Blood Journal
Leading the way in experimental and clinical research in hematology

Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature

  1. Barbara Kiesewetter and
  2. Markus Raderer
  1. Division of Oncology, Department of Internal Medicine I, Medical University Vienna, Vienna, Austria

Abstract

Although antibiotic therapy has been established as the standard of care in patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, much less is known about the value of antibiotic therapy in nongastrointestinal (non-GI) MALT lymphomas. A computerized search (Medline) accompanied by a manual search to identify clinical reports on the topic of antibacterial therapy in patients with non-GI MALT lymphomas was performed. The majority of data were available for MALT lymphoma of the ocular adnexa (OAML) including a total of 131 patients in 4 retrospective studies, 3 prospective series (including 81 patients), and 1 case report. Treatment was exclusively targeting Chlamydophila psittaci (CP), using doxycycline in all but 2 studies. The median follow-up for these studies was 25 months, and both CP-positive as well as CP-negative patients responded. Complete remission was achieved in 23 patients (18%), 36 (27%) had a partial remission, 55 (42%) had stable disease, and 8 patients (6%) had progressive disease accounting for an overall response rate of 45%. In the largest study, a better response was suggested in CP-positive patients. By contrast, only scattered reports could be found for other non-GI localizations, allowing no conclusion about the benefit of antibiotic therapy and probably resulting in a publication bias toward positive cases. Based on these results, antibiotic therapy using doxycycline appears to be a reasonable first-line therapy for patients with OAML. Antibiotics, however, remain experimental for the time being in patients with other non-GI MALT lymphomas. Further preclinical studies as well as large-scale therapeutic trials are warranted to define the role of antibiotic therapy in such patients.

Introduction

Extranodal marginal-zone B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) represent ∼8% of all B-cell lymphomas with a currently estimated worldwide prevalence of 2/100 000. Although MALT lymphomas can develop in mucosal tissues throughout the entire body, gastric MALT lymphomas still constitute ∼50% of new diagnoses. Further common sites include the ocular adnexa, salivary glands, and the lung but also rarer sites such as the skin, bladder, breast, and highly “exotic” localizations like the dura mater, where the presence of acquired lymphoid tissue is difficult to explain.1,2

Various contributing factors have been defined in terms of pathogenesis, including autoimmune diseases (eg, Sjögren syndrome and chronic autoimmune thyroiditis) particularly in women with lymphomas developing at extragastric sites,3 infections such as hepatitis C virus in certain geographic areas,4,5 but most prominently bacterial infections exemplified by Helicobacter pylori (HP) in gastric MALT lymphoma. This close association has led to definition of antibiotic therapy as the standard approach to this cohort of patients. According to the current knowledge, this antigenic-driven process involves the bacteria, but also autoantigenic processing of B cells within the gastric mucosa augmented by HP-specific T cells featuring cross-reactivity with gastric autoantigens resulting in the development of a specific monoclonal B-cell clone.6 According to the literature, roughly 90% of gastric MALT lymphomas are associated with HP infection, and HP eradication has become the first-line therapy in gastric MALT lymphoma including the rare cohort of HP-negative patients.7 Several study groups in the last 2 decades have underlined the high efficacy of HP eradication reporting long-lasting complete remissions (CRs) in up to 80% of patients without any need for more aggressive therapies in the case of response to antibiotics.7-10

Although there is little doubt about the value of HP eradication in gastric MALT lymphomas, a potential bacterial background in extragastric MALT lymphomas has been more difficult to establish. Conflicting data on the efficacy of HP eradication in disseminated as well as localized extragastric MALT lymphomas have been published, mostly in the form of case reports and small retrospective analyses. Apart from HP, Chlamydia (or more recently Chlamydophila) psittaci (CP) has been reported as a potential trigger for MALT lymphoma of the ocular adnexa (OAML), and the benefit of antibiotic treatment has been documented by Ferreri et al.11 In addition, Borrelia burgdorferi12 as well as Campylobacter jejuni have been implicated in cutaneous MALT lymphoma and immunoproliferative intestinal diseases,13 a relatively rare variant of MALT lymphoma predominately found in the Middle East.

