Practical clinical experience with bendamustine

Alkylating agents are often the basis for anticancer chemotherapy. They can be subdivided according to various criteria into subclasses such as aziridines, dimethanesulfonates, nitrogen mustards (bischloroethylamines), substituted nitrogen mustard derivatives (oxazaphosphorines) and others. The actions of each of these subclasses have their own particular qualities. Similarly, within each such subclass there are further differences, this being exemplified here by bendamustine. Practical clinical experience with this drug is summarised.

Bendamustine is a unique alkylating agent first developed in the former East German Democratic Republic, and which has been used in East Germany for the treatment of haematologic malignancies since 1969.(1) Bendamustine became available throughout Germany in 1990. Since 1994, many patients have been treated with bendamustine in other European countries. In clinical trials in the US and Europe, bendamustine has proved to be well tolerated and effective in the first-line treatment of chronic lymphocytic leukaemia (CLL) and in patients with rituximab-refractory indolent non-Hodgkin’s lymphoma (iNHL).(2,3) It has been approved in Europe and the US for both indications. Additionally, there is European approval for multiple myeloma for patients who are ineligible for a stem cell transplant or who are precluded for treatment with other novel agents. New clinical trial data supporting the superiority of first-line bendamustine plus rituximab over the widespread use of CHOP-R in iNHL4 will probably increase the use of this combination.

The resistance profile of bendamustine in respect of tumour cells differs from that of other alkylating agents. Tumour cells may be, or may become, resistant to alkylating agents. In principle, the development of resistance by tumour cells can arise through the following mechanisms:

• An increased concentration of glutathione (GSH) as a substitute nucleophile decreases the efficacy of alkylating agents. If this is accompanied by an increase in the concentration of the enzyme GSH-S-transferase, the conjugation of GSH with the alkylating agent is, in turn, facilitated
• The enzyme O6-alkylguanine alkyltransferase cleaves alkyl groups from the O6-position of guanine, thereby resulting in the direct reversal of DNA damage
• DNA cross-links caused by N-mustards (interstrand cross-links) can be cleaved. Although this is not yet fully understood, so-called nucleotide excision repair plays a role here. Also involved is the enzyme poly(adenosine diphosphate ribose) polymerase (PARP).

An increase in anti-apoptotic Bcl-2, as is seen, for example, in follicular lymphomas, likewise causes resistance to nitrogen mustards (summarised in Reference 5). Phenomenologically, the following effects are observed with bendamustine in contrast/comparison with other alkylating agents:

• At equitoxic concentrations, bendamustine causes more DNA double-strand breaks than melphalan, cyclophosphamide or carmustine(6)
• The repair of bendamustine-induced DNA strand breaks in human breast cancer cells appears more difficult than with breaks induced by cyclophosphamide or carmustine. Moreover, this repair seems to proceed more slowly. The consequence is inefficient DNA repair(7) with loss of checkpoint control.(8) (The terminus checkpoint describes a control point and underlying control mechanism that regulates the temporal sequence of events of cell cycle processes. The next step in the cell cycle can take place only once the preceding step has been completed in the correct manner. At such checkpoints there is the possibility of interrupting the cell cycle or even apoptosis, the initiated programmed cell death.)
• Bendamustine results in activation of the nucleotide excision repair pathway rather than the alkyltransferase repair mechanism(9)
• Bendamustine still shows activity in tumour cells that are otherwise resistant to alkylating agents and tumours that are refractory to such treatment.(6,8–12)

The in vitro COMPARE analysis, conducted by Leoni and colleagues according to the standardised protocol of the US National Cancer Institute, showed that bendamustine displays a sensitivity profile different to that of chlorambucil, cyclophosphamide and melphalan.(9) In a gene expression analysis (microarray) in an NHL cell line, differences were likewise observed between bendamustine, phosphoramide mustard (PM; active metabolite of cyclophosphamide) and chlorambucil. Surprisingly, bendamustine was found to bring about approximately 60–80% downregulation of messenger RNA of mitosis-associated genes, including those for polo-like kinase 1 and aurora kinase A.(9) It is therefore understandable that ‘mitotic catastrophes’ are observed in cell lines, because mitotic spindle checkpoints can be ‘overrun’, particularly when there is inhibition of, or deficit in, aurora kinases. Repeated cycles of DNA replication and mitosis occur, but without cytokinesis and cell division. The cells become polyploid and die.

