Brand Name: Treanda

Generic Name: Bendamustine Hydrochloride

Manufacturer: Cephalon

Drug Class: Alkylating Agent; Nitrogen Mustard

Uses^1,2,3:

• Labeled: Chronic lymphoid leukemia
• Unlabeled: Breast cancer, Hodgkin's disease, Multiple myeloma, Non-Hodgkin's lymphoma, Solid tumor configuration
  

Mechanism of Action^1,2,3: Bendamustine works as an alkylating agent by forming covalent bonds with electron-rich nucleophiles. By cross-linking both single and double-strand DNA, bendamustine is able to induce apoptosis and cell death.  A secondary mechanism of action may involve amine and purine antagonism, but more investigation is needed. Bendamustine, nitrogen-mustard derivative, has activity against dividing cells and has only demonstrated partial cross-resistance with other alkylating agents. Bendamustine is metabolized via CYP1A2 to the active metabolites gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4).

Pharmacokinetics^1,2,3:

Efficacy:

• Bergmann MA, Goebeler ME, Herold M, Emmerich B, Wilhelm M, Ruelfs C, Boening L, Hallek MJ; German CLL Study Group. 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 Oct;90(10):1357-64.

Study design: Open label, multicenter trial

Description of study:

Patients were divided into cohorts of three patients each. The first group was started on bendamustine 100 mg/m² on days 1 and 2 every 3-4 weeks. The second group received a dose increase of 10 mg/m² if no dose-limiting toxicities occurred after the initial dose in the first cohort. If dose-limiting toxicities occurred in the initial cohort at a given dose level, the same dose was administered to the next cohort. Dose-limiting toxicities occurring in two cohorts (6 patients) at a given dose level terminating dose escalation and the dose was reduced by 10 mg/m²/day for the next cohort. If dose-limiting toxicities were completely reversed in a patient, that patient was allowed to continue in the study, but at the same dose level, with no further increases. The maximum tolerated dose was the dose level in which no or one dose-limiting toxicity was observed. Patient response dictated duration of treatment. Patients were withdrawn from the study if the disease progressed. Patients in partial remission or stable disease were administered up to six courses of bendamustine, and those in complete remission after six courses received two additional courses.
The primary endpoint of this trial was to define the maximum tolerated dose of bendamustine. The secondary endpoint of the study was the efficacy of bendamustine. Study protocol dictated that a patient must receive three or more cycles of bendamustine to be evaluated for a response to treatment. A complete remission was the time from complete response to progressive disease, whereas partial remission and stable disease were the time from the first day of treatment to progressive disease. Doses of 100 mg/m² of bendamustine were administered to one patient who achieved a partial remission (ongoing, 47.2 months). Doses of 90 mg/m² of bendamustine were administered to one patient who achieved stable disease, which after 8.8 months became progressive. At the 80 mg/m² level, one patient withdrew from the study after four treatment courses and achieved a complete remission. Doses of 70 mg/m² were administered to six patients, with two achieving complete remission (43.6, 41 months), one achieving stable disease (7 months), two achieving partial remission (8.8, 26.6 months), and one achieving nodular partial remission (39.9 months).

Limitations:
A small sample size, open-label design, and no control group are all limiting factors of this study. The authors did not report a power for the primary or secondary outcome and did not report any statistically significant data. Although the authors report using a Kaplan-Meir statistical analysis method, they do not include the results or show the Kaplan-Meir curve.

Conclusion:
This study gathered sufficient information regarding the maximum tolerated dose of bendamustine, however due to a small sample size and no reported power, the clinical application is limited. Data regarding the efficacy of each dose level in patient cannot be ascertained as great variability between patients exists. Future studies of larger sample sizes and a more standardized patient population would establish more clinically relevant data.

• Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. 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 Jan 10;26(2):204-10.

Study design: Open label, multicenter trial

Description of study:

Seventy-four patients were administered bendamustine infusions of 120 mg/m² on days 1 and 2 every 3 weeks. Patients with a response to treatment or stable disease continued treatment for 6 cycles, with a potential of 6 additional cycles until the disease progressed or toxicities developed. The bendamustine dose was reduced to 90 mg/m² after the development of grade 4 hematologic or grade 3/4 nonhematologic toxicities. If toxicities developed at the reduced dose level, bendamustine was reduced to 60 mg/m². Treatment was discontinued if toxicities reappeared after the second reduction or if patients developed progressive disease. The use of growth factors as prophylaxis was not allowed.

