Drugs 61: 631-638, no. 5, 200

ADIS NEW DRUG PROFILE
Adis International Limited. All rights reserved.
Bendamustine
Julia A. Barman Balfour and Karen L. Goa Adis International Limited, Auckland, New Zealand Contents
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631 1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6322. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6323. Therapeutic Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6334. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6365. Bendamustine: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637 Abstract
❤ Bendamustine is a bifunctional alkylating agent
Features and properties of bendamustine
with cytotoxic activity against human ovarian andbreast cancers in vitro. It shows only partial in vitro Indications
cross-resistance with cyclophosphamide, mel- Treatment of Hodgkin’s disease, non-Hodgkin’s lymphoma, multiple myeloma, chronic lymphocytic leukaemia and breast ❤ Bendamustine as monotherapy or as part of com- bination chemotherapy protocols for first-line orsubsequent treatment produced objective response Mechanism of action
rates of 61 to 97% in patients with Hodgkin’s dis- ease or non-Hodgkin’s lymphoma (NHL) [41 to ❤ In patients with multiple myeloma, a bendamustine/ Dosage and administration (in clinical trials)
prednisone regimen produced a higher rate of com- plete response (32 vs 11%) and more durable re- sponses than a melphalan/prednisone regimen.
❤ Substitution of bendamustine for cyclophosph- amide in a standard first-line COP regimen (cyclo-phosphamide, vincristine and prednisolone) yielded similar response rates in patients with ad- ❤ Substituting bendamustine for cyclophosphamide Pharmacokinetic profile
in the CMF protocol (cyclophosphamide, metho- trexate and fluorouracil) prolonged remission from 6.2 to 15.2 months in patients with metastatic ❤ The most common adverse events in patients re- ceiving bendamustine are haematological events Adverse events
and gastrointestinal disturbances. Bendamustinehas a relatively low propensity to induce alopecia.
Haematological toxicity andgastrointestinal disturbances • When used in equitoxic concentrations (IC50s), bendamustine consistently induced more DNA double-strand breaks (measured by pulsed field gelelectrophoresis) than did melphalan, cyclophosph- amide or carmustine. Moreover, bendamustine in- duced more durable double-strand breaks com-pared with carmustine or cyclophosphamide.[3] • Bendamustine induced concentration-depend- Bendamustine
ent apoptosis of B-chronic lymphocytic leukaemia(B-CLL) cells in vitro. A synergistic effect was Bendamustine is a bifunctional alkylating agent seen with fludarabine in this system. Apoptosis consisting of a purine and amino acid antagonist (a rates for bendamustine plus fludarabine at 48 hours benzimidazole ring) and an alkylating nitrogen were 1.4-fold higher than the rates expected when mustard moiety.[1] The drug has been evaluated as an intravenous infusion mainly in the treatment of Effects on Lymphocyte Subsets
lymphomas but also as a therapy for solid tumours, • In a phase I study, bendamustine 60 to 80 mg/m2 given weekly for up to 8 weeks to patients withrefractory solid tumours (n = 12) induced sustained 1. Pharmacodynamic Profile
panlymphocytopenia with predominant B-cell cy-totoxicity. Peripheral blood B-cells, natural killer cells and T cells were reduced by >90, >70 and >60%, respectively, after 4 weeks. The CD4 : CD8
The alkylating toxicity of bendamustine is ratio remained constant throughout treatment.[5] based on crosslinking of DNA single and doublestrands, leading to disruption of the matrix function • However, a ≈50% in the ratio of CD4 : CD8
of DNA in DNA synthesis.[2] The contribution, if lymphocytes was noted (from 1.36 to 0.6) after 4 any, of purine and amino acid antagonism to the courses of treatment with bendamustine 50 or 60 antitumour effect of bendamustine is yet to be dem- mg/m2 (days 1 to 5) in patients with lymphopro- liferative disorders (n = 12). Although 2 patients developed opportunistic infections, no correlation Bendamustine demonstrated cytotoxic activity was found between infectious episodes and CD4 :
against several human ovarian and breast cancer cell lines in vitro. For example, the concentrationrequired to inhibit 50% of cell growth (IC50) was 2. Pharmacokinetic Profile
138 µmol/L against the breast cancer line MCF 7.
