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Treanda

Generic Name: Bendamustine Hydrochloride
Class: Antineoplastic Agents
VA Class: AN100
Chemical Name: 1H-Benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1-methyl, monohydrochloride
Molecular Formula: C16H21Cl2N3O2 • HCl
CAS Number: 3543-75-7

Introduction

Antineoplastic agent; nitrogen mustard-derivative alkylating agent and purine analog.1 2 3 4 6 7 8 12 13

Uses for Treanda

Chronic Lymphocytic Leukemia

Treatment of chronic lymphocytic leukemia (CLL)1 2 3 (designated an orphan drug by FDA for this use).10

Prolonged progression-free survival and increased overall response rate observed with bendamustine compared with chlorambucil in patients with previously untreated, Binet stage B or C (Rai stages I–IV) CLL.1 2 3 4 9 Incidence of adverse effects generally also higher with bendamustine than with chlorambucil.1 4

Slideshow: 2013 Drug News Round-Up: Top 20 Stories

Efficacy of bendamustine relative to first-line therapies other than chlorambucil not established.1 2

Non-Hodgkin’s Lymphoma

Treatment of rituximab-refractory, indolent, B-cell non-Hodgkin’s lymphoma (NHL).1 10004 10005

Use in combination with rituximab for treatment of previously untreated indolent NHL or for treatment of previously untreated mantle cell lymphoma is not fully established because of inadequate data/experience.10001 10008

Use in combination with rituximab may be considered a reasonable choice (accepted, with possible conditions) for treatment of relapsed or refractory, nontransformed indolent NHL in patients who have not received prior radioimmunotherapy, in whom there is a contraindication to anthracycline or purine analog therapy, or in whom therapy with an anti-human antigen CD20 radioimmunoconjugate is not feasible (e.g., because there is a medical contraindication or accessibility issue).10002 10003 10008

Use in combination with rituximab may be considered a reasonable choice (accepted, with possible conditions) for treatment of relapsed or refractory mantle cell lymphoma.10002 10003 10008

Treanda Dosage and Administration

General

  • To minimize risk of infusion-related reactions in patients who have previously experienced grade 1 or 2 infusion reactions, consider premedication with an antihistamine, antipyretic, and corticosteroid during subsequent treatment cycles.1 (See Infusion Reactions and Anaphylaxis under Cautions.)

  • In patients at high risk for tumor lysis syndrome, take appropriate measures (e.g., adequate hydration) during the first few weeks of therapy to prevent hyperuricemia.1 (See Tumor Lysis Syndrome under Cautions.)

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.1

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1

Handle cautiously; use protective equipment (e.g., gloves, safety glasses) to minimize risk of exposure.1 If skin or mucosal contact occurs, immediately and thoroughly wash skin with soap and water and flush mucosa with water.1

Avoid extravasation; monitor infusion site for erythema, swelling, pain, infection, and necrosis during and after administration.1 (See Local Effects under Cautions.)

Reconstitution

Reconstitute vial containing 25 or 100 mg of bendamustine hydrochloride powder with 5 or 20 mL of sterile water for injection, respectively, to provide a solution containing 5 mg/mL.1

Shake well to ensure complete dissolution;1 14 lyophilized powder should dissolve within 5 minutes.1 Must be diluted further before IV administration.1

Reconstituted solution contains no preservatives; solution preferably should be prepared immediately before use.1 Discard any unused portions.1

Dilution

Within 30 minutes of reconstitution, withdraw appropriate volume of reconstituted solution from the vial and further dilute in 500 mL of either 0.9% sodium chloride injection or 2.5% dextrose and 0.45% sodium chloride injection to a final concentration of 0.2–0.6 mg/mL.1 Mix thoroughly.1

Administration must be completed within 24 hours when diluted solution is stored under refrigeration or within 3 hours when stored at room temperature under normal room light conditions.1 (See Storage under Stability.)

