Rituximab-refractory Indolent non-Hodgkin Lymphoma Research Articles

Budgetary Impact of Bendamustine Ready-to-Dilute Products in Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma to a United States Infusion Facility.

BackgroundBendamustine hydrochloride (BND HCl) is indicated for first-line treatment of chronic lymphocytic leukemia (CLL) and rituximab-refractory indolent non-Hodgkin lymphoma (iNHL). There are two ready-to-dilute (RTD) formulations of BND HCl on the US market: a large-volume, long-duration infusion (BND-L) and a small-volume, short-duration infusion (BND-S). It is estimated that the shorter duration infusion could result in cost savings to infusion facilities.ObjectiveEstimate the one-year budget impact between BND-S and BND-L for use in the treatment of CLL and iNHL when all current BND-L utilization is replaced with BND-S, from the US infusion facility perspective.MethodsAn illustrative budget impact model estimated the change in costs associated with a projected increase from 50% to 100% market share for BND-S. The model included CLL and iNHL patient populations. Budgetary costs reflected facility expenditures on drug acquisition and administration based on recommended dosing for BND-S and BND-L. The base-case model assumptions and inputs were derived from scientific literature and publicly available resources. The total budget impact was calculated annually, along with the differences in per patient cost; one-way sensitivity analyses were conducted.ResultsPer-patient savings with BND-S use after the utilization shift were estimated at $2812.24 for CLL and $4769.01 for iNHL. Across both indications, the total annual incremental savings after the utilization shift were estimated at $452,209 for 250 CLL and iNHL patients in a 10,000-patient infusion facility, resulting in cost savings of $150.74 per BND HCI patient per month and $1808.84 per BND HCI patient per year. The model was sensitive to changes in proportion of patients receiving BND HCI infusions for CLL and iNHL, patient body surface area, and BND-S wholesale acquisition cost.ConclusionThis analysis estimated over $450,000 in annual savings for a 10,000-patient chemotherapy infusion facility following a utilization shift from 50% use of each RTD product to 100% use of BND-S in CLL and iNHL patients, driven by lower acquisition costs for BND-S and lower administration labor costs associated with rapid infusion.

Sustained Overall Survival Benefit of Obinutuzumab Plus Bendamustine Followed By Obinutuzumab Maintenance Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Final Results of the Gadolin Study

Sustained Overall Survival Benefit of Obinutuzumab Plus Bendamustine Followed By Obinutuzumab Maintenance Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Final Results of the Gadolin Study

Applying a Multicriteria Decision Analysis (MCDA) Approach to Elicit Stakeholders' Preferences in Italy: The Case of Obinutuzumab for Rituximab-Refractory Indolent Non-Hodgkin Lymphoma (iNHL).

BackgroundHealthcare decision makers need to make trade-offs between different elements of value of new treatments. Multicriteria decision analysis (MCDA) provides a framework that can help decision makers to understand stakeholders’ preferences and be explicit about the trade-offs that are being made.ObjectiveThe objective of this study was to use MCDA to obtain preferences and views on decision criteria across three stakeholder groups (patients, clinicians and payers) in Italy and to use these to assess the performance of obinutuzumab for rituximab-refractory indolent non-Hodgkin lymphoma (iNHL).MethodsWe used EVIDEM V3.0, an MCDA framework, and collected participants’ preferences via an online survey and structured meetings.ResultsPatients and clinicians expressed a preference for interventions targeting severe conditions. Payers expressed preference for treatments targeting areas with an unmet need, which are cheaper than the comparator, and with high-quality evidence. Obinutuzumab in combination with bendamustine, compared with bendamustine alone, received high positive scores for the criteria ‘disease severity’ and ‘type of therapeutic benefit’ by all three groups, and negative scores on the economic-related criteria, according to all stakeholder groups.ConclusionsMCDA can be used to elicit the views of different stakeholder groups and has the potential to structure and inform reimbursement decisions.Electronic supplementary materialThe online version of this article (doi:10.1007/s41669-017-0048-x) contains supplementary material, which is available to authorized users.

