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Originally published as JCO Early Release 10.1200/JCO.2008.17.0001 on July 14 2008 © 2008 American Society of Clinical Oncology. Phase II Multicenter Study of Bendamustine Plus Rituximab in Patients With Relapsed Indolent B-Cell and Mantle Cell Non-Hodgkin's Lymphoma
From the QE II Health Sciences Centre, Halifax, Nova Scotia; Ottawa General Hospital, Ottawa; Northeastern Ontario Regional Cancer Centre, Sudbury, Ontario; Hospital Notre-Dame Du Chum, Montreal, Quebec, Canada; University of Virginia Health System, Charlottesville, VA; Georgetown University Hospital, Washington, DC; University of Southern California/Norris Cancer Hospital, Los Angeles, CA; and West Cancer Clinic, Memphis, TN Corresponding author: Bruce D. Cheson, MD, Georgetown University Hospital, 3800 Reservoir Rd, NW, Washington, DC 20007-2197; e-mail: bdc4{at}georgetown.edu
Purpose Bendamustine HCl is a bifunctional mechlorethamine derivative with clinical activity in the treatment of non-Hodgkin's lymphoma. This study evaluated bendamustine plus rituximab in 67 adults with relapsed, indolent B-cell or mantle cell lymphoma without documented resistance to prior rituximab. Patients and Methods Patients received rituximab 375 mg/m2 intravenously on day 1 and bendamustine 90 mg/m2 intravenously on days 2 and 3 of each 28-day cycle for four to six cycles. An additional dose of rituximab was administered 1 week before the first cycle and 4 weeks after the last cycle. Sixty-six patients (median age, 60 years) received at least one dose of both drugs. Results Overall response rate was 92% (41% complete response, 14% unconfirmed complete response, and 38% partial response). Median duration of response was 21 months (95% CI, 18 to 24 months). Median progression-free survival time was 23 months (95% CI, 20 to 26 months). Outcomes were similar for patients with indolent or mantle cell histologies. The combination was generally well tolerated; the primary toxicity was myelosuppression (grade 3 or 4 neutropenia, 36%; grade 3 or 4 thrombocytopenia, 9%). Conclusion Bendamustine plus rituximab is an active combination in patients with relapsed indolent and mantle cell lymphoma.
In 2008, non-Hodgkin's lymphoma (NHL) will be diagnosed in 66,120 patients, and 20,510 patients will die of the disease.1 Significant gains in response and survival have been achieved with chemoimmunotherapy, particularly with the introduction of rituximab (Rituxan; Genentech, Inc, South San Francisco, CA).2 Data from the National LymphoCare Study indicate that, although a variety of regimens are used as initial therapy for follicular lymphomas, rituximab plus chemotherapy is the most frequent choice (51%).3,4 Given the relapsing nature of indolent lymphomas, patients require re-treatment, and most ultimately become refractory to rituximab and/or various chemotherapies.5 Thus, despite availability of active therapies, indolent B-cell and mantle cell lymphomas remain incurable for most patients. A significant unmet need remains for effective and well-tolerated treatment. Mantle cell lymphoma represents approximately 6% of all NHL and is among the more aggressive subtypes, with a response duration of 1 to 3 years after initial treatment and a median survival time of 3 to 5 years.6 A variety of chemoimmunotherapy approaches have been used in the front-line and relapsed settings, but refractoriness to treatment and the presence of comorbid illness in this typically older population often limit effective therapy.7 Bendamustine (Treanda; Cephalon, Inc, Frazer, PA) is a novel agent consisting of a mechlorethamine (nitrogen mustard) group, a benzimidazole ring, and a butyric acid side chain. In vitro studies demonstrate rapid production of DNA cross-links and strand breaks after bendamustine exposure.8 In addition to direct DNA damage and apoptosis, other mechanisms include inhibition of mitotic checkpoints and induction of mitotic catastrophe.9 These characteristics may explain the activity of bendamustine in drug-resistant cancer cells9 and refractory lymphoma patients.10 Benzimidazole acts as a purine antagonist in experimental models; the contribution of this structure to the overall antitumor activity of bendamustine is unknown. In vitro testing in CD20-positive lymphoma cell lines has demonstrated synergy between bendamustine and rituximab, evidenced by a reduction in the bendamustine concentration required to induce apoptosis in 50% of tumor cells after the addition of rituximab.11 Rituximab has previously been shown to increase the sensitivity of NHL cells to other chemotherapeutic agents.12 Cross resistance has not been observed between rituximab and chemotherapeutic agents. Considering these findings and the widespread use of rituximab in NHL patients, we evaluated the efficacy and safety of bendamustine plus rituximab in patients with indolent B-cell or mantle cell lymphoma experiencing relapse after chemotherapy or chemoimmunotherapy.