Although bendamustine has oral bioavailability of 100% after ingestion on an empty stomach and bioavailability of 63% when taken after or with food,13 there is only an intravenous dosage form. Plasma-protein binding is in excess of 90% (94–96%) and is independent of concentration, plasma albumin level, age (>70 years), and tumour stage. The volume of distribution VD is 20–25 litres and about 25 litres at steady state. Distribution from plasma is swift, with a distribution half-life of seven minutes.(14) Tissue distribution is non-uniform. Studies in mice with 14C-labelled bendamustine showed greater accumulation in the liver and kidneys than in the lungs, heart, spleen or muscle.(15) The ‘true’ elimination half-life is difficult to determine, because of the rapid metabolism and analytical method (radioactivity measurements) that is conventionally used.(16–18) An ‘intermediate’ half-life of 40 minutes has been defined as the effective half-life after a one-hour infusion of 120 mg/m2.(19) Clearance is 700ml/min. Bendamustine is distributed freely in human erythrocytes.(10,12,13,19,20) Bendamustine is excreted mainly in the faeces. About 20% of the administered dose is recovered in urine within 24 hours, in the following proportions: as monohydroxybendamustine >bendamustine >dihydroxybendamustine >gamma-hydroxybendamustine (M3) >N-desmethylbendamustine (M4) (Figure 1).(20) Less than 10% is excreted unchanged in urine. In the older literature, much higher rates of renal elimination were reported, which are likely to have been due to the analytical methods employed. Based on our current level of understanding, claims that bendamustine is eliminated mainly by the kidneys are false,(10,17) in addition to contradicting the reported independence of the dose from renal function.(21)

Bendamustine undergoes non-enzymatic hydrolysis of the bis-chloroethyl subunit, forming mono- and dihydroxybendamustine. The active metabolism of bendamustine takes place in the liver. Phase I metabolism is mediated by the cytochrome P450 isoenzyme 1A2 (CYP1A2). Active metabolites are M3 and M4 (Figure 1). The plasma concentrations of these metabolites are respectively one-tenth and one-hundredth that of the parent substance, thus it is reasonable to attribute the primary cytotoxic effect to the parent substance. The hypothesised β-oxidation of bendamustine at the butyric acid side chain (as still reported in the older literature, for example, Reference 13) has been shown to be incorrect. The metabolite provisionally described as ‘hydroxybendamustine’ was subsequently found to be the M3 metabolite and was characterised by Teichert and colleagues.(22) No β-oxidation takes place. Twenty metabolites are now known in rats.(16) Phase II reactions generate glutathione-mediated cysteine S-conjugates of bendamustine.

Bendamustine is licensed as Levact® in Europe and as Treanda® in the US with different indications (and therefore with different dosages). The ‘most flexible’ dose range results from older use of the product in accordance with previous indications (not currently registered) originating from former East Germany, such as first-line treatment of advanced indolent NHL in combination regimens, advanced multiple myeloma in combination with prednisolone, and CLL).20 Dosages ranged from 60mg/m² over five days to 150mg/m² on two successive days. By contrast, the newer European and US marketing authorisation specifies a dosage of 100mg/m² to 120mg/m² on two successive days of a 28- or 21-day cycle and up to five or seven repeat cycles (that is, six or eight doses).(32) Extensive anecdotal clinical experience, particularly in combination regimens, points to an optimal dose of 90mg/m² on two successive days in combination with rituximab (MabThera®). For Consensus Panel Dose Recommendations for Bendamustine Therapy, see Reference 24.

