Bendamustine, a bifunctional nitrogen mustard-derivative alkylating agent and purine analog, is an antineoplastic agent.1, 2, 3, 4, 6, 7, 8, 12, 13
Bendamustine hydrochloride is used for the treatment of chronic lymphocytic leukemia (CLL)1, 2, 3, 21, 23 and has been designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.10
The current indication for use of bendamustine in the treatment of CLL is based principally on the results of a randomized, controlled, multicenter, open-label, phase 3 study comparing bendamustine with chlorambucil in 301 patients with previously untreated, Binet stage B or C (Rai stages I-IV) CLL.1, 2, 3, 4, 9, 21, 23 Criteria for treatment included hematopoietic insufficiency, constitutional (“B”) symptoms (e.g., weight loss of 10% or more, drenching night sweats, extreme fatigue, unexplained fever of 38°C or greater), rapidly progressive disease, or risk of complications from bulky lymphadenopathy.1, 2, 11, 21, 23 Patients with autoimmune hemolytic anemia, autoimmune thrombocytopenia, Richter syndrome, or transformation to prolymphocytic leukemia were excluded.1, 21, 23 In this study, patients were randomized to receive up to 6 cycles of therapy with bendamustine hydrochloride (100 mg/m2 IV daily on days 1 and 2 of each 28-day treatment cycle) or chlorambucil (0.8 mg/kg orally on days 1 and 15 of each 28-day cycle).1, 2, 4, 21, 23 The overall response rate, assessed according to National Cancer Institute (NCI) Working Group criteria for CLL, was 59% for bendamustine versus 26% for chlorambucil, with 8% of patients receiving bendamustine and less than 1% of those receiving chlorambucil achieving complete responses.1, 2, 3, 21, 23 In addition, median progression-free survival was longer (18 versus 6 months) in patients receiving bendamustine than in those receiving chlorambucil.1, 2, 3, 21, 23 The incidence of adverse effects (most commonly neutropenia, leukopenia, thrombocytopenia, anemia, pyrexia, nausea, and vomiting) generally was higher with bendamustine than with chlorambucil therapy.1, 4, 21, 23
Efficacy of bendamustine relative to first-line therapies other than chlorambucil in the treatment of CLL has not been established.1, 2, 21, 23
Rituximab-refractory, Indolent, B-cell Non-Hodgkin's Lymphoma
Bendamustine hydrochloride is used for the treatment of rituximab-refractory, indolent, B-cell non-Hodgkin's lymphoma (NHL).1, 21, 23, 10004, 10005
The current indication for use of bendamustine in the treatment of rituximab-refractory, indolent, B-cell NHL is based principally on the results of an open-label, single-arm, phase 3 study in 100 patients with indolent B-cell NHL that had progressed during or within 6 months following the first dose of rituximab induction therapy (monotherapy) or completion of a rituximab maintenance regimen or a rituximab-containing combination regimen.1, 21, 23, 10004 Patients received bendamustine hydrochloride 120 mg/m2 IV daily on days 1 and 2 of each 21-day cycle for up to 8 cycles.1, 21, 23, 10004 The overall response rate was 74%; 13% of patients achieved a complete response.1, 21, 23, 10004 At a median follow-up of 11.8 months, median progression-free survival was 9.3 months.10004 Median progression-free survival was longer in patients whose disease was sensitive to their last prior chemotherapy regimen than in those who were refractory to their last prior chemotherapy regimen (11.8 versus 7.5 months).10004
In a phase 2 study of bendamustine therapy in patients with rituximab-refractory NHL, median progression-free survival was shorter in patients with indolent disease that had transformed into a more aggressive subtype (i.e., Richter's transformation) than in those without evidence of such transformation (4.2 versus 8.3 months).10005 In this study, thrombocytopenia requiring discontinuance of bendamustine therapy occurred disproportionately in patients who had received prior therapy with a radioimmunoconjugate (i.e., in 6 of 9 such patients); however, 8 of the 9 patients responded to the drug.10005
Previously Untreated, Indolent Non-Hodgkin's Lymphoma or Mantle Cell Lymphoma
Efficacy and safety of bendamustine in combination with rituximab† for the treatment of previously untreated† advanced-stage indolent NHL or previously untreated advanced-stage mantle cell lymphoma† have been studied in two phase 3 studies (Study Group Indolent Lymphomas [StiL] NHL 1-2003 study and BRIGHT).10001, 10018
The first study (StiL NHL 1-2003) was a phase 3, open-label, randomized, noninferiority study in which 514 patients received up to 6 cycles of therapy with either bendamustine in combination with rituximab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).10001 Patients with previously untreated mantle cell lymphoma or indolent NHL, including the CD20-positive histologic subtypes follicular lymphoma (grade 1 or 2), Waldenstrom macroglobulinemia, small lymphocytic lymphoma, and marginal-zone lymphoma, were eligible for enrollment in the study.10001 Patients receiving the bendamustine-rituximab regimen received rituximab 375 mg/m2 IV on day 1 and bendamustine hydrochloride 90 mg/m2 IV daily on days 1 and 2 of each 28-day cycle.10001 Those receiving R-CHOP received rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, doxorubicin hydrochloride 50 mg/m2 IV, and vincristine sulfate 1.4 mg/m2 (up to 2 mg) IV on day 1, followed by prednisone 100 mg orally daily on days 1-5 of each 21-day cycle.10001 The median patient age was about 64 years (range: 31-83), about 78% of patients had stage IV disease, 19% had stage III disease, 54% had follicular lymphoma, and 18% had mantle cell lymphoma.10001 The primary measure of efficacy was progression-free survival.10001 Tumor responses were assessed using the World Health Organization (WHO) criteria.10001
At a median follow-up of 45 months, bendamustine in combination with rituximab was noninferior to R-CHOP in terms of progression-free survival; median progression-free survival was 69.5 and 31.2 months in patients receiving bendamustine in combination with rituximab and those receiving R-CHOP, respectively.10001 A progression-free survival benefit was observed for the bendamustine-rituximab regimen compared with R-CHOP in subset analyses in patients with mantle cell lymphoma, follicular lymphoma, and Waldenstrom macroglobulinemia, but not in those with marginal-zone lymphoma.10001 Overall response rates were similar in patients receiving bendamustine in combination with rituximab and those receiving R-CHOP (93 versus 91%, respectively); however, the complete response rate was higher in the bendamustine-rituximab group (40 versus 30%).10001 Although median overall survival had not been reached in either group at the time of analysis, substantial differences were not observed between the treatment groups.10001 Subgroup analysis suggested that the progression-free survival benefit observed for the bendamustine-rituximab regimen was independent of age, serum LDH concentration, and Follicular Lymphoma International Prognostic Index (FLIPI) score; however, statistical significance was not reached for elevated serum LDH concentration or unfavorable FLIPI score.10001 Although erythematous (16 versus 9%) or allergic (15 versus 6%) skin reactions occurred more frequently in patients receiving bendamustine in combination with rituximab, serious adverse effects (19 versus 29%), grade 3 or 4 leukopenia (37 versus 72%), grade 3 or 4 neutropenia (29 versus 69%), alopecia (0 versus 100%), paresthesia (7 versus 29%), stomatitis (6 versus 19%), infection (37 versus 50%), and sepsis (less than 1 versus 3%) occurred more frequently in those receiving R-CHOP.10001
