2013, its use for MZLs has not been reimbursed. A phase 2 study assessing R-CVP in this setting reported relatively modest efficacy, with an overall response rate (ORR) of 88%, a complete response (CR) rate of 60%, and a 3-year PFS of only 59% [6].

BR has also shown activity in relapsed or refractory (R/R) indolent lymphoma. Two phase II studies reported an ORR of 90%-92%, CR rate of 41%-60%, and median PFS of 21-23 months [7,8]. The phase III StiL NH2-2003 study, comparing BR to fludarabine and rituximab, further supported the efficacy of BR in the R/R setting [9]. However, these studies differed in prior rituximab exposure, BR cycle number, and histologic distribution, and importantly, MZL represented only 3%-10% of participants—corresponding to only 2-10 patients per study. According to the National Comprehensive Cancer Network guidelines, BR remains a preferred second-line option for EMZL and NMZL in patients without prior bendamustine exposure.

Considering the limited representation of MZL in prior BR studies and the practical constraints limiting access to novel agents, this prospective study was designed to evaluate the efficacy and safety of BR in patients with relapsed or progressive MZL.

Materials and Methods

1. Study design and patients

This open-label, multicenter, investigator-initiated phase II trial was conducted across eight centers of the Korean Cancer Study Group (KCSG) in South Korea (KCSG 14-09). Patients aged ≥ 18 years with histologically confirmed NMZL or EMZL were eligible if they had received ≥ 1 but no more than four prior systemic therapy lines for MZL, with documented relapse or progression during or after previous treatment and had ≥ 1 measurable lesion (> 1.5 cm in the longest dimension defined by computed tomography [CT] scan). Patients whose disease relapsed or progressed within six months after the completion of rituximab, either as monotherapy or as chemoimmunotherapy, were excluded. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and adequate hematologic and organ function. Patients were required to meet the following laboratory criteria at screening: hemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5×10⁹/L; platelets ≥ 75×10⁹/L (ANC ≥ 1.0×10⁹/L, platelets ≥ 50×10⁹/L if bone marrow involvement or hypersplenism due to the splenic involvement); serum creatinine ≤ 1.5×upper limit of normal (ULN) or calculated creatinine clearance ≥ 40 mL/min (Cockcroft Gault formula); and total bilirubin ≤ 1.5×ULN (total bilirubin ≤ 3.0×ULN in patient with Gilbert’s syndrome).

2. Procedures

Baseline evaluation included medical history and physical examination, complete blood count, serum chemistry, and tumor staging using contrast-enhanced CT, magnetic resonance imaging (MRI), and positron tomography (PET) scans. Bone marrow aspiration and biopsy were performed only when involvement was suspected. The BR regimen comprised a 28-day cycle, with six cycles of a combination of rituximab and bendamustine and an additional two cycles of rituximab. Bendamustine was administered intravenously at 90 mg/m² on days 1 and 2 for up to six cycles. Rituximab was administered intravenously at 375 mg/m² on day 1 of cycle 1 and subcutaneously at 1,400 mg on day 1 of cycles 2-8. During each cycle, BR was delayed until the ANC ≥ 1.5×10⁹/L, platelets ≥ 75×10⁹/L, ≤ grade 1 cutaneous adverse events (AEs), or ≤ grade 2 nonhematologic AEs. For bendamustine, two dose reductions to 60 mg/m² (dose level –1) and 40 mg/m² (dose level –2) were allowed for toxicities based on the prespecified criteria (S1 Table). In case of a delay of more than 4 weeks, bendamustine was permanently discontinued, and rituximab was administered according to the protocol, even after the discontinuation of bendamustine. CT or MRI for response assessment was conducted every 2 cycles until 4 weeks after the last cycle, then every 3 months for 2 years, and every 6 months thereafter. A PET scan was performed 4 weeks after the last cycle. In cases with bone marrow involvement, bone marrow examination was required to confirm CR. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE ver. 4.03). Collection of safety data was continued for up to 6 months after the last cycle, with only serious AEs collected thereafter.