The objective of this article is therefore to summarize the currently published data on antibacterial treatment in nongastrointestinal (non-GI) MALT lymphoma and to discuss the impact of these findings on the clinical management of such patients.

Methods

A computerized search using Medline was performed to identify available publications concerning antibiotic therapy in histologically verified non-GI MALT lymphoma. Only articles with at least an English abstract were included; thus, we cannot definitely exclude a minor bias due to nonprovided/nontranslated abstracts and published work with solely the abstract but not the full text online. Full-text publications were reviewed if written in English or German. Articles concerning pediatric patients (eg, under 18 years) were not of interest for this review. No attempts to discover unpublished data were made. In addition to the computerized search in Medline, a manual search in the reference sections of included papers was performed.

The following were the main points of interest for this review: detailed histologic description of MALT lymphoma; number and basic characteristics (age, localization, and stage of disease) of reported patients; suspected pathogen as target for the antibiotic therapy; if assessed, serological/histologic presence of pathogen and method of detection; line of therapy; route of administration, duration, and dosage of antibiotic therapy; and definition of response, overall response rate (ORR), and follow-up time. If available, we have also tried to extract the medical history of patients in terms of prior therapies.

Overall objective response was defined by the sum of CR plus partial remissions (PRs) as reported by the authors. Furthermore, stable disease (SD), minimal response (MR) (<50% regression), and progressive disease (PD) were possible terms for outcome, but the latter 2 were not included as remissions in our review. If the outcome was not classified within this ranking, we used the expression chosen by the author.

Results

OAML

Apart from HP, CP is the most intensively studied pathogen in MALT lymphoma and has repeatedly been defined in OAML as a potential target for antibiotic therapy. In 2004, Ferreri et al11 were the first to report a possible association between CP and OAML and have consecutively contributed 4 further studies on CP eradication in such patients.14-17

We could identify a total of 9 studies14-22 published between 2004 and 2012 on antibacterial therapy in patients with OAML including Korean, Italian, Hungarian, US-American, Chilean, Spanish, Swiss, and Austrian study groups’ experiences, providing a more or less “global” overview. Taken together, a total of 131 patients were enrolled in these 9 series, comprising 4 retrospective trials (number of patients = 58), 1 single case report, and 3 (initially 4) prospective trials including 81 patients. Because the results from the 2005 Ferreri pilot project17 are also part of the 2006 trial,16 these results were not considered separately in our further analysis.

The median follow-up time of these 9 trials was 23 months (range: 1-62), and sufficient information about staging procedure and response criteria was available in all larger trials, although controversial findings with regard to the classification of bilateral orbital involvement were reported. Ferreri et al15 rated bilateral disease in the ocular adnexa as stage IV, whereas Kim et al19 considered the same extent of disease as stage I. Yet both authors refer to the Ann Arbor staging system. For the sake of this review, we have adopted the authors’ classification for further analysis.

For patients’ characteristics and details, see Table 1. A median age of 55 years (range: 18-94) was reported in these trials (excluding the Ferreri et al14 2012 trial data where the median age of 60 years is given for all 47 patients registered, but not separately for the doxycycline-treated cohort), and the stage at the beginning of antibacterial therapy was exclusively stage I in 4 studies, whereas the other studies have included various stages of OAML. One patient collective consisted only of disseminated stage IV patients, but these results were reported only in a brief letter to the editor.15

View this table:
Table 1

Therapy and outcome of antibiotic therapy targeting CP in OAML

CP status was determined in 6 of 9 studies14-19 but remained unknown in 2, resulting in “blind” antibiotic treatment in these latter series.20,21 In addition, Chlamydia trachomatis was the pathogen present in the case report of Yeung et al.22 Six of the study groups used touchdown enzyme time-release polymerase chain reaction (PCR) with the ability to detect CP DNA in either tumor tissues, peripheral blood monocytes, or both,23 whereas the exact method of Chlamydia testing was not explained in the case report by Yeung et al.22 In the most recent study, testing for CP was performed in lymphoma biopsies as well as blood and/or conjunctival swabs.14 Out of the 116 patients tested within these studies, 66 (56%) showed a positive test result, whereas the others were rated negative for CP.