Study Design and Objectives We conducted this multicenter, open-label, single-arm, phase II clinical trial to determine the overall response rate (ORR) to bendamustine plus rituximab in patients with relapsed indolent B-cell or mantle cell lymphoma. ORR was defined as a complete response (CR), unconfirmed complete response (CRu), or partial response (PR) during the study period. Secondary objectives included safety, progression-free survival (PFS), and duration of response (DR). The institutional review board approved the protocol at each site, and an institutional review board–approved consent form was signed before study participation.
Eligibility Patients were excluded if they were refractory to rituximab, had received prior radioimmunotherapy or prior high-dose chemotherapy with allogeneic stem-cell support, or had concurrent treatment with therapeutic doses of systemic corticosteroids. Patients were also excluded if they had an active malignancy other than lymphoma, malignant effusions, or evidence of serious infection, or had not recovered from prior treatment-related adverse effects.
Treatment
Response Criteria Patients were classified by best tumor response (CR, CRu, PR, stable disease, or progressive disease). PFS was calculated as the time from first dose of study drug to first documentation of disease progression or death. DR was calculated as the time from first documentation of best response (CR, CRu, or PR) to first documentation of disease progression or death. Laboratory assessments were performed at baseline and on day 1 of each cycle. The severity of adverse events was determined using Common Terminology Criteria for Adverse Events version 3.0.13
Statistical Methods ORR was calculated as the number of patients achieving a best response of CR, CRu, or PR divided by the number of patients treated with at least one dose of bendamustine. Patients without at least one response assessment were treated as nonresponders. A two-sided 95% exact CI for ORR was calculated using the binomial distribution. The Kaplan-Meier method was used to estimate median DR and PFS, and two-sided 95% CIs were calculated using the Brookmeyer-Crowley nonparametric method.17 Absolute dose-intensity of bendamustine and rituximab (mg/m2/wk) was calculated for each patient as the sum of doses administered divided by the number of weeks in the treatment period. Relative dose-intensity for each agent (%) was then calculated as the dose-intensity divided by the weekly intended dose and then multiplied by 100.
Patient Disposition and Characteristics The study enrolled 67 patients at 22 sites in the United States, Canada, and Australia from April 2004 to December 2005. One patient withdrew consent after the first dose of rituximab, did not receive bendamustine, and was excluded from further analyses. Patient characteristics are listed in Table 1. Fifty-six percent of patients had received prior rituximab; 44% were rituximab naive. Sixty-four patients (97%) received prior chemotherapy; these patients received a median of one prior chemotherapy regimen (range, one to four regimens). Two patients (3%) received prior rituximab without chemotherapy. Although three patients received more than three prior chemotherapy regimens, these occurrences did not constitute protocol violations because two patients received repeated treatment with the same regimen and the third patient received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and, later, cyclophosphamide, vincristine, and prednisone, which was counted as one unique regimen.
Safety Sixty-one patients (92%) received at least four cycles of treatment; 41 patients (62%) received six cycles of treatment (Table 2). Of the total 346 patient-cycles administered, 43 (12%) were delayed; 74% of these delays were  14 days in duration. The mean relative dose-intensities for bendamustine and rituximab were 93% and 95%, respectively. Six patients discontinued bendamustine treatment before completing four cycles as a result of adverse events (n = 2), disease progression (n = 1), patient/investigator decision (n = 2), or loss to follow-up (n = 1).
The combination of bendamustine and rituximab was well tolerated (Tables 3 and 4). The primary toxicity was reversible myelosuppression; grade 3 or 4 neutropenia was reported in 24 patients (36%), including four patients (6%) with febrile neutropenia. Other grade 3 or 4 hematologic toxicities included thrombocytopenia (9%) and anemia (2%). Growth factor or blood product support was administered during 43 (9%) of 463 cycles. Ten patients (15%) received RBC growth factors (darbapoetin or epoetin-alfa), and eight patients (12%) received granulocyte growth factors (pegfilgrastim, filgrastim, or sargramostim). Up to cycle 4, growth factor support increased with the number of treatment cycles administered. Four patients (6%) received transfusions of platelets, plasma, or other blood products during the study. There was no clear trend for an increase in the frequency of transfusions administered over time. No secondary malignancies were reported.