Because renal elimination of bendamustine, including its metabolites, is not more than 20%, modification of the dose in patients with renal impairment is unnecessary. The German prescribing information therefore recommends no dose adjustment when creatinine clearance is >10ml/min. The US prescribing information recommends that, owing to a lack of clinical data, bendamustine should not be used in patients with creatinine clearance <40ml/min.(25,26) In patients with normal liver function or mild hepatic impairment (serum bilirubin <1.2mg/dl), no dose adjustment is necessary.

In patients with moderate hepatic impairment (serum bilirubin 1.2–3.0mg/dl), a 30% reduction in dose is recommended.26 By contrast, the US prescribing information recommends that, owing to a lack of data, bendamustine should not be used in patients with moderate transaminase elevations (2.5–10-times higher than the upper limit of the normal range) and total bilirubin 1.5–3-times higher than the upper limit of the normal range or an isolated bilirubin elevation in excess of three-times the upper limit of the normal range.(25) Of note: a former SPC of bendamustine (Brand: Ribomustin®) recommended a 50% dose reduction in patients with serum bilirubin 1.2–3.0mg/dl and/or 30–70% hepatic tumours/metastases.(20) A third organ for which dose modifications must be considered is the bone marrow, particularly following previous treatment with drugs that cause myelosuppression. In patients with myelosuppression, the dose must be reduced or the interval between cycles extended. For an original dose of 90–100mg/m², a reduction to 70mg/m² is recommended. Doses below 50mg/m² are considered sub-therapeutic. These recommendations apply also to persistent grade 3/4 thrombocytopenia. In patients in whom neutropenia of grade 3 or worse has persisted for a long time, supplementation with granulocyte colony-stimulating factor (G-CSF) can be considered.

The maximum tolerated dose (MTD) of bendamustine in monotherapy depends on the treatment regimen. The maximum tolerated dose after a single intravenous bolus was found to be 215mg/m². Observed side effects were neurotoxicity, manifested as lethargy and confusion, arrhythmias, salivary gland dysfunction and consequent dry mouth.(13) In a phase I study of patients with advanced solid tumours, the MTD was 160mg/m² on days 1 and 8 of a four-week cycle, administered as a 30-min infusion.

Here too, dry mouth and drug-related fatigue were found to be dose-limiting.(27) Another phase I study in patients with solid tumours investigated the MTD when single doses of bendamustine were given at intervals of three weeks. At a dose of 280mg/m², patients exhibited grade 4 thrombocytopenia, grade 3 fatigue, and grade 2 cardiotoxicity. Although the latter was not dose limiting, it was regarded as such in view of the clinical relevance. For further studies of a single dose of bendamustine every three weeks, the authors recommend a dose of not more than 260mg/m².(28)

At the normal therapeutic dose range (90–120mg/m²), no cardiotoxicity is observed with bendamustine, as stated in a bendamustine ECG Assessment Report.(29) When bendamustine was given on two successive days with a three-week interval between cycles, the MTD was found to be 180 mg/m². This was also investigated in patients with solid tumours. The development of thrombocytopenia was dose limiting.(18) With divided doses, the MTD for bendamustine is 85 mg/m² when given on four successive days, with general haematotoxicity (thrombocytopenia, granulocytopenia) predominating.(13)

Bendamustine is generally well tolerated.

Bendamustine causes the myelosuppression typical of alkylating agents, but this is reversible. Grade 3/4 myelosuppression can occur, particularly in often intensively pretreated patients. Febrile neutropenia occurs in well under 10% of such patients.(12,30–32) Occurring, in descending order of frequency, are neutropenia >thrombocytopenia >anaemia. There is no evidence suggesting cumulative haematotoxicity.(32)

Non-haematological toxicity is normally mild (generally grade 1–2).

