ADIS NEW DRUG PROFILE
`
`Drugs 2001; 61 (5): 631-638
`0012-6667/01/0005-0631/$27.50/0
`
`© Adis International Limited. All rights reserved.
`
`Bendamustine
`Julia A. Barman Balfour and Karen L. Goa
`Adis International Limited, Auckland, New Zealand
`
`Contents
`
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
`Abstract
`1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
`2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
`3. Therapeutic Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
`4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
`5. Bendamustine: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
`
`Abstract
`h Bendamustine is a bifunctional alkylating agent
`with cytotoxic activity against human ovarian and
`breast cancers in vitro. It shows only partial in vitro
`cross-resistance with cyclophosphamide, mel-
`phalan, carmustine and cisplatin.
`h Bendamustine as monotherapy or as part of com-
`bination chemotherapy protocols for first-line or
`subsequent treatment produced objective response
`rates of 61 to 97% in patients with Hodgkin’s dis-
`ease or non-Hodgkin’s lymphoma (NHL) [41 to
`48% in high grade NHL].
`h In patients with multiple myeloma, a bendamustine/
`prednisone regimen produced a higher rate of com-
`plete response (32 vs 11%) and more durable re-
`sponses than a melphalan/prednisone regimen.
`h 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-
`vanced low grade NHL.
`h Substituting bendamustine for cyclophosphamide
`in the CMF protocol (cyclophosphamide, metho-
`trexate and fluorouracil) prolonged remission from
`6.2 to 15.2 months in patients with metastatic
`breast cancer.
`h The most common adverse events in patients re-
`ceiving bendamustine are haematological events
`and gastrointestinal disturbances. Bendamustine
`has a relatively low propensity to induce alopecia.
`
`Features and properties of bendamustine
`
`Indications
`Treatment of Hodgkin’s disease, non-Hodgkin’s lymphoma,
`multiple myeloma, chronic lymphocytic leukaemia and breast
`cancer
`
`Mechanism of action
`Alkylating agent
`
`Causes crosslinking of DNA
`single and double strands
`
`Dosage and administration (in clinical trials)
`50-60 mg/m2/day for 3 or 5
`Haematological
`days or 100-120 mg/m2 every 3
`to 4 weeks
`120-150 mg/m2 every 4 weeks
`Intravenous (30-60 min infusion)
`Once daily
`
`Solid tumours
`Route of administration
`Frequency of administration
`
`Pharmacokinetic profile
`Volume of distribution at
`steady state
`Mean total clearance
`Plasma elimination half-life
`
`Adverse events
`Most frequent
`
`19.80-20.51L
`
`31.7-49.6 L/h (mostly renal)
`32-36 min
`
`Haematological toxicity and
`gastrointestinal disturbances
`
`AGILA ET AL - EXHIBIT 1012
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`632
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`Barman Balfour & Goa
`
`CH3
`N
`
`N
`
`CH2CH2CH2COOH
`
`CICH2CH2
`
`CICH2CH2
`
`N
`
`Bendamustine
`
`Bendamustine is a bifunctional alkylating agent
`consisting of a purine and amino acid antagonist (a
`benzimidazole ring) and an alkylating nitrogen
`mustard moiety.[1] The drug has been evaluated as
`an intravenous infusion mainly in the treatment of
`lymphomas but also as a therapy for solid tumours,
`particularly breast cancer.
`
`1. Pharmacodynamic Profile
`
`Alkylating Activity
`• The alkylating toxicity of bendamustine is
`based on crosslinking of DNA single and double
`strands, leading to disruption of the matrix function
`of DNA in DNA synthesis.[2] The contribution, if
`any, of purine and amino acid antagonism to the
`antitumour effect of bendamustine is yet to be dem-
`onstrated.
`• Bendamustine demonstrated cytotoxic activity
`against several human ovarian and breast cancer
`cell lines in vitro. For example, the concentration
`required to inhibit 50% of cell growth (IC50) was
`138 μmol/L against the breast cancer line MCF 7.
