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Abstract

Background:

Radioimmunotherapy (RIT) is a rare treatment option for relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL). We investigated the safety and efficacy of ¹³¹I-rituximab in patients with relapsed or refractory marginal zone lymphomas.

Methods:

Patients with pathologically confirmed marginal zone lymphoma who relapsed or were resistant to prior therapy were enrolled. The patients received 250 mg/m² of unlabeled rituximab immediately before receiving a therapeutic ¹³¹I-rituximab dose. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were toxicity assessment, progression-free survival (PFS), and overall survival (OS).

Results:

Ten patients (median age = 57.5 years; range = 32-71) were included. Owing to poor enrollment, only 10 of the initially intended 25 patients were included in the study, rendering it unfeasible to perform the primary endpoint analysis. Before RIT, patients received chemotherapy, with 40% (n = 4) receiving rituximab therapy. Median PFS and OS were 18.9 months (95% confidence interval [CI]: 0.0-38.9) and 100.0 months (95% CI: 39.8-160.1), respectively. The ORR was 90%, and the duration of response was 29.7 months (95% CI: 0.0-61.3). Considering a median follow-up of 78.5 months (95% CI: 42.7-114.3), 4 patients (40%) were diagnosed with secondary malignancy. Hematological toxicities were common treatment-related adverse events, and 60% and 50% of the patients experienced grade 3 to 4 thrombocytopenia and neutropenia, respectively.

Conclusions:

¹³¹I-rituximab showed marked efficacy in patients with relapsed or refractory marginal zone lymphoma, with a considerable risk of secondary malignancies during long-term follow-up. Radioimmunotherapy is not a recommended treatment option for relapsed or refractory marginal zone lymphoma but may be considered when other treatment options are not feasible.

Keywords

phase II trial radioimmunotherapy marginal zone lymphoma

Introduction

Marginal zone lymphoma (MZL) is the second most common indolent B-cell non-Hodgkin’s lymphoma (NHL), accounting for 3% to 17% of all NHL cases.^1,2 The 3 most typical manifestations of MZL are extranodal marginal zone lymphoma (EMZL), nodal marginal zone lymphoma (NMZL), and splenic marginal zone lymphoma (SMZL).^3,4 Owing to its indolent course of presentation, most patients with MZL have a favorable prognosis compared with those with aggressive lymphomas. The 5-year overall survival (OS) rate is approximately 80% after diagnosis.⁵ Involved site radiation therapy is currently considered a treatment option for early stage nodal disease or localized EMZL.^6,7 In several prospective studies assessing patients with disseminated stage MZL, rituximab-bendamustine, rituximab-cyclophosphamide, vincristine, and prednisolone (CVP) have demonstrated promising efficacy outcomes.^8
-10 Radioimmunotherapy (RIT) combines radiotherapy and immunotherapy and involves attaching a radioisotope to a monoclonal antibody. Radioimmunotherapy can be an alternative option for patients who cannot undergo systemic chemotherapy in the case of disseminated lymphoma.¹¹ Previous phase II studies have confirmed the efficacy and safety of ¹³¹I-rituximab as salvage therapy in patients with relapsed or refractory B-cell NHL.^12
-14 In addition, ⁹⁰Y-ibritumomab tiuxetan (⁹⁰Y-ibritumomab tiuxetan; Zevalin; Biogen Idec Inc., San Diego, CA, USA; Schering AG, Berlin, Germany) has shown favorable efficacy outcomes in patients with MZL.^15,16 However, rarely long-term clinical outcomes of ¹³¹I-rituximab in patients with MZL have been reported. We performed an investigator-initiated, prospective, single-center, open-label, nonrandomized study to investigate the safety and efficacy of ¹³¹I-rituximab in patients with recurrent or resistant MZL.

Methods

Study design and endpoints

This investigator-initiated, single-center, nonrandomized phase II trial was conducted between 2011 and 2018 at the Korea Cancer Center Hospital (KCCH) in South Korea. This study evaluated the efficacy and safety of ¹³¹I-rituximab in patients with MZL who had relapsed or were resistant to prior therapy. The primary endpoint was the objective response rate (ORR), whereas toxicity, progression-free survival (PFS), and OS were the secondary endpoints. Written informed consent was obtained from each patient before participation in the trial, following the guidelines of the Declaration of Helsinki. The institutional review board (IRB) committee of the KCCH approved the study protocol (IRB No. 2011-09-002) under clinical study number NCT01678404.