The primary end point for this trial was overall response rate to bendamustine. Secondary endpoints were safety, progression-free survival, and duration of response. The overall response rate observed in this study was 77% with 25 (34%) patients achieving complete remission (14 unconfirmed) and 32 (43%) achieving partial remission. In follicular lymphoma (45 patients), the overall response rate was 82% with 17 patients achieving complete remission (10 unconfirmed) and 20 achieving partial remission. In transformed disease (15 patients), 2 patients achieved complete remission (2 unconfirmed) and 8 achieved partial remission. The treatment population demonstrated a median response duration of 6.7 months (95% CI, 5.1 to 9.9). In indolent lymphoma, this increased to 9.0 months (95% CI, 5.8 to 16.7) but decrease to 2.3 months (95% CI, 1.7 to 5.1) in transformed disease. The median follow-up period was 26 months and a median progression-free survival duration of 7.1 months occurred in all patients. Patients with indolent disease demonstrated a progression-free survival duration of 8.3 months (95% CI, 6.6 to 10.9) where patients with transformed disease reported 4.2 months (95% CI, 2.7 to 5.1). In patients who did not respond to alkylator-containing treatment or in whom disease progressed during an alkylator-containing regimen, there was an overall response rate of 61% with a median response duration of 6.5 months (95% CI, 4.7 to 9.9) in alkylator-sensitive patients and 7.7 months (95% CI, 4.4 to 16.7) in alkylator-refractory patients. In patients unresponsive to fludarabine treatment, an overall response rate of 62% was observed. Those patients who had previously been treated with two or more chemotherapy regimens had an overall response rate of 75% and median response duration of 5.3 months (95% CI, 3.5 to 14.6). This was compared to a median response duration of 9.0 months in those previously receiving one or less regimens. In patients previously treated with radioimmunotherapy, 2 developed complete remission and 6 partial remission. In patients previously receiving autologus stem cell transplant, one achieved complete remission and three partial remission, with a median response duration of 2.6 months.

Limitations:

One author is employed by Cephalon, the manufacturer of Treanda, two are working as consultants, and all have received research funding from Cephalon. The benefit of bendamustine, an orphan drug, gaining popularity would be extended to Cephalon’s employees and shareholders, and the potential of that occurring may have swayed interpretation or study design. The open-label design, small sample size, and no control group are limiting factors in this study. The authors did not report a power for the primary or secondary outcomes and did not statistically analyze adverse events.

Conclusion:

A limited sample size, multiple dose cohort groups, and patients with a variety of malignancies introduced an abundance of variability to the study. When baseline comparisons cannot occur due a diverse population, a misinterpretation of results may be likely. However, the observations do demonstrate therapeutic benefit in a patient population showing no response to standard therapy. The information from this clinical study should contribute more to future study than to practice guidelines.

• Weidmann E, Kim SZ, Rost A, Schuppert H, Seipelt G, Hoelzer D, Mitrou PS. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2002 Aug;13(8):1285-9.

Study design: Open label trial

Description of study:
Twenty-one patients were administered bendamustine 120 mg/m² on two consecutive days every three weeks. Prior to each dose, a serotonin antagonist was administered. Patients developing toxicities such as thrombocytopenia or granulocytopenia had a dose reduction of 75%. of this study was objective response.
Eighteen patients were evaluated for results at the completion of the study, with five of these patients completing all six cycles of therapy. Eight patients (44%, CI 21.5-69%) demonstrated an objective response to treatment with bendamustine, with 5 patients (27.8%) achieving a partial remission and 3 patients achieving a complete response.  Progressive disease developed in ten patients (56%) prior to the fourth cycle of bendamustine treatment. No treatment-related deaths were observed and subjective toxicity was reported as moderate to low with no reports of grade 4 nonhematologic toxicities and grade 3 nonhematologic toxicities of less than 10% for the same side effects. Grade 3/4 hematologic toxicities were reported in 8-13% of all treatment cycles. Treatment was discontinued in two patients due to grade 4 thrombocytopenia and leukocytopenia.

Limitations:
A small sample size, open-label design, and no control group are all limiting factors of this study. Additionally, the authors did not define any primary or secondary end points or outcome measures.

Conclusion:
Without any endpoints or outcome measures defined, and with a confidence interval of 21.5-69%, clinical application is difficult. The study appears more to be a haphazard accumulation of some patient cases as opposed to a true, clinical trial. The low occurrence of toxicities was of interest and increases the confidence in bendamustine as a relatively safe agent. Again, this appears to be a study that indicates for future study as opposed to defining practice guidelines.