Ibrutinib in Waldenström's macroglobulinemia: revamping the landscape

In The Lancet Oncology, Meletios Dimopoulos and colleagues 1 Dimopoulos MA Trotman J Tedeschi A et al. Ibrutinib monotherapy for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2016; (published online Dec 9.)http://dx.doi.org/10.1016/S1470-2045(16)30632-5 Google Scholar report that the activity of the BTK inhibitor, ibrutinib, in patients with rituximab-refractory Waldenström's macroglobulinemia is not only remarkable, but eclipses the other available treatment options. When attempting to place these results into perspective, a couple of adages regarding clinical trials come to mind. First, “the better the therapy, the less relevant the prognostic factors and the more important the predictive factors.” In almost all B-cell malignancies, including Waldenström's macroglobulinemia, an anti-CD20 antibody, generally rituximab, has become a standard component of most first-line treatment strategies because this drug improves progression-free survival and, often overall survival. Nonetheless, initial chemoimmunotherapy is associated with three potential outcomes: cure for the curable subtypes, such as diffuse large B-cell lymphoma, and for the remaining subtypes, either response with eventual relapse, in which case retreatment with a CD20-based regimen is reasonable, or the absence of a response where the role of additional rituximab is questionable. As such, rituximab refractoriness is considered highly unfavourable, and is traditionally associated with a poor outcome. Few drugs have provided exceptions to this rule. However, in the GADOLIN study, 2 Sehn LH Chua N Mayer J et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin's lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016; 17: 1081-1093 Summary Full Text Full Text PDF PubMed Scopus (232) Google Scholar , 3 Cheson BD Trneny M Bouabdallah K et al. Obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolongs overall survival compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma: updated results of the GADOLIN study. Blood. 2016; 128 (abstr).: 623 Google Scholar the use of the next generation anti-CD20 obinutuzumab prolonged not only progression-free survival but also overall survival in rituximab-refractory follicular and low-grade lymphoma. In the present study of patients with rituximab-refractory disease, the proportions of patients with a response were similar to those in another cohort 4 Treon SP Tripsas CK Meid K et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. New Engl J Med. 2016; 372: 1430-1440 Crossref Scopus (655) Google Scholar who were not refractory to this drug, thus overcoming that adverse feature. Progression-free survival and overall survival results were also very promising. Traditional prognostic factors used in the International Waldenström Scoring System include age, serum IgM level, β-2 microglobulin, and presence of anaemia and thrombocytopenia. 5 Morel P Duhamel A Gobbi P et al. International prognostic scoring system for Waldenström macroglobulinemia. Blood. 2009; 113: 4163-4170 Crossref PubMed Scopus (280) Google Scholar Nevertheless, the activity of ibrutinib in the present study does not seem to be affected by any of those features. More importantly are the findings that suggest that mutations in MYD88 and CXCR4 are predictive of outcome. Although the present substudy enrolled a fairly small sample size (n=31) as part of a larger randomized trial of ibrutinib in this population, the quality of response seemed to be affected by MYD88 and CXCR4 mutational status; although these data must be interpreted with caution due to the small numbers. 4 Treon SP Tripsas CK Meid K et al. Ibrutinib in previously treated Waldenström's macroglobulinemia. New Engl J Med. 2016; 372: 1430-1440 Crossref Scopus (655) Google Scholar More data will be forthcoming on correlations between genotype and outcome after analysis of the main portion of the current study. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trialThe sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia. Full-Text PDF

Obinutuzumab plus Bendamustine Followed by Obinutuzumab Maintenance Prolongs Overall Survival Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Updated Results of the GADOLIN Study

Obinutuzumab plus Bendamustine Followed by Obinutuzumab Maintenance Prolongs Overall Survival Compared with Bendamustine Alone in Patients with Rituximab-Refractory Indolent Non-Hodgkin Lymphoma: Updated Results of the GADOLIN Study

Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone

We present health-related quality of life (HRQoL) data from GADOLIN, comparing bendamustine (B) alone or combined with obinutuzumab (G-B) in rituximab-refractory indolent non-Hodgkin lymphoma patients. The Functional Assessment of Cancer Treatment-Lymphoma (FACT-Lym) questionnaire was administered on day 1 of cycles 1, 3, and 5 during treatment, at end of induction (EOI), bi-monthly for 2 years during maintenance/follow-up, and annually during extended follow-up until progression/death. Time to first ≥6-point worsening from baseline in the FACT-Lym trial outcome index (TOI) was estimated. Minimally important differences at individual subscale and total score level were used to define the proportion of patients reporting improvement on the FACT-Lym lymphoma-specific subscale (≥3 points), FACT-Lym TOI (≥6 points), and FACT-Lym total score (≥7 points). Overall, 396 patients were randomized. Analysis was conducted when 175 Independent Review Committee-assessed progression-free survival (PFS) events were observed. Questionnaire completion rates were generally balanced between arms at baseline, EOI, and final follow-up. Median time to ≥6-point worsening from baseline on the FACT-Lym TOI was 8.0 months in the G-B arm and 4.6 months in the B arm (HR 0.74; 95% CI 0.56–0.98). More G-B patients reported meaningful improvements on the FACT-Lym questionnaire subscales. Results were similar when follicular lymphoma patients were analyzed separately. The delayed time to worsening and greater proportion of patients reporting meaningful improvement in HRQoL in the G-B arm suggest that benefit in PFS is not at the expense of an increase in treatment-related toxicity that could lead to reduced HRQoL.

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Obinutuzumab for the treatment of indolent lymphoma.

Obinutuzumab is a humanized, type II anti-CD20 monoclonal antibody designed for strong induction of direct cell death and antibody-dependent cell-mediated cytotoxicity. The Phase III GADOLIN trial tested the clinical efficacy of obinutuzumab plus bendamustine followed by obinutuzumab monotherapy in rituximab-refractory indolent non-Hodgkin lymphoma versus treatment with bendamustine alone. It demonstrated significantly longer progression-free survival for the obinutuzumab-containing regimen in this difficult to treat patient group. Based on the results of this trial, US FDA approval was most recently granted for obinutuzumab in the treatment of follicular lymphoma that has relapsed after or was refractory to a rituximab-containing regimen. This article summarizes the available data on chemistry, pharmacokinetics, clinical efficacy and safety of obinutuzumab in the treatment of indolent non-Hodgkin lymphoma.

An open-label expanded-access trial of bendamustine in patients with rituximab-refractory indolent non-Hodgkin lymphoma or previously untreated chronic lymphocytic leukemia: BEND-ACT.

Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll. Study objectives were to assess the safety and tolerability of bendamustine monotherapy and to provide patients with access to bendamustine before Health Canada approval. The study aimed to enrol up to 100 patients. All patients with inhl received an intravenous dose of bendamustine 120 mg/m(2) over 60 minutes on days 1 and 2 for up to eight 21- or 28-day treatment cycles. All patients with cll received an intravenous dose of bendamustine 100 mg/m(2) over 30 minutes on days 1 and 2 for up to six 28-day treatment cycles. Of 90 patients treated on study (16 with cll and 74 with inhl), 35 completed the study (4 with cll and 31 with inhl). The most common treatment-emergent adverse events (teaes) were nausea (70%), fatigue (57%), vomiting (40%), and diarrhea (33%)-mostly grades 1 and 2. Ondansetron was the most common supportive medication used in the patients (63.5% of those with inhl and 68.8% of those with cll). Neutropenia (32%), anemia (23%), and thrombocytopenia (21%) were the most frequent hematologic teaes, with neutropenia being the most common grade 3 or 4 teae leading to dose modification. Dose delays occurred in 28 patients (31.3%) because of grade 3 or 4 teaes, with a higher incidence of dose delays being observed in inhl patients on the 21-day treatment cycle than in those on the 28-day treatment cycle (50.0% vs. 24.1%). During the study, 33 patients (36.7%) experienced at least 1 serious adverse event, and 4 deaths were reported (all in patients with inhl). The type and frequency of the teaes reported accorded with observations in earlier clinical trials and post-marketing experiences, thus confirming the acceptable and manageable safety profile of bendamustine.

GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma.

LBA8502 Background: Treatments are limited and outcomes poor in rituximab-refractory (Rit-Ref) iNHL. Bendamustine (B) has a 9 mo median PFS and 10 mo response duration in ph II trials. Obinutuzumab (GA101/Gazyva [G]) is a glycoengineered type II aCD20 mAb with activity and acceptable safety in Rit-Ref NHL. Methods: GADOLIN (NCT01059630) is a ph III open label study in pts with CD20+ Rit-Ref iNHL. In the B arm, pts received B 120 mg/m2 (d1+2, c1–6) alone; GB arm pts received B 90 mg/m2 (d1+2, c1–6) with G 1000 mg (d1, 8, 15 c1, d1 c2–6) for up to six 28d cycles. Non-PD GB pts then received G monotherapy every 2 mo for up to 2 yrs. Primary endpoint was PFS assessed by an independent radiology facility (IRF), with 80% power to detect 43% improvement in median PFS. Results: In the protocol specified interim analysis, 396 pts were randomized to receive B (n = 202 [198 treated]) or GB (n = 194). The IDMC recommended to unblind the study as the primary endpoint had been reached (4 Feb 2015). Baseline characteristics were balanced between arms. Median age was 63 yrs and pts had a median of 2 prior therapies. Median observation time was 20 mo (B) and 22 mo (GB). IRF-assessed median PFS was 14.9 mo (B) and not reached (NR) for GB (HR 0.55, 95% CI 0.4–0.74; p = 0.00011). Median investigator-assessed PFS was 14 mo for B and 29 mo for GB (HR 0.52, 95% CI 0.39–0.70; p < 0.0001). There were no significant differences in IRF-assessed ORR (63.0% B vs 69.1% GB) or CR (12.2% B vs 11.2% GB) at end of induction, in IRF-assessed best overall response up to 12 mo from start of treatment (76.6% B vs 78.6% GB), or in preliminary OS (median OS NR in either arm). In the treatment period, there were fewer Grade ≥ 3 adverse events with B than GB (62.1% B vs 68% GB), notably neutropenia (26.3% B vs 33.0% GB) and infusion-related reactions (3.5% B vs 8.8% GB), but more Grade ≥ 3 thrombocytopenia (16.2% B vs 10.8% GB), anemia (10.1% B vs 7.7% GB) and pneumonia (5.6% B vs 2.6% GB). Conclusions: G combined with B (90 mg/m2) followed by G maintenance significantly improved PFS vs B alone (120 mg/m2) in Rit-Ref iNHL. The clinically meaningful PFS improvement with GB is the first randomized evidence of benefit for a novel aCD20 mAb in Rit-Ref iNHL. Clinical trial information: NCT01059630.

GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma.

GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma.