A single course of oral doxycycline at a dose of 100 mg given twice a day for 3 weeks was the most popular regimen and was used by most investigators.14-17,19-22 By contrast, Kim and coworkers19 added a second course after an interval of 3 weeks for patients with residual eye-related symptoms after the initial cycle. The activity of a 6-month oral application of 500 mg clarithromycin twice a day was assessed in an Italian pilot study,18 assuming potential additional direct anticancer effects of macrolide antibiotics through changes in apoptotic mechanisms of tumor cells. In addition, 1 patient received HP eradication as first-line treatment of OAML.

As reported by the authors, a CR was achieved in 23 patients (18%) out of the collective of all 131 patients reported. Thirty-six (27%) had a PR, 5 (4%) were rated as MR or mild response, 55 (42%) were rated as SD, and 8 patients (6%) had PD as assessed after finishing the respective treatment period. In summary, the numbers of CR and PR account for an ORR of 45%, excluding patients with a documented MR/mild improvement. However, 1 trial disclosed no response at all in 11 patients.20 Response rates of different trials were comparable and in the range of 45%, whereas the international phase 2 trial published in 201214 had a notably better response at 65% in the treated collective.

Information on a potential influence of CP status on outcome is given in 3 trials, 1 reporting an equal response in both groups,19 whereas the 2 Ferreri et al14,16 trials found better results in CP-positive patients (66% vs 50%, respectively, 64% vs 38%, response rate). An association between Chlamydia eradication with response rate (86% in patients achieving clearance of CP vs 47%, P = .02), as well as with progression-free survival at 5 years (68% vs 47%, P = .11), was documented in the most recent trial.14 Regarding the single- vs double-course regimen used by Kim and coworkers,19 a trend toward better results in the double-course regimen was stated.

In analogy to HP eradication in gastric MALT lymphoma, trials with short follow-up might have underestimated the response to antibiotics, as Ferreri and coworkers16 have emphasized the possibility of slow, respectively late, responders showing best outcome after up to 36 months following therapy. By contrast, Grünberger et al20 did not see any responses after a median observation time of 9 months (range: 7-14), and all patients underwent consecutive therapy with either chemotherapy or radiotherapy, which might have biased the findings against antibiotic therapy due to insufficient follow-up time.

Interesting results have been obtained with application of clarithromycin as used by Govi et al18 who applied a 6-month regimen in patients with relapsed or refractory extranodal MALT lymphoma. This study was based on preclinical data proposing not only antibiotic but also direct antineoplastic and immunmodulatory effects of macrolids as has been shown also in murine cancer models. Eleven patients with OAML and 2 further patients with either MALT lymphoma of the stomach or the breast, respectively, were included in the trial. However, an objective response was only achieved in patients with OAML. The ORR was 38%, respectively 45%, in OAML and seems comparable to studies using doxycycline.15-17,19 Remarkably, all patients included had been previously treated with doxycycline, but this had not resulted in lymphoma regressions. Five patients had a history of chronic infection with CP or HP, respectively, which had been successfully eradicated 10 to 40 months before entering the study. Thus, tumor regression due to elimination of bacteria may be ruled out, and the authors suggest that the response achieved was based on the direct antitumoral activity of the drug and not by antimicrobial effects.

Five trials provide clear information about observed side effects, and the toxicity of antibiotics was extremely low, as only a single case of grade 2 dizziness in a patient receiving doxycycline was reported, and 2 cases with episodic grade 1 stomatitis and nausea in the clarithromycin trial.14,16-19

In a retrospective analysis, Grünberger et al24 have assessed the potential of HP eradication to induce responses in patients with extragastric MALT lymphoma. Out of a total of 77 patients, 16 had undergone HP eradication with metronidazole and clarithromycin as initial therapy for the lymphoma, including 5 patients with OAML. All patients were found to have evidence of HP infection, but none of these patients responded to treatment, and all required alternative therapy. Ferreri and coworkers25 have assessed HP status during staging in a group of 31 OAML patients. HP positivity was documented in 10 patients (32%), and they were immediately treated with HP eradication. None of the patients receiving HP eradication responded with lymphoma regression to the eradication regimen, but 3 patients who had CP-positive lymphomas received consecutive doxycycline, which resulted in 2 CRs and 1 PR. This confirms again the nonactivity of HP-eradication therapy in OAML patients and the potential benefits of doxycycline irrespective of the persistence of HP infection.