Nonhematologic adverse events attributed to bendamustine included (all grades) nausea (70%), infection (64%), fatigue (59%), constipation (44%), diarrhea (36%), headache (36%), and vomiting (29%; Table 4). Most events were grade 1 or 2 in severity. Sixty-two patients (94%) received antiemetics. Ten grade 3 or 4 infections were reported in six patients (diverticulitis, fungal respiratory tract infection, herpes simplex, herpes zoster, neutropenic infection [n = 2], oropharyngeal candidiasis, pneumonia, pseudomonal sepsis, and grade 4 cytomegalovirus infection). Other grade 4 nonhematologic toxicities included compartment syndrome, pulmonary edema, and toxic epidermal necrolysis (one patient each). Events commonly attributed to rituximab by investigators included fatigue (45%) and nausea (30%). There was no evidence of cardiac, renal, or hepatic toxicity. Grade 1 alopecia was reported in one patient (2%). Infusion-related or injection site reactions were associated with bendamustine and rituximab in 10 (15%) and 13 patients (20%), respectively. These were mostly mild to moderate in severity, consisting of chills, fever, phlebitis, and rash. Two patients experienced grade 3 infusion reactions attributed to rituximab. There were no infusion-related reactions specifically attributed to bendamustine. Five deaths reported during the study included three attributed to disease progression, one attributed to compartment syndrome and pulmonary edema, and one attributed to toxic epidermal necrolysis. All but the latter event were considered unrelated to bendamustine or rituximab. Toxic epidermal necrolysis was considered possibly related to rituximab or bendamustine, although the patient received multiple other medications that could have contributed.
Efficacy
Twelve patients with mantle cell lymphoma exhibited an ORR of 92%, including 42% CR, 17% CRu, and 33% PR. Median DR for the mantle cell population was 19 months (95% CI, 12 to 24 months).
Bendamustine is a cytotoxic compound that acts primarily as an alkylating agent inducing extensive and durable DNA breaks. Its benzimidazole ring structure may explain differences between bendamustine and other alkylating agents, such as slower repair of damaged DNA, activity against multidrug-resistant cells, and only partial cross resistance with other alkylating agents.8 In this study, the response to bendamustine plus rituximab was high, with an ORR of 92% and a CR rate of 41%. These responses were also durable, with a median duration of 21 months. CR occurred less frequently in patients previously treated with rituximab compared with rituximab-naive patients (35% v 48%, respectively). One additional notable finding was a high rate of durable responses in the mantle cell lymphoma patients (ORR, 92%; median DR, 19 months). These results are comparable to those from a German study conducted in a similar population of lymphoma patients receiving bendamustine plus rituximab.15 In that study, previous rituximab was not allowed, whereas in the present study, 56% of patients received prior rituximab. Otherwise, the overall history of previous treatment was similar in the two study populations. In the German study (N = 63), ORR was 90% (v 92% in the present study), with a median PFS time of 24 months (v 23 months in the present study). The CR rate was higher in the German study compared with the present study (60% v 41%, respectively), possibly because of differences in prior rituximab treatment. The safety profile of combined bendamustine-rituximab was also similar in the two studies, with a relatively low incidence of grade 3 or 4 hematologic and nonhematologic adverse events. Bendamustine has also been administered in combination with mitoxantrone and rituximab.18 In a study of 54 patients with relapsed and refractory CD20-positive indolent malignancies, mitoxantrone (10 mg/m2 on day 1) and bendamustine (90 mg/m2 on days 1 and 2) were followed by four weekly doses of rituximab (375 mg/m2); bendamustine and mitoxantrone were repeated every 4 weeks for five additional cycles. Grade 3 or 4 adverse events included anemia (7%), thrombocytopenia (14%), and leukopenia (50%); no cardiotoxicity was reported. ORR was 96%, including a CR rate of 41%, similar to the present study. Among patients with indolent lymphoma, median time to progression had not been reached after a median observation time of 27 months. Results from the present study compare favorably with other established treatments for relapsed indolent lymphoma, including rituximab monotherapy and radioimmunotherapy.19,20 A recent phase III study of CHOP versus rituximab plus CHOP (R-CHOP) in 474 patients with relapsed/refractory follicular lymphoma showed an ORR of 85% for R-CHOP and a CR rate of 29%.21 PFS for patients treated with R-CHOP was longer than in the present study, but the comparison is complicated by the use of rituximab maintenance after the completion of