`Cross-resistance between bendamustine and other
`alkylating agents such as cyclophosphamide, mel-
`phalan and carmustine and to cisplatin was only
`partial.[3]
`• Notably, bendamustine also showed good activ-
`ity against the cisplatin-resistant ovarian cell line
`A2780-CP2 (IC50 157 μmol/L) and the doxorubicin-
`resistant breast adenocarcinoma cell line MCF 7
`AD [mean IC50 187 μmol/L];[3] indeed, the drug
`has shown activity against breast cancer in women
`pretreated with anthracyclines (see section 3.)
`
`• When used in equitoxic concentrations (IC50s),
`bendamustine consistently induced more DNA
`double-strand breaks (measured by pulsed field gel
`electrophoresis) 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-
`ent apoptosis of B-chronic lymphocytic leukaemia
`(B-CLL) cells in vitro. A synergistic effect was
`seen with fludarabine in this system. Apoptosis
`rates for bendamustine plus fludarabine at 48 hours
`were 1.4-fold higher than the rates expected when
`the 2 drugs were added together.[4]
`
`Effects on Lymphocyte Subsets
`• In a phase I study, bendamustine 60 to 80 mg/m2
`given weekly for up to 8 weeks to patients with
`refractory solid tumours (n = 12) induced sustained
`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
`ratio remained constant throughout treatment.[5]
`• However, a ≈50% in the ratio of CD4 : CD8
`lymphocytes was noted (from 1.36 to 0.6) after 4
`courses of treatment with bendamustine 50 or 60
`mg/m2 (days 1 to 5) in patients with lymphopro-
`liferative disorders (n = 12). Although 2 patients
`developed opportunistic infections, no correlation
`was found between infectious episodes and CD4 :
`CD8 ratio.[6]
`
`2. Pharmacokinetic Profile
`• Bendamustine undergoes extensive first-pass
`metabolism.[7]
`• Bendamustine is highly (>95%) protein bound,
`primarily to albumin, at clinically relevant concen-
`trations. Protein binding is not affected by ad-
`vanced age (>70 years), low serum albumin levels
`(31 g/L) or presence of advanced tumours.[8]
`• After intravenous administration of bendamust-
`ine to >20 patients with tumours, volume of distri-
`bution at steady state (Vdss) was 19.80L. Elimina-
`tion of bendamustine was rapid and occurred
`
`© Adis International Limited. All rights reserved.
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`Drugs 2001; 61 (5)
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`Bendamustine: New Drug Profile
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`633
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`predominantly by the renal route, with a smaller
`amount being eliminated by the liver. Mean total
`clearance was 49.6 L/h and was independent of
`dosage over the range 0.5 to 5 mg/kg. Plasma elim-
`ination half-life (t1/2β) was 32 minutes.[7]
`• Similarly, Vdss was 20.51L, total clearance was
`31.7 L/h and t1/2β was 36 minutes in 7 patients who
`received bendamustine 4.2 to 5.5 mg/kg intrave-
`nously. Elimination of the drug was biphasic.[9]
`• 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]
`24%), other hydroxy derivatives and N-dimethyl-
`bendamustine. Biliary elimination occurs mainly
`as polar metabolites.[7]
`• As bendamustine is eliminated primarily by re-
`nal mechanisms, it should not be given to patients
`with glomerular filtration rate <1.8 L/h. The drug
`also undergoes hepatic metabolism and should not
`be given to patients with severe hepatic parenchy-
`mal damage and jaundice.[1]
`• There are at present no published data on pla-
`cental transfer of bendamustine or excretion in breast
`milk.
`
`3. Therapeutic Trials
`Bendamustine has been evaluated as monother-
`apy and as part of combination chemotherapy pro-
`tocols for first-line or subsequent treatment of lym-
`phomas and solid tumours. Most of the studies,
`including 2 large phase III studies,[10-12] were re-
`ported as abstracts and provided few details of
`methodology and results. In particular, the length
`of the treatment cycle and response criteria used
`were frequently not stated.