There has been no classification of the emetogenic potential of bendamustine. Bendamustine appeared in guidelines for the first time in 2009 (Multinational Association of Supportive Care in Cancer (MASCC); German Working Group on Supportive Measures in Oncology, Rehabilitation and Social Medicine (ASORS); US National Comprehensive Cancer Network (NCCN)). Based on clinical experience, bendamustine is moderately emetogenic. Acute vomiting during, or within 24 hours of, the infusion is rare (if it is not given in combination with other emetogenic drugs). Grade 3 or 4 toxicity is hardly ever seen.

Even though systematic data on the emetogenicity of bendamustine are scarce, delayed-onset nausea should not be underestimated. Bendamustine is often given on two successive days on an outpatient basis. It is estimated that one-third of all patients experience delayed nausea for up to one week after the end of bendamustine therapy despite prophylaxis with a 5-HT3 receptor antagonist (+ dexamethasone). Patients should therefore always receive a 5-HT3 receptor antagonist on each day of a bendamustine infusion. If delayed nausea still develops, it is recommended that the patient undergo prophylaxis with the long-acting palonosetron (Aloxi®) on day one of bendamustine therapy or adjuvant treatment with a neurokinin-1 (NK1) receptor antagonist (currently only aprepitant (Emend®)).

Alopecia is, at the very most, minimal or, in contrast to the cited frequencies in the prescribing information, absent. Nail toxicity has not been reported. Skin reactions such as pruritus, rash (grade 1–2), bullous exanthema and toxic epidermal necrosis have occurred. Bullous exanthema and toxic epidermal necrosis were observed in patients who had been treated with other drugs for which such reactions are considered typical (allopurinol, antibiotics, rituximab). The contribution of bendamustine to these side effects is unknown; nevertheless, these symptoms were included in the US prescribing information in January 2009.(33)

Because bendamustine can itself cause mild cutaneous side effects, other skin reactions caused by drugs broadly described as dermatotoxic may be intensified by bendamustine. Conversely, such drugs may act as the trigger for skin reactions during bendamustine therapy. Wherever possible, such co-medication should be avoided. Allopurinol, in particular, should be avoided, its use being restricted to the treatment of leukaemic lymphomas and cases where there is a real risk of tumour lysis syndrome. In non-leukaemic lymphomas of low malignancy, tumour lysis syndrome occurs only very rarely, except, for example, in CLL, aggressive lymphomas or in Burkitt’s lymphoma. The allopurinol-related, sometimes severe-to-life-threatening dermatotoxicity has since been confirmed in a large study and led to further warnings.(34,35) Antibiotic prophylaxis should not be routinely given, with its use confined to cases where the indication has been rigorously established, even though grade 3/4 neutropenia occurs only in about 11% of cases during treatment with bendamustine/rituximab (toxicity outcome from the NHL 1-2003 study B-R vs. CHOP-R).(36)

Fluoroquinolones and co-trimoxazole (sulfamethoxazole + trimethoprim) in particular are regarded as dermatotoxic and, together with bendamustine, can contribute to an intensification of possible dermatotoxicity. In particular, routine pneumocystis jiroveci pneumonia (PJP) prophylaxis with co-trimoxazole can be avoided; no cases of PJP have occurred during the Study Group on Indolent Lymphomas (StiL) studies on first-line therapy (for example, NHL 1-2003). (StiL is a nationwide affiliation of German haematological/oncological clinics and specialist practices. The scientific focus of the study group is the performance of non-commercial, prospective, randomised studies/phase II studies of modern treatment methodologies with the aim of optimising treatment. The study centre is at the hospital of the Justus Liebig University in Giessen.) CYP1A2 inhibitors cause increased bendamustine concentrations. If concentrations are raised for long periods, this can in theory be reflected in an increased risk of skin reactions.

