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© 2002 American Society for Clinical Oncology Treatment of Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue Type With Cladribine: A Phase II StudyByFrom the Division of Hematology, Division of Gastroenterology, Institute of Medical Informatics, Statistics and Documentation and Institute of Pathology, Karl-Franzens University of Graz, Graz; Departments of Internal Medicine I, Division of Oncology and Division of Clinical Pathology, University of Vienna, and 3.Med Division, Kaiser Franz Josef-Spital, Vienna; and Internal Medicine S. Veit, Department of Hematology and Oncology, General Hospital Salzburg, Salzburg, Austria. Address reprint requests to Gerald Jäger, MD, Department of Internal Medicine, Division of Hematology, Karl-Franzens-University, Auenbruggerplatz 38, 8036 Graz, Austria; email: gerald.jaeger{at}kfunigraz.ac.at
PURPOSE: As chemotherapy has not been extensively studied in patients with lymphoma of the mucosa-associated lymphoid tissue (MALT), we initiated a prospective study to evaluate the activity of the nucleoside analog cladribine (2-chlorodeoxyadenosine [2-CdA]) in this disease. PATIENTS AND METHODS: Patients with histologically verified MALT-type lymphoma were enrolled. 2-CdA was administered at a dose of 0.12 mg/kg body weight on 5 consecutive days, as a 2-hour infusion. Cycles were repeated every 4 weeks for a maximum of six cycles. RESULTS: Nineteen patients with gastric and seven patients with extragastric MALT lymphoma were enrolled. All patients were chemotherapy-naive, and two had been locally irradiated before systemic relapse of the lymphoma. A total of 102 cycles was administered to our patients (median number of cycles per patient, four). All 25 assessable patients responded to treatment: 21 patients (84%) achieved complete remission (CR) and four patients achieved partial remission. All patients (100%) with gastric presentation, but only three patients (43%) with extragastric presentation, achieved CR. Toxicities were moderate and mainly hematologic and required dose reduction and/or premature discontinuation of therapy in only three cases. Two patients died from vascular events, one shortly after the first cycle because of myocardial infarction and the other from stroke 3 months after the second course. Three patients relapsed after 13, 18, and 22 months and one patient showed progressive disease after 15 months. At present, 24 patients are alive at a median follow-up time of 32 months. CONCLUSION: Our data demonstrate that 2-CdA is highly effective in inducing CR in 84% of patients with MALT-type lymphoma.
LYMPHOMA OF THE mucosa-associated lymphoid tissue (MALT) type is a distinct clinicopathologic entity initially defined by Isaacson and Wright1 in 1983; it has been incorporated into the Revised European-American Lymphoma classification under the term "extranodal marginal zone B-cell lymphoma of MALT-type."2 MALT-type lymphomas arise in lymphoid tissue acquired through chronic antigenic stimulation because of persistent inflammation/infection as exemplified by Helicobacter pylori (HP) in patients with gastric lymphoma.3,4 This close association has provided the basis for successful treatment of early-stage gastric MALT-type lymphomas with HP eradication, which can be considered standard therapy for such patients.4,5 Although the majority of cases are diagnosed within the stomach, this type of lymphoma can be found throughout the entire body, sometimes occurring in a multifocal fashion.6 Although surgery has been the most widely applied therapy in the past, recent years have seen a trend toward organ-preserving therapy in gastric MALT-type lymphoma. Radiation has been intensively investigated in extranodal lymphomas of gastric as well as 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 pathologic assessment adhering to the MALT lymphoma concept have been scarce in the literature (for review, see Zucca et al7 and Schechter et al8). In a prospective trial performed at the Memorial Sloan-Kettering Cancer Center, 17 patients with gastric MALT-type lymphoma in stages EI to EII2 persisting after HP eradication were irradiated at a median dose of 30 Gy (range, 28.5 to 43.5 Gy) to the stomach and adjacent lymph nodes.9 At a median follow-up of 27 months after completion of therapy, the event-free survival was 100% in this uncontrolled series. Relapses involving a distant site after local therapy of the original localization, however, have been reported, and thus the evaluation of systemic approaches to MALT-type lymphoma appears to be reasonable. Nevertheless, only limited prospective data including untreated patients with localized disease exist to date, and it has repeatedly been stated that chemotherapy has not been adequately tested so far.7 The reluctance to administer chemotherapy in patients with localized gastric MALT-type lymphoma might have been based on retrospective results demonstrating that patients undergoing chemotherapy alone had a lower survival. However, the majority of patients had disseminated disease on presentation, resulting in a profound selection bias10 as compared with the patients in limited stages treated surgically (with or