The second study (BRIGHT) was a phase 3, open-label, randomized, noninferiority study in which 447 patients received 6-8 cycles of therapy with either bendamustine in combination with rituximab or standard combination chemotherapy (R-CHOP or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]).10018 Patients with previously untreated mantle cell lymphoma or CD20-positive indolent NHL, including the histologic subtypes follicular lymphoma (grade 1 or 2), Waldenstrom macroglobulinemia, and marginal-zone lymphoma, were eligible for enrollment in the study.10018 Patients receiving the bendamustine-rituximab regimen received rituximab 375 mg/m2 IV on day 1 and bendamustine hydrochloride 90 mg/m2 IV daily on days 1 and 2 of each 28-day cycle.10018 Those receiving R-CHOP received rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 IV, doxorubicin hydrochloride 50 mg/m2 IV, and vincristine sulfate 1.4 mg/m2 (up to 2 mg) IV on day 1, followed by prednisone 100 mg daily on days 1-5 of each 21-day cycle, while those receiving R-CVP received rituximab 375 mg/m2 IV, cyclophosphamide 750 mg/m2 (option of 1 g/m2) IV, and vincristine sulfate 1.4 mg/m2 (up to 2 mg) IV on day 1, followed by prednisone 100 mg daily on days 1-5 of each 21-day cycle.10018 The median patient age was about 60 years (range: 25-86); about 68% of patients had stage IV disease, 22% had stage III disease, 70% had follicular lymphoma, and 17% had mantle cell lymphoma.10018 The primary measure of efficacy was the rate of complete response, as defined by the International Working Group (IWG) criteria and assessed by a blinded independent review committee.10018
Bendamustine in combination with rituximab was noninferior to R-CHOP and R-CVP for attainment of complete response; complete response was achieved in 31% of patients receiving bendamustine in combination with rituximab compared with 25% of those receiving R-CHOP or R-CVP.10018 Although complete response rates in patients with indolent NHL (mainly follicular lymphoma) tended to favor the bendamustine-rituximab regimen over R-CHOP or R-CVP, subset analysis failed to establish noninferiority of the bendamustine-rituximab regimen in patients with indolent NHL or follicular lymphoma.10018 In the subset of patients with mantle cell lymphoma, complete response rates were higher in patients receiving bendamustine in combination with rituximab compared with those receiving R-CHOP or R-CVP.10018 Overall response rates were higher in patients receiving bendamustine in combination with rituximab compared with those receiving R-CHOP or R-CVP (97 versus 91%).10018 Follow-up to establish long-term efficacy is ongoing for this study.10018 Hypersensitivity reactions, vomiting, and nausea occurred more frequently in patients receiving bendamustine in combination with rituximab, while peripheral neuropathy, paresthesia, alopecia, constipation, and grade 3 or 4 leukopenia or neutropenia occurred more frequently in patients receiving R-CHOP and/or those receiving R-CVP.10018 Although use of type 3 serotoninergic (5-HT3) receptor antagonists was similar in all treatment groups, concomitant use of aprepitant was more common in patients receiving R-CHOP than in those receiving bendamustine in combination with rituximab or those receiving R-CVP.10018
Based on current evidence,10001, 10018 use of bendamustine in combination with rituximab may be considered a reasonable choice (accepted, with possible conditions) for the treatment of previously untreated advanced-stage indolent NHL or mantle cell lymphoma; however, the histologic subtype of NHL should be considered when selecting a combination chemotherapy regimen.10019
Relapsed or Refractory Non-Hodgkin's Lymphoma or Mantle Cell Lymphoma
Efficacy and safety of bendamustine in combination with rituximab† for the treatment of relapsed or refractory† indolent NHL or relapsed or refractory mantle cell lymphoma† in patients who had received up to 3 prior treatment regimens has been studied in 2 open-label, phase 2 studies.10002, 10003
In the first study, 63 patients received rituximab 375 mg/m2 as an IV infusion on day 1, followed by bendamustine hydrochloride 90 mg/m2 daily as an IV infusion on days 2 and 3, administered on a 28-day cycle for a total of 4 cycles.10002 An additional dose of rituximab was administered one week prior to the first bendamustine-rituximab treatment cycle and repeated at 28 days following the last bendamustine-rituximab treatment cycle.10002 Patients with relapsed or refractory mantle cell lymphoma or indolent NHL, including the histologic subtypes follicular lymphoma (grade 1 or 2), Waldenstrom macroglobulinemia, and marginal-zone lymphoma, were eligible for enrollment in the study.10002 Patients who previously received immunotherapy (i.e., rituximab) were excluded from the study.10002 The median patient age was 64 years; 38% of patients had follicular lymphoma, 27% had Waldenstrom macroglobulinemia, and 25% had mantle cell lymphoma.10002 Most patients (68%) enrolled in the study had received 1 prior therapy for their disease and 30% of patients were refractory to their last prior therapy.10002 The primary efficacy end point was progression-free survival.10002 At a median follow-up of 20 months, median progression-free survival was 24 months.10002 Overall response rate was 90%; 60% of patients achieved complete response.10002 Median progression-free survival for the 16 patients with mantle cell lymphoma was 18 months and overall response rate was 75%; 50% of patients with mantle cell lymphoma achieved complete response.10002 Median overall survival had not been reached at the time of analysis; however, the actuarial 48-month survival rate was 55%.10002 Grade 3 or 4 leukopenia, thrombocytopenia, and anemia occurred during 16, 3, and 1% of treatment cycles, respectively.10002
