The Experts below are selected from a list of 7944 Experts worldwide ranked by ideXlab platform
Lorenzo M Leoni - One of the best experts on this subject based on the ideXlab platform.
-
Bendamustine rescue of an effective antineoplastic agent from the mid twentieth century
Seminars in Hematology, 2011Co-Authors: Lorenzo M LeoniAbstract: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.
-
Mechanism of action: the unique pattern of Bendamustine-induced cytotoxicity.
Seminars in hematology, 2011Co-Authors: Lorenzo M Leoni, John A HartleyAbstract:Bendamustine has demonstrated substantial efficacy in the treatment of hematologic malignancies and continues to distinguish itself from other alkylating agents with regard to its activity in tumor cells. The mechanistic and clinical differences associated with Bendamustine may be directly related to its unique structural features. Although the precise mechanisms of action are still poorly understood, Bendamustine is associated with extensive and durable DNA damage. The increased potency of Bendamustine may be due to secondary mechanisms such as inhibition of mitotic checkpoints, inefficient DNA repair, and initiation of p53-dependent DNA-damage stress response, all of which lead to mitotic catastrophe and apoptosis. It has also been hypothesized that the presence of a benzimidazole ring in addition to the nitrogen mustard group may influence the way Bendamustine interacts with DNA and/or confer antimetabolite properties. Further elucidation of the mechanisms of action for Bendamustine and the signaling pathways involved in the response to Bendamustine-induced DNA damage is essential to maximize its therapeutic potential, identify biomarkers for response, and understand the potential for synergy with other agents involved in DNA damage and inhibition of DNA repair. This review will discuss the current understanding and hypotheses regarding Bendamustine mechanisms of action and suggest future investigations that would shed light on the many unanswered questions.
-
Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents
Clinical cancer research : an official journal of the American Association for Cancer Research, 2008Co-Authors: Lorenzo M Leoni, Brandi Bailey, Jack Reifert, Heather Bendall, Robert W. Zeller, Jacques Corbeil, Gary Elliott, Christina NiemeyerAbstract:Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of Bendamustine and to compare it with structurally related compounds. Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to Bendamustine and compare it with chlorambucil and phosphoramide mustard. Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, Bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. Conclusion: These results suggest that Bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
-
Bendamustine treanda displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents
Clinical Cancer Research, 2008Co-Authors: Lorenzo M Leoni, Brandi Bailey, Jack Reifert, Heather Bendall, Robert W. Zeller, Jacques Corbeil, Gary Elliott, Christina NiemeyerAbstract:Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of Bendamustine and to compare it with structurally related compounds. Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to Bendamustine and compare it with chlorambucil and phosphoramide mustard. Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, Bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. Conclusion: These results suggest that Bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
Bruce D. Cheson - One of the best experts on this subject based on the ideXlab platform.
-
long term outcomes secondary malignancies and stem cell collection following Bendamustine in patients with previously treated non hodgkin lymphoma
British Journal of Haematology, 2017Co-Authors: Peter Martin, Jonathan W. Friedberg, Bruce D. Cheson, Zhengming Chen, Katherine Sue Robinson, Michael D Williams, Saurabh Rajguru, Richard Van Der Jagt, Ann S Lacasce, Robin JoyceAbstract:Summary 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.
