Bendamustine

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Bendamustine, a well-tolerated cytotoxic agent used in Germany for many years, is soon to be marketed in the rest of Europe for a range of indications including chronic lymphocytic leukaemia

Judith Thiesen
PhD
Department of Pharmacy
University Medical Center of the Johannes Gutenberg University Mainz, Germany

Bendamustine is an alkylating agent belonging to the N-lost group, first synthesised in East Germany in the 1960s.[1] It has been in clinical use in Germany for 40 years for the treatment of several malignancies. In Germany it is marketed as Ribomustin for first-line treatment of advanced indolent non-Hodgkin’s lymphoma (NHL) in a combination protocol, for multiple myeloma (MM) stage II and III (Salmon and Durie) in combination with prednisone and for chronic lymphocytic leukaemia (CLL).[2] In the United States bendamustine (Treanda) received FDA approval in 2008 for first-line treatment of CLL and for treatment of indolent B-cell-NHL that has progressed during or within six months of treatment with rituximab or a rituximab-based regimen.[3] In Switzerland bendamustine has been approved (Ribomustin) for the treatment of CLL since March 2009.
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) announced in March 2010 that the marketing authorisation can be granted in all Member States for three indications – CLL in patients for whom treatment with fludarabine is not appropriate, NHL in patients who have had a relapse following treatment containing rituximab and MM in combination with prednisone for patients older than 65 years who are not eligible for autologous stem cell transplantation and cannot be treated with thalidomide or bortezomib.[4] Marketing of bendamustine as Levact will start in the second half of 2010.

Mechanism of action
Bendamustine is a bifunctional alkylating agent with an alkylating bis-2-chloroethylamine group (like cyclophosphamide, melphalan and chlorambucil), a purine-like benzimidazole ring and a butyric acid side chain. The butyric acid side chain enhances the water solubility of bendamustine (like chlorambucil). The bis-2-chloroethylamine moiety forms electrophilic alkyl groups, which bind covalently to electron-rich nucleophilic moieties of DNA, resulting in intra- and interstrand DNA crosslinks, which cause DNA single and double strand breaks. In contrast to other alkylators bendamustine induces cell death not only by apoptosis but also by several pathways including down-regulation of mRNA expression of genes responsible for mitotic checkpoints. Hence, cells with DNA damage caused by prior alkylation enter mitosis without DNA repair, resulting in a non-apoptotic cell death called ‘mitotic catastrophe’.[5] In addition, bendamustine seems to induce a different DNA repair pathway from other nitrogen mustards. It activates a base excision mechanism rather than an alkyltransferase mechanism of DNA repair.[5] These differences may be responsible for the more extensive and more durable DNA strand breakage caused by bendamustine compared to other alkylators and the limited cross-resistance shown in vitro to other alkylating agents such as  cyclophosphamide or chlorambucil.[6] The purine-like benzimidazole ring, which has the characteristics of an antimetabolite, is specific to bendamustine. However, no antimetabolite effects have been shown clinically.

[[HPE51.37a]]

Pharmacokinetics
Binding of bendamustine to human plasma proteins (primarily albumin) averages 95%, independent of drug concentration,[3] age (<70 years), low serum albumin levels and tumour stage.[2] In vitro data suggest that Bendamustine does not displace and is not displaced by other highly protein bound drugs.[3]
Bendamustine is primarily metabolised via hydrolysis to the inactive metabolites monohydroxy- and dihydroxybendamustine. In addition, two active metabolites are formed via CYP1A2: γ-hydroxy-bendamustine (M3) and N-demethyl-bendamustine (M4). M3 has equivalent cytotoxic activity to the parent drug whilst M4 is five-10 fold less active.[7] They only contribute marginally to the overall cytotoxicity because their plasma levels are low (M3 – 1/10 and M4 – 1/100 of bendamustine plasma level).[8] Bendamustine causes neither inhibition nor induction of cytochrome p450 isoforms. No clinical studies regarding potential drug interactions were conducted.[2]
Bendamustine is primarily eliminated in the faeces. Only about 20% of the given dose is found in the urine within 24 hours, in the following order of fractions: monohydroxybendamustine > bendamustine > dihydroxybendamustine > γ-hydroxy-bendamustine (M3) > N-demethyl-bendamustine (M4).[2] Following a single dose of 120mg/m² given intravenously over one hour bendamustine plasma levels declined in three phases: a rapid distribution phase (t1/2α 17 minutes), followed by an intermediate phase (t1/2ß 42 minutes) and a slow terminal phase with t1/2γ of 110 hours. The ß-phase is determined to be the relevant elimination half-life.[8] The pharmacokinetics of bendamustine are not altered by mild to moderate renal impairment, mild liver impairment, sex and age (>65 years of age).[8]

Indications and efficacy
Bendamustine shows a broad spectrum of cytotoxic activity not only in haematological malignancies but also in some solid tumours entities (ie, breast cancer and non small cell lung cancer (NSCLC).