`In this section, objective response (OR) rate re-
`fers to the summed total of complete and partial
`remissions (CR + PR). CR is defined as disappear-
`ance of signs and symptoms of disease and PR is
`generally broadly defined as a >50% reduction of
`tumour mass. The proportion of patients with no
`change (NC) and disease progression (PD) are also
`shown, where stated in the study report.
`
`In a study in patients with multiple myeloma,
`Southwest Oncology Group (SWOG) response cri-
`teria were used. Response to treatment was deter-
`mined by change in tumour cell mass (TCM), as
`measured by myeloma protein concentrations. CR
`was defined as TCM reduction >75% and PR as
`TCM reduction of 25 to 74%. For either category,
`additional criteria were no progression of previous
`osteolytic bone lesions/appearance of new lesions
`on skeletal x-ray and serum calcium <120 mg/L.[11]
`
`Non-Hodgkin’s Lymphoma
`
`Previously Untreated Patients
`• Substitution of bendamustine (60 mg/m2) for
`cyclophosphamide in a standard first-line COP
`regimen did not compromise efficacy in previously
`untreated patients with advanced low grade non-
`Hodgkin’s lymphoma (NHL) randomised to either
`treatment (n = 162 in total). The COP regimen con-
`sisted of cyclophosphamide 400 mg/m2 day 1 to 5,
`vincristine 2mg day 1 and prednisolone 100 mg/m2
`day 1 to 5. Objective responses were achieved in
`66% of the BOP group (CR 22%, PR 44%) versus
`76% of COP recipients (CR 20%, PR 56%) [fig.
`1].[10]
`• Freedom from treatment failure and overall sur-
`vival rates were 59 and 73%, respectively, for BOP
`versus 55 and 84% for COP after a median follow-
`up of 20 months in this trial.[10]
`
`Previously Treated Patients
`• A combination of bendamustine (60 mg/m2 on
`day 1 to 5), vincristine and prednisolone achieved
`a 90% OR (CR 39%, PR 51%; PD 10%) in 31
`patients with refractory NHL.[13] A similar combi-
`nation using bendamustine 50 or 60 mg/m2 yielded
`an OR of 86% (CR 45%, PR 41%) in another 22
`such patients.[14]
`• A combination of bendamustine (25 or 50 mg/
`m2) and fludarabine (12.5 or 25 mg/m2) on days 1
`to 3 of a 3- or 4-week cycle achieved a 77% OR in
`13 patients (most previously treated) with low
`grade NHL.[15]
`• Among 38 patients (12 pretreated) with NHL
`(n = 22) or chronic lymphocytic leukaemia (CLL)
`
`© Adis International Limited. All rights reserved.
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`Drugs 2001; 61 (5)
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`Barman Balfour & Goa
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`to 3, alone or in combination with mitoxantrone 6
`mg/m2 on days 1 to 2.[20]
`
`High Grade Non-Hodgkin’s Lymphoma
`• 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 patients
`with 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%, PD
`48%).[21]
`• Bendamustine as monotherapy (120 mg/m2/day
`on days 1 and 2 every 3 weeks) produced an OR of
`41% (CR 18%, PR 23%) in 17 outpatients with
`refractory (n = 8) and/or relapsed high grade NHL,
`most of whom had been pretreated with ≥2 other
`therapeutic regimens.[22]
`
`Hodgkin’s Disease
`
`Previously Untreated Patients
`• A combined modality risk-adapted treatment
`consisting of CVPP/ABVB hybrid chemotherapy
`and low dose involved-field radiotherapy (25Gy)
`was evaluated in previously untreated patients with
`Hodgkin’s disease with elevated risk factors (e.g.