Dermatotoxic CYP1A2 inhibitors or competing substrates include, for example, amitryptyline*, clomipramine*, clozapine*, estradiol*, fluvoxamine*, haloperidol*, imipramine (N-desmethyl metabolite)*, mexiletine*, naproxen*, olanzapine*, propranolol*, theophylline* and verapamil*, the incidence of skin reactions being defined in the prescribing information as very common (>1/10) to common (>1/100, < 1/10) for the drugs marked with an asterisk and rare/uncommon (>1/10,000, <1/100) to very rare (<1/10,000) for those with an asterisk in brackets. The usual sequence for a bendamustine/rituximab regimen is rituximab (substance with more side effects, longer infusion time) followed by bendamustine on day one. If a patient reacts to rituximab on day 1, the StiL recommendation, based on clinical experience, is for the bendamustine/rituximab regimen to be modified from rituximab day 1 plus bendamustine days

1 + 2 to rituximab day 1 plus bendamustine days 2 + 3.

There are reports of tumour lysis syndrome during treatment with bendamustine. These concern patients with CLL.14 Regular hyperuricaemia prophylaxis before or during administration of bendamustine is not indicated, particularly in non-leukaemic NHL.

Administration of bendamustine into a peripheral vein can result – particularly in the case of intravenous boli – in local irritation and even thrombophlebitis. In the event of extravasation, the infiltrated tissue will be painful. Bendamustine is classified as an irritant and, according to currently available data, is not necrotic.(37)

The need for antiemetic prophylaxis has already been mentioned. Tumour lysis prophylaxis, particularly in non-leukaemic clinical pictures, is not necessary. Even though the above-mentioned skin reactions may be the first signs of a hypersensitivity reaction (HSR) to an active substance or to a constituent of a pharmaceutical product, genuine hypersensitivity reactions are so rare, there is no need for HSR prophylaxis.

Bendamustine undergoes hydrolysis in aqueous solutions (including the blood).(38) Because of hydrolysis and its rapid metabolism and elimination, a short infusion time of 30–60 min is recommended in order to achieve adequate tissue concentrations. It is noteworthy that ex vivo studies demonstrated that high concentrations of bendamustine are more efficient than prolonged exposure.(39)

The 30-min short infusion that is standard in Germany is easily administered with infusion volumes of 100–250ml 0.9% saline. Why the US prescribing information specifies 500ml 0.9% saline or an end concentration of 0.2–0.6mg/ml is unclear. A short infusion with such a high volume presents considerable practical difficulties. The only vehicle solution used should be saline, as chloride ions help suppress the hydrolysis of bendamustine – and of melphalan – and boost physicochemical stability.

Bendamustine must, however, first be dissolved in water and then diluted as swiftly as possible with 0.9% saline. Thereafter, its shelf life is given as nine hours at room temperature and 120 hours if stored in a refrigerator.(38) These data were also given in the former German prescribing information but are shortened in the newer version without comprehensible reasons (3.5 hours at room temperature, two days refrigerated). According to the US prescribing information, half-isotonic saline–glucose solution (0.45%/2.5%) can also be used as the vehicle solution. The stability of Treanda® at room temperature is given as only three hours for both vehicle solutions.

• The resistance profile of bendamustine in respect of tumour cells differs from that of other alkylating agents, including other drugs in its class.
• Bendamustine displays a sensitivity profile different to that of chlorambucil, cyclophosphamide and melphalan.
• Tissue distribution of bendamustine is non-uniform, showing a greater accumulation in the liver and kidneys than in the lungs, heart, spleen or muscle.
• Because renal elimination of bendamustine, including its metabolites, is not more than 20%, modification of the dose in patients with renal impairment is, in practice, unnecessary. In patients with moderate hepatic impairment (serum bilirubin 1.2-3.0mg/dl), a 30% reduction in dose is recommended (German SPC).
• Bendamustine is generally well tolerated and has a good toxicity profile. Highly effective doses range in the lower third of the maximum tolerated dose-single dose.

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