3. Statistical analysis

The primary endpoint was the ORR in accordance with the 2007 International Working Group criteria [10]. For the primary efficacy analysis, ORR was defined as the proportion of patients achieving CR or partial response (PR) among all treated patients, with unevaluable or missing response assessments counted as non-responders. Secondary endpoints included the CR rate, duration of response, PFS, overall survival (OS), and safety. PFS was defined as the time from the first administration of the treatment to the date of documented disease progression or death from any cause, whichever occurred first. OS was defined as the time from entry into the study to death due to any reason. Patients who did not demonstrate disease progression or died were censored on July 31, 2019. Patients who withdrew consent were censored on the date of withdrawal.

Additional exploratory post-hoc subgroup analyses were performed to further assess treatment efficacy across key clinical factors, including histologic subtype, prior treatment sequence, time from last rituximab exposure, treatment line, International Prognostic Index (IPI) risk group, stage, lactate dehydrogenase (LDH) level, bendamustine relative dose intensity (RDI), and treatment completion status. Comparisons of response rates between subgroups were performed using Fisher’s exact test or chi-square test, as appropriate, and subgroup differences in PFS were compared using the log-rank test.

The initial sample size calculation was based on an expected ORR of 80% (p1) compared with a threshold ORR of 60% (p0), derived from historical outcomes of available salvage therapies in Korea at the time, with one-sided alpha of 0.05 and 80% power. According to Simon’s minimax two-stage design, a total of 39 evaluable patients were required, with an allowance for a 10% dropout rate. Owing to slow accrual, an interim analysis was performed following the completion of stage 1, in which 10 of the 13 enrolled patients were responders. Based on this interim outcome, the required sample size was reestimated using an inference procedure [11]. For stage 2, an additional 14 evaluable patients were required, resulting in a total of 27 patients, accounting for a 10% dropout rate. The final sample size was determined based on a conditional power of 70%, which was considered appropriate to maintain statistical validity while ensuring feasibility given the slow accrual rate. Patients who received at least one treatment cycle were included in the efficacy and safety analyses. The final response rate was calculated using a bias-reduced estimator, and corresponding two-sided 90% confidence intervals (CIs) and p-values were derived using the BREW tool, developed at Vanderbilt University (http://data.vanderbilt.edu/~graywh/brew/twostage.html). Survival curves were estimated using the Kaplan-Meier method with two-sided 95% CI. Statistical significance was set at p < 0.05.

Dose delay was defined as a postponement of ≥ 7 days beyond the planned administration date in any cycle. Missing doses were identified when the patient did not receive at least one scheduled dose within a cycle. The RDI for each drug was calculated by dividing the patient-specific dose intensity by the planned dose intensity and multiplying it by 100. Dose delays, missing doses, and RDIs were assessed for patients who received at least two cycles of the BR regimen.

Results

1. Patients and baseline characteristics

A total of 28 patients were enrolled between May 2015 and May 2018. Of these, 27 received the BR regimen. One patient who withdrew consent during screening did not receive treatment and was excluded from the analysis. The baseline demographics and disease characteristics are summarized in Table 1. The median patient age at enrollment was 66 years (range, 38 to 81 years). Fourteen patients (52%) had EMZL, and 13 (48%) had NMZL. At the study entry, 21 patients (78%) had Ann Arbor stage IV disease, and 11 (41%) were classified as high-intermediate or high-risk International Prognostic Index. The median time from initial diagnosis of MZL to enrollment was 4.5 years (range, 0.96 to 15.54 years). Patients had received a median of one prior systemic chemotherapy regimen (range, 1 to 5), with 22% having received three or more lines of prior therapy. Twenty-three patients (85.2%) had previously been treated with rituximab. The most common regimen was R-CVP (n=22), followed by rituximab monotherapy (n=3), and R-CHOP (n=1). Among them, 21 patients received R-CVP or R-CHOP as first-line therapy.