In the second study, 66 patients received rituximab 375 mg/m2 on day 1, followed by bendamustine hydrochloride 90 mg/m2 daily as an IV infusion on days 2 and 3, administered on a 28-day cycle for a total of 4 cycles.10003 An additional dose of rituximab was administered one week prior to the first bendamustine-rituximab treatment cycle and repeated at 28 days following the last bendamustine-rituximab treatment cycle.10003 Patients achieving a response between the second and fourth treatment cycles were permitted to receive an additional 2 cycles of bendamustine-rituximab treatment.10003 Patients with relapsed, CD20-positive mantle cell lymphoma or indolent NHL, including the histologic subtypes follicular lymphoma, small lymphocytic lymphoma, Waldenstrom macroglobulinemia, and marginal-zone lymphoma, were eligible for enrollment in the study.10003 Patients who received prior radioimmunotherapy or high-dose chemotherapy with allogeneic stem-cell transplantation, those receiving concurrent therapy with therapeutic dosages of systemic corticosteroids, and those with rituximab-refractory disease were excluded from the study.10003 The median patient age was 60 years; 61% of patients had follicular lymphoma, and 18% had mantle cell lymphoma.10003 All patients enrolled in the study had a World Health Organization (WHO) performance status of 0-2.10003 The primary efficacy end point was overall response rate.10003 At a median follow-up of 20 months, the overall response rate was 92%; 41% of patients achieved complete response.10003 The median duration of response for all responders was 21 months (range: 18-24 months).10003 Among patients who received prior therapy with rituximab or those who were rituximab-naive, the overall response rate was 86 or 100%, respectively, and the complete response rate was 35 or 48%, respectively.10003 At the time of analysis, median progression-free survival was 23 months.10003 Overall response rate for the 12 patients with mantle cell lymphoma was 92% with a median duration of response of 19 months; 42% of patients with mantle cell lymphoma achieved complete response.10003 Grade 3 or 4 leukopenia, neutropenia, febrile neutropenia, thrombocytopenia, and anemia occurred in 30, 36, 6, 9, and 2% of patients, respectively.10003
Based on current evidence and because of the favorable toxicity profile,10002, 10003 combination therapy with bendamustine and rituximab is recommended (accepted) for use in the treatment of relapsed or refractory indolent NHL or mantle cell lymphoma.10020
Bendamustine hydrochloride is commercially available as an injection concentrate (Bendeka®, Belrapzo®) and as a lyophilized powder (Treanda®).1, 21, 23 The injection concentrate formulation of Treanda® has been discontinued by the manufacturer because of incompatibility with devices, adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).16, 17, 19, 20, 24
Treanda® and Belrapzo® are administered by IV infusion over 30 minutes in patients with chronic lymphocytic leukemia (CLL) or over 60 minutes in patients with rituximab-refractory, indolent, B-cell non-Hodgkin's lymphoma (NHL).1, 23 Bendeka® is administered by IV infusion over 10 minutes in patients with either CLL or rituximab-refractory, indolent, B-cell NHL.21 Care should be taken to avoid extravasation of the drug.1, 21, 23 (See Local Effects under Cautions.)
Appropriate measures (e.g., adequate hydration) should be taken during therapy to prevent tumor lysis syndrome.1, 21, 23 Although allopurinol has been used during the initiation of bendamustine therapy to prevent hyperuricemia, concomitant use of these drugs may increase the risk of severe skin reactions.1, 21, 23 (See Dermatologic Reactions under Cautions.)
In patients who have experienced grade 1 or 2 infusion reactions to the drug, a premedication regimen (e.g., antihistamine, antipyretic, and corticosteroid) should be considered during subsequent treatment cycles.1, 21, 23 (See Dosage under Dosage and Administration.)
The usual precautions for handling and preparing solutions of cytotoxic drugs should be observed with bendamustine.1, 21, 23 The manufacturers recommend use of gloves and safety glasses when handling the drug.1, 21, 23 If bendamustine comes in contact with skin or mucosa, affected areas of skin should be washed immediately and thoroughly with soap and water and affected mucosa should be rinsed thoroughly with water.1, 21, 23 If undiluted Belrapzo® comes in contact with gloves, the manufacturer states that the gloves should be removed and discarded according to usual procedures for handling cytotoxic drugs.23
Bendamustine hydrochloride is commercially available as an injection concentrate (Bendeka®, Belrapzo®) and as a lyophilized powder (Treanda®).1, 21, 23 The injection concentrate formulation of Treanda® has been discontinued by the manufacturer because of incompatibility with devices, adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS).16, 17, 19, 20, 24
The lyophilized powder must be reconstituted and then diluted to prepare a final bendamustine infusion solution.1 Bendamustine hydrochloride injection concentrate must be diluted prior to IV administration.21, 23 Bendamustine hydrochloride injection concentrate is commercially available as a 25-mg/mL solution (Bendeka®, Belrapzo®),21, 23 but the concentration of reconstituted bendamustine hydrochloride lyophilized powder is 5 mg/mL.1
Because bendamustine hydrochloride injection concentrates (Bendeka®, Belrapzo®) and powder for injection (Treanda®) contain no preservatives, infusion solutions should be prepared as close as possible to the time of administration.1, 21, 23 Any unused portions of Treanda® solution should be discarded.1 Because Bendeka® and Belrapzo® injection concentrates are bacteriostatic, partially used vials may be stored at 2-8°C for up to 28 days in the original package for protection from light; however, the manufacturers do not recommend more than 6 withdrawals per vial.21, 23
Dilution of Bendamustine Hydrochloride Injection Concentrate (Belrapzo®)
Belrapzo® injection concentrate is diluted by withdrawing the appropriate dose of bendamustine hydrochloride injection concentrate (containing 25 mg/mL) and immediately adding the concentrate to an infusion bag containing 500 mL of 0.9% sodium chloride or 2.5% dextrose and 0.45% sodium chloride, to yield a final concentration of 0.2-0.7 mg/mL.23 The injection concentrate should be allowed to reach room temperature prior to dilution.23 The injection concentrate and final diluted solution of the drug should be inspected visually for particulate matter and discoloration.23 The contents of the vials may partially freeze during refrigeration; the injection concentrate should be discarded if particulate matter is visible after the solution has reached room temperature.23 Diluted bendamustine hydrochloride solutions should be clear and colorless to slightly yellow.23 When prepared as directed using Belrapzo® injection concentrate in 0.9% sodium chloride or 2.5% dextrose and 0.45% sodium chloride injection, infusion solutions of bendamustine hydrochloride are stable for 24 hours when stored at 2-8°C and for 3 hours when stored at room temperature under normal room light conditions.23 Administration of the drug must be completed within these time periods.23 Any unused portions of the final diluted solution should be discarded.23