Contraindications^1,2,3:

• Hypersensitivity
• Bendamustine should be avoided in patients with a hypersensitivity to the drug, to mannitol, or to any other component of the product.

Precautions^1,2,3: Bendamustine should be used with precaution in patients with:

• Bone marrow suppression:
• Myelosuppression (neutropenia, thrombocytopenia and anemia) may require therapy delay or dose reduction
• Hypersensitivity/infusion reaction:
• Infusion reactions, which may include chills, fever, pruritus, and rash, are common. Anaphylactic and anaphylactoid reactions have occurred, particularly with the second cycle.
• Infection:
•  Infections may require hospitalization and septic shock and fatalities have occurred.
• Tumor lysis syndrome:
•  Tumor lysis syndrome may occur as a consequence of leukemia treatment and may lead to acute renal failure.
• Hepatic impairment:
• Use is not recommended in patients with moderate or severe hepatic impairment.
• Renal impairment:
• Use is not recommended in patient with Clcr <40 mL/minute.

Special Handling^1,2,3:

• Bendamustine is a hazardous agent. Appropriate precautions should be used for handling and disposal.

Adverse Effects (≥10% of patients) ^1,2,3:

• Central nervous system:
• Fever (24%)
• Gastrointestinal:
• Nausea (20%)
• Vomiting (16%)
• Hematologic:
• Myelosuppression
• Anemia (19% – 89%)
• Thrombocytopenia (23% – 77%)
• Neutropenia (28% – 75%)
• Lymphopenia (7% – 68%)
• Leukopenia  (18% – 61%)
• Hepatic:
• Bilirubin increased (34%)

Adverse Effects (1% to 10% of patients) ^1,2,3:

• Cardiovascular:
• Hypertension aggravated (3%)
• Central nervous system:
• Fatigue (9%)
• Chills (6%)  
• Dermatologic:
• Rash (8%)
• Pruritus (5%)  
• Endocrine & metabolic:
• Hyperuricemia (7%)
• Gastrointestinal:
• Diarrhea (9%)
• Weight loss (7%)  
• Hematologic:
• Febrile neutropenia (3%)
• Hepatic:
• ALT increased (3%)   
• AST increased (1%)  
• Neuromuscular & skeletal:
• Weakness (8%)
• Respiratory:
• Nasopharyngitis (7%)
• Cough (4%) 
• Miscellaneous:
• Infection (6%)
• Hypersensitivity (5%)
• Herpes simplex (3%)
  

Drug Interactions^1,2,3: Substrate of CYP1A2; P-glycoprotein (ABCB1); BCRP (ABCG2)

• CYP1A2 inducers: [Ex: Carbamazepine, Phenobarbital, Rifampin, Grapefruit juice]
• May decrease the levels and effects of bendamustine, and may increase the levels and effects of the active metabolites of bendamustine. 
• CYP1A2 inhibitors: [Ex: Amiodarone, Ciprofloxacin, Fluvoxamine, Verapamil]
• May increase the levels and effects of bendamustine, and may decrease the levels and effects of the active metabolites of bendamustine.
  

Dosing/Administration ^2,4,5,6: Doses are administered via IV. 

• Usual dose:
• CLL: 100 mg/m² on days 1 and 2 of a 28-day treatment cycle (for up to 6 cycles)
• Breast Cancer: 150 mg/m² on days 1 and 2 of a 28-day cycle ; 240 mg/m² per cycle in place of cyclophosphomide in the CMF regimen in metastatic breast cancer
• Multiple myeloma: 150 mg/m² on days 1 and 2 of a 28-day cycle, with prednisone given on days 1-4
• Non-Hodgkins Lymphoma: 120 mg/m² on days 1 and 2 of a 21-day cycle, or 50-60 mg/m² on days 1-5 of a 28-35-day cycle; 50-60 mg/m² on days 1-5 of a 21-28-day cycle in combination with vincristine and prednisolone; 100 mg/m² on day 1 of a 21-day cycle in combination with etoposide; 50 mg/m² on days 1-3 of 28-day cycle in combination with fludarabine and rituximab; 70 mg/m² on days 1-3 of a 21-day cycle in combination with idarubicin and dexamethasone;
• Geriatric dose: No adjustment necessary
• Pediatric dose:
• The safety and efficacy of bendamustine have not been established in children
• Renal impairment dose:
• Clcr <40 mL/minute: Use is not recommended
• Hepatic impairment dose:
• Moderate or Severe hepatic impairment (AST or ALT 2.5-10 times normal, total bilirubin 1.5-3 times normal): Use is not recommended
• Dosage adjustment for toxicity:
• Hematologic toxicity ≥grade 3: Reduce dose to 50 mg/m2 on days 1 and 2 of each treatment cycle.
• Hematologic toxicity ≥grade 4: Delay treatment until resolves (ANC ≥1000/mm³, platelets ≥75,000/mm³)
• Recurrent hematologic toxicity (≥grade 3): Reduce dose to 25 mg/m² on days 1 and 2 of the treatment cycle; may cautiously increase dose in subsequent cycles.
• Nonhematologic toxicity ≥grade 3 (clinically significant): Reduce dose to 50 mg/m² on days 1 and 2 of the treatment cycle with discretion; may cautiously increase dose in subsequent cycles.
  

