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

Adis International Limited. All rights reserved.
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
19. Heider A, Kress M, Niederle N. Bendamustin as second-line 1. Ribosepharm GmbH. Bendamustine product monograph.
therapy in patients with relapsed low grade non-Hodgkin’s lymphoma and multiple myeloma [in German]. Tumor Diagn 2. Bremer K, Roth W. Bendamustine, a low toxic nitrogen-mustard derivative with high efficacy in malignant lymphomas. Tumor 20. Preiss J, Heck HK, Schmidt P. Bendamustine in the therapy of low-grade malignant lymphomas [abstract]. Eur J Cancer 3. Strumberg D, Harstrick A, Doll K, et al. Bendamustine hydro- chloride activity against doxorubicin-resistant human breast 21. Kahl C, Herold M, Höffkes HG, et al. Bendamustine, metho- carcinoma cell lines. Anticancer Drugs 1996 Jun; 7: 415-21 trexate, mitoxantrone, and prednisolone (BMMP) for the 4. Schwaenen C, Karakas T, Schrader M. Bendamustin in induc- treatment of relapsed or refractory high-grade non-Hodgkin’s tion of apoptosis in B-cell chronic lymphocytic leukemia [ab- stract]. Ann Oncol 1999; 10 Suppl. 3: 132 22. Weidmann E, Kim ZC, Geduldig K, et al. Palliative treatment 5. Schöffski P, Seeland G, Engel H, et al. Weekly administration of high grade non Hodgkin’s lymphoma with bendamustine: of bendamustine: a phase I study in patients with advanced a phase II study [abstract]. Onkologie 2000; 23 (Sonderheft progressive solid tumours. Ann Oncol 2000 Jun; 11: 729-34 6. Kath R, Blumenstengel K, Fricke HJ, et al. Bendamustine 23. Herold M, Keinert K, Anger G, et al. Risk-adapted combined monotherapy in advanced and refractory chronic lympho- radiotherapy and chemotherapy for Hodgkin’s disease − re- cytic leukemia. J Cancer Res Clin Oncol 2001; 127: 48-54 sults of a pilot study. Onkologie 1992; 15: 502-5  Adis International Limited. All rights reserved.
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.
ized multicenter trial [abstract no. P-85]. Leuk Lymphoma 36th Proc Am Soc Clin Oncol, New Orleans, 20-23 May2000; 19: 426 34. Ridwelski K, Rudolph St, Fahlke J, et al. Combination benda- 26. Aivado M, Becker K, Neise M, et al. Bendamustine (B) is an mustin (B), mitomycin (M), 5-FU (FU) and prednisolon (P) efficient and well-tolerated option in the palliation of pre- in advanced gastrointestinal tumours with progress under treated B-cell chronic lymphocytic leukemias (CLL) [poster].
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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Erika Sifrit v. State of Maryland No. 139, September Term, 2003AGREEMENT BETWEEN THE STATE AND DEFENDANT — When the defendant breaches anagreement between himself/herself and the State, the State is not required to honor its obligationspursuant to the agreement. DUE PROCESS — INCONSISTENT THEORIES OF PROSECUTION — For a due process violationto exist the inconsistency must exit at the core


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