Patients

Patients with histologically confirmed MZL who relapsed or became refractory to prior therapy were included. The enrollment criteria are as follows: patients aged ⩾20 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, measurable lesions >1 cm as detected by spiral computed tomography (CT) or positron emission tomography (PET)-CT, and adequate major organ functions. Adequate renal and hepatic function was defined as a serum creatinine level less than or equal to 1.5 mg/dL, a bilirubin level of 2.0 mg/dL or lower, and serum transaminase levels within 3 times the upper normal limit. Adequate bone marrow function is characterized by an absolute neutrophil count of 1500/μL or higher and a platelet count of 75 000/μL or greater. Patients who had another type of cancer within the past 5 years, had incomplete recovery from a previous illness, or had been in a hemodynamically unstable state due to severe heart disease within the past 12 months were ineligible.

Radioiodination of antibody

Na ¹³¹I (11.1 GBq [300 mCi] in 0.5 mL) 0.1 mol/L sodium hydroxide was purchased from the Korea Atomic Energy Research Institute (KAERI, Daejeon, Republic of Korea). Rituximab (Rituxan, Roche Pharma, Reinach, Switzerland; 10 mg/mL) was labeled with Na ¹³¹I using Iodo-Beads (Pierce Chemical Co, Rockford, Ill., USA). Briefly, 18 beads were rinsed thrice in phosphate-buffered saline (pH = 7.4), and 3 beads were placed in each of the 6 test tubes. An equal volume of 0.2 mol/L phosphate buffer (pH = 6.5) was then added to the Na ¹³¹I in 0.1 mol/L sodium hydroxide to neutralize the pH, and a 1.85-GBq (50-mCi) solution of Na ¹³¹I in 0.2 mol/L phosphate buffer was then added to all 6 test tubes containing the beads. After incubating for 20 minutes at room temperature, rituximab (10 mg/mL and 0.5 mL) was added to each tube and incubated for 30 minutes at room temperature. The labeling reaction was stopped by adding 3 mL saline to each tube. The reaction mixtures were purified via a 0.22 mm filter, and the radiolabeling efficiency of rituximab was measured using a radio thin-layer chromatogram scanner (Bioscan Inc., Washington, D.C., USA). Silica-gel-based thin-layer chromatograms were obtained using acetone as the mobile phase.¹⁷

Treatment

To prevent the thyroid gland from absorbing ¹³¹I-rituximab, patients were required to consume a diluted Lugol’s solution (potassium iodide, 1 g; iodine, 0.5 g/10 mL) orally once daily for up to 2 weeks before initiating ¹³¹I-rituximab treatment. Before treatment, patients were admitted to a general ward and transferred to an isolation room on the day of treatment. Cold rituximab (250 mg/m²) was administered to inhibit the peripheral B cells before ¹³¹I-rituximab therapy. Chlorpheniramine (8 mg) and acetaminophen (650 mg) were administered to prevent any anaphylactic reactions. ¹³¹I-rituximab was prepared by labeling 30 mg of rituximab with ¹³¹I (within 200 mCi) and administered within 2 to 4 hours of completing cold rituximab administration. After treatment, the patients were monitored in an isolation room for up to 96 hours. To evaluate the radioisotope dose, the dose absorbed in the whole body was evaluated using a spatial dosimeter. Blood was collected at 5 different time points (immediately after injection, 6 hours after injection, 24 hours after injection, 48 hours after injection, and on day 10) to evaluate the dose.