`mediastinal bulky disease, systemic B symptoms,
`extranodal lesions, unfavourable histology). CVPP/
`ABVB consisted of cyclophosphamide, vinblas-
`tine, procarbazine, prednisolone, doxorubicin, bleo-
`mycin and vincristine with bendamustine 30 mg/m2
`on days 8 to 12 of a 28-day cycle. The OR was 93%
`in 43 evaluable patients (CR 81%, PR 12%). Three
`of the partial responders and 1 nonresponder
`achieved CR after salvage treatment.[23]
`• Ten-year follow-up showed that 5- and 10-year
`relapse-free survival rates were 82 and 70%, re-
`spectively. Overall survival at 5 and 10 years was
`83 and 73%, respectively. Secondary neoplasms
`occurred in only 2 patients, both of whom had re-
`ceived intensive retreatment after relapse.[24]
`
`BOP
`COP
`
`Complete
`response
`
`Partial
`response
`
`20-Month
`survival
`
`634
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Patients (%)
`
`Fig. 1. Substitution of bendamustine for cyclophosphamide in
`the COP regimen for advanced low grade non-Hodgkin’s lym-
`phoma. Outcome of treatment with BOP (bendamustine 60
`mg/m2, vincristine 2mg day 1 and prednisolone 100 mg/m2
`days 1 to 5) versus COP (cyclophosphamide 400 mg/m2 day
`1 to 5, vincristine 2mg day 1 and prednisolone 100 mg/m2 days
`1 to 5) in a randomised study (n = 162).[10]
`
`[n = 16] given bendamustine 100 mg/m2 on day 1
`and etoposide 50mg orally on days 1 to 5 of a 21-
`day cycle for 8 courses, the OR was 97% (CR 67%,
`PR 30%). The median duration of remission was
`about 15 months in patients with CR or PR.[16]
`• Bendamustine 70 mg/m2 days 1 to 3 combined
`with idarubicin 6 mg/m2 days 1 and 2 and dexa-
`methasone 4 to 8 mg/m2 days 1 to 4 in a 21-day
`cycle produced an OR of 79% (CR 29%, PR 50%)
`in 14 heavily pretreated patients with NHL (n = 9)
`or CLL (n = 5). Median duration of remission was
`7 months.[17]
`• Bendamustine monotherapy (120 mg/m2 on 2
`consecutive days of a 3-week cycle) achieved an
`OR of 64% (CR 12%, PR 52%) in 33 previously
`treated patients with relapsed or progressive NHL
`or multiple myeloma.[18,19]
`• An OR of 61% (CR 29%; PR 32%; NC 24%; PD
`15%) was achieved in a retrospective analysis of
`34 patients with low grade NHL after palliative
`treatment with bendamustine 100 mg/m2 on days 1
`
`© Adis International Limited. All rights reserved.
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`Drugs 2001; 61 (5)
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`Bendamustine: New Drug Profile
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`635
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`the bendamustine than the melphalan group. The
`30-month probability of progression-free survival
`was 23 versus 8%. The overall probability of 30-
`month post-diagnosis survival was the same for the
`2 treatment groups (56%). However, the protocol
`allowed patients who had PD while on therapy or
`within a 3-month therapy-free interval
`to be
`switched to the alternative treatment,[11] and this
`likely explains the similarity in survival rates.
`
`Breast Cancer and Other Solid Tumours
`
`Bendamustine has also shown promising results
`in the treatment of solid tumours, particularly
`breast cancer.[27-30]
`• Substituting bendamustine (240 mg/m2 per cy-
`cle) [n = 25] for cyclophosphamide in the CMF
`protocol (cyclophosphamide, methotrexate and
`fluorouracil) [n = 24] extended the median dura-
`tion of remission from 6.2 to 15.2 months in pa-
`tients with metastatic breast cancer. OR were 52%
`for the bendamustine and 46% for the cyclophos-
`phamide group.[27]
`
`BP
`MP
`
`*
`
`Complete
`response
`
`Partial
`response
`
`No
`change
`
`Disease
`progression
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Patients (%)
`
`Fig. 2. Comparative efficacy of bendamustine/prednisone in
`previously untreated stage II/III multiple myeloma. Patients
`were randomised to receive bendamustine 150 mg/m2 days 1
`and 2 plus prednisone 60 mg/m2 days 1 to 4 (BP; n = 68), or
`melphalan 15 mg/m2 day 1 plus prednisone 60 mg/m2 days 1
`to 4, (MP; n = 63) of a 4-week cycle.[11,12] * p < 0.003 vs MP.