-
long term outcomes secondary malignancies and stem cell collection following Bendamustine in patients with previously treated indolent non hodgkin lymphoma
Blood, 2015Co-Authors: Peter Martin, Jonathan W. Friedberg, Bruce D. Cheson, Zhengming Chen, Katherine Sue Robinson, Saurabh Rajguru, Richard Van Der Jagt, Michael E Williams, Tricia Ellis, Ann S LacasceAbstract:Background Given the widespread use of Bendamustine, data on long-term outcomes are essential for patients and clinicians to understand potential risks and benefits of therapy. Despite a long history as treatment for indolent non-Hodgkin lymphoma (iNHL), such information has been limited. We retrospectively reviewed the registration SDX-105-01 and SDX-105-03 trials (Bendamustine 120 mg/m2 days 1+2 q21 days) and SDX-105-02 trial (Bendamustine 90 mg/m2 days 1+2 plus rituximab 375 mg/m2 day 1 q28 days) to characterize long-term toxicity and efficacy of patients treated with Bendamustine. Methods Patient level data was retrospectively collected from patients treated on the SDX-01, 02, and 03 trials. Descriptive statistics were used to summarize patient characteristics and events. The Kaplan-Meier method was used to report time-to-event outcomes. Wilcoxon Rank sum test was used to test the difference between events for continuous variables. Results Out of the total 245 subjects at 45 sites, data were available for 149 subjects (60 men, 89 women; SDX-01 N = 40, SDX-02 N = 43, SDX-03 N = 66) at 21 sites (included based on willingness to participate). The median age was 60 years at the start of Bendamustine (range 39-84). The histologies included grade 1-2 follicular lymphoma (FL; N = 73), grade 3 FL (N = 23), SLL (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 average time from diagnosis to study entry was 41 months (range 2-229). The median number of therapies prior to Bendamustine was 2.5 (range 1-8). Patients received a median of 6 cycles and a median total dose of Bendamustine of 1408 mg (max 5216, min 240). With a median follow up of 8.8 years after study entry, 80 patients had experienced progression. The median PFS was 18.4 months (95% C.I. 11.9-27.8); the 3-year PFS was 37%. During follow up, 93 patients had died at a median time of 22.3 months after the start of Bendamustine. The median OS after start of Bendamustine was 65.9 months (95% C.I. 38.8-91.8). The causes of death were lymphoma (N = 45), Bendamustine toxicity (N = 2), subsequent treatment toxicity (N = 8), MDS/AML (N = 5), other cancer (N = 2), other (N = 6), and unknown (N = 25). A total of 98 patients received a median of 2 therapies following Bendamustine (range 1-9), with the first treatment occurring a median of 13.2 months (range 0-111.3) following the final dose of Bendamustine. The reported best response to the first subsequent treatment was CR (N = 11), PR (N = 6), SD (N = 21), PD (N = 12), not evaluable (N = 25), and unknown (N = 22) and the median OS of these patients was 51.3 months (95% C.I. 33.4-80.3). Fourteen patients had attempted stem cell collection following Bendamustine, 10 of which had stem cells collected successfully. Eight patients had stem cells collected with GCSF alone (N = 7) or GCSF plus chemotherapy (N = 1). Twenty-three patients developed 25 cancers following Bendamustine. Six patients developed MDS and 2 more developed AML. The median time to MDS/AML following Bendamustine was 24 months (range 10-103) with an annualized incidence rate of 0.52%/year. One of patient had a prior myeloid neoplasm and one had a prior germ cell tumor. In univariate analysis, neither age at lymphoma diagnosis (P=0.438), nor total number of systemic regimens (P=0.443), nor total dose of Bendamustine (P=0.291) was associated with MDS/AML. Other cancers included adenocarcinoma (colon N = 2; prostate N = 2; lung N = 2; breast N = 1), non-melanoma skin cancer (N = 6), squamous cell carcinoma (N = 2), hepatocellular carcinoma (N = 1), and bladder cancer (N = 1). None of these occurred in the 12 patients with a history of solid tumor before Bendamustine. Conclusions With a median follow up of survivors of > 8 years, there was no evidence that Bendamustine in the setting of previously treated iNHL was associated with a high rate of long-term bone marrow toxicity. Rates of MDS/AML and failure to collect stem cells were lower than expected. However, roughly half of all patients died within 5 years of starting Bendamustine, thereby limiting the long-term follow up. 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 many patients with relapsed or refractory iNHL. Disclosures Martin:Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Cheson:AstraZeneca: Consultancy; Ascenta: Research Funding; Spectrum: Consultancy; Astellas: Consultancy; MedImmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; Teva: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding. Williams:Celgene: Consultancy, Other: Research funding to my institution; Takeda: Consultancy, Other: Research Funding to my institution; Genentech: Other: Research funding to my institution. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding. Szer:Pfizer: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Alexion: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Smith:celegene, spectrum, genentech: Honoraria. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy.
-
Optimal use of Bendamustine in hematologic disorders: Treatment recommendations from an international consensus panel - an update.
Leukemia & lymphoma, 2015Co-Authors: Bruce D. Cheson, Wolfram Brugger, Gandhi Damaj, Martin Dreyling, Brad S. Kahl, Eva Kimby, Michinori Ogura, Eckhart Weidmann, Clemens-martin Wendtner, Pier Luigi ZinzaniAbstract:Bendamustine has achieved widespread international regulatory approval and is a standard agent for the treatment for chronic lymphocytic leukemia (CLL), indolent non-Hodgkin lymphoma and multiple myeloma. Since approval, the number of indications for Bendamustine has expanded to include aggressive non-Hodgkin lymphoma and Hodgkin lymphoma and novel targeted therapies, based on new Bendamustine regimens/combinations, are being developed against CLL and lymphomas. In 2010, an international panel of Bendamustine experts met and published a set of recommendations on the safe and effective use of Bendamustine in patients suffering from hematologic disorders. In 2014, this panel met again to update these recommendations since the clarification of issues including optimal dosing and management of Bendamustine-related toxicities. The aim of this report is to communicate the latest consensus on the use of Bendamustine, permitting the expansion of its safe and effective administration, particularly in new combination therapies.
