A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma.

Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-week cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clinical benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, respectively. Progression-free survival ranged from 1·8 to 22·8 months and 11·8 to 26·3 months in responders with DLBCL and FL, respectively. The most frequent treatment-related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhoea (61·1%). Although mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clinical benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.

Long-term outcomes, secondary malignancies and stem cell collection following bendamustine in patients with previously treated non-Hodgkin lymphoma.

Despite the long history of bendamustine as treatment for indolent non-Hodgkin lymphoma, long-term efficacy and toxicity data are minimal. We reviewed long-term data from three clinical trials to characterize the toxicity and efficacy of patients receiving bendamustine. Data were available for 149 subjects at 21 sites. The median age was 60 years at the start of bendamustine (range 39-84), and patients had received a median of 3 prior therapies. The histologies included grades 1-2 follicular lymphoma (FL; n = 73), grade 3 FL (n = 23), small lymphocytic lymphoma (n = 20), marginal zone lymphoma (n = 15), mantle cell lymphoma (n = 9), transformed lymphomas (n = 5), lymphoplasmacytic lymphoma (n = 2) and not reported (n = 2). The median event-free survival was 14·1 months. Nine of 12 attempted stem cell collections were successful. With a median follow-up of 8·9 years, 23 patients developed 25 cancers, including 8 patients with myelodysplastic syndrome/acute myeloid leukaemia. These data provide important information regarding the long-term toxicity of bendamustine in previously treated patients. A small but meaningful number of patients achieved durable remissions following bendamustine. These rigorously collected, patient-level, long-term follow-up data provide reassurance that bendamustine or bendamustine plus rituximab is associated with efficacy and safety for patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Cognitive function and its relationship to other psychosocial factors in lymphoma survivors.

PURPOSE: The purpose of this study was to estimate the prevalence of cognitive disturbance in lymphoma survivors and to explore relationships between cognitive function and other psychosocial factors. METHODS: A package of standardized questionnaires was sent to 622 lymphoma patients treated at the Ottawa Hospital in the preceding 5 years. Patients with central nervous system involvement were excluded. The questionnaires addressed cognitive function, pain, insomnia, fatigue, and mood. Of the patients in the sampling frame, 54 % responded to the survey and 42 % met inclusion/exclusion criteria. Sixteen percent (99/622) agreed to undergo computerized neuropsychological testing with CNS vital signs (CNSVS). Scores on the objective and subjective cognitive measures were compared to those of a healthy female control group from a previous study. RESULTS: The lymphoma group scored significantly lower than the controls on a cognitive rating scale (p = .018) and on CNSVS (p = .035). The difference on the CNSVS was primarily due to poorer attention and executive function scores in the lymphoma patients. The patients also had a higher frequency of impairment on both the objective (p = .009) and subjective (p < .001) cognitive measures. Among the lymphoma survivors, fatigue and anxiety were related to subjective cognitive disturbance (p < .001 for both), whereas pain was the only psychosocial measure associated with objective cognitive performance (p < .001). CONCLUSIONS: These results suggest that cognitive disturbance may be a significant survivorship issue for lymphoma patients and should be more thoroughly investigated in this population.

Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study.

This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.

Impact of renal impairment on outcomes with lenalidomide and dexamethasone treatment in the FIRST trial, a randomized, open-label phase 3 trial in transplant-ineligible patients with multiple myeloma.

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone-treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment. Trial registration: ClinicalTrials.gov (NCT00689936); EudraCT (2007-004823-39). Funding: Intergroupe Francophone du Myélome and the Celgene Corporation.

Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma.

BACKGROUND: Patients with T-cell lymphomas face a poorer prognosis compared with patients with B-cell lymphomas. New therapeutic approaches need to be developed to improve outcomes for these patients. METHODS: Forty patients with recurrent and refractory T-cell lymphomas other than mycosis fungoides and patients with untreated T-cell lymphoma who were not candidates for combination chemotherapy were prescribed oral lenalidomide at a dose of 25 mg daily on days 1 to 21 of each 28-day cycle, with standardized dose reductions for toxicity. The primary endpoint was overall response rate (ORR), and secondary endpoints were complete and partial response rates, progression-free survival (PFS), overall survival (OS), and safety. The authors also determined duration of response (DoR). RESULTS: A total of 40 patients were enrolled in the current study; 1 patient was subsequently deemed ineligible. The ORR was 10 of 39 patients (26%); 3 patients (8%) achieved complete responses and 7 patients achieved partial responses. Three patients had stable disease for ≥5 cycles. The median OS was 12 months (range <1 month to ≥69 months), the median PFS was 4 months (range, <1 month to ≥50 months), and the median DoR was 13 months (range 2 months to ≥37 months), including 5 responses that lasted >1 year. Toxicity was in keeping with the known safety profile of lenalidomide. Among the patients who had recurrent/refractory peripheral T-cell lymphoma (29 patients), the ORR was 24%, the median OS was 12 months, the median PFS was 4 months, and the median DoR was 5 months (range, 2 months to ≥37 months). CONCLUSIONS: In the current study, the use of oral lenalidomide monotherapy demonstrated clinically relevant efficacy among patients with systemic T-cell lymphomas. It appears to have excellent potential as an agent in combination therapy for patients with T-cell lymphoma.