R-CHOP and because prior treatment with rituximab was not allowed. The efficacy outcomes associated with bendamustine and rituximab in the subgroup of patients with mantle cell lymphoma are particularly good for this relatively poorly responsive population after initial relapse. Although the number of patients treated is small (n = 12), the ORR of 92% and median PFS time of 23 months compare favorably with the ORR of 58% and median PFS time of 8 months reported for 24 relapsed mantle cell patients treated with rituximab plus fludarabine, cyclophosphamide, and mitoxantrone regimen.22 Given the efficacy of bendamustine demonstrated in the relapsed setting, Rummel et al23 are currently comparing the bendamustine plus rituximab combination and R-CHOP as initial therapy in a multicenter, randomized phase III trial. Interim results in 315 assessable patients with indolent (80%) and mantle cell (20%) lymphomas show similar rates of response (ORR, 93% for bendamustine plus rituximab v 94% R-CHOP) between treatments. After a median 18-month observation period, median PFS time is 39 months for R-CHOP–treated patients and has not been reached for bendamustine/rituximab-treated patients. Bendamustine plus rituximab, compared with R-CHOP, was associated with lower incidences of myelosuppression (grade 3 or 4 leukopenia, 16% v 41%, respectively), infection (23% v 41%, respectively), and alopecia (0% v 94%, respectively). Tolerability of treatment is an important consideration for patients with relapsed lymphoma. Large studies of alternative combination regimens, such as rituximab plus fludarabine, cyclophosphamide, and mitoxantrone22; R-CHOP21; and rituximab plus cyclophosphamide, vincristine, and prednisone,24 demonstrate frequencies of nonhematologic toxicities similar to the bendamustine and rituximab combination with two exceptions. First, severe nausea and vomiting were not observed in the present study but were reported for a small proportion of chemotherapy-naive patients receiving R-CHOP for follicular NHL.25 Whether this difference is meaningful is not clear because antiemetic use may differ between protocols. A second major difference was in the incidence of alopecia. This was reported for only one patient in the present study (grade 1), whereas the majority of patients receiving R-CHOP experience grade 3 or 4 alopecia.25 The hematologic toxicities observed in the present study seem similar to those reported for other rituximab plus chemotherapy combinations, although no comparative studies have been conducted. The observed incidence of grade 3 or 4 neutropenia and thrombocytopenia is lower than in the previous study of bendamustine monotherapy in rituximab-refractory indolent NHL patients.10 This finding may be related to a higher dose-intensity of the monotherapy regimen (120 mg/m2 on days 1 and 2 every 21 days) and a more heavily pretreated population with more advanced disease. However, the incidence of grade 3 or 4 lymphopenia was higher with combined bendamustine-rituximab compared with bendamustine alone, likely reflecting the contribution of rituximab to the combination regimen. Results of this study support the efficacy of combined bendamustine and rituximab for patients with relapsed indolent and mantle cell NHL. This combination elicited durable responses without evidence of additive toxicity and a low incidence of severe and life-threatening events. High response rates were observed in all subgroups; response rates and PFS for patients with mantle cell lymphoma were similar to those in patients with follicular NHL. This combination represents an effective and tolerable treatment option in patients with relapsed indolent and mantle cell NHL.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Philip Cohen, Genentech Research Funding: Michael E. Williams, Cephalon Inc, Genentech, Biogen Idec; Richard H. van der Jagt, Cephalon Inc; Philip Cohen, Cephalon Inc, Genentech; Jordan A. Herst, Salmedix Inc; Anil Tulpule, Salmedix Inc Expert Testimony: None Other Remuneration: Richard H. van der Jagt, Cephalon Inc
Conception and design: Richard H. van der Jagt Provision of study materials or patients: K. Sue Robinson, Michael E. Williams, Richard H. van der Jagt, Philip Cohen, Jordan A. Herst, Anil Tulpule, Lee S. Schwartzberg, Bernard Lemieux, Bruce D. Cheson Collection and assembly of data: Michael E. Williams, Richard H. van der Jagt, Anil Tulpule Data analysis and interpretation: K. Sue Robinson, Michael E. Williams, Richard H. van der Jagt, Anil Tulpule, Bruce D. Cheson Manuscript writing: K. Sue Robinson, Michael E. Williams, Richard H. van der Jagt, Bruce D. Cheson Final approval of manuscript: K. Sue Robinson, Michael E. Williams, Richard H. van der Jagt, Philip Cohen, Jordan A. Herst, Anil Tulpule, Lee S. Schwartzberg, Bernard Lemieux, Bruce D. Cheson
We acknowledge the editorial assistance of Jill Luer, PharmD, in the preparation of this article.