Dilution of Bendamustine Hydrochloride Injection Concentrate (Bendeka®)
Bendeka® injection concentrate is diluted by withdrawing the appropriate dose of bendamustine hydrochloride injection concentrate (containing 25 mg/mL) and immediately adding the concentrate to an infusion bag containing 50 mL of 0.9% sodium chloride, 2.5% dextrose and 0.45% sodium chloride, or 5% dextrose injection to yield a final concentration of 1.85-5.6 mg/mL.21 The injection concentrate should be allowed to reach room temperature prior to dilution.21 The injection concentrate and final diluted solution of the drug should be inspected visually for particulate matter and discoloration.21 The contents of the vials may partially freeze during refrigeration; the injection concentrate should be discarded if particulate matter is visible after the solution has reached room temperature.21 Diluted bendamustine hydrochloride solutions should be clear and colorless to yellow.21 When prepared as directed using Bendeka® injection concentrate in 0.9% sodium chloride or 2.5% dextrose and 0.45% sodium chloride injection, infusion solutions of bendamustine hydrochloride are stable for 24 hours when stored at 2-8°C and for 6 hours when stored at room temperature under normal room light conditions.21 When prepared as directed using Bendeka® injection concentrate in 5% dextrose injection, infusion solutions of bendamustine hydrochloride are stable for 24 hours when stored at 2-8°C and for 3 hours when stored at room temperature under normal room light conditions.21 Administration of the drug must be completed within these time periods.21 Any unused portions of the final diluted solution should be discarded.21
Reconstitution and Dilution of Bendamustine Hydrochloride Lyophilized Powder (Treanda®)
Bendamustine hydrochloride powder for injection is reconstituted by adding 5 or 20 mL of sterile water for injection to a vial labeled as containing 25 or 100 mg, respectively, of the drug to provide a solution containing 5 mg/mL.1 The lyophilized powder should dissolve within 5 minutes;1 the vial should be shaken well to facilitate dissolution.1 Within 30 minutes of reconstitution, the appropriate volume of reconstituted solution should be withdrawn from the vial and further diluted immediately in 500 mL of either 0.9% sodium chloride injection or 2.5% dextrose and 0.45% sodium chloride injection, to yield a final concentration of 0.2-0.6 mg/mL.1 The diluted bendamustine hydrochloride solution should be mixed thoroughly.1 Reconstituted and diluted solutions of the drug should be inspected visually for particulate matter and discoloration.1 Reconstituted and diluted bendamustine hydrochloride solutions should be clear and colorless to slightly yellow.1 When prepared as directed using the lyophilized powder, infusion solutions of bendamustine hydrochloride are stable for 24 hours when stored at 2-8°C and for 3 hours when stored at room temperature under normal room light conditions.1 Administration of the drug must be completed within these time periods.1
Appropriate measures (e.g., adequate hydration) should be taken during therapy to prevent hyperuricemia.1, 21, 23 (See Tumor Lysis Syndrome under Cautions.)
Although measures to prevent infusion reactions are not routinely recommended by the manufacturer prior to the initial dose of bendamustine, a premedication regimen (e.g., antihistamine, antipyretic, and corticosteroid) should be considered during subsequent treatment cycles in patients who have experienced grade 1 or 2 infusion reactions to the drug.1, 21, 23 Bendamustine should be discontinued in patients who experience grade 4 infusion reactions.1, 21, 23 Discontinuance of bendamustine therapy should be considered in patients who experience grade 3 infusion reactions.1, 21, 23 (See Infusion Reactions under Cautions.)
The recommended adult dosage of bendamustine hydrochloride for the treatment of CLL is 100 mg/m2 administered by IV infusion over 10 minutes (Bendeka®) or over 30 minutes (Treanda®, Belrapzo®) on days 1 and 2 of each 28-day cycle, for up to 6 cycles.1, 5, 21, 23
Dosage reduction and/or interruption of bendamustine therapy may be necessary in patients experiencing hematologic toxicity.1, 21, 23 Dose delays may be required if blood counts have not recovered to recommended values (absolute neutrophil count [ANC] of at least 1000/mm3 and platelet count of at least 75,000/mm3) prior to initiation of a new treatment cycle.1, 21, 23 Therapy should be interrupted in patients with grade 4 hematologic toxicity.1, 21, 23 Once blood counts have improved and the ANC is at least 1000/mm3 and the platelet count is at least 75,000/mm3, therapy with bendamustine can be resumed at the discretion of the clinician.1, 21, 23 In patients who experience grade 3 or 4 hematologic toxicity, dosage of the drug should be reduced to 50 mg/m2 on days 1 and 2 of each treatment cycle; if grade 3 or 4 toxicity recurs, dosage should be further reduced to 25 mg/m2 on days 1 and 2 of each cycle.1, 21, 23 In patients who have required dosage reductions for toxicity, re-escalation of dosage in subsequent cycles may be considered.1, 21, 23
Dosage reduction and/or interruption of bendamustine therapy also may be necessary in patients experiencing nonhematologic toxicity.1, 21, 23 Therapy should be interrupted in patients with clinically important nonhematologic toxicity of grade 2 or greater.1, 21, 23 Once nonhematologic toxicity has improved to grade 1 or better, therapy with bendamustine can be resumed at the discretion of the clinician.1, 21, 23 In patients with clinically important nonhematologic toxicity of grade 3 or greater, dosage of the drug should be reduced to 50 mg/m2 on days 1 and 2 of each treatment cycle.1, 21, 23 In patients who have required dosage reductions for toxicity, re-escalation of dosage in subsequent cycles may be considered.1, 21, 23
The recommended adult dosage of bendamustine hydrochloride for the treatment of rituximab-refractory, indolent, B-cell NHL is 120 mg/m2 administered by IV infusion over 10 minutes (Bendeka®) or over 60 minutes (Treanda®, Belrapzo®) on days 1 and 2 of each 21-day cycle, for up to 8 cycles.1, 21, 23, 10004
