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Journal of Clinical Oncology, Vol 23, No 29 (October 10), 2005: pp. 7361-7362 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.6138
Persistent Residual Disease in t(11;18)(q21;q21) Positive Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Treated With Chemotherapy or RituximabDepartments of Clinical Hematology and Pathology, Hospital del Mar, Barcelona, Spain To the Editor: We read with interest the article by Martinelli et al1 in the March 20, 2005, issue of the Journal of Clinical Oncology reporting the clinical activity of rituximab in gastric marginal-zone non-Hodgkin's lymphoma resistant/refractory or not suitable for eradication treatment. In this study, fluorescence in situ hybridization analysis for evaluation of the t(11;18)(q21;q21) was performed in 21 patients and was positive in eight cases. The presence of this translocation at diagnosis was not associated with tumor response to rituximab since 75% of patients with t(11;18)(q21;q21) achieved a clinical response, a proportion which was not statistically different from the response rate of patients without this translocation. Recently, it has been shown that patients with mucosa-associated lymphoid tissue (MALT) -type gastric lymphoma carrying this translocation are unresponsive to antibacterial treatment, even those with localized stages.2 Some of these patients who achieve clinical response after eradication therapy are characterized by persistent lymphoid infiltrates despite normal endoscopy and endoscopic ultrasound examinations, but the natural course of minimal residual disease is not yet known.3 Streubel at el have reported that t(11;18)(q21;q21) did not adversely affect the response of gastric MALT lymphoma to treatment with 2-chlorodeoxyadenosine (cladribine), but molecular response was not reported.4 It is well known that monoclonality is observed in the majority of MALT lymphomas at diagnosis, and as many as 50% of patients who have complete histologic remissions of MALT lymphoma after eradication therapy have persisting monoclonal populations in follow-up monitoring by polymerase chain reaction (PCR). The meaning of persisting monoclonal populations remains unclear, because positive PCR could indicate amplification of DNA from resting memory cells in the gastric mucosa, but on the other hand, it could result from the presence of residual lymphoma cells, which might result in a higher risk of relapse. The t(11;18)(q21;q21) is the most common genetic alteration found in gastric MALT lymphoma. Detection of this translocation after therapy may be a more specific marker of the presence of residual lymphoma cells than analysis of clonality. Although several studies have examined PCR detection of t(11;18)(q21;q21) in gastric MALT lymphoma after eradication therapy, no study to date has examined the role of PCR amplification to assess residual disease after chemotherapy. For this reason, we have established a prospective follow-up of all of our patients by means of upper endoscopy at the end of treatment and later every 6 months. Gastric mapping protocol was used to obtain multiple biopsies that allowed us to prospectively monitor the histologic and molecular status. Clonality was determined by PCR assays for analysis of the immunoglobulin heavy chain (IgH) gene rearrangements analyzing CDR1, CDR2, and CDR3 regions.5 Presence of t(11;18)(q21;q21) was done by reverse transcriptase (RT-) PCR for API2/MALT1 fusion product, using previously described primers that cover all the known breakpoints,6 in those patients who were positive at the time of diagnosis. Here we report on our experience on the molecular follow-up of three gastric MALT lymphoma patients with t(11;18)(q21;q21) who have molecular monitoring longer than 12 months after last therapy. Clinical characteristics and response to first-line treatment are shown in Table 1. The first two patients, who had multifocal and large disease, were treated with eradication therapy combined with chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone in the first case and fludarabine in the second). Both patients became asymptomatic and achieved a clinical complete response, but endoscopic gastric biopsies showed histologic criteria of partial response.7 For this reason, two courses of rituximab were administered (375 mg/m2/week x 4 weeks, every 6 months) but residual lymphoid infiltrates could still be seen at the end of this treatment and at last follow-up (18 months and 14 months from last treatment, respectively). This lymphoid infiltrates expressed BCL10 in both the nucleus and cytoplasm confirming the neoplastic origin of these cells. Moderate nuclear and cytoplasmic BCL10 expression determined by immunohistochemistry correlates well with the presence of t(11;18)(q21;q21).8 The third patient, who had had disease localized in mucosa and submucosa at diagnosis, progressed after eradication therapy. This patient was treated with fludarabine and achieved both a complete clinical and histologic remission. No significant residual lymphocytes could be seen and was considered to be in complete histologic remission.