Cross-resistance between bendamustine and other • Bendamustine undergoes extensive first-pass alkylating agents such as cyclophosphamide, mel- phalan and carmustine and to cisplatin was only • Bendamustine is highly (>95%) protein bound, primarily to albumin, at clinically relevant concen- • Notably, bendamustine also showed good activ- trations. Protein binding is not affected by ad- ity against the cisplatin-resistant ovarian cell line vanced age (>70 years), low serum albumin levels (31 g/L) or presence of advanced tumours.[8] resistant breast adenocarcinoma cell line MCF 7 • After intravenous administration of bendamust- AD [mean IC50 187 µmol/L];[3] indeed, the drug ine to >20 patients with tumours, volume of distri- has shown activity against breast cancer in women bution at steady state (Vdss) was 19.80L. Elimina- pretreated with anthracyclines (see section 3.) tion of bendamustine was rapid and occurred  Adis International Limited. All rights reserved.
predominantly by the renal route, with a smaller In a study in patients with multiple myeloma, amount being eliminated by the liver. Mean total Southwest Oncology Group (SWOG) response cri- clearance was 49.6 L/h and was independent of teria were used. Response to treatment was deter- dosage over the range 0.5 to 5 mg/kg. Plasma elim- mined by change in tumour cell mass (TCM), as ination half-life (t1/2β) was 32 minutes.[7] measured by myeloma protein concentrations. CR was defined as TCM reduction >75% and PR as TCM reduction of 25 to 74%. For either category, received bendamustine 4.2 to 5.5 mg/kg intrave- additional criteria were no progression of previous nously. Elimination of the drug was biphasic.[9] osteolytic bone lesions/appearance of new lesionson skeletal x-ray and serum calcium <120 mg/L.[11] • Unchanged bendamustine accounted for 45% of the total amount of drug recovered in the urine.
Metabolites included the major metabolite β-hydroxybendamustine (which is also cytotoxic;[1] Previously Untreated Patients
24%), other hydroxy derivatives and N-dimethyl- • Substitution of bendamustine (60 mg/m2) for bendamustine. Biliary elimination occurs mainly cyclophosphamide in a standard first-line COP regimen did not compromise efficacy in previously untreated patients with advanced low grade non- As bendamustine is eliminated primarily by re- Hodgkin’s lymphoma (NHL) randomised to either nal mechanisms, it should not be given to patients treatment (n = 162 in total). The COP regimen con- with glomerular filtration rate <1.8 L/h. The drug sisted of cyclophosphamide 400 mg/m2 day 1 to 5, also undergoes hepatic metabolism and should not vincristine 2mg day 1 and prednisolone 100 mg/m2 be given to patients with severe hepatic parenchy- day 1 to 5. Objective responses were achieved in 66% of the BOP group (CR 22%, PR 44%) versus • There are at present no published data on pla- 76% of COP recipients (CR 20%, PR 56%) [fig.
cental transfer of bendamustine or excretion in breast • Freedom from treatment failure and overall sur- vival rates were 59 and 73%, respectively, for BOP 3. Therapeutic Trials
versus 55 and 84% for COP after a median follow- Bendamustine has been evaluated as monother- apy and as part of combination chemotherapy pro- Previously Treated Patients
tocols for first-line or subsequent treatment of lym- • A combination of bendamustine (60 mg/m2 on phomas and solid tumours. Most of the studies, day 1 to 5), vincristine and prednisolone achieved including 2 large phase III studies,[10-12] were re- ported as abstracts and provided few details of patients with refractory NHL.[13] A similar combi- methodology and results. In particular, the length nation using bendamustine 50 or 60 mg/m2 yielded of the treatment cycle and response criteria used an OR of 86% (CR 45%, PR 41%) in another 22 In this section, objective response (OR) rate re- fers to the summed total of complete and partial A combination of bendamustine (25 or 50 mg/ remissions (CR + PR). CR is defined as disappear- m2) and fludarabine (12.5 or 25 mg/m2) on days 1 ance of signs and symptoms of disease and PR is to 3 of a 3- or 4-week cycle achieved a 77% OR in generally broadly defined as a >50% reduction of 13 patients (most previously treated) with low tumour mass. The proportion of patients with no change (NC) and disease progression (PD) are also • Among 38 patients (12 pretreated) with NHL shown, where stated in the study report.