without chemotherapy). As opposed to such retrospective analyses, Hammel et al11 have prospectively investigated the use of single-agent chemotherapy in 24 patients (17 patients in stage I and seven patients in stage IV) with MALT-type lymphoma, the majority of whom had gastric lymphoma. Treatment consisted of daily oral cyclophosphamide at a dose of 100 mg (n = 21) or daily oral chlorambucil at a dose of 6 mg (n = 3). The data were encouraging, as complete remission was documented in 18 patients (75%) after a median treatment duration of 12 months. Five patients relapsed at a time between 12 and 96 months after treatment, and two patients were successfully retreated. With the exception of one patient, who developed transformation to diffuse large-cell lymphoma, none of the patients died of a lymphoma-related cause. A theoretically compelling chemotherapeutic approach is the administration of nucleoside analogs, which have demonstrated therapeutic potential in various types of indolent lymphoma including chronic lymphatic leukemia and hairy cell leukemia. Both fludarabine monophosphate and cladribine (2-chlorodeoxyadenosine [2-CdA]) have been associated with a pronounced T-cell–depletory activity, which constitutes an interesting additional mechanism of activity apart from direct cytotoxicity, given the potential role of HP-specific T cells in the development and maintenance of (at least gastric) MALT-type lymphoma.3,12-15 In view of these facts, we have prospectively investigated the therapeutic potential of the nucleoside analog 2-CdA for treatment of patients with MALT-type lymphoma.
Patients Patients with histologically verified extranodal marginal zone B-cell MALT-type lymphoma1,2 were enrolled onto this prospective phase II study. Prior chemotherapy served as an exclusion criterion, whereas patients relapsing after radiation were included in the series. In cases of prior radiation, an interval of at least 4 weeks between completion of radiotherapy and initiation of treatment with 2-CdA was required. Only patients aged older than 18 years with a World Health Organization performance status  2 were eligible for study entry, and adequate renal (serum creatinine < 1.5 mg/dL), liver (total bilirubin < 2.0 mg/dL and transaminase level < two times the upper limits of normal), and bone marrow (leukocyte count > 4,000/mm3, platelet count > 100,000/mm3) functions were also prerequisites for study entry. Patients with severe concomitant diseases including a history of another malignancy within the past 5 years, florid infections, and psychiatric disorders were not eligible for treatment. In female patients of childbearing age, pregnancy had to be excluded before inclusion on the trial, and patients were required to perform adequate contraception during the entire duration of treatment. All patients gave informed consent, either in writing or orally, in the presence of a witness according to institutional guidelines before study entry, and application of 2-CdA to patients with MALT-type lymphoma had been approved by the local ethical committee. Pathologic assessment of biopsy samples was performed by three pathologists for all patients included on the study (A.C., G.H., C.B.-S.), according to the criteria of Isaacson and Wright1 and adopted in the Revised European-American Lymphoma classification for extranodal marginal zone B-cell MALT-type lymphoma.2 In all patients, immunologic phenotyping on paraffin sections was performed for demonstration of light-chain restriction and for the phenotype CD20+CD5-CD10-cyclin D1- which, in context with the microscopic appearance, is consistent with marginal zone B-cell MALT-type lymphoma. In addition, gastric biopsy specimens were assessed for the presence of HP or signs of chronic HP-associated gastritis, and serologic testing for the presence of HP antibodies was performed in all patients with gastric MALT-type lymphoma. All patients underwent extensive staging before initiation of therapy, consisting of ophthalmologic examination, otorhinolaryngologic investigation including sonography of the salivary glands or magnetic resonance imaging if indicated, gastroscopy with multiple biopsies, endosonography of the upper gastrointestinal tract, enteroclysis, colonoscopy, computed tomography scan of the thorax and abdomen, and bone marrow biopsy. Staging was performed according to the Ann Arbor staging system as modified by Mushoff16 and Radaszkiewicz et al.17 This system was applied because recently published series on extranodal lymphomas have adhered to this concept and it enables staging of both gastrointestinal and extraintestinal MALT-type lymphomas, as opposed to the Lugano classification system for gastrointestinal lymphomas.18 According to the modification by Radaszkiewicz et al,17 stage EI1 describes restriction of the lymphoma to mucosa and submucosa, and stage EI2 is used for localized gastric lymphoma penetrating to deeper layers of the stomach, but without lymph node involvement.
Treatment Assessment of response was performed according to published guidelines.21 In cases of lymphoma restricted to the stomach/gastrointestinal tract, histologic assessment of biopsy specimens served as the ultimate standard.