Molecular studies are shown in Table 1. We detected t(11;18)(q21;q21)-positive cells in all three of our patients at the end of the treatment and in all determinations performed during follow-up. Therefore, these positive results should be assessed as persistent minimal residual disease because t(11;18)(q21;q21) does not occur in normal B cells. Of note, rearrangements of the IgH gene were not detected in our third patient, a fact that suggests that RT-PCR for t(11;18)(q21;q21) is more sensitive for detecting minimal residual disease in this context. In patients with indolent lymphomas, the use of rituximab as a single agent has shown a response rate of approximately 50% to 75% and 40% to 60% in previously untreated and in relapsed patients, respectively. These figures are similar to those obtained by Martinelli et al1 in their series of gastric MALT lymphoma treated with the same schedule of rituximab. In addition, maintenance therapy with rituximab is increasingly being used to eliminate minimal residual disease, further delaying or preventing disease relapse. In follicular lymphoma, several studies have recently demonstrated a prolonged event-free and progression-free survival in those patients who were treated with rituximab maintenance.9 Because of this, we treated our first two patients with two cycles of rituximab, spaced 6 months between them, in order to improve the response. Treatment was well tolerated but, no significant histologic changes could be seen and residual disease was persistently found 2 months after rituximab and in all samples taken during follow-up. Our experience is in accordance with the evidence that gastric MALT lymphoma associated with t(11;18)(q21;q21) does respond to chemotherapy. However, residual disease can be found in these patients, both microscopically and by PCR, although the clinical significance of this finding remains uncertain. In our experience, the best method of follow up for these patients is RT-PCR for t(11;18)(q21;q21) instead of PCR for the IgH gene. Because t(11;18)(q21;q21)-positive cells are capable of surviving and remaining dormant for a long period, we suggest that long-term molecular follow-up is reasonable in these patients. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Martinelli G, Laszlo D, Ferreri AJM, et al: Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma to or not elegible for anti-Helicobacter pylori therapy. J Clin Oncol 23:1979-1983, 2005 2. Liu H, Ruskone-Fourmestraux A, Lavergne-Slove A, et al: Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Lancet 6:39-40, 2001 3. Fischbach W, Goebeler-Kolve M, Starostic P, et al: Minimal residual low-grade gastric MALT-type lymphoma after eradication of Helicobacter pylori. Lancet 360:547-548, 2002[CrossRef][Medline] 4. Streubel B, Ye H, Du MQ, et al: Translocation t(11;18)(q21;q21) is not predictive of response to chemotherapy with 2CdA in patients with gastric MALT lymphoma. Oncology 66:476-480, 2004[CrossRef][Medline] 5. Van Dongen JJ, Langerak AW, Brüggemann M, et al: Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 17:2257-2317, 2003[CrossRef][Medline]
6. Baens M, Maes B, Steyls A, et al: The product of the t(11;18), an API2-MLT fusion marks nearly half of gastric MALT type lymphomas without large cell proliferation. Am J Pathol 156:1433-1439, 2000 7. Wotherspoon AC, Doglioni C, Diss TC, et al: Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 342:575-577, 1993[CrossRef][Medline]
8. Ye H, Digan A, Karran L, et al: BCL10 expression in normal and neoplastic lymphoid tissue: nuclear localization in MALT lymphoma. Am J Pathol 157:1147-1154, 2000
9. Hainsworth JD, Litchy S, Burris HA, et al: Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma. J Clin Oncol 20:4261-4267, 2002 Related Reply
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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