2. Efficacy

Of the 27 eligible patients, 26 were evaluated for a response. One patient, a 78-year-old female, was not evaluated because of early treatment discontinuation following the development of life-threatening pneumonia and acute respiratory failure after the first cycle. The patient flow throughout the study is summarized in Fig. 1. The ORR was 81.80% (90% CI, 64.99 to 89.91), with 11 patients (40.7%) achieving CR and 11 (40.7%) demonstrating a PR. Three patients (11.1%) had stable disease, and one (3.7%) experienced disease progression after the first cycle. Considering the data cutoff on July 31, 2019, the median follow-up duration was 25 months (range, 1 to 50.0 months). The median PFS was 46.06 months (95% CI, 30.12 to not estimable). The estimated 2- and 3-year PFS rates were 79.8% (95% CI, 58.04 to 91.10) and 64.5% (95% CI, 37.14 to 82.37), respectively (Fig. 2). The duration of the responses for the 22 respondents is illustrated in Fig. 3. At the time of analysis, two deaths had occurred, both of which were attributable to disease progression. The median OS had not yet been reached, with the estimated 3-year survival rate calculated as 92.28% (95% CI, 72.48 to 98.02) (Fig. 4).

In S2 Table and S3 Table, exploratory post-hoc subgroup analyses are summarized. Overall, ORR and PFS did not differ significantly across most clinical subgroups, including histologic subtype, prior treatment sequence, treatment line, IPI risk group, disease stage, LDH level, and bendamustine RDI. Notably, among the 12 patients who received first-line R-CVP followed by second-line BR, those with a ≥ 24-month interval from the last rituximab exposure to BR initiation achieved a significantly higher ORR (100% vs. 42.9%, p=0.026), although this difference did not reach significance for PFS. Completion of all eight planned cycles was associated with a higher ORR (95.2% vs. 33.3%, p=0.004) and longer median PFS (46.0 vs. 30.0 months, p=0.005).

3. Safety

Twenty-two patients (81.5%) received all six planned cycles of BR, among whom 21 patients (77.8%) completed the full treatment course, including two additional doses of rituximab. Six patients discontinued treatment prematurely owing to disease progression (n=2), AEs (n=3) or withdrawal of consent (n=1). Discontinuation occurred after cycle 1 (n=2), cycle 4 (n=2), cycle 5 (n=1), and cycle 7 (n=1) (Fig. 1). A total of 190 treatment cycles were administered, including 147 BR cycles. Among the 25 patients who received at least 2 cycles of BR, 145 BR cycles were analyzed, of which 35 cycles (24.1%) in 19 patients were delayed. The median and mean duration of delays were 10 and 14 days, respectively (range, 7 to 46 days). Bendamustine dose reduction was required for 24 cycles (16.6%) in 12 patients. In 10 patients, bendamustine was omitted in at least one dose in 17 cycles (11.7%). Neutropenia was the most common reason for both dose reductions and omissions, accounting for 18 of 24 dose-reduced cycles (75.0%) and 7 of 17 missed cycles (41.2%). The mean RDIs for bendamustine and rituximab were 76.9% (range, 31.5 to 100) and 91.3% (range, 72.7 to 100), respectively (Table 2). Neutropenia was the most frequently observed hematologic toxicity, with grade 3 or 4 neutropenia reported in 33 of 190 cycles (17.4%) and 13 of 27 patients (48.1%) (Table 3). The most common nonhematologic AEs were nausea (51.9%), anorexia (37.0%), fatigue (33.3%), and skin rash (29.6%), which were mostly grade 1 or 2 in severity (Table 4). Three patients discontinued treatment because of AEs: two cases of pneumonia and one case of hepatitis B reactivation in a patient positive hepatitis B core antibody. No treatment-related deaths were recorded.

