1 Department of Medicine III, University Hospital, Frankfurt am Main; 2 Department of Medicine V, Städtische Kliniken Darmstadt, Germany
Received 4 October 2001; revised 24 January 2002; accepted 19 February 2002
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Abstract |
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Bendamustine, an alkylating agent with a nitrogen mustard group and a purine-like benzimidazol group, has been shown to be effective in several solid tumors and indolent non-Hodgkins lymphomas, but has not yet been studied for efficacy in aggressive lymphomas.
Patients and methods:
We conducted a phase II study in patients with relapsed or refractory high-grade non-Hodgkins lymphomas, using bendamustine at a dose of 120 mg/m2 on days 1 and 2, every 3 weeks for up to six cycles. Twenty-one patients were enrolled; 18 were evaluable for response and toxicity, 10 of whom were refractory to previous chemotherapy.
Results:
With three patients achieving a complete response (at 6, 8 and
22 months) and five a partial response (three at 2 months, one at 3 months and one at 10 months), the total response rate of the evaluable patients was 44% (eight out of 18; 38% of all patients). Two complete and two partial responders were refractory to prior treatment. In 10 patients, treatment had to be stopped after one to three cycles due to progressive disease or hematological toxicity (n = 2). Non-hematological side effects were mild. Eight (13%) WHO grade 3 and no grade 4 events were observed in 60 evaluable treatment cycles. Hematologic toxicity was moderate (grade 3 and 4): anemia in five cycles (8%), leukopenia in seven (12%) and thrombocytopenia in eight (13%).
Conclusions:
Bendamustine as a single agent is effective against aggressive lymphoma, even in cases of refractory disease. Further studies are warranted to determine the significance of bendamustine in the treatment of aggressive lymphomas.
Key words: aggressive lymphoma, bendamustine, refractory disease, relapse
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Introduction |
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Bendamustine hydrochloride was developed in the 1960s in former East Germany, but was never systematically studied in patients until the 1990s. The drug consists of an alkylating nitrogen mustard group and a purine-like benzimidazol compound with a suggested purine-analog effect [7]. Bendamustine has been shown to have substantial activity against low-grade lymphomas [8], multiple myelomas [9] and several solid tumors [10, 11]. We recently reported that bendamustine effectively induces apoptosis in lymphoma cells [12].
The main toxicities of bendamustine are hematological WHO grade 3 and 4 events, occurring in 640% of patients [9, 13]. Subjective toxicity, which is usually low, includes nausea and emesis (usually well manageable with serotonine antagonists), diarrhea and allergy-like skin reactions, but hardly any alopecia [7].
Herein we report the results of the first study using bendamustine as a single agent in aggressive non-Hodgkins lymphoma.
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Patients and methods |
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Bendamustine 120 mg/m2 was administered as a 30-min infusion on two consecutive days once every 3 weeks. The dose was reduced to 75% in cases of thrombocytopenia <10 cells/nl or granulocytopenia <0.1 cells/nl for >5 days. A serotonine antagonist was administered before every infusion. Blood cell counts, blood smears and biochemistry profiles were determined at least once a week.
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Results |
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Toxicity
Subjective toxicity was moderate to low. No WHO grade 4 toxicity was observed with respect to nausea/emesis, fever, infections, alopecia or diarrhea, and grade 3 toxicity for these side effects was <10% of all evaluated treatment cycles (Table 2). Hepatic, renal, pulmonary or cardiac toxicity was unremarkable (Table 2). Hematological WHO grade 3 and 4 toxicity was generally moderate (813% of all treatment cycles; Table 2). In two patients, however, bendamustine had to be stopped due to prolonged grade 4 thrombo- and leukocytopenia. Altogether, hematological toxicities resulted in delays or dose reduction in 13 (21.7%) of the scheduled treatment cycles. None of the patients received myeloid growth factors. No treatment-related deaths were observed.
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Discussion |
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The patient population had an extremely poor prognosis, defined by criteria as having a high rate of refractory aggressive lymphoma, heavy pretreatment, advanced stage disease or extranodal manifestations in the majority of the patients, relapse or resistant disease in three HIV-positive individuals, and a high median age. The response rate of 44% is somewhat higher than could be expected with other single agent therapies in this palliative setting. For example, with the CD20 antibodies rituximab or gemcitabine, response rates of 30% have been described in comparable patient populations [3, 6]. In comparison with salvage treatment regimens, the response rates of bendamustine are certainly inferior [16]; however, one has to consider that our patient population did not qualify for aggressive regimens, mostly due to age or previously performed salvage therapy without response in younger patients.
From the results obtained in the present study, with responses to bendamustine therapy in heavily pretreated patients or patients with refractory disease, we can definitely conclude that it has substantial activity against aggressive lymphomas and that consideration of bendamustine as a treatment option in such patients is justified.
The palliative concept of using bendamustine in cases of aggressive lymphoma is supported by some patients, who did not achieve objective responses, but experienced short periods of relief of lymphoma-associated symptoms, while the non-hematological toxicity was mild, resulting in a short-term increase in quality of life. Subjective toxicity was generally mild, as reported in previous studies [7], and comparable to that of gemcitabine or rituximab [3, 6]. In most patients, hematological toxicity was moderate. In two patients, however, treatment had to be discontinued due to long lasting hematologic toxicity, most likely due to intense pretreatment.
Different schedules, ranging from daily administration of low doses of bendamustine (i.e. 25 mg/m2 for 1421 days) to single doses of 150 mg/m2 on two consecutive days every 3 weeks have been used arbitrarily [7, 9], but effective doses with tolerable toxicities have not been well defined. A recent report demonstrated rather low hematological toxicity using a weekly administration of 60 mg/m2 in advanced progressive solid tumors [13]. Thus, dose modifications in order to reduce adverse effects may be possible. Whether the response in aggressive lymphomas can be maintained with such regimens needs to be evaluated.
Due to the efficacy and tolerability of bendamustine, the question arises of whether the drug should be included in combination chemotherapy regimens for treatment of aggressive non-Hodgkins lymphoma prior to the palliative situation. We recently published an in vitro study demonstrating the synergistic effects of bendamustine with cladribine on apoptosis of lymphoma cells [12]. Unpublished data from our group demonstrate that rituximab sensitizes lymphoma cells for bendamustine-induced apoptosis. Therefore, it seems possible that by combining bendamustine with other chemotherapeutic agents or antibody therapy, the anti-lymphoma effect may be further increased.
In conclusion, bendamustine is effective in aggressive lymphoma and can be recommended for the palliative situation. Further studies will have to define its role for chemotherapy and chemotherapy/antibody combinations in this setting, as well as in patients in the earlier stages of disease.
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Footnotes |
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References |
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