Dosage reduction and/or interruption of bendamustine therapy may be necessary in patients experiencing hematologic toxicity.1, 21, 23 Dose delays may be required if blood counts have not recovered to recommended values (ANC of at least 1000/mm3 and platelet count of at least 75,000/mm3) prior to initiation of a new treatment cycle.1, 21, 23 Therapy should be interrupted in patients with grade 4 hematologic toxicity.1, 21, 23 Once blood counts have improved and the ANC is at least 1000/mm3 and the platelet count is at least 75,000/mm3, therapy with bendamustine can be resumed at the discretion of the clinician.1, 21, 23 In patients who experience grade 4 hematologic toxicity, dosage of the drug should be reduced to 90 mg/m2 on days 1 and 2 of each treatment cycle; if grade 4 toxicity recurs, dosage should be further reduced to 60 mg/m2 on days 1 and 2 of each cycle.1, 21, 23
Dosage reduction and/or interruption of bendamustine therapy also may be necessary in patients experiencing nonhematologic toxicity.1, 21, 23 Therapy should be interrupted in patients with clinically important nonhematologic toxicity of grade 2 or greater.1, 21, 23 Once nonhematologic toxicity has improved to grade 1 or better, therapy with bendamustine can be resumed at the discretion of the clinician.1, 21, 23 In patients with nonhematologic toxicity of grade 3 or greater, dosage of the drug should be reduced to 90 mg/m2 on days 1 and 2 of each treatment cycle; if grade 3 or greater toxicity recurs, dosage should be further reduced to 60 mg/m2 on days 1 and 2 of each cycle.1, 21, 23
When bendamustine has been used in combination with rituximab† in adults with previously untreated† advanced-stage indolent NHL or in adults with previously untreated advanced-stage mantle cell lymphoma†, rituximab 375 mg/m2 has been administered by IV infusion on day 1, followed by IV infusion (over 30-60 minutes) of bendamustine hydrochloride 90 mg/m2 on days 1 and 2.10001, 10018 The bendamustine-rituximab regimen has been administered on a 28-day cycle for up to 8 cycles.10001, 10018
When bendamustine has been used in combination with rituximab† in adults with relapsed or refractory† indolent NHL or in adults with relapsed or refractory mantle cell lymphoma†, rituximab 375 mg/m2 has been administered by IV infusion on day 1, followed by IV infusion (over 30-60 minutes) of bendamustine hydrochloride 90 mg/m2 on days 2 and 3.10002, 10003 The bendamustine-rituximab regimen has been administered on a 28-day cycle for a total of 4-6 cycles.10002, 10003 An additional dose of rituximab has been administered one week prior to the first bendamustine-rituximab treatment cycle and repeated at 28 days following the last bendamustine-rituximab treatment cycle.10002, 10003
Bendamustine should not be used in patients with severe renal impairment (creatinine clearance of less than 30 mL/minute)1, 21, 23 or patients with hepatic impairment with serum AST or ALT concentration of 2.5-10 times the upper limit of normal (ULN) and total serum bilirubin concentration of 1.5-3 times the ULN or total bilirubin concentration exceeding 3 times the ULN.1, 21, 23 (See Renal Impairment and also see Hepatic Impairment under Cautions.)
Known history of hypersensitivity (e.g., anaphylactic or anaphylactoid reaction) to bendamustine or any ingredient in the formulation.1, 21, 23
In clinical trials in patients with rituximab-refractory, indolent, B-cell NHL, grade 3 or 4 myelosuppression occurred in 98% of patients receiving bendamustine, and 2% of patients receiving the drug died from related complications (i.e., neutropenic sepsis, diffuse alveolar hemorrhage, cytomegalovirus [CMV] pneumonia).1, 21, 23
Complete blood cell counts (CBCs) (i.e., leukocytes, platelets, hemoglobin, neutrophils) should be monitored frequently.1, 21, 23 In clinical trials of the drug, blood counts have been monitored weekly initially.1, 21, 23 Data from these studies indicate that blood counts may be expected to reach a nadir during the third week of the treatment cycle; dose delays and/or dosage reductions may be required if recovery to recommended values (i.e., absolute neutrophil count [ANC] of at least 1000/mm3 and platelet count of at least 75,000/mm3) has not occurred prior to initiation of the next cycle of therapy.1, 21, 23 (See Dosage under Dosage and Administration.)
Infections, including pneumonia, sepsis, and hepatitis, have been reported in adults and pediatric patients receiving bendamustine and have been associated with septic shock and death in clinical trials and during postmarketing surveillance.1, 21, 23 Patients with myelosuppression have increased susceptibility to infection and should be advised to contact their clinician immediately if signs or symptoms of infection occur.1, 21, 23 Bendamustine may increase the risk of reactivation of infections, including hepatitis B virus (HBV) infection, CMV infection, tuberculosis, and herpes zoster.1, 21, 23 Appropriate monitoring and measures to prevent reactivation of infections should be instituted prior to initiation of bendamustine therapy.1, 21, 23 If reactivation of an infection occurs, patients should receive appropriate anti-infective therapy.1, 21, 23
Infusion reactions, including fever, chills, pruritus, and rash, occur commonly in patients receiving bendamustine.1, 21, 23 Severe anaphylactic and anaphylactoid reactions have occurred rarely, mainly in the second and subsequent cycles of therapy.1, 21, 23 Patients should be monitored clinically and bendamustine should be discontinued if a severe reaction occurs.1, 21, 23 Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy.1, 21, 23 A premedication regimen (e.g., antihistamine, antipyretic, and corticosteroid) should be considered during subsequent treatment cycles in patients who experience grade 1 or 2 infusion reactions.1, 21, 23 Bendamustine therapy should be discontinued in patients who experience grade 4 infusion reactions.1, 21, 23 If clinically appropriate, discontinuance of bendamustine therapy also may be considered in patients who experience grade 3 infusion reactions.1, 21, 23 Patients who experience grade 3 or worse allergic-type reactions should not be rechallenged with the drug.1, 21, 23
Tumor lysis syndrome has been reported in patients receiving bendamustine in clinical trials and during postmarketing surveillance.1, 21, 23 The onset generally occurs during the first cycle of bendamustine therapy; without appropriate intervention, acute renal failure and death may occur.1, 21, 23 Appropriate measures (e.g., adequate hydration; close monitoring of blood chemistries, particularly potassium and uric acid concentrations) should be used to prevent tumor lysis syndrome.1, 21, 23 Allopurinol has been used during initiation of bendamustine therapy to prevent hyperuricemia; however, concomitant allopurinol therapy may increase the risk of severe skin reactions.1, 21, 23 (See Dermatologic Reactions under Cautions.)