“Other” non-GI MALT lymphomas

Although there is an accumulating body of data concerning antibiotic therapy of OAMLs, only scattered case reports of antibiotic therapy in other non-GI localizations are available. Furthermore, no prospective controlled trials or larger studies have been published so far. Apart from a retrospective analysis performed at our institution24 including 16 patients with extragastric MALT lymphomas (5 ocular adnexal, 6 parotid, 3 pulmonary, 1 mammary, and 1 colonic MALT lymphoma, respectively), an extensive search in Medline resulted in a total of only 12 case reports. In the Austrian series, however, no responses were seen in these 16 patients who underwent HP eradication for primary therapy of their lymphoma, and these patients are not further discussed.

The case reports detected in the literature have included MALT lymphomas localized in the skin; lung; parotid, salivary, and thyroid glands; bladder; and breast treated only with antibacterial therapy. For detailed information about the studies, patient’s characteristics (n = 14), and therapeutic strategies, see Table 2.

View this table:
Table 2

Antibiotic therapy in other non-GI MALT lymphomas: study and patient characteristics

Cutaneous MALT lymphoma

Chronic infection with the gram-negative spirochete B burgdorferi is a known initiator of a characteristic cutaneous B-cell infiltration termed “pseudolymphoma.”26 Because of a similar histologic appearance, a potential role as a promoter for other B-cell lymphomas of the skin has been assumed.12 In analogy with geographic incidence variations of CP positivity in OAMZL, endemic as well as nonendemic regions have been defined for this pathogen. Areas seen as endemic, such as the Scottish Highlands or Austria, have demonstrated up to 40% Borrelia infection in cutaneous marginal-zone lymphomas,12,27 whereas in a large Italian series by Ponzoni et al,28 no association was observed. In addition, a series of 60 cases of primary cutaneous marginal-zone lymphoma collected in Germany, Asia, and the United States found no evidence for Borrelia infection.29 Interestingly, a French series (nonendemic region) found Borrelia DNA in 19% of 16 cases with primary cutaneous MALT lymphoma.30

Antibiotic therapy for B burgdorferi in cutaneous MALT lymphoma (also formerly referred to as “skin-associated lymphoid tissue” lymphoma) has been described in 4 case reports31-34 comprising a total of 5 patients. Interestingly, in an additional case report, amplified DNA of B afzelii was found.35 Three of these articles have been published in pathological journals and have thus concentrated on histopathological information rather than providing detailed clinical information. In addition, 1 article could only be obtained in abstract form. This paper was still included due to the rarity of experiences and reports concerning antibacterial treatment of cutaneous MALT lymphoma.32 In the 4 reports providing complete information,31,33-35 3 patients were male and 2 were female, with the patients’ ages being between 28 and 88 years. The detailed follow-up time in months was given in 4 patients (see Table 2). Interestingly, 1 patient had a (histologically verified) history of lichen ruber planus,33 and in 2 other patients, erythematous papules and plaques had been present for more than a year.34 In all patients, a detailed histologic assessment of intralesional biopsies disclosed the presence of marginal-zone B-cell lymphoma. An attempt to culture B burgdorferi from affected skin was made in 2 studies, resulting in 2 positive results out of 3 patients; in the patient with a negative culture, a subsequent PCR for B burgdorferi DNA was positive.33,34 Serological testing for B burgdorferi was performed using enzyme-linked immunosorbent assay, although titers were only marginally elevated in 2 patients.34 Extracutaneous manifestations were ruled out by regular staging procedures in all patients. Treatment of B burgdorferi or B afzelii, as known for stage II or III Lyme disease, was administered to all patients (ie, IV application of 2 g ceftriaxone daily for 2 or 3 weeks). This resulted in an initial PR in 2 patients, who were still improving at last follow-up, and in another patient only residual infiltrations were seen in the final histologic reassessment.31,33,35 However, in the case reports of Kütting and coworkers,34 the standard ceftriaxone regimen did not result in regression of cutaneous MALT lymphoma, and patients achieved CR only after second-line therapy with cefotaxime or third-line therapy with intralesional interferon α-2a injections at a cumulative dosage of 64.5 million IU in a 3-week period. The sixth patient received antibiotic therapy stated as “specific antibiotic therapy for B burgdorferi” in the abstract and was also rated as nonresponding disease.32 In the French series described previously, 1 of the 3 detected Borrelia-associated cutaneous MALT lymphomas responded to antibiotic treatment, but no further clinical data on follow-up were available.30