Bendamustine

Bendamustine (Levact®) is an alkylating agent consisting of three structural elements: a 2-chloroethylamine alkylating group; a butyric acid side chain; and a benzimidazole ring. Although its precise mechanism of action is as yet unknown, it appears to exert its antineoplastic effects via a different mechanism to those of other alkylating agents. This article reviews the utilization of intravenous bendamustine in patients with chronic lymphocytic leukaemia (CLL), rituximab-refractory indolent non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), focusing on indications for which the agent is approved in the EU. As monotherapy, bendamustine was effective in the first-line treatment of adults with CLL, significantly prolonging progression-free survival (PFS) and improving the overall response (OR) rate after a median duration of follow-up of 35 months compared with chlorambucil in a randomized, open-label, multinational, phase III study. PFS and the OR rate were at least 2-fold greater with bendamustine than with chlorambucil when data from the overall patient population were stratified by Binet stage. In the treatment of adults with rituximab-refractory indolent NHL, monotherapy with bendamustine was efficacious, with an OR achieved by at least three-quarters of patients in two noncomparative multicentre studies. Patients with follicular histology or those who had responded or were refractory to their previous chemotherapy regimen (including alkylator therapy) also appeared to respond to bendamustine monotherapy. Front-line combination therapy with bendamustine plus prednisone was significantly more effective than combination therapy with melphalan plus prednisone in prolonging the time to treatment failure, according to a randomized, open-label multicentre, phase III study in adults with MM. Moreover, the benefits of bendamustine plus prednisone appeared to be maintained beyond 30 months, with a retrospective calculation of PFS demonstrating a borderline statistical significance in favour of bendamustine plus prednisone over melphalan plus prednisone. The tolerability profile of bendamustine in adults with CLL, indolent NHL or MM was mostly consistent with the known toxicities of the agent, with adverse events often managed with dose modifications. Although further data are required to fully establish the comparative efficacy of intravenous bendamustine in the management of CLL, rituximab-refractory indolent NHL or MM, it appears to be a useful addition to the armamentarium of currently available therapies for these haematological malignancies.

Optimizing Premedications in the Prevention of Bendamustine Infusion-Related Reactions

Bendamustine is indicated for the treatment of chronic lymphocytic leukemia (CLL) and rituximab refractory indolent non-Hodgkin lymphoma. Clinical trials have reported a 25% incidence of infusion-related reactions (IRRs) in patients receiving bendamustine. While these reactions are well documented, there is no consensus on the optimal premedication regimen for the prevention of these adverse effects. At our center, we utilize a regimen of ondansetron 16 mg orally and dexamethasone 10 mg IV push prior to each infusion of bendamustine. This report describes our experience with our current premedication regimen with regard to IRRs and the incidence of febrile neutropenia (FN). We retrospectively analyzed 73 consecutive patients receiving bendamustine infusions at our institute from June 2008 to June 2010 to determine the incidence of IRRs and FN. The primary objective was to determine the incidence of IRRs. Secondary objectives included incidence of FN and hospital admission rate. A total of 478 infusions of bendamustine were administered to 73 consecutive patients. The median patient age was 69 years. IRRs affected 19% of our population, and 10.9% experienced FN. Notably, all IRRs were attributed to rituximab infusions and no patients experienced an IRR when receiving bendamustine alone. This compares favorably to the initial reported IRRs of 25% with bendamustine alone. Based on our experience with bendamustine, ondansetron and dexamethasone provide a safe and effective prevention of IRRs associated with bendamustine. By avoiding the use of other premedications, the likelihood of additional complications or adverse affects can be minimized.

Bendamustine: Rescue of an Effective Antineoplastic Agent From the Mid-Twentieth Century

Although the alkylating agent bendamustine was developed in Germany in the mid-twentieth century, it has only recently come to the forefront in the rest of the world as an effective chemotherapeutic agent for the treatment of several hematologic malignancies. Based on the activity demonstrated in single-arm and randomized trials, this nitrogen mustard is approved by the US Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia and rituximab-refractory indolent non-Hodgkin lymphoma. The unique structural and mechanistic features of bendamustine differentiate it from other alkylating agents, providing increased stability and potency in DNA cross linking and subsequent cytotoxicity. Due to its unusual development, few studies have closely examined the mechanisms of action for this nitrogen mustard and many unanswered questions remain. Additionally, phase I and pharmacokinetic studies are limited, although increased understanding of the clinical pharmacology of bendamustine led to development of dosing recommendations by international experts based on the available data. The clinical activity of bendamustine as a single agent and in combination with other chemotherapeutic and immunotherapeutic drugs, coupled with its potential lack of cross-resistance with many other chemotherapy agents, make bendamustine an attractive therapy for patients with newly diagnosed and refractory hematologic malignancies. This review will discuss the development of bendamustine, its structural and pharmacologic characteristics, and current data regarding the optimal dosing of this agent in specific clinical settings.