(n = 22) or chronic lymphocytic leukaemia (CLL)  Adis International Limited. All rights reserved.
to 3, alone or in combination with mitoxantrone 6 • A combination of bendamustine (50 mg/m2 on days 1 to 5 or 60 mg/m2 on days 1 to 3 of a 28-day cycle), methotrexate (30 mg/m2 on day 3), mitox-antrone (12 mg/m2 on day 1) and prednisolone (60 mg/m2 days 1 to 5) was evaluated in 23 patientswith resistant or relapsed stage I to IV high grade NHL. Patients (who were mostly aged >60 years) also received granulocyte colony-stimulating fac-tor. OR was 48% (CR 13%, PR 35%, NC 4%, PD48%).[21] Fig. 1. Substitution of bendamustine for cyclophosphamide in
• Bendamustine as monotherapy (120 mg/m2/day the COP regimen for advanced low grade non-Hodgkin’s lym- on days 1 and 2 every 3 weeks) produced an OR of phoma. Outcome of treatment with BOP (bendamustine 60 41% (CR 18%, PR 23%) in 17 outpatients with mg/m2, vincristine 2mg day 1 and prednisolone 100 mg/m2days 1 to 5) versus COP (cyclophosphamide 400 mg/m2 day refractory (n = 8) and/or relapsed high grade NHL, 1 to 5, vincristine 2mg day 1 and prednisolone 100 mg/m2 days most of whom had been pretreated with ≥2 other 1 to 5) in a randomised study (n = 162).[10] [n = 16] given bendamustine 100 mg/m2 on day 1and etoposide 50mg orally on days 1 to 5 of a 21- Previously Untreated Patients
day cycle for 8 courses, the OR was 97% (CR 67%, • A combined modality risk-adapted treatment PR 30%). The median duration of remission was consisting of CVPP/ABVB hybrid chemotherapy about 15 months in patients with CR or PR.[16] and low dose involved-field radiotherapy (25Gy) was evaluated in previously untreated patients with Bendamustine 70 mg/m2 days 1 to 3 combined Hodgkin’s disease with elevated risk factors (e.g.
with idarubicin 6 mg/m2 days 1 and 2 and dexa- mediastinal bulky disease, systemic B symptoms, methasone 4 to 8 mg/m2 days 1 to 4 in a 21-day extranodal lesions, unfavourable histology). CVPP/ cycle produced an OR of 79% (CR 29%, PR 50%) ABVB consisted of cyclophosphamide, vinblas- in 14 heavily pretreated patients with NHL (n = 9) tine, procarbazine, prednisolone, doxorubicin, bleo- or CLL (n = 5). Median duration of remission was mycin and vincristine with bendamustine 30 mg/m2 on days 8 to 12 of a 28-day cycle. The OR was 93% • Bendamustine monotherapy (120 mg/m2 on 2 in 43 evaluable patients (CR 81%, PR 12%). Three consecutive days of a 3-week cycle) achieved an of the partial responders and 1 nonresponder OR of 64% (CR 12%, PR 52%) in 33 previously treated patients with relapsed or progressive NHL • Ten-year follow-up showed that 5- and 10-year relapse-free survival rates were 82 and 70%, re- • An OR of 61% (CR 29%; PR 32%; NC 24%; PD spectively. Overall survival at 5 and 10 years was 15%) was achieved in a retrospective analysis of 83 and 73%, respectively. Secondary neoplasms 34 patients with low grade NHL after palliative occurred in only 2 patients, both of whom had re- treatment with bendamustine 100 mg/m2 on days 1 ceived intensive retreatment after relapse.[24]  Adis International Limited. All rights reserved.
• These results were confirmed in a subsequent the bendamustine than the melphalan group. The comparative multicentre study in 100 nonpre- 30-month probability of progression-free survival treated patients. CR was achieved in 88% of pa- was 23 versus 8%. The overall probability of 30- tients given bendamustine versus 81% of those month post-diagnosis survival was the same for the treated with cyclophosphamide, each in combina- 2 treatment groups (56%). However, the protocol tion with vinblastine, procarbazine, prednisolone, allowed patients who had PD while on therapy or doxorubicin, vincristine and bleomycin with radio- within a 3-month therapy-free interval to be switched to the alternative treatment,[11] and this Previously Treated Patients
likely explains the similarity in survival rates.