published online ahead of print at www.jco.org on July 14, 2008. Preliminary results were presented at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information can be found for the following: NCT00069758 [ClinicalTrials.gov] .
1. American Cancer Society: Cancer Facts and Figures 2008. Atlanta, GA, American Cancer Society, 2008 2. Schulz H, Bohlius JF, Trelle S, et al: Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: A systematic review and meta-analysis. J Natl Cancer Inst 99:706-714, 2007 3. Friedberg JW, Huang J, Dillon H, et al: Initial therapeutic strategy in follicular lymphoma (FL): An analysis from the National LymphoCare Study (NLCS). J Clin Oncol 24:428s, 2006 (suppl, abstr 7527) 4. Fisher RI, Leblanc M, Press OW, et al: New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23:8447-8452, 2005 5. Hainsworth JD, Litchy S, Shaffer DW, et al: Maximizing therapeutic benefit of rituximab: Maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma—A randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 23:1088-1095, 2005 6. Williams ME, Densmore JJ: Biology and therapy of mantle cell lymphoma. Curr Opin Oncol 17:425-431, 2005[CrossRef][Medline] 7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Lymphomas, Version 3, 2008. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf 8. Strumberg D, Harstrick A, Doll K, et al: Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs 7:415-421, 1996[CrossRef][Medline] 9. Leoni LM, Bailey B, Reifert J, et al: Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 14:309-317, 2008 10. Friedberg JW, Cohen P, Chen L, et al: Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: Results from a phase II multicenter, single-agent study. J Clin Oncol 26:204-210, 2008 11. Chow KU, Sommerlad WD, Boehrer S, et al: Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: Role of cytokines, complement, and caspases. Haematologica 87:33-43, 2002 12. Alas S, Emmanouilides C, Bonavida B: Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. Clin Cancer Res 7:709-723, 2001 13. National Cancer Institute: Common Terminology Criteria for Adverse Events v3.0, 2003. http://ctep.cancer.gov/reporting/ctc.html 14. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244, 1999 15. Rummel MJ, Al-Batran SE, Kim SZ, et al: Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol 23:3383-3389, 2005 16. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract] 17. Brookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 39:29-41, 2007[CrossRef] 18. Weide R, Pandorf A, Heymanns J, et al: Bendamustine/mitoxantrone/rituximab (BMR): A very effective, well tolerated outpatient chemoimmunotherapy for relapsed and refractory CD20-positive indolent malignancies—Final results of a pilot study. Leuk Lymphoma 45:2445-2449, 2004[CrossRef][Medline] 19. Witzig TE, Flinn IW, Gordon LI, et al: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol 20:3262-3269, 2002 20. Horning SJ, Younes A, Jain V, et al: Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 23:712-719, 2005 21. Van Oers MH, Klasa R, Marcus RE, et al: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 108:3295-3301, 2006 22. Forstpointner R, Dreyling M, Repp R, et al: The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104:3064-3071, 2004 23. Rummel MJ, von Grunhagen U, Niederle N, et al: Bendamustine plus rituximab versus CHOP plus rituximab in the first-line treatment of patients with indolent and mantle cell lymphomas: First interim results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood 110:385, 2007 (abstr) 24. Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005 25. Hiddemann W, Kneba M, Dreyling M, et al: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725-3732, 2005 Submitted March 7, 2008; accepted May 21, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
18 years with a WHO performance status of 0 to 2 were eligible if they had documented relapsed, CD20-positive mantle cell lymphoma or indolent B-cell (follicular, small lymphocytic, lymphoplasmacytic, or marginal zone) lymphoma. Patients were required to have bidimensionally measurable disease with at least one lesion measuring 