In the context of antibiotic therapy in cutaneous MALT lymphoma, it has to be mentioned that a series published in 1991 has reported on 4 patients with cutaneous lymphomas given anitibiotic therapy.36 Although one may speculate that these might indeed have been MALT lymphomas, a definite diagnosis according to accepted pathohistologic criteria cannot be extracted from this paper.

Pulmonary MALT lymphoma

As the lung is in almost continuous contact with the environment and potential pathogenic substances, one might assume that development of pulmonary lymphoma could be driven by bacterial or other infectious antigens. In a large analysis of 69 paraffin-embedded tissue blocks of primary pulmonary MALT lymphomas, the frequency of Chlamydia infection (C pneumoniae, C trachomatis, and C psittaci) as well as the presence of Mycoplasma pneumoniae was assessed in pulmonary MALT lymphoma. However, the rate of Chlamydia infection was judged to be below 20%, and no evidence for mycoplasms was found, suggesting that these pathogens are rarely associated with pulmonary MALT lymphoma.37 In contrast to this, another study assessed a total of 5 patients with pulmonary MALT lymphoma who all tested positive for CP, whereas no evidence for C pneumoniae or trachomatis was detected.38 Achromobacter xylodosaxidans is another potential candidate pathogen recently demonstrated in patients with pulmonary MALT lymphoma.39

According to these data, the exact role of various pathogens in the lymphomagenesis of bronchus-associated lymphoid tissue lymphoma remains somewhat speculative, and data on antibiotic therapy in patients with pulmonary MALT lymphoma are relatively scarce as no large consistent series have been published so far.

Activity of antibiotic therapy has recently been reported by Ishimatsu and coworkers40 who presented 2 cases of bronchus-associated lymphoid tissue lymphoma. In 1 case, a 70-year-old woman treated with combined chemotherapy followed by radiotherapy achieved only a small reduction of the tumor by these measures. In addition, consecutive long-term therapy with clarithromycin at a dose of 200 mg per day was given for a coexisting chronic sinobronchial syndrome, which, according to the authors, resulted in regression of the lymphoma. Another patient with Sjögren syndrome and pulmonary MALT lymphoma showed regression immediately after HP-eradication therapy and improved to a CR while receiving long-term clarithromycin application at the same dosage.

According to our knowledge, these 2 patients are the only successful reports about antibiotics in pulmonary MALT lymphoma. Although an effect of antibiotics on the lymphoma is indeed possible in the second patient, one has to be cautious in interpreting the results of the first patient who had been given antibiotics after combined chemo-radiotherapy. In fact, it has been shown that MALT lymphomas of the lung might show objective regression following therapy only after prolonged radiologic follow-up, and this disease also might be prone to a spontaneous wax-and-wane phenomenon41 making the interpretation of the authors difficult to verify.

Incidental diagnosis of pulmonary MALT lymphoma in a postsurgical histologic specimen in a patient with Mycobacterium avium was published in 2004. In this patient, the lymphoma showed no evident recurrence after surgery, although positive flow cytometry for bone marrow involvement and the authors have suggested this to be related to the long-term antibiotic treatment of mycobacterial infection and that suppression of this chronic condition might have been crucial for the long-term remission.42 Again, this is difficult to verify, as surgery in limited stages of pulmonary MALT lymphoma has repeatedly been reported as effective therapy resulting in long-term remission by various authors, even in the absence of subsequent antibiotic therapy. In addition, no association between mycobacteria and MALT lymphoma has been reported to date, suggesting that the 2 conditions might in fact not have been related in this patient.