Use in Special Circumstances ^1,3,7:

• Pregnancy
• Pregnancy category D. There are no well-controlled studies of bendamustine in pregnancy women. In pregnant mice, fetal body weight decreases and skeletal malformations are observed. Therefore, based on animal data, there is positive evidence of bendamustine causing fetal harm. Benefits from use in pregnant women may outweigh the risks and use may be acceptable.
• Nursing mothers
• It is not known whether bendamustine is excreted in human breast milk; however, many drugs are excreted in human milk that can cause serious adverse reactions in nursing infants. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
• Pediatric use
• Safety and efficacy of bendamustine in pediatric patients has not been established.
• Geriatric use
• No overall differences in safety and effectiveness of bendamustine were observed between subjects aged 65 years or older and younger subjects, and other reported clinical experiences have not identified differences in responses between the elderly and younger patients.
• Renal impairment
• Bendamustine pharmacokinetics have not been specifically studied in patients with renal impairment or in patients undergoing hemodialysis. However, one case report of a 56-year-old white male patient with membranoproliferative glomerulonephritis was given bendamustine due to an impairment of renal function. The patient achieved a complete remission of the nephrotic syndrome, markedly improved renal function, normalized urinary sediment, and resolution of proteinuria. 
• Hepatic impairment
• There is limited pharmacokinetic data evaluating bendamustine in patients with hepatic impairment. Bendamustine should be used with caution in patients with mild hepatic impairment and is not recommended in patients with moderate (AST, ALT 2.5 to 10 times normal; total bilirubin 1.5 to 3 times normal) or severe (total bilirubin greater than 3 times normal) hepatic impairment.
• Overdose
• There is no known antidote for overdose of bendamustine.

Conclusion: Bendamustine was recently approved for use in CLL and recent studies have demonstrated bendamustine as perhaps an alternative agent in alkylator-resistant malignancies. Attractive features of bendamustine include a low toxicity profile and its ability to be given in 3-5 week cycles. Unfortunately, small sample sizes and patient variability prevent explicit recommendations regarding clinical application in more than just the treatment of CLL. Potentially, bendamustine may be a safe and effective agent in the treatment of refractory malignancies in a difficult to treat patient population.

Prepared by: Kate Priddy, Doctor of Pharmacy Candidate

References:

1. Product Information: TREANDA(R) IV injection, bendamustine hcl IV injection. Cephalon,Inc, Frazer, PA, 2008.
2. Barman Balfour JA & Goa KL: Bendamustine. Drugs 2001; 61(5):631-638.
3. Bendamustine. Micromedex: DrugDex. Accessed online: 20 April 2008.
4. Hoffken K, Merkle KH, Schonfelder M, et al: Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study. J Cancer Res Clin Oncol 1998; 124:627-632.
5. Poenisch W, Mitrou PS, Merkle K-H, et al: Bendamustine/prednisone versus melphalane/prednisone in the primary treatment of multiple myeloma: an updated analysis of the 94BP01 protocol Blood 2000a; 96(11):759a.
6. Heider A & Niederle N: Efficacy and toxicity of bendamustine in patients with relapsed low-grade non-Hodgkin's lymphomas. Anti-Cancer Drugs 2001; 12:725-729.
7. Bartel C, Obermã Ller N, Rummel MJ, Geiger H, Hauser IA. Remission of a B cell CLL-associated membranoproliferative glomerulonephritis Type I with rituximab and bendamustine. Clin Nephrol. 2008 Apr;69(4):285-9.