Rate of Administration

In patients with CLL, administer by IV infusion over 30 minutes.1

In patients with rituximab-refractory, indolent, B-cell NHL, administer by IV infusion over 60 minutes.1

In patients with relapsed or refractory indolent NHL or relapsed or refractory mantle cell lymphoma, bendamustine has been infused IV over 30–60 minutes.10002 10003

Dosage

Available as bendamustine hydrochloride; dosage expressed in terms of the salt.1

Adults

Chronic Lymphocytic Leukemia
IV

100 mg/m2 on days 1 and 2 of each 28-day cycle, for up to 6 cycles.1 5

Dosage Modification for Toxicity in CLL
IV

If toxicity occurs, delay initiation of next treatment cycle until blood counts have recovered to recommended values (ANC ≥1000/mm3 and platelet count ≥75,000/mm3) and nonhematologic toxicity has improved to grade 1 or better.1

If grade 4 hematologic toxicity occurs, interrupt therapy.1 When blood counts improve (ANC ≥1000/mm3 and platelet count ≥75,000/mm3), resume therapy at clinician’s discretion.1 For grade 3 or 4 hematologic toxicity, reduce dosage to 50 mg/m2 on days 1 and 2 of each treatment cycle.1 If grade 3 or 4 toxicity recurs, further reduce dosage to 25 mg/m2 on days 1 and 2 of each cycle.1 Re-escalation of dosage in subsequent cycles may be considered.1

If clinically important grade 2 or greater nonhematologic toxicity occurs, interrupt therapy; when toxicity improves to grade 1 or better, resume therapy at clinician’s discretion.1 If nonhematologic toxicity was grade 3 or 4, reduce subsequent dosage to 50 mg/m2 on days 1 and 2 of each treatment cycle.1 Re-escalation of dosage in subsequent cycles may be considered.1

Non-Hodgkin’s Lymphoma
Rituximab-refractory, Indolent, B-cell NHL
IV

120 mg/m2 on days 1 and 2 of each 21-day cycle, for up to 8 cycles.1 10004

Dosage Modification for Toxicity in Rituximab-refractory, Indolent, B-cell NHL
IV

If toxicity occurs, delay initiation of next treatment cycle until blood counts have recovered to recommended values (ANC ≥1000/mm3 and platelet count ≥75,000/mm3) and nonhematologic toxicity has improved to grade 1 or better.1

I

f grade 4 hematologic toxicity occurs, interrupt therapy.1 When blood counts improve (ANC ≥1000/mm3 and platelet count ≥75,000/mm3), resume therapy at clinician’s discretion; reduce dosage to 90 mg/m2 on days 1 and 2 of each treatment cycle.1 If grade 4 toxicity recurs, further reduce dosage to 60 mg/m2 on days 1 and 2 of each cycle.1

If clinically important grade 2 or greater nonhematologic toxicity occurs, interrupt therapy; when toxicity improves to grade 1 or better, resume therapy at clinician’s discretion.1 If nonhematologic toxicity was grade 3 or 4, reduce subsequent dosage to 90 mg/m2 on days 1 and 2 of each treatment cycle.1 If grade 3 or 4 toxicity recurs, further reduce dosage to 60 mg/m2 on days 1 and 2 of each cycle.1

Relapsed or Refractory Indolent NHL or Relapsed or Refractory Mantle Cell Lymphoma
IV

90 mg/m 2 has been administered on days 2 and 3 of a 28-day cycle for a total of 4–6 cycles, in combination with rituximab (375 mg/m2 IV on day 1).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

Special Populations

Hepatic Impairment

Use not recommended in patients with moderate or severe hepatic impairment.1 No specific dosage recommendations for patients with mild hepatic impairment; use with caution.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Use not recommended in patients with severe renal impairment.1 No specific dosage recommendations for patients with mild or moderate renal impairment; use with caution.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1

Cautions for Treanda

Contraindications

  • Known hypersensitivity (e.g., anaphylactic or anaphylactoid reaction) to bendamustine or mannitol.1