Efficacy of Bendamustine in Rituximab-Refractory Indolent B-Cell Non-Hodgkin Lymphoma: Review of a Pivotal Trial

B-cell malignancies, including B-cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), are the most common hematologic malignancies in the western world. Although excellent response rates are achieved with standard chemoimmunotherapy, patients often relapse and additional treatment is necessary. Bendamustine, a unique cytotoxic agent with alkylating and antimetabolite properties, has been used for decades in Germany for NHL, CLL and multiple myeloma. In 2008, bendamustine was approved by the US FDA for the treatment CLL and rituximab-refractory indolent B-cell NHL. The approval in NHL was based on the results of this multicenter, single-arm trial in which patients with rituximab-refractory indolent NHL received bendamustine 120 mg/m(2) on days 1 and 2 of each 21-day cycle for six to eight cycles. The primary end points were overall response rate and median duration of response, and the secondary end points were progression-free survival and the safety profile. Bendamustine demonstrated significant efficacy with an overall response rate of 75% median duration of response of 9.2 months and median progression-free survival of 9.3 months, as well as easy tolerability. The most common toxicities were nausea, myelosuppression and infection. These results confirm bendamustine's role in rituximab-refractory indolent B-cell NHL.

Optimizing Premedications In the Prevention of Bendamustine Infusion Related Reactions

AbstractAbstract 4370 IntroductionBendamustine is indicated for the treatment of CLL and rituximab-refractory indolent NHL. Clinical trials have reported 25% incidence of infusion related reactions (IRR) in patients receiving bendamustine. While these reactions are well documented, there is no consensus on the optimal premedication regimen for the prevention of these adverse effects. The Moffitt Cancer Center (MCC) utilizes a regimen of ondansetron 16 mg PO and dexamethasone 10 mg IVP prior to each bendamustine infusion. Herein, we report our experience with our current premedication regimen with regards to the IRR as well as the incidence of febrile neutropenia (FN). MethodsWe retrospectively analyzed 79 consecutive patients receiving bendamustine infusions at MCC from June 2008 to June 2010 to determine the incidence of IRR and FN. Data collected include baseline laboratory values, diagnosis, dosing, number of bendamustine infusions, concurrent rituximab use, growth factor utilization, as well as safety data including the rate of adverse reactions, interventions, and hospitalization. The primary objective was to determine the incidence of IRR. Secondary objectives include incidence of febrile neutropenia and hospital admission rate. All analyses were performed using SPSS 17.0. Descriptive statistics were used to analyze data. Results79 consecutive patients received a total of 513 bendamustine infusions at MCC. Median age was 68 years; M:F (52:27). The most common primary malignancies were indolent non-Hodgkin's lymphoma (NHL), 56%; chronic lymphocytic leukemia (CLL), 38%; and multiple myeloma (MM) 6.3%. Patients had received a median of 2 regimens prior to initiation of bendamustine. Bendamustine was utilized as first line treatment in 25% of patients, second line in 17.7%, third line in 25%, and fourth line or greater in 32.3% of patients. Bendamustine infusions were well-tolerated. Infusion-related reactions (IRR) occurred at a rate of 3.35% (17/513) with all reactions attributed to rituximab. Most commonly reported reactions reported were rigors (2%), chills (1%), and fever (<1%). IRR did not occur in patients receiving bendamustine alone. Overall incidence of FN was 11% (9/79). Of 9 patients that developed FN, 7 patients received bendamustine as 3rd line treatment or greater. The incidence of FN in patients that received bendamustine as 1st or 2nd line treatment was 6% (2/36). Patients that received bendamustine as 3rd line or greater had a 16% (7/43) incidence of FN. ConclusionBased on our experience with bendamustine, ondansetron and dexamethasone provide safe and effective prevention of infusion related reactions associated with bendamustine. Notably, all infusion reactions were attributed to rituximab infusions and no patients experienced an infusion related reaction when receiving bendamustine alone. This compares favorably to the initial reported infusion-related reactions with bendamustine alone (25%). In avoiding the use of other premedications, the likelihood of additional complications or adverse affects can be minimized. The overall incidence of FN was comparable to previously published studies. As may be expected, heavily pretreated patients had a higher incidence of FN (6% vs. 16%) than those who had received 1 or no previous treatments and may warrant growth factor support. Disclosures:Tombleson:Cephalon: Research Funding. Off Label Use: Bendamustine used for the treatment of myeloma. Ho:Cephalon: Consultancy, Research Funding. Pinilla-Ibarz:Cephalon: Speakers Bureau. Wetzstein:Cephalon: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Bendamustine HCl (TREANDATM) Treatment Results in High Rates of Objective Response in Patients with Rituximab-Refractory and Alkylator-Refractory Indolent B-Cell Non-Hodgkin's Lymphoma (NHL): Results from a Phase II Multicenter Single-Agent Study (SDX-105-01).