`
`• These results were confirmed in a subsequent
`comparative multicentre study in 100 nonpre-
`treated patients. CR was achieved in 88% of pa-
`tients given bendamustine versus 81% of those
`treated with cyclophosphamide, each in combina-
`tion with vinblastine, procarbazine, prednisolone,
`doxorubicin, vincristine and bleomycin with radio-
`therapy.[25]
`
`Previously Treated Patients
`• 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
`primary or secondary resistance to the CVPP reg-
`imen (see above). The DBVB regimen consisted of
`daunorubicin, bleomycin and vincristine with ben-
`damustine 50 mg/m2 on days 1 to 5 of a 28-day
`cycle. The OR was 69 versus 83% for ABVD.[1]
`
`Chronic Lymphocytic Leukaemia
`• Bendamustine monotherapy (50 or 60 mg/m2
`depending on age, for 5 days of a 28-day cycle) was
`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 4
`weeks.[26]
`
`Multiple Myeloma
`• A bendamustine/prednisone regimen produced
`a 3-fold higher rate of CR (32 vs 11%) than a
`melphalan/prednisone regimen in patients with
`previously 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/m2
`day 1 plus prednisone 60 mg/m2 days 1 to 4 (n =
`63), of a 4-week cycle. OR were 75% in the ben-
`damustine group versus 68% in the melphalan
`group (fig. 2).[12]
`• Response was also more rapid (after 6.7 vs 8.5
`cycles) and durable (14 vs 10 months, p < 0.03) in
`
`© Adis International Limited. All rights reserved.
`
`Drugs 2001; 61 (5)
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`

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`636
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`Barman Balfour & Goa
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`• Bendamustine (150 mg/m2 on days 1 and 2 of a
`4-week cycle) achieved a 25% OR when used as
`salvage therapy in 36 patients with advanced breast
`cancer. The median progression-free interval was
`2 months. The efficacy of bendamustine appeared
`to be independent of previous anthracycline treat-
`ment, consistent with the lack of cross-resistance
`observed in in vitro studies (section 1).[28]
`• Patients with other tumours who responded to
`bendamustine-based therapy (n = 15 to 28 per
`group) included small cell lung cancer (OR 41 to
`45%),[31,32] relapsed head and neck cancers (OR
`73%)[33] and advanced relapsed gastrointestinal
`cancers (OR 18%).[34]
`• However, bendamustine (120 mg/m2 on days 1
`and 2, repeated every 3 weeks) was not effective
`in 19 heavily pretreated patients with cisplatin-
`refractory or relapsed germ cell tumours.[35]
`
`4. Tolerability
`• The most common events in patients receiving
`bendamustine alone or in combination with other
`agents in phase II or subsequent studies are
`haematological events (leucopenia, thrombocyto-
`penia, anaemia) and gastrointestinal disturbances
`(nausea, vomiting and mucositis).[11,20,23]
`
`Haematological
`• Leucopenia and thrombocytopenia (all grades)
`were documented in 58 and 42% (all grades) and
`17 and 6% (grades 3/4) of 36 patients receiving
`bendamustine monotherapy (150 mg/m2 on 2 days
`per cycle) for breast cancer.[28]
`• Grade 3/4 leucopenia occurred in 38 of 74
`courses of bendamustine monotherapy (50 or 60
`mg/m2) in patients with CLL. Three severely im-
`munocompromised patients died from treatment-
`related causes (leucopenia).[6]
`• Bendamustine plus prednisone was associated
`with a similar incidence of leucopenia and thrombo-
`cytopenia to a melphalan/prednisone regimen.
