Clinical Activity of Rituximab in Gastric Marginal Zone Non-Hodgkin's Lymphoma Resistant to or Not Eligible for Anti–Helicobacter Pylori The
http://www.100md.com
《临床肿瘤学》
the European Institute of Oncology
Hospital San Raffaele, Milan, Italy
Pathology Institute, Locarno
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
ABSTRACT
PURPOSE: Preliminary results using rituximab in extranodal marginal zone (MALT) non-Hodgkin's lymphoma (NHL) patients seem to indicate a relevant clinical activity. Aim of the present study is to investigate the efficacy of conventional weekly treatment using rituximab in gastric MALT NHL patients resistant/refractory or not suitable for eradication treatment, and to evaluate the relevance of the t(11; 18)(q21; q21) translocation and its possible role as a predictive criteria of response.
PATIENTS AND METHODS: Twenty-seven patients presenting with gastric MALT NHL at any stage, relapsed/refractory to initial treatment or not suitable for eradication were treated with rituximab in a weekly conventional schedule and evaluated for response and relapse. Flourescence in situ hybridization (FISH) analysis for the presence of 18q21 translocation was performed in 21 patients and was evaluated with clinical outcome.
RESULTS: Among the 26 evaluated patients, 20 (77%) achieved an objective response. Twelve patients (46%) had a pathological and clinical complete remission, and eight (31%) had a partial response. With a median follow-up of 33 months, only two patients relapsed at 26 and 14 months, respectively. No correlation was founded between FISH analysis and response or relapse.
CONCLUSION: Our experience seems to confirm the clinical activity of rituximab in gastric MALT NHL patients resistant/refractory to antibiotics treatment or not presenting with clinical evidence of Helicobacter pylori infection. The t(11; 18)(q21; q21) translocation seems not to be a predictive marker to response or to subsequent relapse.
INTRODUCTION
The majority of stage I marginal zone B-cell lymphomas of extranodal marginal zone (MALT) type (MALT lymphoma) of the stomach are associated with Helicobacter pylori (HP) infection, the eradication of which, with a specific antibiotic therapy, represents the first-line treatment, and is associated with complete lymphoma regression in 60% to 70% of the cases.1 Five to 10% of primary gastric MALT lymphomas do not show any sign of HP infection, and almost 30% of the HP-infected patients are resistant to antibiotic therapy or experience tumor relapse after treatment.2 The t(11;18)(q21;q21) translocation, detectable in approximately one third of the cases of primary gastric MALT lymphomas, has been demonstrated to confer resistance to anti-HP therapy.3 Widely accepted therapeutic guidelines for primary gastric MALT lymphomas failed after antibiotics, and for HP-unrelated lymphomas, have not been established.4 Radiotherapy, chemotherapy, and gastrectomy1,5,6 may represent suitable treatments for this patient setting, but they are often associated with relevant acute toxicity and sequels. Rituximab, an anti-CD20 monoclonal antibody, has been demonstrated to be an effective and well-tolerated therapy in different lymphoma categories alone or in combination with chemotherapy.7-9 The clinical activity in MALT lymphomas arising in different extranodal organs, including the stomach, has been recently ascertained.10 The present study reports our experience with rituximab in 27 patients with relapsed/refractory gastric MALT lymphoma who had undergone anti-HP therapy or who were not eligible for anti-HP therapy because of HP-negative lymphoma.
PATIENTS AND METHODS
Patients Population
The study population included 27 patients (15 men, 12 women), with a median age of 53 years (range, 32 to 80 years). Patient characteristics are outlined in Table 1. The eligibility criteria were age older than 18 years; histologically proven gastric MALT lymphoma, either persistent after anti-HP therapy or relapsing without HP reinfection, or newly diagnosed cases with HP-negative lymphoma therefore not eligible for first-line anti-HP therapy. Stage of disease at diagnosis according to the Lugano staging system11 was I-II1,2 in 23 patients (85%) and IV in four patients because of histologically proven bone marrow (three patients, 11%) or simultaneous lung, pleural, and spleen involvement (one patient, 4%).