Bilateral necrobiotic xanthogranuloma of the eyelids followed by a diagnosis of multiple myeloma 20 years later.

A uniquely indolent case of necrobiotic xanthogranuloma with bilateral, periorbital involvement was presented. This patient presented with cutaneous eyelid lesions of 20 years' duration. Although symptomless, the patient underwent testing for hematologic malignancy, which led to a diagnosis of multiple myeloma. A review of the literature revealed that this is the longest interval between the onset of the skin manifestations and the diagnosis of the systemic malignancy in this rare disease.

Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996).

This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels < 200 mU/mL vs > or = 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein(+) CD34(+) marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

A Prospective Economic Analysis of Early Outcome Data From the Alliance A041202/ CCTG CLC.2 Randomized Phase III Trial Of Bendamustine-Rituximab Compared With Ibrutinib-Based Regimens in Untreated Older Patients With Chronic Lymphocytic Leukemia.

INTRODUCTION: The Alliance A041202/CCTG CLC.2 trial demonstrated superior progression-free survival with ibrutinib-based therapy compared to chemoimmunotherapy with bendamustine-rituximab (BR) in previously untreated older patients with chronic lymphocytic leukemia. We completed a prospective trial-based economic analysis of Canadian patients to study the direct medical costs and quality-adjusted benefit associated with these therapies. METHODS: Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months. Health state utilities were collected using the EuroQOL EQ-5D instrument with Canadian tariffs applied to calculate quality-adjusted life years (QALYs). Costs were applied to resource utilization data (expressed in 2019 US dollars). We examined costs and QALYs associated ibrutinib, ibrutinib with rituximab (IR), and BR therapy. RESULTS: A total of 55 patients were enrolled; two patients were excluded from the analysis. On-protocol costs (associated with protocol-specified resource use) were higher for patients receiving ibrutinib (mean $189,335; P < 0.0001) and IR (mean $219,908; P < 0.0001) compared to BR (mean $51,345), driven by higher acquisition costs for ibrutinib. Total mean costs (over 2-years) were $192,615 with ibrutinib, $223,761 with IR, and $55,413 with BR (P < 0.0001 for ibrutinib vs. BR and P < 0.0001 for IR vs. BR). QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR; therefore, a formal cost-utility analysis was not conducted. CONCLUSIONS: Direct medical costs are higher for patients receiving ibrutinib-based therapies compared to chemoimmunotherapy in frontline chronic lymphocytic leukemia, with the cost of ibrutinib representing a key driver.

Phase II study of the histone deacetylase inhibitor MGCD0103 in patients with previously treated chronic lymphocytic leukaemia.

MGCD0103, an orally available class I histone deacetylase (HDAC) inhibitor, was examined for pre-clinical activity in chronic lymphocytic leukaemia (CLL). A phase II clinical trial was performed, starting at a dose of 85 mg/d, three times per week. Dose escalation to 110 mg or the addition of rituximab was permitted in patients without a response after two or more cycles. MGCD0103 demonstrated pre-clinical activity against CLL cells with a LC(50) (concentration lethal to 50%) of 0.23 micromol/l and increased acetylation of the HDAC class I specific target histone H3. Twenty-one patients received a median of two cycles of MGCD0103 (range, 0-12). All patients had previously received fludarabine, 33% were fludarabine refractory, and 71% had del(11q22.3) or del(17p13.1). No responses according to the National Cancer Institutes 1996 criteria were observed. Three patients received 110 mg and four patients received concomitant rituximab, with no improvement in response. Grade 3-4 toxicity consisted of infections, thrombocytopenia, anaemia, diarrhoea, and fatigue. HDAC inhibition was observed in six out of nine patients on day 8. Limited activity was observed with single agent MGCD0103 in high risk patients with CLL. Future investigations in CLL should focus on broad HDAC inhibition, combination strategies, and approaches to diminish constitutional symptoms associated with this class of drugs.

First-Line Treatment of Patients With Indolent Non-Hodgkin Lymphoma or Mantle-Cell Lymphoma With Bendamustine Plus Rituximab Versus R-CHOP or R-CVP: Results of the BRIGHT 5-Year Follow-Up Study.