MALT lymphoma of the thyroid gland and parotid gland

MALT lymphomas of both the parotid gland and the thyroid gland often appear in a background of chronic autoimmune disease (eg, Hashimoto thyroiditis or Sjögren syndrome), and the presence of an infectious trigger has therefore so far not been a common assumption. Thus, only 3 reports of single cases dealing with antibiotics in those lymphomas were available.43-45 Two patients were female, 1 was male, and their ages ranged between 60 and 69 years.

One patient had recurrent parotid MALT lymphoma presenting with stage I disease, another one MALT lymphoma involving both submandibular glands with additional lesions in the parotid, while the patient with thyroid MALT also had involvement of local lymph nodes (ie, stage II). Concerning comorbidity, 2 patients had a known history of Sjögren syndrome; 1 presented with Hashimoto disease, hepatitis C virus infection, and concomitant tubular adenocarcinoma of the stomach resulting in subtotal gastrectomy before therapy of MALT lymphoma. For staging, all patients underwent a gastroscopy to rule out gastric involvement, and histologic assessment of gastric biopsies for HP was positive in all 3 cases. All 3 patients received HP-eradication therapy resulting in CR of the lymphoma in all 3 cases. The combinations of substances used were amoxicillin/clarithromycin plus a proton pump inhibitor in 2 patients and doxycycline/metronidazole/bismuth plus a proton pump inhibitor in another case (for exact dosing, see Table 2). In view of the data published so far, one might potentially attribute the antilymphoma effect of the combinations including clarithromycin to direct antineoplastic rather than antibacterial effects. The time to best response was 6 months in 1 patient with parotid MALT lymphoma and 3 weeks in the other, whereas no information was provided in the patient with salivary gland lymphoma. After a follow-up time of 5, 22, and 48 months, none of the patients showed a relapse of the disease.

MALT lymphoma of the bladder

Primary MALT lymphomas of the urinary bladder are exceedingly rare. Interestingly, we could still find 3 case reports on the topic of antibiotic therapy for primary management of MALT lymphoma of the bladder.46-48 In 1 case report, only the abstract was in English, whereas the original work was in Japanese.46 The 3 patients reported in the literature were 59 to 78 years old, and the reported follow-up time ranged between 19 and 36 months. Two patients presented with macrohematuria, whereas the other one had a history of recurrent urinary tract infections with Escherichia coli bacteria. In the 2 patients treated with HP-eradication therapy (exact dosing and substances not reported by the authors), HP was identified either by gastroscopy or serological assessment, and both patients subsequently developed a CR of their MALT lymphoma in the bladder. The third patient, who suffered from recurring E coli infections, received a combination of antibiotics for complicated urinary tract infections (trimethoprim, nitrofurantoin, and cephradine for long-term treatment at an unspecified dosage), and he also achieved a CR of the lymphoma.

MALT lymphoma of the breast

In the prospective trial on oral clarithromycin as described earlier in this review, Govi et al18 have included not only OAMLs (n = 11), but also 1 patient each with gastric and mammary MALT lymphoma. The patient with MALT lymphoma of the breast was also treated with clarithromycin administered at a dose of 500 mg twice a day for 6 months. This patient had a long history of former therapies including combined chemotherapy according to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisolone) as first line, followed by radiotherapy twice, chlorambucil monotherapy, and doxycycline (dosage unknown). In this patient, application of clarithromycin did not influence lymphoma growth, and the patient progressed during antibiotic therapy with the macrolide.

Discussion

According to the data extracted from the literature, MALT lymphomas of various localizations have been treated with antibiotics, resulting in scattered case reports in most cases. The most solid data published exist for patients with OAMLs, where preclinical data have also been generated to support the use of antibiotics targeting CP as a first-line treatment.