Previous Treatment
Eleven patients (41%) had documented HP infection at diagnosis: five had eradication antibiotic therapy as the sole initial treatment, and six received eradication antibiotic therapy associated with chemotherapy. All these patients relapsed.
The remaining 16 patients (HP-negative) received rituximab as first-line treatment (two patients), surgery (two patients), eradication antibiotic therapy (eight patients), and chemotherapy with alkylating agents as single therapy (four patients) or associated with antibiotic therapy (two patients) or surgery (one patient). All the patients had persistent/progressive disease at rituximab therapy. Local radiotherapy was planned for those patients who eventually progressed after rituximab treatment.
The median time from diagnosis to treatment with rituximab was 12 months (range, 0.6 to 89 months). The median follow-up was 28 months (range, 3 to 46 months).
Samples and Histologic Diagnosis
In each case, at least six samples taken from the three gastric regions by fibroptic endoscopy were available for histologic examination. The original diagnosis of MALT lymphoma was confirmed in all the cases by three expert pathologists (E.P., M.P., G.P.) using hematoxylin and eosin and/or Giemsa-stained slides, and immunohistochemistry with antibodies recognizing B- (CD20) and T- (CD3) cell–associated antigens as well as CD5 and CD10. All the cases were composed by monocytoid-, lymphocytic-, and/or centrocyticlike cells that were immunoreactive for CD20 and not for CD3, CD5, or CD10. None of the cases showed extensive plasma cell differentiation.
Flourescence In Situ Hybridization
Flourescence in situ hybridization (FISH) analysis for the evaluation of the 18q21 translocation was performed in 21 cases in interphase nuclei from 2-μm-thick sections by hybridization with the LSI MALT1 dual color break apart DNA probe (Vysis Inc, Downers Grove, IL), according to the manufacturer's instructions. A mean of 54.09 ± 22.56 nuclei (range, 20 to 100 nuclei) were analyzed in each case. Only cases with split signals in more than 10% of the nuclei were considered positive. Digital images were obtained using a Leica DMR epifluorescence microscope (Leica Imaging Systems Ltd, Cambridge, UK) equipped with a CCD camera (Cohu Inc, San Diego, CA). FITC-avidin, Cy3 and DAPI fluorescent signals were detected using specific filters. The images were recorded, colored, and merged using the QFISH software (Leica Imaging Systems Ltd), and finally edited using Adobe Photoshop Version 6.0 (Adobe Systems, Mountain View, CA).
Treatment
All the patients received rituximab (Mabthera; Roche Pharma, Basel, Switzerland) at weekly standard dose (375 mg/m2) for 4 consecutive weeks, following the standard guidelines.
Assessment of Response
All the patients were re-evaluated at 2, 6, and 12 months post-therapy by endoscopy with biopsies from the three gastric regions. Beyond 1 year from the treatment, endoscopy with biopsy and computed tomography scans were performed every 6 months for 2 years, and then once yearly or according to specific clinical situations.
Histologic complete (CR) and partial (PR) responses were defined as the complete absence of neoplastic lymphoid cells or presence of lymphocytes and plasma cells scattered or in small aggregates, or the persistence of atypical lymphoid cells in larger sheets, with or without lymphoepithelial lesions, respectively. Stable (SD) and relapsing/progressive (R/PD) disease were characterized by a lymphoid proliferation fulfilling the criteria of Wotherspoon et al for the diagnosis of MALT lymphoma.12
The presence of a positive gastric biopsy (ie, Wotherspoon score 4 or 5)12 after a CR was a sufficient criterion to define a clinical relapse. In the four cases with extragastric localization, the clinical response to therapy was evaluated according to the standard international criteria.13
RESULTS
The main hematologic and nonhematologic toxicities according to National Cancer Institute criteria14 are listed in Table 2. The most frequent nonhematologic toxicity was mild infusion-related symptoms during the first infusion. One patient experienced severe infusion-related symptoms (glottic edema and pruritus), which were resolved by reducing the infusion rate. None of the patients discontinued the treatment for acute nonhematologic toxicity. One patient developed pneumonia during the second week of treatment and therefore discontinued the treatment.