Response and toxicity evaluation

To evaluate the response of each cycle, International Working Group response criteria were used.^17,18F-fuorodeoxyglucose (FDG) PET/CT was performed before and after treatment. Computed tomography images were acquired with intravenous iodinated contrast, and treatment responses were evaluated based on these CT images. Treatment response was evaluated using PET/CT performed 1 month after RIT. If the disease exhibited no progression, ¹³¹I-rituximab was administered again every 4 weeks, as long as the laboratory results were in accordance with the inclusion criteria. The number of repeated treatments was increased to one for complete response (CR) and up to 6 for partial response (PR) and stable disease (SD). The dose of ¹³¹I used for repeated treatment depended on adverse events and responses to prior treatment and ranged from 100 to 200 mCi. The National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) was used to evaluate toxicity. Follow-up examinations after RIT were performed every 3 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. Follow-up tests included imaging and laboratory tests.

Statistical analysis

The required sample size was calculated to reject a 50% lower activity level (p0) in favor of a target level of interest of 75% (p1) with a significance level of 0.05 and a power of 80%, using Simon’s optimal 2-stage design. Initially, 11 patients were recruited and evaluated for their responses. If 6 or more responses were observed, 17 additional patients were enrolled in the second stage to achieve a target sample size of 28 patients, assuming a 10% dropout rate. If the total number of responses was less than or equal to 13 in 28 patients, the drug was rejected. Progression-free survival was defined as the period from the start of the treatment to the date of progression, death, or last follow-up, and OS was calculated from the date of commencement of RIT treatment until the date of death from any cause or last follow-up. Overall survival and PFS were estimated using the Kaplan-Meier method. All statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).

Results

Patient characteristics

This study was prematurely terminated because of poor enrollment. Ten patients were enrolled between October 2011 and June 2018. Table 1 summarizes the clinical and therapeutic characteristics of the patients. The median patient age was 57.5 years (range = 32-71 years), and 50% of the patients were male (n = 5). All the patients had an ECOG score of 0 or 1 (n = 10, 100%). According to the histological classification, EMZL was the most common manifestation (n = 7, 70%), followed by NMZL (n = 2, 20%) and primary cutaneous marginal zone lymphoma (PCMZL; n = 1, 10%). Each of the 4 (40%) had Ann Arbor stages II and IV, while each patient (10%) had Ann Arbor stages I and III. The International Prognostic Index (IPI) scores were 0, 1, and 2 in 3 (30%), 3 (30%), and 4 (40%) patients, respectively. In most patients, except one (n = 9, 90%), lactate dehydrogenase (LDH) levels were within the normal range. Three patients underwent radiotherapy before RIT. Among them, 2 received a total radiation dose of 45 gray/20 fractions; the received gray dose could not be confirmed for 1 patient. The median time from diagnosis to RIT was 48.1 months (95% CI: 0.0-116.6 months). All patients received chemotherapy before RIT, and 40% (n = 4) of patients received rituximab treatment.

Table 1.

Clinical and therapeutic details along with the outcomes of patients included in the study.

Case No.	Age (y)	Sex	ECOG PS	Type of MZL	Ann arbor stage	IPI	Prior rituximab	Prior radiotherapy	RIT cycle	RIT total dose (mCi)	Best response	Subsequent chemotherapy	Subsequent radiotherapy	PFS (mo)	OS (mo)	t-MNs	Final MZL status	Death
1	55	F	0	EMZL	4	2	Y	N	1	201	SD	Y	N	0.8	68.8		PD	Yes
2	54	F	0	EMZL	2	0	N	N	3	520	CR	N	N	49.7	49.7	t-MDS	CR	Yes
3	66	M	0	EMZL	2	1	N	N	3	485	CR	N	N	117.0+	117.0+		CR	No
4	45	M	0	EMZL	1	0	N	N	3	576	CR	N	N	100	100	t-AML	CR	Yes
5	32	F	1	NMZL	3	1	N	N	1	210	PR	Y	N	8.2+	105+	t-AML	PD	No
6	60	M	1	EMZL	2	1	Y	N	2	376	CR	Y	N	43.7+	78.5+		PD	No
7	71	M	0	PCMZL	2	2	N	Y	1	110	CR	Y	Y	16.8+	66.8+	t-MDS	PD	No
8	68	F	1	EMZL	4	1	N	Y	2	214	CR	N	N	18.9+	63.5+		PD	No
9	46	F	1	EMZL	4	2	Y	Y	2	253	CR	Y	N	29.7+	54.0+		PD	No
10	71	M	1	NMZL	4	1	Y	N	2	205	PR	Y	N	15.0	49.8		PD	Yes