`Grade 1 to 2 and 3 to 4 leucopenia occurred in 38
`and 40% of patients with multiple myeloma, re-
`spectively, treated with bendamustine/prednisone
`
`and grade 1 to 2 and 3 to 4 thrombocytopenia in
`18 and 13% of patients. Respective values for
`melphalan/prednisone were 39 and 33% for leuco-
`penia, and 27 and 15% for thrombocytopenia.[11]
`• A bendamustine-containing regimen (BOP; in
`which bendamustine 60 mg/m2 was substituted for
`cyclophosphamide) was associated with signifi-
`cantly less grade 3/4 leucopenia (19 vs 34%; p <
`0.0001) but significantly more grade 3/4 thrombo-
`cytopenia (4.0 vs 0.9%; p < 0.001) than a standard
`COP regimen (see section 3) in patients with NHL
`(n = 162).[10]
`• When bendamustine (120 mg/m2) was substi-
`tuted for cyclophosphamide in the CMF protocol
`for breast cancer (section 3), haematological tox-
`icity was more common with the bendamustine-
`containing regimen. Leucopenia, febrile neutro-
`penia, anaemia and thrombocytopenia occurred in
`28 versus 23, 13 versus 2, 11 versus 0 and 11 versus
`2 patients, respectively.[36] This interim analysis
`led to a protocol amendment.
`• According to the manufacturer’s information,
`leucocyte and platelet nadirs are reached after 14
`to 20 days and bone marrow recovers within 3 to 5
`weeks.[1]
`
`Gastrointestinal
`
`• Grade 1 to 3 nausea/vomiting occurred in 50% of
`83 patients receiving a bendamustine/prednisone
`regimen, versus 25% of 75 patients receiving
`melphalan/prednisone.[11]
`• Mucositis was reported in 16 versus 4 patients,
`respectively, when bendamustine (120 mg/m2) was
`substituted for cyclophosphamide in the CMF pro-
`tocol for breast cancer.[36]
`• Grade 2 nausea or emesis developed in 11 of 34
`and grade 3 nausea/emesis in 3 of 34 patients with
`low grade lymphomas treated with bendamustine
`with or without mitoxantrone in a retrospective
`analysis.[20]
`
`© Adis International Limited. All rights reserved.
`
`Drugs 2001; 61 (5)
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`Bendamustine: New Drug Profile
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`
`Allergic/Hypersensitivity
`• Allergic and hypersensitivity reactions are less
`common events. Allergic skin reactions occurred
`in 25% of 16 patients who received bendamustine
`50 or 60 mg/m2 for 5 days of a 28-day cycle[37] and
`in 9% of 43 patients treated with bendamustine 120
`mg/m2 on 2 consecutive days of a 3-week cycle.[18]
`• Moderate (grade ≤2) allergic skin reactions
`were more common with the bendamustine- than
`the cyclophosphamide-containing regimen in the
`above study in patients with NHL (30 vs 14%; p =
`0.02).[10]
`
`Alopecia
`• Bendamustine has a relatively low propensity
`to induce alopecia. In several studies, alopecia did
`not develop[13,15,16,19] or was only mild (maximum
`WHO grade I).[28-30]
`• Grade 3 alopecia was significantly less common
`with a bendamustine- than a cyclophosphamide-
`based regimen (3.6 vs 48%, p < 0.0001) in patients
`with NHL.[10]
`
`5. Bendamustine: Current Status
`Bendamustine as single-agent or combination
`therapy is indicated in Germany for the treatment
`of Hodgkin’s disease, NHL, multiple myeloma, CLL
`and breast cancer.[1]
`
`References
`1. Ribosepharm GmbH. Bendamustine product monograph.
`München, Germany, 2000
`2. Bremer K, Roth W. Bendamustine, a low toxic nitrogen-mustard
`derivative with high efficacy in malignant lymphomas. Tumor
`Diagn Ther 1996; 17 (1): 1-6
`3. Strumberg D, Harstrick A, Doll K, et al. Bendamustine hydro-
`chloride activity against doxorubicin-resistant human breast
`carcinoma cell lines. Anticancer Drugs 1996 Jun; 7: 415-21
`4. Schwaenen C, Karakas T, Schrader M. Bendamustin in induc-
`tion of apoptosis in B-cell chronic lymphocytic leukemia [ab-
`stract]. Ann Oncol 1999; 10 Suppl. 3: 132
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`Correspondence: Karen L. Goa, Adis International Limited,
`41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auck-
`land 10, New Zealand.
`E-mail: demail@adis.co.nz
`
`© Adis International Limited. All rights reserved.
`
`Drugs 2001; 61 (5)