-
Bendamustine: role and evidence in lymphoma therapy, an overview
Leukemia & lymphoma, 2014Co-Authors: Enrico Derenzini, Pier Luigi Zinzani, Bruce D. ChesonAbstract:Bendamustine is a bifunctional molecule with both alkylating and antimetabolite properties, synthesized in 1963 by Ozegowski and Krebs in East Germany (German Democratic Republic). Widely used in Eastern Europe for lymphoma and myeloma therapy during the 1970s and 1980s, Bendamustine was not studied in well-designed clinical trials until the 2000s. Unique among other recently developed antineoplastic drugs, Bendamustine shows high activity and is now approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), being part of the therapeutic armamentarium in indolent and aggressive B-cell non-Hodgkin lymphomas (NHLs), chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL) and multiple myeloma (MM). "Bendamustine: role and clinical evidence in lymphoma therapy" is the title of a workshop which took place in Bologna, Italy, on 28 January 2013. This meeting focused on the development, mechanisms of action and evidence supporting the use of Bendamustine in lymphoma therapy. This report summarizes the drug development steps, mechanisms of action, clinical results and rationale of use of Bendamustine in different lymphoma subtypes, as discussed during the meeting, with the aim of helping the clinician regarding optimal use of this compound in a wide spectrum of lymphoproliferative disorders.
-
Bendamustine: mechanism of action and clinical data.
Clinical advances in hematology & oncology : H&O, 2011Co-Authors: Bruce D. Cheson, Lorenzo LeoniAbstract:Bendamustine is a chemotherapeutic agent that displays a unique pattern of cytotoxicity compared with conventional alkylating agents. Bendamustine was originally synthesized in the former East German Democratic Republic in the 1960s. It was designed to have both alkylating and antimetabolite properties. The alkylating agent properties are similar to those seen with cyclophosphamide, chlorambucil, and melphalan, and the benzimidazole ring is similar to cladribine. Molecular analyses have revealed that Bendamustine differs from other alkylating agents in its mechanism of action. Differences have been observed in regard to its effects on DNA repair and cell cycle progression. Moreover, Bendamustine can induce cell death through both apoptotic and nonapoptotic pathways, thereby retaining activity even in cells without a functional apoptotic pathway. Bendamustine has demonstrated significant efficacy in patients with indolent lymphomas and chronic lymphocytic leukemia (CLL), including in patients with disease refractory to conventional alkylating agents and rituximab. The toxicity profile of Bendamustine is also superior to that of conventional alkylating agents. Combination therapy with Bendamustine and rituximab has demonstrated superior efficacy to a standard rituximab-containing chemotherapy regimen in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, and it is currently being compared against the standard first-line regimen in CLL: fludarabine, cyclophosphamide, and rituximab. Ongoing and planned studies are evaluating new strategies in which Bendamustine is being combined with existing agents and with novel therapies to optimize use in different clinical settings.
Mathias J Rummel - One of the best experts on this subject based on the ideXlab platform.
-
Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle cell lymphomas a multicentre randomised open label non inferiority phase 3 trial
Lancet Oncology, 2016Co-Authors: Mathias J Rummel, Wolfram Brugger, Norbert Niederle, Ulrich Kaiser, Christina Balser, Martina Stauch, Manfred Welslau, Christoph Losem, Hanspeter Boeck, Eckhart WeidmannAbstract:Summary Background Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to compare the efficacy and safety of rituximab with Bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma. Methods For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m 2 , day 1) plus either Bendamustine (90 mg/m 2 , days 1 and 2) or fludarabine (25 mg/m 2 , days 1–3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0–2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, Bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of Bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m 2 every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov, number NCT01456351 (closed to enrolment, follow-up is ongoing). Findings Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 Bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the Bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 Bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with Bendamustine plus rituximab was 0·76 (95% CI 0·68–0·84) and 0·48 (0·39–0·58) with fludarabine plus rituximab (non-inferiority p Interpretation In combination with rituximab, Bendamustine was more effective than fludarabine, suggesting that Bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas. Funding Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL).
-
Bendamustine's emerging role in the management of lymphoid malignancies.