Discussion

This multicenter, phase II study evaluated the efficacy and safety of the BR regimen in patients with R/R MZL. BR demonstrated meaningful activity, with an ORR of 81.8%, including a CR rate of 40.7%. The median PFS of 46.1 months and 3-year OS of 92.3% were comparable to outcomes reported in prior BR trials for indolent lymphomas, despite the small representation of MZL in those studies [7-9]. Although the number of prior treatment lines was similar, our cohort included more heavily pretreated patients—15% receiving fifth-line or later therapy and 85% with prior rituximab exposure—whereas earlier German studies excluded patients with prior rituximab exposure or refractoriness [7,9]. Additionally, the bendamustine RDI in our study (mean 76.9%, median 82.1%) was below the 93% and 97.1% reported by Robinson et al. and the 96.3% full-dose delivery achieved in the German studies [8,9].

Advances in the understanding of MZL biology have led to the development of several targeted agents for the R/R setting. Since ibrutinib’s approval in 2017, options such as lenalidomide–rituximab, umbralisib, copanlisib, and zanubrutinib have shown durable activity [12-16], though their broader use may be constrained by high cost, long-term toxicity concerns, and generally lower CR rates compared with chemoimmunotherapy.

The optimal treatment cycle and dose intensity of BR for MZL are yet to be established. Although six cycles are commonly employed, previous studies have explored shorter BR schedules [7,17]. The MALT 2008-01 trial demonstrated the feasibility of a response-adapted approach in treatment-naïve EMZL [17], and Rummel et al. [7] reported that four cycles of BR were effective in R/R low-grade lymphomas and mantle cell lymphomas.

Our study employed a fixed schedule of six BR cycles followed by two additional rituximab doses, and 21 of 27 patients (77.8%) completed the full treatment course, supporting the feasibility of the planned regimen. Notably, our protocol implemented a two-step dose reduction strategy for bendamustine, with allowances for omission when toxicity occurred. Patients were able to continue treatment with rituximab alone, enabling the completion of scheduled cycles. This approach resulted in relatively modest bendamustine RDI but preserved a high rituximab RDI (mean 91.3%, median 93.3%), underscoring rituximab’s central role in disease control and potentially contributing to the favorable efficacy outcomes observed. Overall, most patients were able to maintain the planned treatment schedule despite dose modifications. Exploratory post-hoc analyses showed that no statistically significant association between RDI and either response or PFS, whereas completion of the full planned course was significantly associated with better outcomes. Although a slight separation of survival curves by RDI appeared after approximately two years, this was not sufficient to suggest a clinically meaningful long-term effect. Mean and median bendamustine RDI values were similar between completers and non-completers (78%/84% vs. 80%/79%). These findings indicate that maintaining treatment continuity may be more important than preserving full bendamustine dose intensity, supporting the use of appropriate dose adjustments when clinically necessary. However, given the post-hoc nature of the analysis and the small sample size, these results should be interpreted with caution and validated in larger prospective studies.

Neutropenia was the most common AE (81.5%), with grade 3/4 events in 48.1% of patients. Per cycle, any-grade and grade 3/4 neutropenia occurred in 51.6% and 17.4% of cycles, leading to bendamustine dose reductions and omissions in 16.6% and 11.7% of cycles, respectively. Despite the lower bendamustine dose intensity, neutropenia rates were comparable to studies with higher RDI, suggesting a relatively higher hematologic vulnerability. This observation may reflect intrinsic patient factors such as reduced marrow reserve or genetic predispositions, particularly among Asian patients. Although chemotherapy-induced neutropenia is known to occur more frequently in Asian population with solid tumors [18-20], bendamustine metabolism—driven mainly by hydrolysis with minimal involvement of cytochrome P450 or UDP-glucuronosyltransferase, shows no major pharmacogenetic differences, and pharmacokinetic data demonstrate similar exposure in Asian and Western populations [21-23]. Nonetheless, higher rates of bendamustine dose modification and granulocyte colony-stimulating factor (G-CSF) use have been reported in several Asian cohorts [24,25]. These observations support the need for further study of inter-ethnic variability and underscore the value of individualized dosing strategies in optimizing BR therapy for Asian patients.