Abbreviations: CR, complete response; ECOG, Eastern Cooperative Oncology Group; EMZL, extranodal marginal zone lymphoma; F, female; IPI, International Prognostic Index; M, male; mo, months; MZL, marginal zone lymphoma; NMZL, nodal marginal zone lymphoma; OS, overall survival; PCMZL, primary cutaneous marginal zone lymphoma; PD, progressive disease; PFS, progression-free survival; PR, partial response; PS, performance status; RIT, radioimmunotherapy; SD, stable disease; t-AML, therapy-related acute myeloid leukemia; t-MDS, therapy-related myelodysplastic syndrome; t-MNs, therapy-related myeloid neoplasms.

Efficacy outcomes

The key patient characteristics and effectiveness outcomes are presented at the patient level in Table 1. According to a retrospective review, among patients, 7 (70%) achieved CR, while none achieved progressive disease (PD) (Figure 1). When patients achieved at least PR, the median duration of response was 29.7 months (95% CI: 0.0-61.3 months). The median PFS was 18.9 months (95% CI: 0.0-38.9 months), and the median OS was 100.0 months (95% CI: 39.8-160.1 months) during the median follow-up of 78.5 months (95% CI: 42.7-114.3 months) in patients who survived. Figure 2 summarizes individual clinical outcomes.

Figure 1.

Efficacy parameters of radioimmunotherapy and types of secondary malignancies. CR indicates complete response; PR, partial response; SD, stable disease; PD, progressive disease; t-AML, therapy-related acute myeloid leukemia; t-MDS, therapy-related myelodysplastic syndrome.

Figure 2.

Clinical history of 10 patients with MZL who underwent RIT. The treatment history of 10 patients with MZL who received RIT is described in timelines. The orange X indicates the time of progression of MZL, and the yellow-green square indicates death. The blue allow shows that the patient is alive, and the red circle indicates the diagnosis point of therapy-related myeloid neoplasm (t-MN). MZL indicates marginal zone lymphoma; RIT, radioimmunotherapy; t-MN, therapy-related myeloid neoplasm.

Safety outcomes

Treatment-related adverse events are shown in Table 2. Thrombocytopenia was the most common treatment-related adverse event (n = 9, 90%), followed by neutropenia (n = 7, 70%) and anemia (n = 6, 60%). All patients, except one (n = 9, 90%), experienced hematological toxicities regardless of grade, with more than half the patients (n = 6, 60%) experiencing sustained grade ⩾3 hematologic toxicity. The median time for patients to recover to an absolute neutrophil count of 1500/μL or higher and a platelet count of 75 000/μL or greater after RIT treatment was 24 days (range = 23-70). Except for hematological toxicity, no grade 3 adverse events were observed. Other patients reported fatigue and constipation (n = 3, 30%). None of the patients discontinued RIT due to treatment-related adverse events.

Table 2.

Treatment-related adverse events associated with radioimmunotherapy.

Adverse event, n (%)	Adverse events (n = 10)
Adverse event, n (%)	Any grade	Grade 3 or 4
Hematologic
Neutropenia	7 (70%)	5 (50%)
Thrombocytopenia	9 (90%)	6 (60%)
Anemia	6 (60%)	1 (10%)
Nonhematologic
Oral mucositis	2 (20%)
Allergic reaction	1 (10%)
Urticaria	1 (10%)
Nausea/vomiting	6 (60%)
Constipation	3 (30%)
Diarrhea	1 (10%)
Fatigue	3 (30%)
Thyroid function abnormality	1 (10%)
Depression	1 (10%)
Anorexia	6 (60%)
Muscle pain	2 (20%)

In 10 patients, some data points were absent due to the patient’s refusal. For the 7 patients who were assessable for dosimetry, during each therapy dose of ¹³¹I-rituximab (median 157.5 mCi; range = 100-210 mCi), the median delivered dose was 37.9 rad (range = 13.4-98.9 rad) and 58.6 rad (range = 31.8-91.7 rad) to the total body and bone marrow, respectively.