Background: Bendamustine HCl (TreandaTM) is a multifunctional, alkylating agent with novel mechanisms of action. Unlike other commonly used chemotherapeutic agents, bendamustine in vitro induces durable cell damage resulting in rapid cell death in apoptosis-resistant cancer cell lines through the apoptosis independent pathway of mitotic catastrophe. European studies have reported single-agent activity in patients with relapsed/refractory NHL, chronic lymphocytic leukemia, multiple myeloma, and breast cancer.Aim: This study evaluated the efficacy and toxicity of bendamustine in patients with NHL who have relapsed or are refractory to previous chemotherapy regimens. Patients refractory to Rituximab had disease progression within 6 months of treatment.Methods: This Phase II multicenter trial enrolled patients with relapsed indolent or transformed rituximab-refractory B-cell NHL from 17 sites in the US and Canada. Indolent histologic phenotype was seen in 84% of patients, while 16% had transformed disease. Median age of patients was 63 years (range: 38–84) and 88% had Stage III/IV disease. Patients received bendamustine 120 mg/m2 IV over 30–60 minutes, days 1 and 2, every 21 days for up to 6 cycles. Response was measured using the International Working Group criteria.Results: The intent-to-treat (ITT) population consisted of 75 heavily pretreated patients with a median of 2 prior chemotherapies. The overall objective response rate (ORR) in the ITT population was 74%; 25% had a complete response, 49% had a partial response, 12% had stable disease, and 14% had disease progression. Of 15 patients who were refractory to prior alkylator treatment (patients who progressed after at least one prior alkylator-containing therapy), 10 (67%) experienced an objective response to bendamustine. The median duration of response was 6.6 months for all patients, 9.3 months for indolent patients, and 2.4 months for transformed patients. The most frequent nonhematologic adverse events were nausea (63%), fatigue (39%), vomiting (38%), fever (25%), and diarrhea (22%). Most of these events were grade 1 or 2; alopecia and hemorrhagic cystitis were not observed. Grade 3 or 4 reversible hematologic toxicities seen included neutropenia (47%), thrombocytopenia (24%), and anemia (11%).Conclusions: Single-agent bendamustine produced durable objective responses with acceptable toxicity, despite unfavorable prognostic features, in heavily pretreated rituximab-refractory indolent and transformed NHL patients. Durable response has been seen in alkylator-resistant patients. A Phase III trial with bendamustine as a single agent in patients with rituximab-refractory indolent NHL is ongoing.