The nonhematologic toxicities observed in our study were comparable to those reported in previous BR studies. Pneumonia occurred in five patients (18.5%), predominantly after the fourth cycle, with three episodes accompanied by grade 3-4 neutropenia. Two patients discontinued treatment due to pneumonia, and one patient stopped bendamustine after cycle 4 but was able to complete therapy with rituximab alone. All pneumonia cases were clinically or radiologically diagnosed and managed as presumed bacterial pneumonia without microbiological confirmation. A single case of grade 2 herpes zoster was recorded. Systematic data on lymphocyte counts and immunoglobulin levels were not collected, limiting assessment of underlying immune vulnerability. Compared with prior BR reports, our cohort showed a relatively low incidence of infectious or opportunistic complications [5,8,21]. However, variations in bendamustine dose intensity, rituximab maintenance, follow-up duration, G-CSF use, and baseline immune status may affect infection rates, warranting caution when comparing studies. In clinical practice, individualized infection monitoring and targeted preventive strategies—such as antimicrobial prophylaxis or immunoglobulin replacement in patients with proven hypogammaglobulinemia—may help reduce infection risk, particularly in later cycles when cumulative immunosuppression increases susceptibility.

This study has several limitations. First, the small sample size and lower-than-expected accrual reduced statistical power and limit the generalizability of the findings. Second, the absence of mandatory re-biopsy at relapse and the lack of central pathology review may have led to misclassification, including missed histologic transformation. Third, the etiology of pneumonia and other infectious episodes could not be fully defined because microbiological testing, lymphocyte subsets, and immunoglobulin levels were not systematically assessed.

Nevertheless, the exclusive focus of this prospective study on patients with MZL provides meaningful insight into the efficacy and safety of BR in this population. The inclusion of heavily pretreated individuals—15% receiving fifth-line or later therapy and 85% with prior rituximab exposure—adds to its real-world relevance. In addition, the two-stage dose reduction and flexible bendamustine dosing strategy preserved efficacy while mitigating toxicity, supporting its practicality in clinical care.

In conclusion, this study supports BR as an effective and tolerable treatment option for R/R MZL, achieving durable responses with manageable toxicities. Treatment completion was feasible for most patients despite the need for dose adjustments, supporting the practical feasibility of a flexible dosing approach that offers an optimal balance between efficacy and safety, particularly in Asian patients who may be more susceptible to hematologic toxicity. Larger prospective studies are needed to refine optimal dosing strategies and confirm the broader applicability of these findings.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2025-815_S1_Table.pdf

crt-2025-815_S2_Table.pdf

crt-2025-815_S3_Table.pdf

NOTES

Ethical Statement

The protocol amendment was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. H-1405-116-582, November 1, 2017) and the Ministry of Food and Drug Safety (No. 30384, October 26, 2017). This study was registered at ClinicalTrials.gov (NCT02433795), approved by each institutional review board, and conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines. All the patients provided written informed consent.

Author Contributions

Conceived and designed the analysis: Kim TM.

Collected the data: Lee JO, Park J, Kang HJ, Hyun SY, Lee GW, Yhim HY, Kim HJ, Lee JS, Heo DS, Kim TM.

Contributed data or analysis tools: Lee JO, Park J, Kang HJ, Hyun SY, Lee GW, Yhim HY, Kim HJ, Lee JS, Heo DS, Kim TM.

Performed the analysis: Lee JO, Kim TM.

Wrote the paper: Lee JO, Kim TM.

Conflicts of Interest

J-O Lee reports receiving clinical trial research funding to their institution from AbbVie, Genmab, Roche, BeiGene, TiCARos, Bristol Myers Squibb and Novartis.