• A bendamustine-containing regimen (DBVB) was as effective as a standard ABVD regimen (doxorubicin, bleomycin, vincristine and dacar-bazine) in 73 patients with Hodgkin’s disease with Bendamustine has also shown promising results primary or secondary resistance to the CVPP reg- in the treatment of solid tumours, particularly imen (see above). The DBVB regimen consisted of daunorubicin, bleomycin and vincristine with ben- • Substituting bendamustine (240 mg/m2 per cy- damustine 50 mg/m2 on days 1 to 5 of a 28-day cle) [n = 25] for cyclophosphamide in the CMF cycle. The OR was 69 versus 83% for ABVD.[1] protocol (cyclophosphamide, methotrexate and fluorouracil) [n = 24] extended the median dura-tion of remission from 6.2 to 15.2 months in pa- • Bendamustine monotherapy (50 or 60 mg/m2 tients with metastatic breast cancer. OR were 52% depending on age, for 5 days of a 28-day cycle) was for the bendamustine and 46% for the cyclophos- evaluated in 20 patients with advanced or refrac- tory CLL. The OR was 75% (CR 30%, PR 45%).[6] • Of 14 elderly pretreated patients with poor prognosis, 4 had a partial and 5 had a complete haematological remission after treatment with bendamustine 100 mg/m2 days 1 and 2 every 4weeks.[26] A bendamustine/prednisone regimen produced a 3-fold higher rate of CR (32 vs 11%) than a melphalan/prednisone regimen in patients withpreviously untreated stage II/III multiple my- eloma. Patients were randomised to receive benda- mustine 150 mg/m2 day 1 and 2 plus prednisone 60 mg/m2 days 1 to 4 (n = 68), or melphalan 15 mg/m2day 1 plus prednisone 60 mg/m2 days 1 to 4 (n =63), of a 4-week cycle. OR were 75% in the ben- Fig. 2. Comparative efficacy of bendamustine/prednisone in
damustine group versus 68% in the melphalan previously untreated stage II/III multiple myeloma. Patients were randomised to receive bendamustine 150 mg/m2 days 1and 2 plus prednisone 60 mg/m2 days 1 to 4 (BP; n = 68), or • Response was also more rapid (after 6.7 vs 8.5 melphalan 15 mg/m2 day 1 plus prednisone 60 mg/m2 days 1 cycles) and durable (14 vs 10 months, p < 0.03) in to 4, (MP; n = 63) of a 4-week cycle.[11,12] * p < 0.003 vs MP.
 Adis International Limited. All rights reserved.
• Bendamustine (150 mg/m2 on days 1 and 2 of a and grade 1 to 2 and 3 to 4 thrombocytopenia in 4-week cycle) achieved a 25% OR when used as 18 and 13% of patients. Respective values for salvage therapy in 36 patients with advanced breast melphalan/prednisone were 39 and 33% for leuco- cancer. The median progression-free interval was penia, and 27 and 15% for thrombocytopenia.[11] 2 months. The efficacy of bendamustine appeared • A bendamustine-containing regimen (BOP; in to be independent of previous anthracycline treat- which bendamustine 60 mg/m2 was substituted for ment, consistent with the lack of cross-resistance cyclophosphamide) was associated with signifi- observed in in vitro studies (section 1).[28] cantly less grade 3/4 leucopenia (19 vs 34%; p < • Patients with other tumours who responded to 0.0001) but significantly more grade 3/4 thrombo- bendamustine-based therapy (n = 15 to 28 per cytopenia (4.0 vs 0.9%; p < 0.001) than a standard group) included small cell lung cancer (OR 41 to COP regimen (see section 3) in patients with NHL 45%),[31,32] relapsed head and neck cancers (OR 73%)[33] and advanced relapsed gastrointestinalcancers (OR 18%).[34] • When bendamustine (120 mg/m2) was substi- • However, bendamustine (120 mg/m2 on days 1 tuted for cyclophosphamide in the CMF protocol and 2, repeated every 3 weeks) was not effective for breast cancer (section 3), haematological tox- in 19 heavily pretreated patients with cisplatin- icity was more common with the bendamustine- refractory or relapsed germ cell tumours.[35] containing regimen. Leucopenia, febrile neutro-penia, anaemia and thrombocytopenia occurred in 4. Tolerability