Warnings/Precautions

Sensitivity Reactions

Infusion Reactions and Anaphylaxis

Infusion reactions (e.g., fever, chills, pruritus, rash) occur commonly.1 Severe anaphylactic and anaphylactoid reactions reported rarely, mainly in the second and subsequent cycles of therapy.1

Monitor patients clinically; discontinue therapy if a severe reaction occurs.1 After the first cycle of therapy, ask the patient about symptoms suggestive of infusion reactions.1

If grade 1 or 2 infusion reactions occur, consider a premedication regimen (e.g., antihistamine, antipyretic, and corticosteroid) during subsequent treatment cycles.1

If grade 3 or 4 infusion reactions occur, consider discontinuing therapy.1 In clinical trials, patients experiencing grade 3 or worse allergic-type reactions typically were not rechallenged with the drug.1

Hematologic Effects

Risk of severe (grade 3 or 4) and potentially fatal myelosuppression, manifested primarily as lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia.1 Neutropenic sepsis, diffuse alveolar hemorrhage, and cytomegalovirus pneumonia reported.1

Monitor leukocytes, platelets, hemoglobin, and neutrophils closely;1 in clinical trials, blood counts were monitored weekly initially.1

Hematologic nadirs occur during the third week of the treatment cycle; dose delays may be required if recovery to recommended values (i.e., ANC ≥1000/mm3 and platelet count ≥75,000/mm3) has not occurred prior to initiation of the next cycle of therapy.1 (See Dosage under Dosage and Administration.)

Infectious Complications

Infections (e.g., pneumonia, sepsis) resulting in hospitalization, septic shock, and death have occurred.1 Increased risk of infection in patients with myelosuppression.1 (See Hematologic Effects under Cautions.)

Tumor Lysis Syndrome

Tumor lysis syndrome reported, generally during the first cycle of therapy; without appropriate intervention, acute renal failure and death may occur.1

Closely monitor blood chemistries (particularly potassium and uric acid concentrations) and take appropriate measures (e.g., adequate hydration) in patients at high risk for tumor lysis syndrome.1

Manufacturer no longer recommends concomitant allopurinol therapy; such use may increase the risk of severe skin reactions.1 15 (See Dermatologic Reactions under Cautions.)

Dermatologic Reactions

Possible dermatologic reactions (e.g., rash, toxic skin reactions, bullous exanthema);1 may be progressive and increase in severity with continued therapy.1 Monitor closely if dermatologic reactions occur; if reaction is severe or progressive, withhold or discontinue bendamustine.1

Stevens-Johnson syndrome and toxic epidermal necrolysis, including fatalities, reported with concomitant use of bendamustine with allopurinol and other drugs, including rituximab, known to cause these reactions.1

Precise relationship between bendamustine and dermatologic reactions not established.1

Carcinogenicity

Development of premalignant (e.g., myelodysplastic syndrome, myeloproliferative disorders) and malignant diseases (e.g., acute myelogenous leukemia, bronchial carcinoma) reported; however, a causal relationship not fully established.1

Local Effects

Extravasation may cause pain, erythema, and marked swelling and may result in hospitalization.1 Monitor infusion site for erythema, swelling, pain, infection, and necrosis during and after administration of bendamustine.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; increased resorptions, skeletal and visceral malformations, and decreased fetal body weights demonstrated in animals.1

Avoid pregnancy during and for 3 months after discontinuance of therapy.1 If used during pregnancy or patient becomes pregnant, apprise of potential fetal hazard.1 Advise men with partners of childbearing potential to use a reliable method of contraception during and for ≥90 days after therapy.14

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether bendamustine is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Pharmacokinetic and adverse effect profiles similar to those in younger adults.1

Decreased progression-free survival and overall response rate observed in patients ≥65 years of age with CLL compared with younger adults.1 Overall response rate was 47% in patients ≥65 years of age versus 70% in younger adults.1 Median progression-free survival was 12 months in patients ≥65 years of age versus 19 months in younger adults.1