All patients except one were therefore assessable for tumor response: 20 (77%) of 26 patients (95% CI, 56% to 91%) achieved an objective response, including 12 (46%; 95% CI, 27% to 67%) CR and eight (31%; 95% CI, 14% to 52%) PR. Six patients (23%; 95% CI, 9% to 44%) showed SD (Table 3). The median time for achieving the best clinical response was 2.3 months (range, 1 to 7 months). No patients with stage IV disease at study entry obtained a CR (two PR and two SD).
All patients are alive, and 14 of them (54%) are free of disease with a median follow-up of 28 months from rituximab administration. Figure 1 shows the time-to-treatment-failure curve.
Among the patients in PR or SD, five received a further treatment. One patient, who remained symptomatic even after PR with rituximab, received local radiotherapy achieving a CR; the remaining patients (two PR and two SD) received rituximab alone or in combination with chemotherapy (see Discussion).
Two patients (8%) relapsed 14 and 26 months after study entry, respectively. One of them, relapsed in the testis, received rituximab in combination with chlorambucil (6 mg/m2 daily for 6 weeks) and again achieved a CR, while the other patient with a local relapse (stomach, fundus) was successfully treated by local radiotherapy and is alive and free of disease.
The 18q21 locus translocation was detected in eight (38%) of the 21 cases analyzed by FISH. The mean ± SD prevalence of nuclei with split signals was 46.87% ± 27.37% (range, 15% to 100%). The occurrence of the 18q21 translocation was not correlated to the response to treatment; in particular, a clinical response (CR or PR) was observed in six (75%) of eight patients with, and in nine (69%) of 13 patients without evidence of 18q21 locus translocation (P = .99, Fisher's exact test).
DISCUSSION
MALT lymphomas represent approximately 8% of the non-Hodgkin’s lymphoma cases in the Western countries and express CD20 except for a minority of cases showing extensive plasma cell differentiation. Preliminary evidence of rituximab activity has recently been reported in 14 patients with gastric MALT lymphomas, with an overall response rate and complete remission rate of 64% and 29%, respectively.10 Raderer et al15 recently described a moderate activity (with three CR and two PR) of rituximab as a single agent in nine advanced MALT lymphoma cases. In their series, the persistence of CD20+ B cell within lymphoepithelial lesions was observed in one case, thus suggesting that the penetration of the anti-CD20 monoclonal antibody in the gastric mucosa might be suboptimal. In the present larger study, we observed an overall response rate of 77% and a complete remission rate of 46%. This is higher than previously reported in follicular lymphomas. One possible explanation for this finding may be that rituximab activity is dependent on the tumor burden, which is usually lower in MALT patients than in follicular lymphoma patients. In this regard, it is of note that we observed a CR rate higher in early clinical stage patients than in advanced clinical stage patients (Table 3); moreover, no patients in stage IV at study entry obtained a CR. Overall, we observed a low degree of toxicity—a finding in line with previous studies dealing with rituximab administered weekly at standard usage.16 The lack of acute and late side effects should be a critical decision-making point in indolent lymphomas such as MALT lymphomas, which are not suitable for definitive cure, but patients can nevertheless have prolonged survival.
Two patients in the study were treated with local radiotherapy on the stomach: one because of local relapse after a CR and the other one due to symptomatic disease after a PR with rituximab. Both patients obtained a CR with local radiotherapy, confirming the utility of radiotherapy in the treatment of patients who fail to respond to a less toxic approach.17
Interestingly, one of the two patients who relapsed after rituximab was subsequently also treated with rituximab in association with chlorambucil according to a recently published regimen,18 achieving a complete remission, suggesting that rituximab, alone or in combination with chemotherapy, may be effective in relapsing patients previously treated with the anti-CD20 monoclonal antibody.