Seminars in hematology, 2011Co-Authors: Mathias J Rummel, Stephanie A GregoryAbstract:The potent alkylating agent Bendamustine has demonstrated substantial efficacy in patients with non-Hodgkin lymphomas (NHLs), including chronic lymphocytic leukemia (CLL), follicular lymphoma, and mantle cell lymphoma. Due to incomplete cross-reactivity between Bendamustine and other chemotherapeutic agents, Bendamustine has been extensively tested in the relapsed/refractory setting. Bendamustine is highly effective in rituximab-refractory NHL and in patients whose disease is refractory to chemotherapy, including other alkylating agents. It has also demonstrated considerable efficacy in previously untreated NHLs, both alone and in combination with rituximab or other chemotherapeutic agents. Studies suggest complete responses and durability of remission achieved with Bendamustine are superior to those achieved with standard regimens. However, longer follow-up is needed to fully establish long-term response duration. Additionally, Bendamustine is associated with hematologic toxicity and risk of infection, which must be carefully monitored and managed. This is particularly important in elderly patients with advanced disease. Increased understanding of the mechanisms of action of Bendamustine and the efficacy of Bendamustine in combination with rituximab in newly diagnosed or relapsed/refractory CLL and indolent lymphomas led to investigation of other combinations. Ongoing studies are examining Bendamustine with bortezomib, lenalidomide, temsirolimus, ofatumumab, alemtuzumab, and other novel agents. Bendamustine is also undergoing clinical investigation in patients with relapsed/refractory diffuse large B-cell lymphomas, a patient population with limited therapeutic options currently. This review will summarize current clinical data regarding the efficacy and safety of Bendamustine in patients with lymphoma and highlight ongoing clinical trials expanding the role of this alkylating agent in the treatment of hematologic malignancies.
-
Bendamustine: Rebirth of an Old Drug
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2009Co-Authors: Bruce D. Cheson, Mathias J RummelAbstract:Bendamustine is a unique cytotoxic agent with structural similarities to alkylating agents and antimetabolites, but which is non–cross-resistant with alkylating agents and other drugs in vitro and in the clinic. Early clinical studies conducted in the German Democratic Republic more than 30 years ago suggested promising activity in indolent non-Hodgkin's lymphoma (NHL). Two North American trials reported responses in more than 70% of patients with chemotherapy- and rituximab-refractory disease, suggesting that Bendamustine may be the most effective drug available for this patient population. Response rates of 90% to 92%, with complete remission in 55% to 60%, have been reported in patients with follicular and mantle-cell lymphoma with the combination of Bendamustine and rituximab. Superiority over chlorambucil in previously untreated patients with chronic lymphocytic leukemia (CLL) led to its recent approval for this disease in the United States. Bendamustine is approved in Germany for the treatment of pa...
-
German Experience with Bendamustine in B-cell Lymphoid Malignancies
Clinical advances in hematology & oncology, 2009Co-Authors: Mathias J RummelAbstract:Non-Hodgkin's lymphoma (NHL) is a challenging disease to treat, due to an inability to achieve a cure with conventional therapeutic regimens and a high likelihood of relapse after treatment. There are many subtypes of lymphoma; some are indolent, such as follicular lymphoma (FL), while others are aggressive and require aggressive therapies. Bendamustine, a novel agent that is a hybrid of nitrogen mustard with a purine antimetabolite, has shown promise in relapsed/refractory patients with FL and other indolent lymphomas. In a multicenter phase II study, Bendamustine as a single agent has induced responses even in heavily pretreated patients. Several German clinical trials have explored and are continuing to explore the effects of Bendamustine in combination with other agents for lymphomas. Bendamustine has been combined with rituximab in several trials with promising results. Other trials have combined Bendamustine with fludarabine, vincristine and prednisolone, or mitoxantrone with or without rituximab. These studies by the German groups should offer new insights into the utility of Bendamustine in the treatment of B-cell lymphomas.
-
Bendamustine in Chronic Lymphocytic Leukemia and Refractory Lymphoma
Seminars in hematology, 2008Co-Authors: Mathias J RummelAbstract:Bendamustine is a water-soluble, bifunctional chemotherapeutic agent with characteristics of both an alkylator and a purine analog. Bendamustine combined with rituximab in vitro shows synergistic effects against various leukemia and lymphoma cell lines. Clinical trials supporting these results show that Bendamustine plus rituximab is highly effective in relapsed and refractory patients with indolent lymphoma. The results have been found in rituximab-naive, rituximab-pretreated, and rituximab-refractory patients with excellent response rates and toxicity profiles. Bendamustine is effective both with rituximab and as a monotherapy in rituximab-refractory patients. Interim results from a phase III, randomized trial comparing Bendamustine and rituximab to a standard CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab regimen suggest that combination Bendamustine and rituximab may provide a viable alternative for treatment of many indolent lymphomas.