Indolent Non-Hodgkin’s lymphoma
Recently two clinical trials with bendamustine monotherapy in rituximab-refractory indolent NHL have been completed. Friedberg et al[9] treated 76 patients with relapsed or refractory indolent and transformed NHL. Bendamustine 120mg/m² was administered on days 1 and 2 every three weeks for six to 12 cycles. The overall response rate (ORR) was 77%, 34% of patients showed complete response (CR) or unconfirmed CR (CRu) and the median progression free survival (PFS) was 7.1 months. The phase III study of Kahl et al[10] was conducted in 100 patients with the same bendamustine regime, given for six to eight cycles. An ORR of 75% (17% CR and CRu) and a median PFS of 9.3 months were found.
The efficacy and safety of the combination of bendamustine and rituximab (BR) (B 90mg/m² d1+2, R 375mg/m² d1) was evaluated in several clinical trials mainly of the German StiL group (study group indolent lymphomas). The first trial of the StiL group included 63 patients with relapsed or refractory indolent NHL (a prior treatment with rituximab was excluded). BR was given every four weeks for up to four cycles. Additional doses of R were given one week before the first and four weeks after the last cycle of BR. The ORR was 90% (CR 60%) and the median PFS was 24 months.
In three subsequent randomised clinical trials the StiL group compared BR to standard chemotherapy. In the NHL 1-2003 trial 549 previously untreated patients were randomised to receive either BR (every four weeks) or R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) (every three weeks) for a maximum of six cycles. Preliminary data show that BR was much better tolerated than R-CHOP with an ORR of 92.7% versus 91.3%, a CR 39.6% versus 30.0%, and a median PFS 54.9 versus 34.8 months. With BR there was a significantly lower incidence of grade 3–4 neutropenia and leukopenia and consequent infection and sepsis. In addition, peripheral neuropathy, stomatitis and alopecia (0% versus 100% complete alopecia) were clearly reduced in the BR group.[11] The final publication is still awaited but  on the basis of these encouraging data in April 2009 StiL started the NHL 7-2008 trial. This compares first-line treatment with BR with two versus four years of rituximab maintenance therapy in follicular lymphomas, and in indolent NHL compares two years of rituximab therapy with observation alone. The ongoing StiL NHL 2-2003 trial compares BR with FR (fludarabine 25mg/m² d1–3 plus rituximab 375mg/m² d1) in patients with relapsed or refractory indolent NHL.

Chronic lymphocytic lymphoma
The efficacy and safety of bendamustine monotherapy were shown in a randomised multicentre European phase III study in 319 patients with previously untreated CLL (Binet stage B or C). Bendamustine was given at  a dose of 100mg/m² on days 1 and 2, the control arm received chlorambucil at 0.8mg/kg orally on days 1 and 15 every four weeks for up to six cycles. The results of this trial revealed a higher response rate  in the bendamustine group (ORR 68% versus 31%, CR 31% versus 2%, partial response (PR) 27% versus 26%) and a longer median PFS (21.6 versus 8.3 months).[12]
The combination of bendamustine and rituximab (BR) was evaluated in a multicentre phase II study of the German CLL study group (GCLLSG) in patients with relapsed CLL. Treatment consisted of bendamustine 70mg/m² on days 1 and 2 combined with rituximab 375mg/m² on day 0 for the first and 500mg/m² on day 1 for the following cycles every four weeks. Preliminary data show an ORR of 77.4% with CR in 14.5% of the patients. Nevertheless molecular remission could not be shown.[13]
In a current randomised phase III trial the GCLLSG is evaluating the efficacy and safety of the combination BR (bendamustine 90mg/m² plus rituximab) versus FCR (fludarabine/cyclophosphamide/rituximab) for first-line treatment of CLL.