PURPOSE: The BRIGHT study ( ClinicalTrials.gov identifier: NCT00877006) was initiated to compare the efficacy and safety of bendamustine plus rituximab (BR) with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) for treatment-naive patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma. This publication provides long-term follow-up data. PATIENTS AND METHODS: Patients were monitored for a minimum of 5 years after completion of study treatment for the time-to-event end points of progression-free survival (PFS), event-free survival, duration of response, and overall survival per investigator assessment. Data on the number of patients who received second-line anticancer treatment and the occurrence of other malignancies were also collected. RESULTS: The medians were not reached for any of the time-to event end points for either the BR or R-CHOP/R-CVP study treatment groups by study completion. PFS rates at 5 years were 65.5% in the BR treatment group and 55.8% in the R-CHOP/R-CVP group. The difference in PFS was considered significant with a hazard ratio of 0.61 (95% CI, 0.45 to 0.85; P = .0025). The hazard ratio for event-free survival and duration of response (P = .0020 and .0134, respectively) also favored the BR regimen over R-CHOP/R-CVP. However, no significant difference in overall survival was observed. The overall safety profiles of BR, R-CHOP, and R-CVP were as expected; no new safety data were collected during long-term follow-up. A higher number of secondary malignancies was noted in the BR treatment group. CONCLUSION: Overall, BR demonstrated better long-term disease control than R-CHOP/R-CVP and should be considered as a first-line treatment option for patients with indolent and mantle-cell lymphoma.

Sequential response-adapted induction and consolidation regimens idarubicin/cytarabine and mitoxantrone/etoposide in adult acute myelogenous leukemia: 10 year follow-up of a study by the Canadian Leukemia Studies Group.

PURPOSE: The Canadian Leukemia Studies Group (CLSG) sought to test the safety and efficacy of response-adapted, non-cross resistant chemotherapy in de novo acute myeloid leukemia (AML). The combinations of idarubicin 12 mg/m(2)/d on days 1 - 3 and Ara-C (200 mg/m(2)/d) on days 1 - 7 (IDAC) followed by mitoxantrone 10 mg/m(2)/day, and etoposide 100 mg/m(2)/day, on days 1 - 5 (NOVE) were used according to patient response to induction and consolidation. PATIENTS AND METHODS: In this multi-centre open-label phase II study, 140 patients up to age 80 were given induction with IDAC. Patients were entered between March 1993 and August 1995. If patients had persistent blasts at day 14 or on recovery, they were given NOVE. As consolidation, patients achieving complete remission (CR) with IDAC were given 1 further cycle of IDAC and 1 cycle of NOVE. Patients achieving CR after NOVE were given 2 further cycles of NOVE. RESULTS: 76% of all patients achieved remission after IDAC +/- NOVE, 81% in patients aged < or =60 years and 67% in patients aged >60. Overall, induction mortality was 11% and toxicity was similar to other cooperative group studies. Median follow-up was 104.0 months with 95% CI: (100.0, 105.2). Median overall survival (OS) in responding patients < or =60 was not reached: of the 79 responders < or =60, 35 died. The median disease free survival (DFS) in these responding patients was 22.7 (14.9, na) months. Median OS and DFS in responding patients >60 was 10.0 (7.3, 15.2) months and 7.5 (6.2, 15.2) months, respectively. CONCLUSION: The results of this trial are very encouraging and suggest that there may be long-term benefit to this method. On the basis of these results, a randomized phase III trial has been performed.

Pesticide assessment: Protecting public health on the home turf.

Pesticide regulation is examined in the context of Health Canada's Pest Management Regulatory Agency's assessment of the chlorophenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) for turf. 2,4-D is the most common herbicide used to kill weeds in grass.The medical literature does not uniformly indicate harms from herbicides. However, the balance of epidemiological research suggests that 2,4-D can be persuasively linked to cancers, neurological impairment and reproductive problems. These may arise from 2,4-D itself, from breakdown products or dioxin contamination, or from a combination of chemicals.Regulators rely largely on toxicology, but experiments may not replicate exposures from 2,4-D application to lawns because environmental breakdown products (eg, 2,4-dichlorophenol) may not accumulate and selected herbicides are possibly less contaminated. Dioxins are bioaccumulative chemicals that may cause cancer, harm neurological development, impair reproduction, disrupt the endocrine system and alter immune function. No dioxin analyses were submitted to the Pest Management Regulatory Agency, and the principal contaminants of 2,4-D are not among the 17 congeners covered in pesticide regulation. Independent assessment of all dioxins is needed, in tissues and in the environment.The 2,4-D assessment does not approach standards for ethics, rigour or transparency in medical research. Canada needs a stronger regulator for pesticides. Potentially toxic chemicals should not be registered when more benign solutions exist, risks are not clearly quantifiable or potential risks outweigh benefits. Until landscaping pesticides are curtailed nationally, local bylaws and Quebec's Pesticide Code are prudent measures to protect public health. Physicians have a role in public education regarding pesticides.

Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma.

BACKGROUND: We previously reported results of the phase III, randomized, noninferiority trial comparing bendamustine-rituximab (BR) with standard R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone)/R-CVP (rituximab/cyclophosphamide/vincristine/prednisone) in previously untreated advanced indolent non-Hodgkin and mantle cell lymphomas. Here we report health-related quality of life (HRQOL) results from the trial. METHODS: HRQOL, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), was a secondary end point. Differences between group means in global health status (GHS), 5-item functioning, and 9 symptoms/single-item measures at week 1 of cycle 1 and end-of- cycles 3 and 6 were examined using the screening (baseline) score as a covariate in analysis of covariance. RESULTS: Overall EORTC QLQ-C30 compliance was 75.2%, 89.5%, and 89.9% at week 1 of cycle 1 and end-of-cycles 3 and 6, respectively. Patients treated with BR reported improvements in Cognitive Functioning, Physical Functioning, Social Functioning, Emotional Functioning, and GHS as well as reduction in dyspnea, constipation, and fatigue at some, but not all, time points. Patients treated with standard therapy reported less nausea/vomiting at one time point. CONCLUSION: Compared with patients treated with standard therapy, patients treated with BR reported better quality of life in several areas.

Effect of bendamustine in combination with rituximab on QT interval duration in patients with advanced de novo indolent non-Hodgkin or mantle cell lymphoma.

PURPOSE: Bendamustine is used in chronic lymphocytic leukemia (first-line) and indolent B-cell non-Hodgkin lymphoma (NHL) that progressed during/within 6 months of treatment with rituximab or a rituximab-containing regimen. This study was a postapproval commitment to investigate bendamustine's effect on cardiac repolarization in treatment-naïve adults with advanced indolent NHL/mantle cell lymphoma (MCL). METHODS: In this multicenter, open-label, phase 3 study, patients received 6-8 28-day cycles of bendamustine (90 mg/m(2), days 1 and 2) and rituximab (375 mg/m(2), day 1). Exclusions included a history of cardiac conditions with potential for QT prolongation. The primary endpoint was change in Fridericia-corrected QT (QTcF; 3 electrocardiograms per time point) on day 2 of cycle 1, from just before infusion to end of infusion (immediately postinfusion, coinciding with maximum plasma concentration of bendamustine). Change 1 h postinfusion was also measured. Exploratory assessments included specific QTcF outlier analyses (new QTcF >500 ms, change >60 ms) and morphological changes. RESULTS: Of the 54 enrolled patients (mean age, 62.9 years), 53 received ≥1 dose; 49 completed ≥6 cycles. Mean QTcF change from baseline was 6.7 ms at end of infusion; no mean changes >20 ms were detected ≤1 h postinfusion. No patients met specific outlier criteria at end of infusion or 1 h postinfusion. No morphological changes were detected. CONCLUSIONS: In this small treatment-naïve population with advanced NHL/MCL, bendamustine did not produce a clinically relevant increase in mean QTcF on the second infusion day. The potential for delayed effects on QT interval after 1 h was not evaluated.

Coexisting mantle cell lymphoma and prostate adenocarcinoma.

Prostatic mantle cell lymphoma (MCL) is a very rare entity with only 5 reported cases in the literature. We report a case of coexisting MCL and prostate adenocarcinoma (PCa) in an elderly male and review the morphologic features of classic and rare prostatic MCL subtypes. Careful morphologic evaluation and immunohistochemical findings of positive CD5, CD20, and cyclin D1 and negative CD23 and CD3 can guide us to the diagnosis of MCL. Given the fact that transurethral resection of prostate is done quite routinely, this paper draws attention to the manner in which long standing bladder outlet obstruction and postbiopsy prostate specimens with dense lymphoid infiltration can masquerade as lymphoma. It highlights the importance of exercising care while reviewing prostate specimens with evidence of chronic prostatitis so as not to miss this rare neoplasm.

Bendamustine for indolent non-Hodgkin lymphoma in the front-line or relapsed setting: a review of pharmacokinetics and clinical trial outcomes.

Bendamustine is an agent with mostly alkylating properties, which acts on dividing cells through multiple pathways. As an agent with little cross-resistance with other chemotherapeutic agents, bendamustine has received approval for second-line use in relapsed/refractory indolent lymphomas. A growing body of data showing good efficacy and acceptable tolerability of bendamustine in first-line use has led to recognition that this agent has an important role in this setting. This article outlines the pharmacology and clinical studies supporting the use of bendamustine and discusses the role of this agent in the first- and second-line treatment of indolent lymphomas.