Statistical Methods
A total of 26 consecutive patients (11 women and 15 men) with a median age of 65 years (range, 40 to 82 years) were included on the study (Table 1). Nineteen patients had gastric lymphoma, seven of whom showed additional involvement of another organ. Extragastric presentation was found in seven patients. One patient presented with multifocal liver lymphoma, and one patient presented with isolated recurrence in perirenal lymph nodes after successful local irradiation of a lacrimal gland lymphoma 3 years previously. Five patients presented with an autoimmune condition, (ie, Sjögren’s syndrome in two; and polymyalgia rheumatica, autoimmune thyroiditis, and psoriasis plus autoimmune thyroiditis in one patient each).
Six patients with gastric lymphoma in stage EI1 were judged to be refractory because of persistence of lymphoma for a time span of at least 1 year after successful eradication of HP, which was achieved after a single course of antibiotic therapy in all these patients, and no signs of reinfection occurred during the follow-up period. In addition, 12 patients in stages higher than EI1 (EI2 [n = 3], EII1 [n = 1], EII2 [n = 1], EIII [n = 2], and EIV [n = 5]) received antibiotic therapy parallel to initiation of treatment with 2-CdA; antibiotic treatment was successful in 16 patients, whereas two patients received second-line therapy because of persistence of HP. A total of 102 cycles was administered to our patients, the median number per patient being four cycles (range, one to six cycles). One patient with relapse in the hypopharynx and the stomach after initial successful irradiation of a conjunctival lymphoma died from myocardial infarction 3 weeks after the first cycle of therapy. Although autopsy showed only slight amounts of residual lymphomatous involvement, the patient was rated as a treatment failure in the final evaluation. Another patient was rated as a CR because of the absence of lymphomatous involvement in the gastric biopsy samples obtained after two cycles of therapy; however, she suffered a severe debilitating stroke 2 weeks after endoscopic reassessment. Accordingly, she did not return for further treatment, and she died 3 months after her stroke. All assessable patients enrolled onto the study responded to therapy (Table 2): 21 patients (84%; 95% CI, 63% to 96%) achieved CR, and four had a partial response. Among the patients with a CR, 18 had a gastric primary tumor and correspondingly a CR rate of 100% (95% CI, 81% to 100%) in this cohort, whereas only three patients (43%; 95% CI, 18% to 91%) with initial extragastric presentation (two located in the parotid and one patient with bilateral lacrimal lymphoma) achieved a CR. As opposed to this, all patients with partial remission (PR) suffered from primary extragastric MALT-type lymphoma. In one of these patients (a case of perirenal lymph node relapse after lacrimal lymphoma), however, extended follow-up for a duration of 8 months continues to demonstrate further shrinkage of the tumor in the absence of additional therapy. The median time to response was 2 months (range, 2 to 7 months). Two patients underwent surgical resection of residual lymphoma after four cycles of treatment (located in the liver in one and in both parotids in the other patient, who was also irradiated after surgery), which confirmed the presence of lymphomatous remnants, and both patients were thus rated as PR in the analysis.
Toxicities were generally mild, and were mainly hematologic (Table 3). Treatment was discontinued because of persisting pancytopenia in only one patient, whereas three patients were given therapy at a reduced dose of 0.1 mg/kg body weight over 5 days because of protracted World Health Organization grade 3 leukocytopenia after the first cycle in two patients and a severe episode of herpes zoster shortly after the first course of treatment in one patient.
The median time to progression had not yet been reached (Fig 1). After a median follow-up of 32 months (range, 13 to 45 months), two patients have died from unrelated causes, whereas the remaining 24 patients are alive. Three patients with gastric lymphoma have relapsed locally after 13, 18, and 22 months, and could be salvaged with radiotherapy, whereas one patient showed progressive disease 15 months after obtaining PR. He achieved a second PR after initiation of therapy with oral cyclophosphamide and is currently alive and in ongoing second PR 25 months after initiation of 2-CdA. In all but one of these patients, however, therapy was administered at a reduced dose of 0.1 mg/kg over 5 days because of severe leukocytopenia in two cases and herpes infection during the first cycle of treatment in the other case.