Serious or fatal dermatologic reactions, including rash, toxic skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms [DRESS]), and bullous exanthema, have been reported in patients receiving bendamustine as a single agent, in combination with other antineoplastic agents, or concomitantly with allopurinol.1, 21, 23 Dermatologic reactions in patients receiving the drug may be progressive and increase in severity with continued therapy.1, 21, 23 Patients receiving bendamustine who experience dermatologic reactions should be monitored closely.1, 21, 23 If the reaction is severe or progressive, bendamustine should be withheld or discontinued.1, 21, 23
Liver injury, sometimes fatal or serious, has been reported in patients receiving bendamustine, although confounding factors (e.g., concomitant use of other antineoplastic agents, progressive disease, reactivation of HBV) may have been present in some cases.1, 21, 23 Liver injury generally occurred within the initial 3 months of bendamustine therapy.1, 21, 23 Liver function tests should be monitored prior to and during therapy.1, 21, 23
Development of Other Malignancies
Development of premalignant (e.g., myelodysplastic syndrome, myeloproliferative disorders) and malignant diseases (e.g., acute myelogenous leukemia, bronchial carcinoma) has been reported in patients treated with bendamustine.1, 21, 23 However, an association between development of premalignant and malignant diseases and use of bendamustine has not been established.1, 21, 23
Extravasation of bendamustine has resulted in pain, erythema, and marked swelling that required hospitalization.1, 21, 23 Care should be taken to avoid extravasation of the drug (e.g., by ensuring good venous access prior to administration); the infusion site should be monitored for erythema, swelling, pain, infection, and necrosis during and after administration.1, 21, 23
Fetal/Neonatal Morbidity and Mortality
Bendamustine can cause fetal harm; single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.1, 21, 23
Pregnancy should be avoided during bendamustine therapy.1, 21, 23 The manufacturers recommend that a pregnancy test be performed prior to initiation of bendamustine therapy in females of reproductive potential and that such women should use a reliable method of contraception during and for at least 6 months after discontinuance of bendamustine therapy (see Advice to Patients).1, 21, 23 Men with partners of reproductive potential should be advised to use a reliable method of contraception during and for at least 3 months after discontinuance of bendamustine therapy.1, 21, 23 If bendamustine is used during pregnancy or if the patient becomes pregnant, the patient should be apprised of the potential fetal hazard.1, 21, 23
Based on its mechanism of action and animal studies, bendamustine can cause fetal harm when administered to pregnant females.1, 21, 23 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Males of Reproductive Potential
Results of animal studies suggest that bendamustine may impair male fertility. 1, 21, 23 The long-term effects of bendamustine on male fertility, including the reversibility of adverse effects, have not been established. 1, 21, 23
It is not known whether bendamustine is distributed into milk.1, 21, 23 Because of the potential for serious adverse reactions to bendamustine in breast-fed infants, the manufacturers do not recommend breast-feeding during bendamustine therapy and for at least 1 week after the last dose.1, 21, 23
Pharmacokinetic and adverse effect profiles of bendamustine in pediatric patients (1-19 years of age) with relapsed or refractory acute leukemia are similar to those in adults.1, 21, 23
Efficacy of bendamustine has not been established in pediatric patients.1, 21, 23 Bendamustine hydrochloride (90 or 120 mg/m2 IV daily on days 1 and 2 of each 21-day cycle) was evaluated in a phase 1-2 study in pediatric patients with relapsed or refractory acute leukemia.1, 21, 23 No responses were observed in 32 patients evaluated in the phase 2 portion of the study; however, complete responses were observed in 2 patients with acute lymphocytic leukemia (ALL) receiving bendamustine hydrochloride 90 mg/m2 during the phase 1 portion of the study.1, 21, 23
Pharmacokinetic and adverse effect profiles are similar to those in younger adults.1, 21, 23 In the phase 3 study in chronic lymphocytic leukemia (CLL), overall response rates for bendamustine and chlorambucil were 47 and 22%, respectively, in patients 65 years of age or older versus 70 and 30%, respectively, in those younger than 65 years of age.1, 21, 23, 25, 26 Median durations of progression-free survival with bendamustine and chlorambucil were 12 and 8 months, respectively, in patients 65 years of age or older versus 19 and 8 months, respectively, in those younger than 65 years of age.1, 21, 23, 25, 26
Among patients with rituximab-refractory, indolent, B-cell NHL, overall response rate and duration of response in individuals 65 years of age or older were similar to results in younger adults.1, 21, 23
The pharmacokinetics of bendamustine are not substantially altered in patients with total serum bilirubin concentration less than 1.5 times the ULN and serum AST or ALT concentration less than 2.5 times the ULN.1, 21, 23 The combined effect of serum AST or ALT concentration of 2.5-10 times the ULN and total serum bilirubin concentration of 1.5-3 times the ULN or the effect of total bilirubin concentration exceeding 3 times the ULN on the pharmacokinetics of the drug has not been evaluated to date;1, 21, 23 the manufacturers state that bendamustine should not be used in patients with such aminotransferase or bilirubin concentrations.1, 21, 23
The pharmacokinetics of bendamustine are not substantially altered in patients with mild or moderate renal impairment (creatinine clearance of 30 mL/minute or greater);1, 21, 22, 23 effects of severe renal impairment on the pharmacokinetics of the drug have not been evaluated to date.1, 21, 23 Bendamustine should not be used in patients with severe renal impairment (creatinine clearance of less than 30 mL/minute).1, 21, 23
Limited data suggest that exposure to bendamustine may be increased in Japanese individuals; however, clinical importance in terms of safety and efficacy has not been established.1, 21, 23
Pharmacokinetic and adverse effect profiles are not affected substantially by gender in patients with either CLL or indolent NHL.1, 21, 23, 25, 26 No clinically important differences in efficacy between men and women were observed in patients with rituximab-refractory, indolent B-cell NHL.25, 26 In the phase 3 study in CLL, overall response rates for bendamustine and chlorambucil were 60 and 24%, respectively, in men versus 57 and 28%, respectively, in women.25, 26 Median durations of progression-free survival with bendamustine and chlorambucil were 19 and 6 months, respectively, in men versus 13 and 8 months, respectively, in women.25, 26