Multiple myeloma
The safety and efficacy of bendamustine combination therapy for multiple myeloma has been evaluated in several clinical trials. In 2006 Pönisch et al compared the combination of bendamustine plus prednisone (BP, B 150mg/m² d1+2, P 60mg/m² d 1-4) to melphalan plus prednisone (MP, M 15mg/m² d1, P 60mg/m² d1-4) as first-line treatment in 131 patients with MM (stage II or III). The ORRs were comparable (75% versus 70%), but CR was significantly higher with BP (32% versus 13%). Safety was similar in both groups with exception of a higher rate of nausea and vomiting grade 3 and 4 under BP (12% versus 0%).[14] Thereafter the combination of bendamustine (60–80mg/m² d1+2) with prednisone (100mg d1+2+4+8+11) and bortezomib (1.3mg/m² d1+4+8+11)) (BPV) in 49 elderly patients with relapsed or refractory MM was evaluated. The combination therapy was well tolerated and the ORR was 78%.[15]  Another study examined the combination of bendamustine (60mg/m² d1+8+15), prednisone (100mg p.o. d1+8+15+21) and thalidomide (50, 100 or 200mg p.o. d 1-28) (BPT) in a phase I thalidomide dose escalating clinical trial in 28 patients with refractory or relapsed MM after autologous stem-cell transplantation or conventional chemotherapy. The ORR was 85% and median PFS was 11 months.[16]

Adverse reactions and supportive therapy
In general bendamustine is well tolerated and toxicities are usually mild to moderate and mainly haematologic.[8–14,17–20] The dose limiting toxicity of bendamustine is myelosuppression, which is normally reversible.[20] Leucopenia and thrombocytopenia occur very frequently and  development of WHO grades 3 – 4 is possible[11,17] most commonly in pretreated patients and after a few cycles. Haematologic nadirs are observed 14–20 days after chemotherapy and bone marrow function normally regenerates after three-five weeks.[2] Delays in giving the next dose may be necessary if cell counts do not recover until the next cycle. Prophylactic administration of haematopoetic growth factors is indicated in patients who had severe or dose delaying myelosuppression in previous cycles. For patients who experienced extensive myelosuppression dose reduction should be considered in subsequent cycles (see dose adjustment).
As a consequence of myelosuppression infections are common (urinary tract infections, upper respiratory tract infections, pneumonia, sinusitis[10]) but sepsis is rare.[2] Since bendamustine is normally given in an ambulatory setting, patients should be instructed to contact a physician if they notice signs of infection. Prophylactic administration of antibiotics is not necessary.
In clinical trials infusion reactions including fever, hypotension, pain, allergic dermatitis and urticaria were often observed within 24 hours of bendamustine infusion. Anaphylactic reactions occurred rarely. Symptoms most commonly occur during the second and third cycles.[9,10] The administration of antihistamines, antipyretics or corticosteroids should be considered for patients who experienced grade 1–2 infusion reactions in the previous cycle. If grade 3 or higher allergic-type reactions occur, bendamustine should be discontinued.[3]
Patients often develop mild to moderate nausea and vomiting after administration of bendamustine. There is a significant correlation between the peak plasma level cmax and incidence of nausea.[8] Prophylactic administration of a 5-HT3-antagonist and corticosteroids before each dose of bendamustine is recommended in all patients. If a patient still suffers from nausea and vomiting administration of a neurokinin-1-receptor antagonist should be considered next time.
A few cases of tumour lysis syndrome have been reported[10,20] with the onset most common during the first cycle of bendamustine. The patient’s potassium, phosphate and uric acid blood levels should be monitored. Usually administration of intravenous fluids and allopurinol are recommended in such cases. However three cases of Stevens-Johnson syndrome have been  reported in patients with concomitant administration of bendamustine and allopurinol with or without rituximab. Therefore concomitant allopurinol should only be given if really necessary and patients should be observed closely for skin reactions.[3]