The t(11;18)(q21;q21) translocation is the most common genetic abnormality in gastric MALT lymphomas, being detectable in approximately 30% of cases. It leads to the juxtaposition of the MALT1 and API2 genes and to the transcription of the MALT1/API2 fusion protein that is capable of counteracting the apoptotic pathways.19 There is evidence that the t(11;18)(q21; q21) translocation is associated with resistance to anti-HP therapy in MALT lymphoma patients.3 Since immunotherapy acts by promoting apoptosis, complement activation, and cell-mediated cytotoxicity,20 we were interested in evaluating the clinical relevance of the t(11;18)(q21; q21) translocation in our MALT lymphoma patients treated with rituximab. We used a tool that simply indicates the presence of a translocation at locus 18q21, where MALT1 is mapped. Nevertheless, since the t(14;18)(q32; q21) translocation, which juxtaposes MALT1 to the IgH gene, is nearly always absent in gastric MALT lymphomas,21 our data strongly indicate the occurrence of a t(11;18)(q21; q21) translocation in approximately 30% of the cases, which is in line with previous findings. Nevertheless, the occurrence of a translocation at locus 18q21 was not associated with tumor response to therapy, thus suggesting that alternative aberrations in MALT lymphoma cells may contribute to conferring resistance to immunotherapy.
In conclusion, clinical results observed in our experience confirm that the use of rituximab in a weekly schedule and at standard dosage could be considered a very effective modality treatment in gastric MALT resistant to or not eligible for anti-HP therapy. Further studies evaluating rituximab and chemotherapy or new radioimmunolabeled monoclonal antibody used alone or in combination, are warranted in order to define the better modality treatment in this patient setting.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
G.M. and D.L. contributed equally to this article.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Zucca E, Bertoni F, Roggero E, et al: The gastric marginal zone B-cell lymphoma of MALT type. Blood 96:410-419, 2000
Steinbach G, Ford R, Glober G, et al: Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue: An uncontrolled trial. Ann Intern Med 131:88-95, 1999
Liu H, Ruskone-Fourmestraux A, Lavergne-Scove A, et al: Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet 357:39-40, 2001
de Jong D, Aleman BM, Taal BG, et al: Controversies and consensus in the diagnosis, work-up and treatment of gastric lymphoma: An international survey. Ann Oncol 10:275-280, 1999
Hammel P, Haioun C, Chaumette MT, 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
Tsang RW, Gospodarowicz MK, Pintilie M, et al: Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 21:4157-4164, 2003
McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998
Hiddeman W, Dreyling MH, Forstpointner R, et al: Combined immuno-chemotherapy (R-Chop) significantly improves time to treatment failure in first line therapy of follicular lymphoma: Results of a prospective randomized trial of the german low grade lymphoma study group (GLSG). Blood 102:1049, 2003 (abstr 352)
Marcus R, Imrie K, Belch A, et al: An international multi-centre, randomized, open-lable, phase III trial comparing rituximab added to CVP chemoterapy to CVP chemoterapy alone in untreated stage III/IV follicular non Hodgkin's Lymphoma. Blood 102:289, 2003 (abstr 87)
Conconi A, Martinelli G, Thieblemont C, et al: Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood 102:2741-2745, 2003
Rohatiner A, d'Amore F, Coiffer 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
Wotherspoon AC, Doglioni C, Isaacson PG: Low grade gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT): A multifocal disease. Histopathology 20:29-34, 1992
Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI sponsored international working group. J Clin Oncol 17:1244-1253, 1999
National Cancer Institute. Common Toxicity Criteria. NCI-CTC version 2.0 Jan 30, 1998. http://ctep.cancer.gov/reporting/CTC-3.html
Raderer M, Jager G, Brugger S, et al: Rituximab for treatment of advanced extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue lymphoma. Oncology 65:306-310, 2003
Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (Rituximab) anti CD20 monoclonal antibody therapy in patients with relapsed low-grade non Hodgkin's lymphoma. Blood 90:2188-2195, 1997