Overall response rate and duration of response in patients ≥65 years of age with NHL are similar to results in younger adults.1

Hepatic Impairment

Limited data indicate that pharmacokinetics are not substantially altered in patients with mild hepatic impairment; pharmacokinetics not evaluated in patients with moderate or severe hepatic impairment.1

Use with caution in patients with mild hepatic impairment; use not recommended in moderate hepatic impairment (serum AST/ALT 2.5–10 times the ULN and total serum bilirubin 1.5–3 times the ULN) or severe hepatic impairment (total bilirubin >3 times the ULN).1

Renal Impairment

Limited data indicate that pharmacokinetics are not substantially altered in patients with mild or moderate renal impairment; pharmacokinetics not evaluated in patients with severe renal impairment.1

Use with caution in patients with mild or moderate renal impairment; use not recommended in patients with severe renal impairment (Clcr <40 mL/minute).1

Gender

Pharmacokinetic and adverse effect profiles not affected substantially by gender.1

No clinically important differences in efficacy between men and women observed in patients with rituximab-refractory, indolent B-cell NHL.1

Overall response rates in men and women with CLL were 60 and 57%, respectively;1 median durations of progression-free survival in men and women with CLL were 19 and 13 months, respectively.1

Common Adverse Effects

Neutropenia,1 4 thrombocytopenia,1 4 5 6 7 anemia,1 4 5 6 leukopenia,1 4 6 7 pyrexia,1 nausea,1 6 vomiting,1 5 6 decreased lymphocyte counts,1 elevated bilirubin concentrations, fatigue,1 diarrhea,1 constipation,1 decreased weight,1 anorexia, 1 dyspnea,1 cough, 1 headache,1 rash,1 stomatitis.1

Interactions for Treanda

No formal drug interaction studies performed to date.1

Metabolized mainly by hydrolysis and, to a lesser extent, by CYP1A2.1

Does not appear to inhibit CYP isoenzymes 1A2, 2C9, 2C10, 2D6, 2E1, 3A4, or 3A5 or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, or 3A5 in vitro.1

P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may affect bendamustine transport in vitro; role of active transport systems not fully evaluated.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP1A2: Potential pharmacokinetic interaction (increased plasma concentrations of bendamustine).1 Use concomitantly with caution or consider alternative therapy.1

Inducers of CYP1A2: Potential pharmacokinetic interaction (decreased plasma concentrations of bendamustine).1 Use concomitantly with caution or consider alternative therapy.1

Protein-bound Drugs

Bendamustine unlikely to displace or be displaced by other highly protein-bound drugs.1

Specific Drugs

Drug

Interaction

Comments

Cigarette smoking

Possible decreased bendamustine concentrations1

Use concomitantly with caution or consider alternative therapy1

Ciprofloxacin

Possible increased bendamustine concentrations1

Use concomitantly with caution or consider alternative therapy1

Fluvoxamine

Possible increased bendamustine concentrations1

Use concomitantly with caution or consider alternative therapy1

Omeprazole

Possible decreased bendamustine concentrations1

Use concomitantly with caution or consider alternative therapy1

Treanda Pharmacokinetics

Absorption

Bioavailability

Following IV administration, peak plasma concentration attained at the end of the infusion.1

Plasma Concentrations

Correlation between nausea and peak plasma concentration observed in patients with NHL.1

Special Populations

Age (≥65 years versus <65 years) has no apparent effect on bendamustine exposure (AUC, peak plasma concentration).1

Distribution

Extent

Distributed into RBCs.1

Role of active transport systems in distribution not fully evaluated; however, P-glycoprotein, BCRP, and/or other efflux transporters may affect bendamustine transport in vitro.1

Plasma Protein Binding

94–96%.1

Elimination

Metabolism

Metabolized mainly via hydrolysis to form metabolites with low cytotoxic activity and, to a lesser extent, via CYP1A2 to form 2 active minor metabolites, γ-hydroxybendamustine (M3) and N-desmethylbendamustine (M4).1