Secondary malignancies

Therapy-related myeloid neoplasms were identified in 4 (40%) out of 10 patients. Two patients (20%) had therapy-related acute myeloid leukemia (t-AML), and 2 (20%) had therapy-related myelodysplastic syndrome (t-MDS) (Figure 1). The mean time to t-MN diagnosis after RIT treatment was 53.2 months (95% CI: 1.45-104.94 months). The molecular characteristics of patients with t-MN have not been verified. Prior to RIT, chemotherapy was administered to all patients, and CVP treatment was the first-line chemotherapy. Two patients (20%) received chemotherapy, and 1 (10%) patient received radiotherapy after RIT. The treatment details are listed in Supplementary Table 1.

Discussion

This prospective, phase II study investigated the efficacy of RIT in patients with relapsed or refractory MZL. Although RIT had considerable efficacy, a significant adverse event of t-MNs occurred in 4 of the 10 patients, resulting in 2 deaths. Considering these adverse effects, RIT is not a recommended treatment option for relapsed or refractory MZL.

Radioimmunotherapy treatment using ⁹⁰Y-ibritumomab tiuxetan has been previously assessed in patients with MZL.^15,16 The authors showed that ORRs ranged between 87.5% and 90%. Furthermore, 5-year PFS and OS were 40% (90% CI: 19.9-59.5) and 71.8% (90% CI: 46.8-86.5), respectively. ¹³¹I-rituximab therapy in patients with MZL yielded similar results in previous prospective trials, with ORRs of 60% to 100% and a median duration of response ranging from 2.4 to 16.8 months.^12,18 The ORR value observed in this study falls within the range of previous research findings, but the duration of the response was prolonged. In a previous study assessing ¹³¹I-rituximab, low-dose cold rituximab (70 mg) was used to block nonspecific binding before ¹³¹I-rituximab administration. However, in the present trial, the cold rituximab dose was increased to 250 mg/m², similar to ⁹⁰Y-ibritumomab, which could explain the prolonged response duration. ¹³¹I-rituximab has been shown to be well tolerated in previous clinical studies. Prior adverse events were primarily hematological; grade 3 or higher hematologic events were observed in 21% to 66% of patients.^13,18 The adverse event profile of ¹³¹I-rituximab in MZL was consistent with that reported in previous RIT studies, indicating that ¹³¹I-rituximab is typically well tolerated.

The median delivered dose in the whole body and bone marrow during treatment was 37.9 rad (range = 13.4-98.9 rad) and 58.6 rad (range = 31.8-91.7 rad). In previous studies, the median delivered dose was 26 rad (12-95 rad) and 38 rad (12-161 rad), which was slightly higher in our study, but the results are consistent when considering the range.¹²

During the follow-up period after RIT treatment, 4 patients died, and 2 of these patients had t-MNs discovered during follow-up after RIT treatment. Among the 4 patients who died, it was confirmed that only 1 patient died in our hospital due to an intra-abdominal infection (Patient Number 10). Because the remaining 3 patients died at another hospital, the cause of death was undisclosed.

Secondary malignancies occurred in 40% of the patients (n = 4). The secondary malignancy frequencies in our study were considerably higher than those reported in other studies.^19,20 These findings can be attributed to several factors. First, it is important to note that differences in the patient populations under study could contribute to discrepancies in the results. Patients with MZL included in the long-term follow-up data from other trials were those who had not received any prior treatment and were diagnosed with the disease. In contrast, our study exclusively focused on patients with relapsed or refractory MZL. Furthermore, chemotherapy and radiotherapy, in addition to RIT, are significant factors that influence the incidence of t-MNs and may influence this outcome. Another potential reason is the inclusion of patients who underwent repeated RIT treatments. In addition, it is imperative to acknowledge that both our clinical trial and previous studies had limitations, notably small sample sizes. Because of these restrictions, it was difficult to determine the exact reason for the observed variations in the results.

Our study has several limitations. Due to poor enrollment, this study had a small sample size. Univariate analysis could not be performed to determine the prognostic factors for ¹³¹I-rituximab effectiveness given the low statistical power of the small sample size. Furthermore, secondary malignancies are common; however, the underlying attributing factors could not be established because of the small patient population. In addition, all patients diagnosed with t-MNs were diagnosed at other hospitals, and medical records were limited; therefore, the molecular characteristics could not be verified. Despite these limitations, we believe that our long-term follow-up study that assessed the effectiveness and safety of RIT for relapsed or refractory MZL is valuable.