TM Kim reports receiving clinical trial research funding to their institution from AbbVie, Amgen, AstraZeneca/Medimmune, Bayer, BeiGene, Black Diamond Therapeutics, Blueprint Medicines, Boehringer Ingelheim, Boryung Pharmaceutical, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Dizal Pharmaceutical, EMD Serono Inc., Enliven Therapeutics, F. Hoffmann-La Roche Ltd/Genentech, Inc., Fore Biotherapeutics, Hanmi Pharmaceutical, Genmab, Incyte, Janssen, Merck & Co., Inc., Novartis, Pfizer, RAPT Therapeutics, Regeneron Pharmaceuticals, Samsung Bioepis, Sanofi, Takeda, Taiho, and Yuhan, consulting fees from AstraZeneca, Daiichi-Sankyo, HK inno.N, IMBDx. Inc., Janssen, Merck KGaA, Novartis, Regeneron, Roche/Genentech, Samsung Bioepis, and Chong Kun Dang Pharmaceutical, honoraria from AstraZeneca/MedImmune, Amgen, Janssen Research & Development, and Takeda, and Safety monitoring board participation for AstraZeneca, Janssen, Regeneron, Roche/Genentech, Samsung Bioepis, and Takeda.

Funding

This research received funding from Eisai Korea. Bendamustine and rituximab were provided by Eisai Korea and Roche Korea, respectively.

Fig. 1.

CONSORT diagram of patient enrollment and treatment progression. BR, bendamustine plus rituximab; CR, complete response; IC, informed consent; PD, progressive disease; SD, stable disease.

Fig. 2.

Progression-free survival.

Fig. 3.

Duration of response to bendamustine and rituximab.

Fig. 4.

Overall survival.

Table 1.

Patient characteristics

Characteristic	Value
Male sex	14 (51.9)
Age (yr)	66 (38-81)
ECOG performance status
0-1	26 (96.3)
2	1 (3.7)
Subtype
Extranodal	14 (51.9)
Nodal	13 (48.1)
Ann Arbor stage
II	4 (14.8)
III	2 (7.4)
IV	21 (77.8)
LDH	183 (105-902)
International prognostic index
Low risk	4 (14.8)
Low-intermediate risk	12 (44.4)
High-intermediate risk	9 (33.3)
High risk	2 (7.4)
Years since MZL diagnosis	4.5 (0.96-15.54)
No. of prior systemic therapies
Median (range)	1 (1-5)
1	18 (66.7)
2	3 (11.1)
3	2 (7.4)
≥ 4	4 (14.8)
Prior rituximab treatment	23 (85.2)
Prior chemotherapy^a)
Rituximab based chemo-immunotherapy	23 (85.2)
Rituximab monotherapy	3 (11.1)
CHOP	3 (11.1)
CEOP	3 (11.1)
CVP	2 (7.4)
Autologous hematopoietic stem cell transplantation	2 (7.4)
Others	8 (29.6)
Prior radiotherapy	6 (22.2)

Values are presented as number (%) or median (range). CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone; CEOP, cyclophosphamide, etoposide, vincristine, and prednisolone; CVP, cyclophosphamide, vincristine, and prednisolone; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; MZL, marginal zone lymphoma.

^a) A patient could have been included under multiple regimens.

Table 2.

Dose intensity

Category	Parameter	No. (%)
Treatment cycles	Total treatment cycles	190
	BR cycles administered	147
	BR cycles analyzed for dose modification and intensity	145
Dose modification (cycle-level, n=145)	Dose delays	35 (24.1)
	Dose reductions of bendamustine^a)	24 (16.6)
	Cycles with missing bendamustine doses^b)	17 (11.7)
Relative dose intensity (patient-level, n=25)	Rituximab, mean/median (range)	91.3/93.3 (72.7-100)
	Bendamustine, mean/median (range)	76.9/82.1 (31.5-100)
	Bendamustine DI < 60%	5 (20.0)
	60 ≤ Bendamustine DI < 75%	5 (20.0)

BR, bendamustine and rituximab; DI, dose intensity; LFT, liver function test.

^a) Causes included neutropenia (n=18), LFT abnormalities (n=2), vomiting (n=2), and anorexia/fatigue (n=2),

^b) Causes included neutropenia (n=7), skin rash (n=2), LFT abnormalities (n=2), anorexia/fatigue (n=2), vomiting (n=1), fever (n=1), hypotension (n=1), and pneumonia (n=1).

Table 3.