Elimination Route

Excreted principally (90%) in feces.1

Half-life

Intermediate half-life of bendamustine is approximately 40 minutes.1 Mean terminal half-lives of γ-hydroxybendamustine and N-desmethylbendamustine are approximately 3 hours and 30 minutes, respectively.1

Special Populations

In Japanese individuals, exposure to bendamustine may be increased; however, clinical importance not established.1

Mild hepatic impairment (total serum bilirubin at or below the ULN, serum AST 1–2.5 times the ULN, and/or serum alkaline phosphatase 1–5 times the ULN) does not appear to substantially alter bendamustine pharmacokinetics.1 Effect of moderate or severe hepatic impairment not established.1

Mild or moderate renal impairment (Clcr 40–80 mL/minute) does not appear to substantially alter bendamustine pharmacokinetics.1 Effect of severe renal impairment not established.1

Gender does not substantially affect bendamustine pharmacokinetics.1

Stability

Storage

Parenteral

Powder for Injection

≤25°C; may be exposed to temperatures up to 30°C.1 Protect from light.1

Diluted solutions are stable for 24 hours when stored at 2–8°C and for 3 hours when stored at 15–30°C under normal room light conditions.1 Administration must be completed within these time periods.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Sodium chloride 0.9%1

Dextrose 2.5% in sodium chloride 0.45%1

Actions

  • Mechanism(s) of action not conclusively established,1 but may interfere with DNA replication and transcription of RNA, ultimately resulting in disruption of nucleic acid function.1 3 8

  • Cytotoxic activity may also result from induction of p53-dependent genes that activate apoptosis and inhibition of several mitotic checkpoints.3 8 As a result, DNA-damaged cells entering the M phase of the cell cycle may undergo mitotic catastrophe, a premature form of necrotic cell death.3 8

  • Active against both quiescent and dividing cells.1

  • Cross-resistance between bendamustine and other alkylating agents or fludarabine appears to be incomplete.3 5 6 7 8 12

Advice to Patients

  • Risk of allergic reactions; importance of immediately reporting rash, facial swelling, or difficulty breathing during or soon after bendamustine infusion.1

  • Importance of immediately reporting severe or worsening rash or pruritus to clinician.1

  • 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

  • Risk of increased fatigue; importance of avoiding driving a vehicle or operating machinery if fatigue occurs.1

  • Risk of nausea, vomiting, and diarrhea; importance of reporting these adverse GI effects so that symptomatic treatment may be provided.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women of childbearing potential and men with partners of childbearing potential to avoid pregnancy and to use effective contraceptive methods during therapy and for 3 months following discontinuance of therapy.1 Importance of advising male patients that bendamustine may impair spermatogenesis.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Bendamustine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV infusion only

25 mg

Treanda

Cephalon

100 mg

Treanda

Cephalon

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 11, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Cephalon Inc. Treanda(bendamustine hydrochloride) injection prescribing information. Frazer, PA: 2010 Jul.

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. [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 ().

11. National Cancer Institute. FDA approval for bendamustine hydrochloride. (Last updated: 3/20/08). Available at: http://www.cancer.gov/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]

14. Cephalon, Frazer, PA: Personal communication; 2008 September 26.

15. Cephalon Inc. Treanda (bendamustine hydrochloride) injection prescribing information. Frazer, PA; 2008 Apr.

10001. Rummel MJ, von Gruenhagen U, Niederle N et al. Bendamustine plus rituximab versus CHOP plus rituximab in the first-line treatment of patients with indolent and mantle cell lymphomas: first interim results of a randomized phase III study of the Study Group Indolent Lymphomas, Germany. Proceedings of the 49th Annual Meeting of ASH, Atlanta, GA, 2007 Dec 8-11. Abstract No. 385.

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.

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.

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.

10008. AHFS Oncology Expert Committee reviewer’s comments (personal observations).

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.

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.

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