Ref Yahalom J, Isaacson PJ, Zucca E: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, in Mauch PM, Armitage J, Coiffier B, et al (eds): Non-Hodgkin's Lymphomas. Philadelphia, PA, Lippincott Williams and Wilkins, 2004, pp 345-360
Martinelli G, Laszlo D, Bertolini F, et al: Chlorambucil in combination with induction and maintenance rituximab is feasible and active in indolent non-Hodgkin's lymphoma. Br J Haematol 123:271-277, 2003
Auer IA, Gascoyne RD, Connors JM, et al: t(11;18)(q21;q21) is the most common traslocation in MALT lymphomas. Ann Oncol 8:975-985, 1997
Smith SL, Watson SG, Ratschiller D, et al: Maspin—The most commonly-expressed gene of the 18q21.3 serpin cluster in lung cancer—is strongly expressed in preneoplastic bronchial lesions. Oncogene 22:8677-8687, 2003
Streubel B, Lamprecht A, Dierlamm J, et al: t(14;18)(q32;q21) involving IgH and MALT1 is a frequent chromosome aberration in MALT lymphoma. Blood 101:2335-2339, 2003(Giovanni Martinelli, Dani)
Hospital San Raffaele, Milan, Italy
Pathology Institute, Locarno
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
ABSTRACT
PURPOSE: Preliminary results using rituximab in extranodal marginal zone (MALT) non-Hodgkin's lymphoma (NHL) patients seem to indicate a relevant clinical activity. Aim of the present study is to investigate the efficacy of conventional weekly treatment using rituximab in gastric MALT NHL patients resistant/refractory or not suitable for eradication treatment, and to evaluate the relevance of the t(11; 18)(q21; q21) translocation and its possible role as a predictive criteria of response.
PATIENTS AND METHODS: Twenty-seven patients presenting with gastric MALT NHL at any stage, relapsed/refractory to initial treatment or not suitable for eradication were treated with rituximab in a weekly conventional schedule and evaluated for response and relapse. Flourescence in situ hybridization (FISH) analysis for the presence of 18q21 translocation was performed in 21 patients and was evaluated with clinical outcome.
RESULTS: Among the 26 evaluated patients, 20 (77%) achieved an objective response. Twelve patients (46%) had a pathological and clinical complete remission, and eight (31%) had a partial response. With a median follow-up of 33 months, only two patients relapsed at 26 and 14 months, respectively. No correlation was founded between FISH analysis and response or relapse.
CONCLUSION: Our experience seems to confirm the clinical activity of rituximab in gastric MALT NHL patients resistant/refractory to antibiotics treatment or not presenting with clinical evidence of Helicobacter pylori infection. The t(11; 18)(q21; q21) translocation seems not to be a predictive marker to response or to subsequent relapse.
INTRODUCTION
The majority of stage I marginal zone B-cell lymphomas of extranodal marginal zone (MALT) type (MALT lymphoma) of the stomach are associated with Helicobacter pylori (HP) infection, the eradication of which, with a specific antibiotic therapy, represents the first-line treatment, and is associated with complete lymphoma regression in 60% to 70% of the cases.1 Five to 10% of primary gastric MALT lymphomas do not show any sign of HP infection, and almost 30% of the HP-infected patients are resistant to antibiotic therapy or experience tumor relapse after treatment.2 The t(11;18)(q21;q21) translocation, detectable in approximately one third of the cases of primary gastric MALT lymphomas, has been demonstrated to confer resistance to anti-HP therapy.3 Widely accepted therapeutic guidelines for primary gastric MALT lymphomas failed after antibiotics, and for HP-unrelated lymphomas, have not been established.4 Radiotherapy, chemotherapy, and gastrectomy1,5,6 may represent suitable treatments for this patient setting, but they are often associated with relevant acute toxicity and sequels. Rituximab, an anti-CD20 monoclonal antibody, has been demonstrated to be an effective and well-tolerated therapy in different lymphoma categories alone or in combination with chemotherapy.7-9 The clinical activity in MALT lymphomas arising in different extranodal organs, including the stomach, has been recently ascertained.10 The present study reports our experience with rituximab in 27 patients with relapsed/refractory gastric MALT lymphoma who had undergone anti-HP therapy or who were not eligible for anti-HP therapy because of HP-negative lymphoma.