28 versus 23, 13 versus 2, 11 versus 0 and 11 versus 2 patients, respectively.[36] This interim analysis The most common events in patients receiving bendamustine alone or in combination with otheragents in phase II or subsequent studies are • According to the manufacturer’s information, haematological events (leucopenia, thrombocyto- leucocyte and platelet nadirs are reached after 14 penia, anaemia) and gastrointestinal disturbances to 20 days and bone marrow recovers within 3 to 5 (nausea, vomiting and mucositis).[11,20,23] Leucopenia and thrombocytopenia (all grades) were documented in 58 and 42% (all grades) and17 and 6% (grades 3/4) of 36 patients receiving • Grade 1 to 3 nausea/vomiting occurred in 50% of bendamustine monotherapy (150 mg/m2 on 2 days 83 patients receiving a bendamustine/prednisone regimen, versus 25% of 75 patients receiving • Grade 3/4 leucopenia occurred in 38 of 74 courses of bendamustine monotherapy (50 or 60 • Mucositis was reported in 16 versus 4 patients, mg/m2) in patients with CLL. Three severely im- respectively, when bendamustine (120 mg/m2) was munocompromised patients died from treatment- substituted for cyclophosphamide in the CMF pro- • Bendamustine plus prednisone was associated with a similar incidence of leucopenia and thrombo- • Grade 2 nausea or emesis developed in 11 of 34 cytopenia to a melphalan/prednisone regimen.
and grade 3 nausea/emesis in 3 of 34 patients with Grade 1 to 2 and 3 to 4 leucopenia occurred in 38 low grade lymphomas treated with bendamustine and 40% of patients with multiple myeloma, re- with or without mitoxantrone in a retrospective spectively, treated with bendamustine/prednisone  Adis International Limited. All rights reserved.
7. Matthias M, Preiss R, Sohr R, et al. Pharmacokinetics of benda- mustine in patients with malignant tumors [abstract]. Proc Allergic and hypersensitivity reactions are less 8. Haase D, Preiss R, Sohr R. Untersuchungen zur Plasmaei- common events. Allergic skin reactions occurred weiβbindung von Bendamustin (Cytostasan) und Ambazon.
in 25% of 16 patients who received bendamustine 9. Preiss R, Sohr R, Matthias M, et al. Pharmacokinetics of 50 or 60 mg/m2 for 5 days of a 28-day cycle[37] and bendamustine (Cytostasane) in patients [in German]. Phar- in 9% of 43 patients treated with bendamustine 120 mg/m2 on 2 consecutive days of a 3-week cycle.[18] 10. Herold M, Schulze A, Mantovani L, et al. BOP versus COP in advanced low grade non-Hodgkin’s lymphomas − results of • Moderate (grade ≤2) allergic skin reactions a randomized multicenter study [abstract]. Blood 1999 Nov15; 94 Suppl. 1 (Pt 2): 262 were more common with the bendamustine- than 11. Pönisch W, Mitrou PS, Merkle K, et al. A randomized multi- the cyclophosphamide-containing regimen in the center study of bendamustine/prednisone versus melphalane/ above study in patients with NHL (30 vs 14%; p = prednisone in the primary treatment of multiple myeloma [ab-stract no. 542]. Blood 1999; 94 (10) Suppl. 1: 123a 12. Poenisch W, Mitrou PS, Merkle KH, et al. Bendamustine/pre- dnisone versus melphalan/prednisone in the primary treat-ment of multiple myeloma: an updated analysis of the 94BP01 protocol [abstract]. Blood 2000 Nov 16; 96 Suppl. 11 (Pt 1):759a • Bendamustine has a relatively low propensity 13. Ruffert K, Jahn H, Syrbe G, et al. Cytostasan (Bendamustin) in to induce alopecia. In several studies, alopecia did der Alternativetherapie maligner Non-Hodgkin-Lymphome[in German]. Z Klin Med 1989; 44: 671-4 not develop[13,15,16,19] or was only mild (maximum 14. Blumenstengel K, Fricke H-J, Kath R, et al. Bendamustin (B), vincristin (O), prednisolon (P) in relapsed and refractory low-grade non-Hodgkin-lymphomas (NHL) [abstract no. 591].