Dosage and administration
Bendamustine is administered intravenously as short infusion over 30 to 60 minutes. The usual dosage in indolent NHL is 120mg/m² d1+2 every three weeks as monotherapy[9,10] and 90mg/m² d1+2 every four weeks in a combination protocol (ie, with rituximab 375mg/m²).[11,18,19,21] The recommended dose in CLL patients is marginally lower: 100mg/m² (70mg/m² in patients with myelosuppression ie, due to pre-treatment with fludarabine) d1+2 every 4 weeks as monotherapy[12,20,22] and 70–90mg/m² d1+2 every four weeks in combination therapy.13 In MM bendamustine is dosed slightly higher: 120–150mg/m² (pretreated patients 100mg/m²)[23] d1+2 every 4 weeks in monotherapy,[14] and 60–100mg/m² d1+2 or d1+8 every 3–4 weeks when combined with other cytotoxic drugs.[15,16,24]

Dose adjustment
In patients with a 30–70% metastatic or tumour affected liver and bilirubin level of 1.2–3.0mg/dL the bendamustine dose should be reduced to 50%.[2] According to the US prescribing information bendamustine should not be given to patients with transaminase levels >2.5–10 fold and bilirubin levels >1.5–3 fold over normal or bilirubin levels >3 fold over normal.3 In mild liver impairment (bilirubin levels <1.2mg/dL)[2] no dose adjustment is necessary.
In addition mild to moderate renal impairment (creatinine clearance >40mL/min3 or >10mL/min in dialysis-dependent patients)2 requires no dose reduction.
Since bendamustine is likely to cause myelosuppression, haematologic nadirs may necessitate dose delays if blood counts are not recovered by the beginning of the next cycle. Prior to the next dose, the absolute neutrophil count should be >1,000/µL and platelet count >75,000/µL3 respectively >4,000/µL and >100,000/µL according to the German product information.[2] In myelosuppressed patients (ie, caused by intensive pre-treatment) bendamustine doses should be reduced to about 70% of normal dose.[20,23]

Preparation and stability
In Germany the current parenteral formulation of bendamustine (Ribomustin) is supplied as a dry, white to off-white, lyophilized powder, containing 25mg or 100mg of bendamustine as hydrochloride with mannitol as bulking agent. The powder has to be reconstituted with 10mL or 40mL, respectively, of water for injection, yielding a final concentration of 2.5mg/mL.[2] Although the dissolution process should be enhanced by shaking, it can take up to 10 minutes until the powder is completely dissolved.[2,3] Since bendamustine is chemically very unstable in water, the required dose of the reconstituted solution must immediately be transferred to a 500mL infusion bag of 0.9% sodium chloride[2,3] or 2.5% dextrose/0.45% sodium chloride.[3] Other infusion solutions should not be used for dilution. In aqueous solution bendamustine is very unstable. Obviously, like the structural analogue melphalan, the bis-2-chloroethylamine group of bendamustine hydrolyses via an aziridinium-ion first to the monohydroxy- afterwards to the dihydroxy-derivative.[25] As shown for melphalan,[25,26,27] besides a strongly acidic pH value and low temperature, the chloride ion concentration of the solution mainly influences the hydrolysis-equilibrium, with high chloride ion concentration favouring the intact bendamustine. Therefore it is crucial to use a sodium chloride-containing infusion solution, preferable 0.9% sodium chloride. However, due to the poor solubility of bendamustine in sodium chloride, water for injection must be used for reconstitution.The stability of the reconstituted drug solution is limited to 30 minutes.[3]

[[HPE51.40]]

According to the German product information[2] bendamustine infusion solutions in 0.9% sodium chloride are stable for five days under refrigeration and for five hours at room temperature. In a stability study by Maas et al[28] dilute solutions of 0.25mg/mL in 0.9% sodium chloride were determined to be stable (at a limit of 90%) for 5 days at 4°C and for 9 hours at 23°C. For the European approval (as Levact) new stability data have been generated but not yet published.[29]

Conclusion
Bendamustine is a well-tolerated cytotoxic drug with mild acute toxicities. In our clinical practice patients experience a good quality of life under bendamustine chemotherapy. Remission rates primarily in follicular lymphomas are very promising and, additionally, we observe very long durations of response. Thus, bendamustine containing treatments (ie, with rituximab) may be the preferred therapy option in elderly patients. Attention must be paid to the distinct myelosuppression experienced after bendamustine, in particular in pretreated patients (ie, after previous fludarabine treatment), which becomes increasingly important with further cycles of bendamustine (>4–6 cycles). Exhaustion of bone marrow reserves is a problem whose importance should not be underestimated, especially in younger patients. Therefore we consider bendamustine-containing therapies in these patients with some reservation.

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