PATIENTS AND METHODS
Patients Population
The study population included 27 patients (15 men, 12 women), with a median age of 53 years (range, 32 to 80 years). Patient characteristics are outlined in Table 1. The eligibility criteria were age older than 18 years; histologically proven gastric MALT lymphoma, either persistent after anti-HP therapy or relapsing without HP reinfection, or newly diagnosed cases with HP-negative lymphoma therefore not eligible for first-line anti-HP therapy. Stage of disease at diagnosis according to the Lugano staging system11 was I-II1,2 in 23 patients (85%) and IV in four patients because of histologically proven bone marrow (three patients, 11%) or simultaneous lung, pleural, and spleen involvement (one patient, 4%).
Previous Treatment
Eleven patients (41%) had documented HP infection at diagnosis: five had eradication antibiotic therapy as the sole initial treatment, and six received eradication antibiotic therapy associated with chemotherapy. All these patients relapsed.
The remaining 16 patients (HP-negative) received rituximab as first-line treatment (two patients), surgery (two patients), eradication antibiotic therapy (eight patients), and chemotherapy with alkylating agents as single therapy (four patients) or associated with antibiotic therapy (two patients) or surgery (one patient). All the patients had persistent/progressive disease at rituximab therapy. Local radiotherapy was planned for those patients who eventually progressed after rituximab treatment.
The median time from diagnosis to treatment with rituximab was 12 months (range, 0.6 to 89 months). The median follow-up was 28 months (range, 3 to 46 months).
Samples and Histologic Diagnosis
In each case, at least six samples taken from the three gastric regions by fibroptic endoscopy were available for histologic examination. The original diagnosis of MALT lymphoma was confirmed in all the cases by three expert pathologists (E.P., M.P., G.P.) using hematoxylin and eosin and/or Giemsa-stained slides, and immunohistochemistry with antibodies recognizing B- (CD20) and T- (CD3) cell–associated antigens as well as CD5 and CD10. All the cases were composed by monocytoid-, lymphocytic-, and/or centrocyticlike cells that were immunoreactive for CD20 and not for CD3, CD5, or CD10. None of the cases showed extensive plasma cell differentiation.
Flourescence In Situ Hybridization
Flourescence in situ hybridization (FISH) analysis for the evaluation of the 18q21 translocation was performed in 21 cases in interphase nuclei from 2-μm-thick sections by hybridization with the LSI MALT1 dual color break apart DNA probe (Vysis Inc, Downers Grove, IL), according to the manufacturer's instructions. A mean of 54.09 ± 22.56 nuclei (range, 20 to 100 nuclei) were analyzed in each case. Only cases with split signals in more than 10% of the nuclei were considered positive. Digital images were obtained using a Leica DMR epifluorescence microscope (Leica Imaging Systems Ltd, Cambridge, UK) equipped with a CCD camera (Cohu Inc, San Diego, CA). FITC-avidin, Cy3 and DAPI fluorescent signals were detected using specific filters. The images were recorded, colored, and merged using the QFISH software (Leica Imaging Systems Ltd), and finally edited using Adobe Photoshop Version 6.0 (Adobe Systems, Mountain View, CA).
Treatment
All the patients received rituximab (Mabthera; Roche Pharma, Basel, Switzerland) at weekly standard dose (375 mg/m2) for 4 consecutive weeks, following the standard guidelines.