Adverse effects reported in 15% or more of patients with rituximab-refractory, indolent, B-cell NHL or with CLL receiving bendamustine therapy include neutropenia,1, 4, 21, 23 thrombocytopenia,1, 4, 5, 6, 7, 21, 23 anemia,1, 4, 5, 6, 21, 23 leukopenia,1, 4, 6, 7, 21, 23 pyrexia,1, 21, 23 nausea,1, 6, 21, 23 vomiting,1, 5, 6, 21, 23 hyperbilirubinemia,1, 21, 23 and lymphopenia.1, 21, 23 Elevated bilirubin concentrations also have been reported in more than 15% of patients with CLL receiving the drug,1, 21, 23 and fatigue,1, 21, 23 diarrhea,1, 21, 23 constipation,1, 21, 23 decreased weight,1, 21, 23 anorexia,1, 21, 23 dyspnea,1, 21, 23 cough,1, 21, 23 headache,1, 21, 23 rash,1, 21, 23 and stomatitis1, 21, 23 also have been reported in 15% or more of patients with rituximab-refractory, indolent, B-cell NHL receiving the drug.1, 21, 23 Adverse effects reported in more than 5% of patients during or within 24 hours post-infusion include nausea and fatigue.1, 21, 23
Adverse effects are similar following administration of bendamustine as a 10-minute IV infusion (Bendeka®) or following IV infusion over 30-60 minutes (Treanda®).21
Drugs Affecting Hepatic Microsomal Enzymes
Bendamustine is metabolized mainly via hydrolysis to form metabolites with low cytotoxic activity and, to a lesser extent, via cytochrome P-450 (CYP) isoenzyme 1A2 to form 2 minor active metabolites, γ-hydroxybendamustine (M3) and N -desmethylbendamustine (M4).1, 21, 23
CYP1A2 inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of bendamustine and increased risk of adverse effects).1, 21, 23 Consider alternative therapy without CYP1A2 inhibition potential.1, 21, 23
CYP1A2 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of bendamustine and reduced efficacy of bendamustine).1, 21, 23 Consider alternative therapy without CYP1A2 induction potential.1, 21, 23
Drugs Metabolized by Hepatic Microsomal Enzymes
In vitro data indicate that bendamustine does not inhibit CYP isoenzymes 1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4/5.1, 21, 23
Drugs that Affect Transport Systems
In vitro data indicate that bendamustine is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP).1, 21, 23
Bendamustine, a bifunctional nitrogen mustard-derivative alkylating agent and purine analog, is an antineoplastic agent.1, 2, 3, 4, 6, 7, 8, 12, 13, 21, 23 Bendamustine is structurally related to chlorambucil, with the molecules differing only in the central ring structure; whereas chlorambucil contains a benzene ring, bendamustine contains a purine-like benzimidazole ring.3, 8, 13
The exact mechanism(s) of action of bendamustine has not been conclusively established.1, 21, 23 As an alkylating agent, bendamustine interferes with DNA replication and transcription of RNA, ultimately resulting in disruption of nucleic acid function.1, 3, 8, 21, 23 In vitro data suggest that bendamustine activates different DNA repair pathways compared with conventional alkylating agents.8 In addition, other effects of bendamustine may contribute to its antineoplastic activity, including induction of p53-dependent genes that activate apoptosis and inhibition of several mitotic checkpoints.3, 8 As a consequence of the latter effect, DNA-damaged cells entering the M phase of the cell cycle may undergo a premature form of necrotic cell death known as mitotic catastrophe.3, 8 The drug is active against both quiescent and dividing cells.1, 21, 23 Cross-resistance between bendamustine and other alkylating agents or fludarabine appears to be incomplete.3, 5, 6, 7, 8, 12
Following IV infusion of bendamustine hydrochloride over 10 minutes (Bendeka®) or over 60 minutes (Treanda®), systemic exposure to the drug is equivalent although peak plasma concentrations are higher following the shorter infusion.25 Bendamustine is metabolized extensively by hydrolysis, oxidation, and conjugation.1, 21, 23 In vitro data indicate that bendamustine is metabolized mainly via hydrolysis to form 2 metabolites with low cytotoxic activity, monohydroxybendamustine (HP1) and dihydroxybendamustine (HP2), and to a lesser extent via cytochrome P-450 (CYP) isoenzyme 1A2 to form 2 active metabolites, γ-hydroxybendamustine (M3) and N -desmethylbendamustine (M4).1, 21, 23 However, because plasma concentrations of γ-hydroxybendamustine and N -desmethylbendamustine are only 10 and 1%, respectively, that of the parent drug, the cytotoxic activity of bendamustine appears to result mainly from the parent drug.1, 21, 23 Following administration of radiolabeled bendamustine hydrochloride, plasma radioactivity levels were more sustained than plasma concentrations of the drug and its active metabolites, suggesting the presence of bendamustine-derived compounds with longer half-lives.1, 21, 23 Approximately 50% of the radiolabeled dose was recovered in urine (approximately 3.3% of the dose as unchanged drug, less than 6% as the dihydroxy, γ-hydroxy, and N -desmethyl metabolites) and 25% was recovered in feces.1, 21, 23 Following IV administration of bendamustine hydrochloride as a single 120-mg/m2 dose over 1 hour, the intermediate half-life of the parent drug was approximately 40 minutes.1, 21, 23 Little or no accumulation of bendamustine in plasma is expected when the drug is administered on days 1 and 2 of a 28-day treatment cycle.1, 21, 23
Risk of allergic reactions; importance of immediately reporting rash, facial swelling, or difficulty breathing during or soon after bendamustine infusion.1, 21, 23
Importance of immediately reporting severe or worsening rash or itching to clinician.1, 21, 23
Risk of leukopenia, thrombocytopenia, and anemia; importance of frequent monitoring of blood cell counts; importance of reporting any shortness of breath, marked fatigue, bleeding, or fever or other manifestations of infection.1, 21, 23
Risk of hepatic toxicity; importance of immediately reporting signs and symptoms of hepatic failure (e.g., jaundice, anorexia, bleeding, bruising).1, 21, 23
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise females of reproductive potential and males with partners of reproductive potential to avoid pregnancy and to use effective contraceptive methods during therapy and for at least 3 months (males with female partners of reproductive potential) or at least 6 months (females of reproductive potential) following discontinuance of therapy.1, 21, 23 Importance of advising male patients that alkylating agents may impair spermatogenesis.1, 21, 23
Importance of advising females to avoid breast-feeding while receiving the drug and for at least 1 week following discontinuance of therapy.1, 21, 23
Risk of increased fatigue; importance of avoiding driving a vehicle or operating machinery if fatigue occurs.1, 21, 23
Risk of nausea, vomiting, and diarrhea; importance of reporting these adverse GI effects so that symptomatic treatment may be provided.1, 21, 23
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1, 21, 23
Importance of informing patients of other important precautionary information.1, 21, 23 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Teva Pharmaceuticals. Treanda® (bendamustine hydrochloride) for injection and injection for intravenous infusion prescribing information. North Wales, PA: 2019 Nov.
