Departments of Internal Medicine I, 1 Divisions of Oncology and 2 Radiology, Internal Medicine IV, 3 Divisions of Gastroenterology and 4 Clinical Pathology, University of Vienna, Vienna, Austria
Received 21 May 2003; revised 11 June 2003; accepted 12 August 2003
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Abstract |
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Mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively common type of lymphoma arising in various tissues throughout the human body. Currently, there is no standard chemotherapy for advanced stage MALT lymphoma. This has prompted us to retrospectively analyse our experience with the MCP regimen (mitoxantrone, chlorambucil and prednisone) in patients with MALT lymphoma.
Patients and methods:
Patients with histologically verified MALT lymphoma undergoing chemotherapy with MCP were evaluated retrospectively. The MCP regimen consists of mitoxantrone 8 mg/m2 intravenously on days 1 and 2, chlorambucil 3 x 3 mg/m2 per os (p.o.) on days 15 and prednisone 25 mg/m2 p.o. on days 15. Information analysed included localisation of the lymphoma, clinical stage, pretreatment, number of chemotherapy cycles administered, toxicity, response to treatment, follow-up time, relapse and survival.
Results:
A total of 15 patients (six females and nine males aged between 34 and 88 years) with histologically ascertained MALT lymphoma undergoing treatment with the MCP regimen were identified from our records. Ten patients had extragastric lymphoma, while five patients suffered from gastric MALT lymphoma. All patients were chemotherapy-naïve, while two had been locally irradiated before application of MCP for recurrent disease. A total of 74 cycles was administered to our patients, with a median number of five cycles per patient. Eight (53%) patients achieved complete remission, six (40%) patients partial response and only one (7%) patient had progressive disease. Subjective tolerance was excellent, and toxicities were mainly haematological, including granulocytopenia World Health Organisation grade 3 and 4 in three patients each. In two patients, this was accompanied by single episodes of uncomplicated herpes simplex infection. At the time of analysis, all patients are still alive. No relapses have occurred after a median follow-up time of 16 (range 1229) months.
Conclusions:
Our data suggest that MCP is an effective and well-tolerated regimen for treatment of patients with MALT lymphoma irrespective of localisation. Judging from our data, MCP also appears to be a feasible regimen in elderly patients.
Key words: chemotherapy, chlorambucil, MALT lymphoma, mitoxantrone
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Introduction |
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Surgery has been the most widely applied therapy in the past, but recent years have seen a trend towards organ-preserving therapy. Radiation has been intensively investigated in extranodal lymphomas of gastric, but also extragastric origin. For series including patients with extranodal lymphoma using radiotherapy either as sole management or as an adjunct to surgery, data interpretation, however, remains difficult, as uniform staging and pathological assessment adhering to the MALT lymphoma concept has been scarce in the literature [9, 10]. Recent data nevertheless suggest that low-dose radiation therapy alone is feasible and safe in patients with MALT lymphoma of the stomach [11].
Relapses involving a distant site following local therapy of the original localisation, however, have been reported, and thus the evaluation of systemic approaches to MALT lymphoma appears to be reasonable. Nevertheless, only limited data exist to date, and it has repeatedly been stated that chemotherapy has not been adequately tested so far [9, 12]. Results from the application of alkylating agents such as oral cyclophosphamide or oral chlorambucil [13] were highly encouraging. In addition, application of the nucleoside analogue 2CdA for treatment of MALT lymphoma [14] has yielded high response rates, i.e. 80% complete remissions (CR) and 19% partial remissions (PR).
To our knowledge, no results from the combination of mitoxantrone, chlorambucil and prednisone (MCP), which has widely been applied in various other types of indolent lymphomas [1518], have been reported in patients with MALT lymphoma. In view of the fact that chlorambucil is already an effective and frequently used treatment option in MALT lymphomas [13, 1921] and mitoxantrone shows high activity in the treatment of indolent lymphoma [15, 16, 18], this combination appears to be an attractive treatment option. We have therefore performed a retrospective analysis of our results with MCP in the therapy of patients with MALT lymphoma.
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Patients and methods |
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Clinical information evaluated included localisation of the lymphoma, clinical stage, pretreatment, number of chemotherapy cycles administered, toxicity, response to treatment, follow-up time, relapse and survival.