Assessment of Response
All the patients were re-evaluated at 2, 6, and 12 months post-therapy by endoscopy with biopsies from the three gastric regions. Beyond 1 year from the treatment, endoscopy with biopsy and computed tomography scans were performed every 6 months for 2 years, and then once yearly or according to specific clinical situations.
Histologic complete (CR) and partial (PR) responses were defined as the complete absence of neoplastic lymphoid cells or presence of lymphocytes and plasma cells scattered or in small aggregates, or the persistence of atypical lymphoid cells in larger sheets, with or without lymphoepithelial lesions, respectively. Stable (SD) and relapsing/progressive (R/PD) disease were characterized by a lymphoid proliferation fulfilling the criteria of Wotherspoon et al for the diagnosis of MALT lymphoma.12
The presence of a positive gastric biopsy (ie, Wotherspoon score 4 or 5)12 after a CR was a sufficient criterion to define a clinical relapse. In the four cases with extragastric localization, the clinical response to therapy was evaluated according to the standard international criteria.13
RESULTS
The main hematologic and nonhematologic toxicities according to National Cancer Institute criteria14 are listed in Table 2. The most frequent nonhematologic toxicity was mild infusion-related symptoms during the first infusion. One patient experienced severe infusion-related symptoms (glottic edema and pruritus), which were resolved by reducing the infusion rate. None of the patients discontinued the treatment for acute nonhematologic toxicity. One patient developed pneumonia during the second week of treatment and therefore discontinued the treatment.
All patients except one were therefore assessable for tumor response: 20 (77%) of 26 patients (95% CI, 56% to 91%) achieved an objective response, including 12 (46%; 95% CI, 27% to 67%) CR and eight (31%; 95% CI, 14% to 52%) PR. Six patients (23%; 95% CI, 9% to 44%) showed SD (Table 3). The median time for achieving the best clinical response was 2.3 months (range, 1 to 7 months). No patients with stage IV disease at study entry obtained a CR (two PR and two SD).
All patients are alive, and 14 of them (54%) are free of disease with a median follow-up of 28 months from rituximab administration. Figure 1 shows the time-to-treatment-failure curve.
Among the patients in PR or SD, five received a further treatment. One patient, who remained symptomatic even after PR with rituximab, received local radiotherapy achieving a CR; the remaining patients (two PR and two SD) received rituximab alone or in combination with chemotherapy (see Discussion).
Two patients (8%) relapsed 14 and 26 months after study entry, respectively. One of them, relapsed in the testis, received rituximab in combination with chlorambucil (6 mg/m2 daily for 6 weeks) and again achieved a CR, while the other patient with a local relapse (stomach, fundus) was successfully treated by local radiotherapy and is alive and free of disease.
The 18q21 locus translocation was detected in eight (38%) of the 21 cases analyzed by FISH. The mean ± SD prevalence of nuclei with split signals was 46.87% ± 27.37% (range, 15% to 100%). The occurrence of the 18q21 translocation was not correlated to the response to treatment; in particular, a clinical response (CR or PR) was observed in six (75%) of eight patients with, and in nine (69%) of 13 patients without evidence of 18q21 locus translocation (P = .99, Fisher's exact test).