2. Keating MJ, Bach C, Yasothan U et al. Bendamustine. Nat Rev Drug Discov . 2008; 7:473-4. [PubMed 18511926]
3. Apostolopoulos C, Castellano L, Stebbing J et al. Bendamustine as a model for the activity of alkylating agents. Future Oncol . 2008; 4:323-32. [PubMed 18518757]
4. Knauf WU, Lissichkov T, Aldaoud A et al. Bendamustine versus chlorambucil in treatment-naive patients with B-cell chronic lymphocytic leukemia: results of an international phase III study. Blood . 2007; 110 (ASH abstract 2043).
5. Lissitchkov T, Arnaudov G, Peytchev D et al. Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy. J Cancer Res Clin Oncol . 2006; 132:99-104. [PubMed 16292542]
6. Bergmann MA, Goebeler ME, Herold M et al. Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. Haematologica . 2005; 90:1357-64. [PubMed 16219572]
7. Aivado M, Schulte K, Henze L et al. Bendamustine in the treatment of chronic lymphocytic leukemia: results and future perspectives. Semin Oncol . 2002; 29:19-22. [PubMed 12170428]
8. Leoni LM, Bailey B, Reifert J et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res . 2008; 14:309-17. [PubMed 18172283]
9. Hallek M, Cheson BD, Catovsky D et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood . 2008; 111:5446-56. [PubMedCentral][PubMed 18216293]
10. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website ([Web]).
11. National Cancer Institute. FDA approval for bendamustine hydrochloride. (Last updated: 3/20/08). Available at: [Web]/cancertopics/druginfo/fda-bendamustine-hydrochloride. Accessed 2008 Aug 14.
12. Forero-Torres A, Saleh MN. Bendamustine in non-Hodgkin lymphoma: the double-agent that came from the Cold War. Clin Lymphoma Myeloma . 2007; 8 (Suppl 1):S13-7. [PubMed 18282361]
13. Bertoni F, Zucca E. Bendamustine in lymphomas: more to combine?. Leuk Lymphoma . 2007; 48:1264-6. [PubMed 17613752]
16. Food and Drug Administration. Treanda (bendamustine hydrochloride) solution by Teva: FDA statement: - Not compatible with closed system transfer devices, adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene. 2015 Mar 10. From the FDA website. Accessed 2015 Mar 19. [ [Web]
17. Hurtukova D. Dear healthcare provider letter: important safety and incompatibility information for Treanda® (bendamustine HCl) injection (45 mg/0.5 mL or 180 mg/2 mL solution). North Wales, PA: Teva Pharmaceuticals; 2015 Mar 9.
19. Hurtukova D. Dear health care provider letter regarding update: important safety and compatibility information for Treanda® (bendamustine HCl) injection (45 mg/0.5 mL or 180 mg/2 mL solution). North Wales, PA: Teva Pharmaceuticals USA; 2015 Sep 2. From FDA website. [Web]
20. Food and Drug Administration. FDA warns against using Treanda injection (solution) with closed system transfer devices, adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene; provides list of compatible devices. 2015 Sep 4. From the FDA website. [Web]
21. Teva Pharmaceuticals. Bendeka® (bendamustine hydrochloride) injection for intravenous infusion prescribing information. North Wales, PA: 2020 Nov.
22. Farrell AT. Letter to Cephalon regarding supplement approval (Supplemental New Drug Application dated Oct 3, 2017). Silver Spring, MD: US Food and Drug Administration. 2017 Dec 15. [Web]
23. Eagle Pharmaceuticals. Belrapzo® (bendamustine hydrochloride) injection for intravenous infusion prescribing information. Woodcliff Lake, NJ: 2020 Nov.
24. US Food and Drug Administration. Drugs@FDA: FDA-approved drugs. From FDA website. Accessed 2021 May 28. [Web]
25. Teva Pharmaceuticals. Bendeka® (bendamustine hydrochloride) injection for intravenous infusion prescribing information. North Wales, PA: 2017 Sep.
26. Teva Pharmaceuticals. Treanda® (bendamustine hydrochloride) for injection and injection for intravenous infusion prescribing information. North Wales, PA: 2018 Jan.
10001. Rummel MJ, Niederle N, Maschmeyer G et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet . 2013; 381:1203-10. [PubMed 23433739]
10002. Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005;23:3383-9. [PubMed 15908650]
10003. Robinson KS, Williams ME, van der Jagt RH et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008;26:4473-9. [PubMed 18626004]
10004. Kahl B, Bartlett NL, Leonard JP et al. Bendamustine is safe and effective in patients with rituximab-refractory, indolent B-cell non-Hodgkin's lymphoma. Proceedings of the 49th Annual Meeting of ASH, Atlanta, GA, 2007 Dec 8-11. Abstract No. 1351.
10005. Friedberg JW, Cohen PC, Chen L et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008. 26:204-10.
10006. Howard OR, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol. 200220:1288-94.
10007. Kahl BS. New therapeutic strategies for mantle cell lymphoma. In: ASCO 2008 Educational Book. 2008:392-7.
10009. Leoni LM, Bailey B, Reifert J, et al. Bendamustine (Trenda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res. 2008; 14:309-17. [PubMed 18172283]
10010. Indolent, recurrent adult non-Hodgkin lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2008 Oct 20.
10011. Forspointner R, Dreyling M, Repp R, et al The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German low-grade lymphoma study group. Blood. 2004; 104:3064-71.
10012. Fisher RI, Kaminski MS, Wahl RL et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol. 2005; 23:7565-73 [PubMed 16186600]
10013. Witzig TE, Molina A, Gordon I et al. Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with Yttrium 90 ibritumomab tiuxetan. Cancer. 2007;109:1804-10.
10014. Fisher RI, Bernstein SH, Kahl BS et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24:4867-74. [PubMed 17001068]
10015. Leonard JP, Gregory SA, Maloney DG et al. Optimizing the treatment of patients with rituximab-pretreated recurrent indolent non-Hodgkin lymphoma. Clin Adv Hem Oncol. 2008; 6:437-45.
10016. Witzig TE, Flinn IW, Gordon LI et al. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2005; 23:7565-73. [PubMed 16186600]
10017. Horning SJ, Younes A, Jain V et al. Efficacy and safety of tositumomab and iodine-131 tostiumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol. 2005;23:712-9. [PubMed 15613695]
10018. Flinn IW, van der Jagt R, Kahl BS et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood . 2014; 123:2944-52. [PubMedCentral][PubMed 24591201]
10019. AHFS final determination of medical acceptance: Off-label use of rituximab in combination with bendamustine for previously untreated indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Published May 24, 2016.
10020. AHFS final determination of medical acceptance: Off-label use of rituximab in combination with bendamustine for relapsed or refractory indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Published May 24, 2016.