The MCP regimen as administered to our patients consists of mitoxantrone 8 mg/m2 intravenously on days 1 and 2, chlorambucil 3 x 3 mg/m2 per os (p.o.) on days 15 and prednisone 25 mg/m2 p.o. on days 15 every 4 weeks (Table 2). All patients were given chemotherapy on an outpatient basis. Complete blood counts were evaluated immediately at the start of each cycle and 2 weeks later. In case of a persisting nadir of white blood cells 3.0 x 109/l (or neutrophiles
1.5 x 109/l) and/or platelets
100 x 109/l the next treatment cycle was delayed by 1 week until normal values were achieved and prophylactic filgrastim 5 mg/kg for 5 days starting on day 6 was given at the next treatment cycle. Restaging including CT scan of the thorax and abdomen, endosonography and gastroscopy with histological re-assessment in the case of gastric lymphoma, and additional radiological methods such as magnetic resonance imaging (MRI) or sonography for extragastric MALT lymphoma was performed every three cycles, and treatment was continued in the absence of progressive disease for a maximum of eight cycles.
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Results |
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Three patients with HP-associated gastric MALT-type lymphoma restricted to mucosa and submucosa (stage EI1) had been followed for between 13 and 16 months before the lymphoma was judged refractory to HP-eradication and chemotherapy was initiated. Two patients with more advanced gastric lymphoma were given MCP together with HP-eradication.
A total of 74 cycles were administered to our patients, the median number per patient being five cycles (range 38). Taken together, 8 of 15 patients (53%) achieved a complete response (CR), six (40%) had a partial response, while one patient (7%) progressed after three treatment cycles. This patient was given second-line therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), resulting in a CR as judged by CT after four cycles.
After a median follow-up of 16 (range 1228) months, all patients evaluated in this series are alive and no relapses have occurred.
Subjective tolerance of the MCP regimen was excellent in all patients, and no cases of nausea/emesis were encountered. None of our patients developed alopecia. The main toxicity of the MCP regimen was the development of transient leucocytopenia/granulocytopenia grade 3 and 4 in three patients each, which could be prevented by the use of prophylactic G-CSF for the subsequent cycles. In two patients, this was accompanied by a single episode of herpes simplex infection. One patient each had thrombocytopenia WHO grade 3 and 4, respectively, while no cases of anemia exceeding WHO grade 2 were seen.
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Discussion |
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Our data indicate the MCP regimen, which has widely been used for the treatment of indolent lymphomas mostly corresponding to follicular lymphoma according to the current classification, as an active therapeutic option in patients with MALT lymphoma. Subjective tolerance of the regimen was excellent, and toxicities were mainly haematological. The pronounced effect on leucocytes, however, was not complicated by severe infections, as only two episodes of herpes simplex infection were encountered. The low rate of side-effects was also seen in elderly patients, as no apparent difference in toxicities could be seen between younger individuals and the six patients older than 70 years included in our series. The rate of complete responses seen in our patients with MALT lymphoma (58%), however, appears to be lower than that seen with either oral alkylating agents (CR 75%) or administration of 2CdA (81%). In both series the percentage of gastric MALT lymphomas was higher than in our present series, where only five out of 15 patients had gastric MALT lymphoma. This might partly explain the lower CR rate in the current study. In fact, if one compares the subgroup of extragastric MALT lymphomas in the study by Jäger et al. [14] with our results, a higher CR rate can be found in our study with MCP (43% versus 55.5%). No relapses have occurred so far after a median observation time of 16 (range 1228) months, and all patients are currently alive. In view of the generally indolent nature of the disease, however, the follow-up time is too short to draw valid conclusions about the long-term outcome of our patients and a longer observation is needed.
Taken together, our results indicate that the MCP regimen is active and well tolerated in patients with advanced MALT lymphomas and can be administered on an outpatient basis. In the absence of a chemotherapeutic gold standard, MCP can be considered as a therapeutic option even in elderly patients with MALT lymphoma. Nevertheless, further studies are clearly needed to define the optimal systemic approach to the management of this disease.
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Footnotes |
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References |
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