Recent years have seen a profound change in therapeutic approaches to extranodal marginal zone B-cell MALT-type lymphomas because of the discovery of HP eradication as a highly effective form of management for early-stage gastric lymphoma.3-5 As opposed to surgery, which has been the predominant form of therapy in the past, organ-preserving strategies are increasingly used for therapy of gastric MALT-type lymphoma. The notion of radical resection with surgical procedures other than total gastrectomy has clearly been rendered unrealistic by the demonstration of multifocal gastric occurrence of MALT-type lymphoma in all specimens investigated by Wotherspoon et al.23 The fact that gastrectomy may be associated with severe morbidity (and sometimes mortality) also deserves consideration in view of the indolent natural clinical course of the disease and the excellent local control achieved with radiotherapy. In addition, the risk of bleeding and perforation, which has been used as an argument for surgical intervention, has apparently been overestimated in the past. The occurrence of local recurrences after surgery, but also of distant relapses after initial successful local therapy, nevertheless makes the search for effective forms of systemic therapy an important issue. To date, the potential of chemotherapy has not been adequately tested, as only one prospective series using alkylating agents in patients with MALT-type lymphoma has been published.11 Our series is the first prospective evaluation of a nucleoside analog for treatment of extranodal marginal zone B-cell MALT-type lymphoma. 2-CdA was used because of its demonstrated activity in indolent nodal lymphoma and its favorable toxicity profile. The data obtained in our study demonstrate the feasibility and safety of therapy with 2-CdA on an outpatient basis. Tolerance of treatment was excellent, and the high efficacy of the agent in this cohort of patients is demonstrated by the fact that all patients included on the study achieved an objective response. The time to response was relatively short and the majority of patients were administered four cycles of therapy because of the presence of CR after two series, whereas only two patients received six cycles. Of interest is the fact that the rate of CR was higher in the cohort of patients with gastric MALT-type lymphoma as compared with individuals whose disease was of extragastric origin (100% v 43%). We cannot offer a definite explanation for this fact. Given the role of HP-specific T cells in the development (and probably maintenance) of gastric MALT-type lymphoma,3 however, it might be tempting to speculate that the pronounced T-cell–depletory activity of 2-CdA might exert an antilymphoma effect in addition to the direct cytotoxic properties of the agent on lymphoma cells. The fact that the one patient suffering from gastric MALT-type lymphoma without evidence of HP infection experienced local relapse 18 months after initial CR lends further support to this hypothesis. In our series, however, patients in stage EI2 were directly scheduled to receive chemotherapy without checking for potential response to HP eradication. This was determined on the basis of the results of Sackmann et al,24 who have demonstrated gastric MALT-type lymphoma infiltrating beyond the submucosa to be unresponsive to HP eradication. Accordingly, all our patients underwent endosonography for initial staging, as it is currently the most reliable form of evaluating the gastric wall apart from histologic assessment after resection. A recent analysis by Ruskone-Fourmestraux et al25 published after finalization of our series nevertheless has disclosed that only lymph node involvement was predictive for response to HP eradication in a multivariate analysis, whereas extension into the gastric wall alone was not significant on multivariate analysis. As four patients in our series were rated as being in stage EI2 and three of them received additional HP eradication, we cannot rule out the fact that additional HP eradication might have contributed to the high response rate obtained in our series. The same might hold true for some patients with gastric lymphoma rated as having lymph node involvement, as Fischbach et al26 have recently shown that endosonography tends to overestimate the rate of lymph node involvement as compared with surgical assessment, as overstaging was found in 12% of patients. Thus, one might assume that a pro-portion of patients probably erroneously rated as having lymph node involvement might have responded to HP eradication alone. To date, three patients with gastric lymphoma including the patient mentioned above have relapsed locally after 13 to 22 months, respectively, after obtaining CR, whereas one patient with lymphoma of the lacrimal gland and the lung experienced disease progression 15 months after obtaining PR. In three of these patients, however, treatment at a reduced dose had to be administered because of pronounced hematotoxicity during the first cycle of treatment. Therefore, the dose-intensity appears to be an important factor for therapeutic outcome. Both local relapses could undergo salvage treatment by application of radiotherapy, whereas the patient with extragastric disease achieved a second PR with the application of oral cyclophosphamide. Taken together, our data demonstrate that 2-CdA is highly effective in patients with both gastric and extragastric MALT-type lymphoma and can be safely administered on an outpatient basis. Despite the median follow-up of 32 months, a longer follow-up is needed in view of the indolent natural course of the disease in order to evaluate whether these responses can translate into long-term remission or even cure.