Christina Niemeyer - One of the best experts on this subject based on the ideXlab platform.
-
Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents
Clinical cancer research : an official journal of the American Association for Cancer Research, 2008Co-Authors: Lorenzo M Leoni, Brandi Bailey, Jack Reifert, Heather Bendall, Robert W. Zeller, Jacques Corbeil, Gary Elliott, Christina NiemeyerAbstract:Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of Bendamustine and to compare it with structurally related compounds. Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to Bendamustine and compare it with chlorambucil and phosphoramide mustard. Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, Bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. Conclusion: These results suggest that Bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
-
Bendamustine treanda displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents
Clinical Cancer Research, 2008Co-Authors: Lorenzo M Leoni, Brandi Bailey, Jack Reifert, Heather Bendall, Robert W. Zeller, Jacques Corbeil, Gary Elliott, Christina NiemeyerAbstract:Purpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of Bendamustine and to compare it with structurally related compounds. Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to Bendamustine and compare it with chlorambucil and phosphoramide mustard. Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, Bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. Conclusion: These results suggest that Bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
Nishant Tageja - One of the best experts on this subject based on the ideXlab platform.
-
Bendamustine safety and efficacy in the management of indolent non hodgkins lymphoma
Clinical Medicine Insights: Oncology, 2011Co-Authors: Nishant TagejaAbstract:Bendamustine (Treanda, Ribomustin) was recently approved by the US Food and Drug Administration (FDA) for treatment of patients with rituximab refractory indolent lymphoma and is expected to turn into a frontline therapy option for indolent lymphoma. This compound with amphoteric properties was designed in the former Germany Democratic Republic in 1960s and re-discovered in 1990s with multiple successive well-designed studies. Bendamustine possesses a unique mechanism of action with potential anti-metabolite properties, and only partial cross-resistance with other alkylators. Used in combination with rituximab in vitro, Bendamustine shows synergistic effects against various leukemia and lymphoma cell lines. In clinical studies, Bendamustine plus rituximab is highly effective in patients with relapsed-refractory indolent lymphoma, inducing remissions in 90% or more and a median progression-free survival of 23–24 months. The optimal dosing and schedule of Bendamustine administration is largely undecided and varies among studies. Results of ongoing trials and dose-finding studies will help to further help ascertain the optimal place of Bendamustine in the management of indolent NHL.
-
Bendamustine: something old, something new
Cancer Chemotherapy and Pharmacology, 2010Co-Authors: Nishant Tageja, Jasdeepa NagiAbstract:Background Bendamustine (Treanda, Ribomustin) is a water-soluble, bifunctional chemotherapeutic agent that also has potential antimetabolite properties and only partial cross-resistance with other alkylators. Designed in 1963 and re-discovered in 1990s, this drug’s unique mechanism of action and favorable side-effect profile promise a major role in the management of lymphoproliferative disorders. Bendamustine has been designated as an orphan drug in the United States, conferring prolonged market exclusivity. Objective This article provides a comprehensive review of the data on efficacy and toxicity from trials investigating the use of Bendamustine for the treatment of lymphoproliferative neoplasms. The pharmacology, pharmacokinetics, and pre-clinical studies with Bendamustine are also reviewed. Methods MEDLINE and Pubmed databases (1970–2010) were searched using the terms Bendamustine, bendamustin, Treanda, Ribomustin, SDX-105, IMET-3393, and Cytostasan. All relevant articles were reviewed and references screened for additional articles. The databases of the American Society of Hematology (2004–2009) and the American Society of Clinical Oncology (1995–2009) were also searched for relevant abstracts. Results Bendamustine induces a remission in more than three-fourths of patients with rituximab-refractory indolent B cell non-Hodgkin lymphoma (NHL). Combined with rituximab in vitro, Bendamustine shows synergistic effects against various leukemia and lymphoma cell lines. Clinical trials supporting these results show that Bendamustine plus rituximab is highly effective in patients with relapsed-refractory indolent lymphoma, inducing remissions in 90% or more and a median progression-free survival of 23–24 months. Bendamustine has been reasonably well tolerated in clinical trials with low propensity to induce alopecia. Conclusions Combination of Bendamustine and rituximab has the potential to become a new standard first-line treatment option for patients with FL, MCL, and indolent lymphomas. Results of ongoing trials will help to further elucidate the optimal role of Bendamustine in indolent NHL.