Conclusions

In conclusion, ¹³¹I-rituximab was effective in patients with relapsed or refractory MZL. Although adverse events were tolerable during RIT, secondary malignancies were reported at a markedly high rate (40%). As patients with MZL have a longer survival period than those with other aggressive lymphomas, and a significant risk of secondary malignancies was reported over a prolonged follow-up period in this study, our study suggests that RIT is not a recommended treatment option for relapsed or refractory MZL but may be considered when other treatment options are not feasible.

Supplemental Material

sj-docx-1-onc-10.1177_11795549231218082 – Supplemental material for A Phase II Study of 131I-rituximab for Patients With Relapsed or Refractory Marginal Zone Lymphoma

Supplemental material, sj-docx-1-onc-10.1177_11795549231218082 for A Phase II Study of 131I-rituximab for Patients With Relapsed or Refractory Marginal Zone Lymphoma by Yoon Jung Jang, Sang Moo Lim, Inki Lee, Byung Hyun Byun, Ilhan Lim, Byung Il Kim, Chang Woon Choi, Seung-Sook Lee, Sung Hyun Yang, Im Il Na, Hyo-Rak Lee, Dong-Yeop Shin and Hye Jin Kang in Clinical Medicine Insights: Oncology

Footnotes

Acknowledgements

The authors express their sincere gratitude to the Korea Institute of Radiological and Medical Sciences for providing English proofreading services, in support of the Medical Scientist Incubation Program.

Trial registration:

Clinicaltrials.gov NCT01678404

Funding:

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS) funded by the Ministry of Science, ICT (MSIT), Republic of Korea (grant no 50547-2023), (grant no 50574-2023).

Declaration of conflicting interests:

The authors(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions

Yoon Jung Jang: data analysis and interpretation, statistical analysis, manuscript preparation, and editing.

Sang Moo Lim: data analysis and interpretation, manuscript review, and approval.

Inki Lee: data analysis and interpretation.

Byung Hyun Byun: data analysis and interpretation.

Ilhan Lim: data analysis and interpretation.

Byung Il Kim: data analysis and interpretation.

Chang Woon Choi: data analysis and interpretation.

Seung-Sook Lee: data analysis and interpretation.

Sung Hyun Yang: data analysis and interpretation.

Im Il Na: data analysis and interpretation.

Hyo-Rak Lee: data analysis and interpretation.

Dong-Yeop Shin: study concepts and study design.

Hye Jin Kang: study concept, study design, data analysis and interpretation, manuscript editing, and manuscript review and approval.

All authors commented on the previous versions of the manuscript, and have read and approved the final manuscript.

Data Availability Statement

The data supporting the findings of this study are accessible from the corresponding authors on reasonable request.

Ethical Approval

The study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board committee of the Korea Cancer Center Hospital (IRB No. 2011-09-002) and registered at ClinicalTrials.gov (NCT01678404).

Patient Consent Statement

All patients provided written informed consent before participating in the study, which was conducted in accordance with the principles of the Declaration of Helsinki.

ORCID iD

Yoon Jung Jang

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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A Phase II Study of 131 I-rituximab for Patients With Relapsed or Refractory Marginal Zone Lymphoma

Abstract

Background:

Methods:

Results:

Conclusions:

Keywords

Introduction

Methods

Study design and endpoints

Patients

Radioiodination of antibody

Treatment

Response and toxicity evaluation

Statistical analysis

Results

Patient characteristics

Efficacy outcomes

Safety outcomes

Secondary malignancies

Discussion

Conclusions

Supplemental Material

sj-docx-1-onc-10.1177_11795549231218082 – Supplemental material for A Phase II Study of 131I-rituximab for Patients With Relapsed or Refractory Marginal Zone Lymphoma

Footnotes

Acknowledgements

Trial registration:

Funding:

Declaration of conflicting interests:

Author Contributions

Data Availability Statement

Ethical Approval

Patient Consent Statement

ORCID iD

Supplemental Material

References

Supplementary Material