Hematologic adverse events

	All grade	Grade 3/4	Grade 1	Grade 2	Grade 3	Grade 4
Per patient, total (n=27)
Leukopenia	23 (85.2)	7 (25.9)	7	9	6	1
Neutropenia	22 (81.5)	13 (48.1)	1	8	9	4
Anemia	19 (70.4)	1 (3.7)	11	7	1	0
Thrombocytopenia	16 (59.3)	1 (3.7)	12	3	1	0
Per cycle, total (n=190)
Leukopenia	109 (57.4)	22 (11.6)	50	37	21	1
Neutropenia	98 (51.6)	33 (17.4)	28	37	26	7
Anemia	84 (44.2)	1 (0.5)	70	13	1	0
Thrombocytopenia	49 (25.8)	1 (0.5)	39	9	1	0

Values are presented as number (%).

Table 4.

Nonhematologic adverse events

Event	No. (%) (n=27)
Nonhematologic AE (all grade) occurring in > 10% of patients
Nausea	14 (51.9)
Anorexia	10 (37.0)
Fatigue	9 (33.3)
Skin rash	8 (29.6)
Fever	7 (25.9)
Headache	6 (22.2)
Pruritus	6 (22.2)
Cough	5 (18.5)
Lung infection	5 (18.5)
Infusion related reaction	4 (14.8)
Injection site reaction	4 (14.8)
Vomiting	4 (14.8)
Abdominal pain	3 (11.1)
Flu like symptoms	3 (11.1)
Myalgia	3 (11.1)
Upper respiratory infection	3 (11.1)
Urticaria	3 (11.1)
Weight loss	3 (11.1)
Nonhematologic AE (grade ≥ 3)
Anorexia	1 (3.7)
Nausea	1 (3.7)
Vomiting	1 (3.7)
Fatigue	1 (3.7)
AST/ALT increased	1 (3.7)
Hepatitis B reactivation	1 (3.7)
Hyperglycemia	1 (3.7)
Hyponatremia	1 (3.7)
Biliary tract infection	1 (3.7)
Lung infection	3 (11.1)
Thromboembolic event	1 (3.7)
Headache	2 (7.4)

AE, adverse event; ALT, alanine transaminase; AST, aspartate aminotransferase.

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Figure & Data

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A Phase II Study of Bendamustine Plus Rituximab in Patients with Relapsed or Progressive Marginal Zone Lymphoma: KCSG LY14-09

DOI: https://doi.org/10.4143/crt.2025.815

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Abstract
Introduction
Materials and Methods
Results
Discussion
Electronic Supplementary Material
NOTES
REFERENCES

Pembrolizumab for Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma in Korea

A Phase II Study of Bendamustine Plus Rituximab in Patients with Relapsed or Progressive Marginal Zone Lymphoma: KCSG LY14-09

Fig. 1. CONSORT diagram of patient enrollment and treatment progression. BR, bendamustine plus rituximab; CR, complete response; IC, informed consent; PD, progressive disease; SD, stable disease.

Fig. 2. Progression-free survival.

Fig. 3. Duration of response to bendamustine and rituximab.

Fig. 4. Overall survival.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

A Phase II Study of Bendamustine Plus Rituximab in Patients with Relapsed or Progressive Marginal Zone Lymphoma: KCSG LY14-09

Characteristic	Value
Male sex	14 (51.9)
Age (yr)	66 (38-81)
ECOG performance status
0-1	26 (96.3)
2	1 (3.7)
Subtype
Extranodal	14 (51.9)
Nodal	13 (48.1)
Ann Arbor stage
II	4 (14.8)
III	2 (7.4)
IV	21 (77.8)
LDH	183 (105-902)
International prognostic index
Low risk	4 (14.8)
Low-intermediate risk	12 (44.4)
High-intermediate risk	9 (33.3)
High risk	2 (7.4)
Years since MZL diagnosis	4.5 (0.96-15.54)
No. of prior systemic therapies
Median (range)	1 (1-5)
1	18 (66.7)
2	3 (11.1)
3	2 (7.4)
≥ 4	4 (14.8)
Prior rituximab treatment	23 (85.2)
Prior chemotherapy^a)
Rituximab based chemo-immunotherapy	23 (85.2)
Rituximab monotherapy	3 (11.1)
CHOP	3 (11.1)
CEOP	3 (11.1)
CVP	2 (7.4)
Autologous hematopoietic stem cell transplantation	2 (7.4)
Others	8 (29.6)
Prior radiotherapy	6 (22.2)