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3. Isaacson PG: Gastric MALT-lymphoma: From concept to cure. Ann Oncol 10: 637-645, 1999
4. Neubauer A, Thiede C, Morgner A, et al: Cure of Helicobacter pylori expression and duration of remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma. J Natl Cancer Inst 89: 1350-1355, 1997
5. Roggero E, Zucca E, Cavalli F: Gastric mucosa-associated lymphoid tissue lymphomas: More than a fascinating model. J Natl Cancer Inst 89: 1328-1330, 1997 6. Raderer M, Vorbeck F, Formanek M, et al: Importance of extensive staging in patients with mucosa associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer 83: 454-457, 2000[CrossRef][Medline]
7. Zucca E, Bertoni F, Roggero E, et al: The marginal zone gastric B-cell lymphoma of MALT-type. Blood 96: 410-419, 2000 8. Schechter N, Yahalom J: Low-grade MALT-lymphoma of the stomach: A review of treatment options. Int J Radiat Oncol Biol 46: 1093-1103, 2000[CrossRef][Medline] 9. Schechter N, Portlock CS, Yahalom J: Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone. J Clin Oncol 16: 1916-1921, 1998[Abstract]
10. Montalban C, Castrillo J, Abraira V, et al: Gastric B-cell mucosa-associated lymphoid tissue (MALT) lymphoma: Clinicopathological study and evaluation of the prognostic factors in 143 patients. Ann Oncol 6: 355-362, 1995 11. Hammel P, Haioun C, Chaumette M, et al: Efficacy of single-agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol 13: 2524-2529, 1995[Abstract] 12. Hussell T, Isaacson PG, Crabtree JE, et al: The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet 342: 571-574, 1993[CrossRef][Medline] 13. Hussell T, Isaacson PG, Spencer J: Proliferation and differentiation of tumour cells from B-cell lymphoma of mucosa-associated lymphoid tissue in vitro. J Pathol 169: 221-227, 1993[CrossRef][Medline] 14. Greiner A, Knorr C, Qin Y, et al: Low-grade B cell lymphomas of mucosa-associated lymphoid tissue (MALT-type) require CD40-mediated signaling and Th2-type cytokines for in vitro growth and differentiation. Am J Pathol 150: 1583-1593, 1997[Abstract] 15. Hussell T, Isaacson PG, Crabtree JE, et al: Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J Pathol 178: 122-127, 1996[CrossRef][Medline] 16. Musshoff K: Klinische Stadieneinteilung der Non-Hodgkin Lymphome. Strahlentherapie 153: 218-221, 1977[Medline] 17. Radaszkiewicz T, Dragosics B, Bauer P: Gastrointestinal malignant lymphomas of the mucosa associated lymphoid tissue: Factors relevant to prognosis. Gastroenterology 102: 1628-1638, 1992[Medline]
18. Rohatiner A, d’Amore F, Coiffier B, et al: Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 5: 397-400, 1994
19. Juliusson G, Liliemark J: Long-term survival following cladribine (2-chlorodeoxyadenosine) therapy in previously treated patients with chronic lymphocytic leukemia. Ann Oncol 7: 373-379, 1996 20. Robak T, Gora-Tybor J, Krykowski E, et al: Activity of 2-chlorodeoxyadenosine (cladribine) in 2-hour intravenous infusion in 94 previously treated patients with low grade non-Hodgkin’s lymphoma. Leuk Lymphoma 26: 99-105, 1997[Medline]
21. Cheson B, Horning S, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17: 1244-1253, 1999 22. Borgan Ø, Liestøl K: A note on confidence bands for the survival curve based on transformations. Scand J Stat 17: 35-41, 1990 23. Wotherspoon A, Doglioni C, Isaacson PG: Low-grade gastric B-cell lymphoma of mucosa associated lymphoid tissue (MALT): A multifocal disease. Histopathology 20: 29-34, 1992[Medline] 24. Sackmann M, Morgner A, Rudoph B, et al: Regression of gastric MALT-lymphoma after eradication of Helicobacter pylori is predicted by endosonographic staging. Gastroenterology 113: 1087-1090, 1997[CrossRef][Medline]
25. Ruskone-Fourmestraux A, Lavergne A, Aegerter P, et al: Predictive factors for regression of gastric MALT lymphoma after anti-Helicobacter pylori treatment. Gut 48: 297-303, 2001 26. Fischbach W, Dragosics B, Kolve-Goebbeler ME, et al: Primary gastric B-cell lymphoma: Results of a prospective multicenter trial. Gastroenterology 119: 1191-1202, 2000[CrossRef][Medline] Submitted May 24, 2001; accepted June 5, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
stage EI2) or extragastric MALT-type lymphoma were directly enrolled onto the study. 2-CdA was administered at a dose of 0.12 mg/kg body weight by intravenous infusion over 2 hours on days 1 to 5, and treatment was repeated every 4 weeks. In contrast to the treatment schedule with continuous infusion of cladribine, this regimen was chosen in order to allow administration on an outpatient basis according to trials showing equal efficacy.