• Grade 3 alopecia was significantly less common with a bendamustine- than a cyclophosphamide- 15. Gnad M, Reichle A, Andreesen R, et al. Therapy of low-grade non-Hodgkin’s-lymphoma (NHL) with fludarabine and benda- based regimen (3.6 vs 48%, p < 0.0001) in patients mustine [abstract]. Onkologie 1999 Aug; 22 Suppl. 1: 168 16. Ruffert K. Therapy of low grade non-Hodgkins-lymphoma (NHL) with bendamustine and oral etoposide [abstract no.
452]. Ann Oncol 1999; 10 Suppl. 5: 125 5. Bendamustine: Current Status
17. König U, Junghauss C, Decker S, et al. Response of refractory and relapsed low grade non-Hodgkin’s lymphoma and Bendamustine as single-agent or combination chronic lymphocytic leukemia to Dexa-BID, a bendamustine therapy is indicated in Germany for the treatment hydrochloride containing regimen [abstract no. 479]. AnnOncol 1999; 10 Suppl. 3: 132 of Hodgkin’s disease, NHL, multiple myeloma, CLL 18. Heider A, Kress M, Niederle N. Relapse therapy with benda- mustine in patients with low grade non Hodgkin lymphomas(NHL): efficacy and toxicity [abstract]. Blood 1998 Nov 15Suppl. 1 (Pt 2): 236 References
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24. Herold M, Keinert K, Anger G. Risk adapted combined radio- 32. Reck M, Haering B, Koschel G, et al. Chemotherapy of ad- and chemotherapy in Hodgkin’s disease − 10-year follow-up.
vanced SCLC and NSCLC with bendamustine − a phase II study [in German]. Pneumologie 1998 Oct; 52: 570-3 25. Herold M, Siebert S, Schulze A, et al. Reduced combined mo- 33. Schilcher RB, Rahn A, Haase KD. Recurrent ENT tumors dality treatment for Hodgkin’s disease: results of a random- treated with bendamustine or gemcitabine and radiotherapy.
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chemotherapy [abstract]. Eur J Cancer A 1997 Sep; 33 Suppl.
37th Annual Meeting of the American Society of Clinical Oncology (ASCO); 2001 May 12-15; San Francisco (CA) 35. Kollmannsberger C, Gerl A, Schleucher N, et al. Phase II study 27. Ruffert K. Primary chemotherapy of metastatic breast carci- of bendamustine in patients with relapsed or cisplatin-refrac- noma with bendamustine hydrochloride, methotrexate and tory germ cell cancer. Anticancer Drugs 2000 Aug; 11: 535-9 fluorouracil versus cyclophosphamide, methotrexate and flu- 36. Von Minckwitz G, Souchon R, Kleeberg UR, et al. Benda- orouracil [in German]. Zentralbl Chir 1998; 123 Suppl. 5: mustin, MTX, 5-FU (BMF) vs. cyclophosphamide, MTX, 5- FU (CMF) as first line therapy of metastatic breast cancer: 28. Höffken K, Merkle K, Schönfelder M, et al. Bendamustine as a safety interim analysis. 36th Annual Meeting of the Amer- salvage treatment in patients with advanced progressive ican Society of Oncology; 2000 May 20-23; New Orleans breast cancer: a phase II study. J Cancer Res Clin Oncol 1998; 37. Blumenstengel K, Schmalenberg H, Fricke H-J, et al.
Bendamustin monotherapy in advanced and refractory 29. Jamitzky T, Lange OF. Third-line chemotherapy with benda- chronic lymphocytic leukemia [abstract]. Onkologie 1997 mustin for metastatic breast cancer − a prospective pilot study [abstract]. Eur J Cancer A 1996; 32A Suppl. 2: 47 30. Schmidt P, Heck HK, Preiss J. Bendamustin/mitoxantrone in the treatment of advanced breast cancer [abstract]. Eur J Can-cer 1999 Sep; 35 Suppl. 4: 324 Correspondence: Karen L. Goa, Adis International Limited, 31. Heider A, Köster W, Grote-Kiehn J, et al. Bendamustin in un- 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auck- treated small cell lung cancer (SCLC): efficacy and toxicity [abstract]. Eur J Cancer 1999 Sep; 35 Suppl. 4: 254  Adis International Limited. All rights reserved.

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