Category	Parameter	No. (%)
Treatment cycles	Total treatment cycles	190
	BR cycles administered	147
	BR cycles analyzed for dose modification and intensity	145
Dose modification (cycle-level, n=145)	Dose delays	35 (24.1)
	Dose reductions of bendamustine^a)	24 (16.6)
	Cycles with missing bendamustine doses^b)	17 (11.7)
Relative dose intensity (patient-level, n=25)	Rituximab, mean/median (range)	91.3/93.3 (72.7-100)
	Bendamustine, mean/median (range)	76.9/82.1 (31.5-100)
	Bendamustine DI < 60%	5 (20.0)
	60 ≤ Bendamustine DI < 75%	5 (20.0)

	All grade	Grade 3/4	Grade 1	Grade 2	Grade 3	Grade 4
Per patient, total (n=27)
Leukopenia	23 (85.2)	7 (25.9)	7	9	6	1
Neutropenia	22 (81.5)	13 (48.1)	1	8	9	4
Anemia	19 (70.4)	1 (3.7)	11	7	1	0
Thrombocytopenia	16 (59.3)	1 (3.7)	12	3	1	0
Per cycle, total (n=190)
Leukopenia	109 (57.4)	22 (11.6)	50	37	21	1
Neutropenia	98 (51.6)	33 (17.4)	28	37	26	7
Anemia	84 (44.2)	1 (0.5)	70	13	1	0
Thrombocytopenia	49 (25.8)	1 (0.5)	39	9	1	0

Event	No. (%) (n=27)
Nonhematologic AE (all grade) occurring in > 10% of patients
Nausea	14 (51.9)
Anorexia	10 (37.0)
Fatigue	9 (33.3)
Skin rash	8 (29.6)
Fever	7 (25.9)
Headache	6 (22.2)
Pruritus	6 (22.2)
Cough	5 (18.5)
Lung infection	5 (18.5)
Infusion related reaction	4 (14.8)
Injection site reaction	4 (14.8)
Vomiting	4 (14.8)
Abdominal pain	3 (11.1)
Flu like symptoms	3 (11.1)
Myalgia	3 (11.1)
Upper respiratory infection	3 (11.1)
Urticaria	3 (11.1)
Weight loss	3 (11.1)
Nonhematologic AE (grade ≥ 3)
Anorexia	1 (3.7)
Nausea	1 (3.7)
Vomiting	1 (3.7)
Fatigue	1 (3.7)
AST/ALT increased	1 (3.7)
Hepatitis B reactivation	1 (3.7)
Hyperglycemia	1 (3.7)
Hyponatremia	1 (3.7)
Biliary tract infection	1 (3.7)
Lung infection	3 (11.1)
Thromboembolic event	1 (3.7)
Headache	2 (7.4)

Table 1. Patient characteristics

A patient could have been included under multiple regimens.

Table 2. Dose intensity

BR, bendamustine and rituximab; DI, dose intensity; LFT, liver function test.

Causes included neutropenia (n=18), LFT abnormalities (n=2), vomiting (n=2), and anorexia/fatigue (n=2),

Causes included neutropenia (n=7), skin rash (n=2), LFT abnormalities (n=2), anorexia/fatigue (n=2), vomiting (n=1), fever (n=1), hypotension (n=1), and pneumonia (n=1).

Table 3. Hematologic adverse events

Values are presented as number (%).

Table 4. Nonhematologic adverse events

AE, adverse event; ALT, alanine transaminase; AST, aspartate aminotransferase.