DISCUSSION
MALT lymphomas represent approximately 8% of the non-Hodgkin’s lymphoma cases in the Western countries and express CD20 except for a minority of cases showing extensive plasma cell differentiation. Preliminary evidence of rituximab activity has recently been reported in 14 patients with gastric MALT lymphomas, with an overall response rate and complete remission rate of 64% and 29%, respectively.10 Raderer et al15 recently described a moderate activity (with three CR and two PR) of rituximab as a single agent in nine advanced MALT lymphoma cases. In their series, the persistence of CD20+ B cell within lymphoepithelial lesions was observed in one case, thus suggesting that the penetration of the anti-CD20 monoclonal antibody in the gastric mucosa might be suboptimal. In the present larger study, we observed an overall response rate of 77% and a complete remission rate of 46%. This is higher than previously reported in follicular lymphomas. One possible explanation for this finding may be that rituximab activity is dependent on the tumor burden, which is usually lower in MALT patients than in follicular lymphoma patients. In this regard, it is of note that we observed a CR rate higher in early clinical stage patients than in advanced clinical stage patients (Table 3); moreover, no patients in stage IV at study entry obtained a CR. Overall, we observed a low degree of toxicity—a finding in line with previous studies dealing with rituximab administered weekly at standard usage.16 The lack of acute and late side effects should be a critical decision-making point in indolent lymphomas such as MALT lymphomas, which are not suitable for definitive cure, but patients can nevertheless have prolonged survival.
Two patients in the study were treated with local radiotherapy on the stomach: one because of local relapse after a CR and the other one due to symptomatic disease after a PR with rituximab. Both patients obtained a CR with local radiotherapy, confirming the utility of radiotherapy in the treatment of patients who fail to respond to a less toxic approach.17
Interestingly, one of the two patients who relapsed after rituximab was subsequently also treated with rituximab in association with chlorambucil according to a recently published regimen,18 achieving a complete remission, suggesting that rituximab, alone or in combination with chemotherapy, may be effective in relapsing patients previously treated with the anti-CD20 monoclonal antibody.
The t(11;18)(q21;q21) translocation is the most common genetic abnormality in gastric MALT lymphomas, being detectable in approximately 30% of cases. It leads to the juxtaposition of the MALT1 and API2 genes and to the transcription of the MALT1/API2 fusion protein that is capable of counteracting the apoptotic pathways.19 There is evidence that the t(11;18)(q21; q21) translocation is associated with resistance to anti-HP therapy in MALT lymphoma patients.3 Since immunotherapy acts by promoting apoptosis, complement activation, and cell-mediated cytotoxicity,20 we were interested in evaluating the clinical relevance of the t(11;18)(q21; q21) translocation in our MALT lymphoma patients treated with rituximab. We used a tool that simply indicates the presence of a translocation at locus 18q21, where MALT1 is mapped. Nevertheless, since the t(14;18)(q32; q21) translocation, which juxtaposes MALT1 to the IgH gene, is nearly always absent in gastric MALT lymphomas,21 our data strongly indicate the occurrence of a t(11;18)(q21; q21) translocation in approximately 30% of the cases, which is in line with previous findings. Nevertheless, the occurrence of a translocation at locus 18q21 was not associated with tumor response to therapy, thus suggesting that alternative aberrations in MALT lymphoma cells may contribute to conferring resistance to immunotherapy.
In conclusion, clinical results observed in our experience confirm that the use of rituximab in a weekly schedule and at standard dosage could be considered a very effective modality treatment in gastric MALT resistant to or not eligible for anti-HP therapy. Further studies evaluating rituximab and chemotherapy or new radioimmunolabeled monoclonal antibody used alone or in combination, are warranted in order to define the better modality treatment in this patient setting.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
G.M. and D.L. contributed equally to this article.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Zucca E, Bertoni F, Roggero E, et al: The gastric marginal zone B-cell lymphoma of MALT type. Blood 96:410-419, 2000
Steinbach G, Ford R, Glober G, et al: Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue: An uncontrolled trial. Ann Intern Med 131:88-95, 1999
Liu H, Ruskone-Fourmestraux A, Lavergne-Scove A, et al: Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet 357:39-40, 2001
de Jong D, Aleman BM, Taal BG, et al: Controversies and consensus in the diagnosis, work-up and treatment of gastric lymphoma: An international survey. Ann Oncol 10:275-280, 1999
Hammel P, Haioun C, Chaumette MT, 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
Tsang RW, Gospodarowicz MK, Pintilie M, et al: Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 21:4157-4164, 2003
McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998
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