Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with mitoxantrone, chlorambucil and prednisone (MCP)

S. Wöhrer1, J. Drach1, M. Hejna1, W. Scheithauer1, A. Dirisamer2, A. Püspök3, A. Chott4 and M. Raderer1,+

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

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 1–5 and prednisone 25 mg/m2 p.o. on days 1–5. 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 12–29) 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Lymphoma of the mucosa-associated lymphoid tissue (MALT) is a distinct clinicopathological entity initially defined by Isaacson and Wright in 1983 [1], which has been incorporated into the recent World Health Organization (WHO) classification of haematological malignancies (grade 3) under the term ‘extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue’ (MALT lymphoma)[2]. It comprises 7% of all newly diagnosed non-Hodgkin’s lymphomas [3] and is therefore among the more common lymphoma entities. MALT lymphomas arise in lymphoid tissue acquired through chronic antigenic stimulation due to persistent inflammation/infection as exemplified by Helicobacter pylori (HP) in patients with gastric lymphoma [4, 5]. This close association has provided the basis for successful treatment of early-stage gastric MALT-type lymphomas using HP-eradication, which can be considered standard therapy for such patients [5, 6]. While the majority of cases are diagnosed within the stomach, this type of lymphoma can be found throughout the whole body, sometimes occurring in a multifocal fashion [7]. According to the literature, 30–40% of MALT lymphomas arise in an extragastric localisation [8].

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with histologically verified extranodal marginal zone B-cell lymphoma of MALT [1, 22] without transformation to diffuse large B-cell lymphoma were retrospectively evaluated (for patient characteristics see Table 1).


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Table 1. Patient characteristics
 
Biopsy samples were evaluated according to the criteria established by Isaacson and Wright [1] and adopted in the recent WHO classification for MALT lymphoma [23]. In all patients, immunological phenotyping on paraffin sections was carried out for demonstration of light chain restriction and for the phenotype CD20 + CD5–CD10–cyclinD1–, which, in context with the microscopic appearance, is consistent with extranodal marginal zone B-cell lymphoma of MALT. All patients underwent extensive staging before initiation of therapy, consisting of ophthalmological and otorhinolaryngological examination, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal (GI) tract, enteroclysis, colonoscopy, computed tomography (CT) of the thorax and abdomen and bone marrow biopsy as suggested previously [7]. Staging was performed according to the Ann Arbor staging system as modified by Musshoff [24] and Radaszkiewicz [25].

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 1–5 and prednisone 25 mg/m2 p.o. on days 1–5 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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Table 2. MCP regimena
 
Assessment of response was performed according to published guidelines [26]. In the case of lymphoma restricted to the stomach/GI tract, histological assessment of biopsy specimens served as the ultimate gold standard.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Our analysis identified 15 patients (six females, nine males) aged between 34 and 88 years who were given MCP for treatment of MALT lymphoma. Ten patients had extragastric and five patients had gastric MALT lymphoma (Table 1). Five patients had MALT lymphoma of the salivary glands, one patient had a relapse involving cervical lymph nodes and the colon following irradiation of a parotid lymphoma, and two patients each had MALT lymphoma of the ocular adnexa and two of the lung. All patients were chemotherapy-naïve, and three patients had been treated with radiation therapy before chemotherapy with MCP was initiated.

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 3–8). 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 12–28) 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.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
While a profound change in therapeutic approaches to MALT lymphoma has occurred in recent years, data on chemotherapy are still scarce in the literature, as only two prospective series have been published [13, 14]. Hammel et al. [13] have reported 75% CR in a cohort of 24 patients with (predominantly gastric) MALT lymphoma. These patients were given systemic treatment with either oral chlorambucil or cyclophosphamide administered on a daily basis for 12–24 months. In this series, five patients relapsed, and two of them were successfully retreated. More recently, we have reported the nucleoside analogue 2CdA as a promising agent for therapy of MALT lymphoma [14]. In this study including 26 patients, 21 achieved a CR and five had a PR. Among the patients with CR, however, 18 had a gastric lymphoma, while only three had an extragastric MALT lymphoma, indicating a higher responsiveness of gastric MALT lymphoma to treatment with 2CdA. According to the pronounced T-cell depletory effect of 2CdA, it was hypothesised that this might in part reflect the dependence of gastric MALT lymphomas on HP-specific T-cells at least in earlier stages, whereas extragastric forms are thought to arise independently from these T-cells.

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 12–28) 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.


    Footnotes
 
+ Correspondence to: Dr M. Raderer, General Hospital of Vienna, Department of Internal Medicine/Division of Oncology, Waehringer Guertel 18–20, 1090 Vienna, Austria. Tel/Fax: +43-1-40400-2296; E-mail: markus.raderer{at}akh-wien.ac.at Back


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