Apart from the fact that CP has not only been demonstrated in lymphoma tissue, but also isolated from conjunctival swabs of such patients, the analogy between gastric MALT lymphoma/HP infection and OAML/CP is also underscored by recent data on the immunoglobulin repertoire in OAML.49 In this evaluation, it was shown that lymphoma cells express a distinct repertoire of immunoglobulins resembling autoantibodies. In keeping with data from gastric MALT lymphoma associated with HP, the pathogens do not directly stimulate the malignant B cells, but rather generate an inflammatory milieu, which presents autoantigens and thus drives expansion of malignant cells. In this environment, a preferential selection of IGHV genes, especially of the IGHV3 subgroup, has been reported in this analysis. In HP-associated gastric MALT lymphoma, however, a “point of no return” (ie, independence from the pathogens in lymphoma growth and maintenance) has been shown, which is marked by t(11;18)(q21;q21) in the majority of cases. According to the current knowledge, no such hallmark has been defined in OAML so far.7

To date, it has been reported that a total of 131 patients have undergone antibiotic therapy consisting mostly of 100 mg doxycycline twice daily for 21 days. Although the benefit from antibiotic therapy does not appear as pronounced as in gastric MALT lymphoma, these data clearly suggest a significant activity of antibiotics in OAML. According to the published results, activity was better in 2 of 3 studies in patients testing positive for CP, resulting in a response rate of 66% and 64% in the positive cohort, whereas it was 38% and 50%, respectively, in the negative patients.14,16 These data nevertheless suggest that testing for CP might not be necessary in clinical practice, because patients with a negative CP status might also respond to therapy with doxycycline and testing for CP has not been uniformly standardized so far. In addition, the side effects of this therapy were negligible, and doxycycline has been suggested as a reasonable first-line therapy for patients with OAML.14 Given the indolent natural course of the disease, this approach appears to be especially attractive because it might spare a significant cohort of patients the potential side effects of systemic therapy or radiation.

The efficacy of doxycycline, however, has been debated in the past because various studies have not shown lymphoma regression in patients given the tetracycline either in an empirical way without prior testing for CP or in a more controlled setting.20-22 Various explanations for the discrepancy have been offered, including pronounced geographic variations in the incidence of CP infection.50 One might question the uncritical use of antibiotics targeting CP in areas with a virtually absent infection rate. In the case of the study from our own institution, which did not find an objective response to therapy in 11 patients with OAML,20 a note of caution has to be added, even though a recent series has found evidence for CP infection in 15% of OAML samples.38 One of the major caveats in interpreting these findings is the fact that the follow-up might simply have been too short for demonstration of remissions, as Ferreri and coworkers14 have repeatedly emphasized the potential for delayed response to therapy reflected by the median follow-up of 37 months in the most recent series. Based on the data presented so far, it appears reasonable to treat patients with OAML upfront with doxycycline, provided that patients are closely monitored in order to guarantee salvage therapy in the case of nonresponse or progression. Whether doxycycline is indeed the antibiotic of choice nevertheless remains to be seen given recent data reported by Govi et al18 on the use of high-dose clarithromycin in MALT lymphoma. Especially intriguing is the finding that patients relapsing from or refractory to therapy with doxycycline have also responded to clarithromycin, which appears to be highly concentrated in the conjunctival fluid of patients.18 Whether this finding or an alternative, the immunomodulatory property of the drugs that is responsible for these results remains to be determined.

Although the pioneering work of Ferreri and collaborators has firmly established OAML as potentially sensitive to antibiotic therapy, the data in other non-GI MALT lymphomas are less clear. Recently, preclinical data have suggested that CP might also be of interest in other non-GI MALT lymphomas. By using PCR amplification and direct sequencing in MALT lymphoma samples, Aigeslreiter et al38 have detected evidence for CP DNA in 5 of 5 (100%) lung, 3 of 10 (30%) thyroid gland, 2 of 15 (15%) salivary gland, 2 of 13 (15%) OAML, and 1 of 4 (25%) cutaneous MALT lymphomas. Especially the latter finding is intriguing because the potential association between cutaneous MALT lymphoma and Borrelia infection has not resulted in convincing clinical results. Although the numbers in some subgroups are small, these data warrant further assessment in order to form the rational basis for potential clinical trials on anti-CP therapies in MALT lymphomas of these specific localizations. In addition, these results are in conflict with results published by Chanudet and coworkers,37 who have reported virtual absence of CP in patients with pulmonary MALT lymphoma and thus need further confirmation.

In addition, a recent large-scale study by the International Extranodal Lymphoma Study Group identified a high rate of infection with A xylodosoxidans in pulmonary MALT lymphoma but has only been published in abstract form so far.39 A small pilot study applying broad-spectrum antibacterial PCR in samples from patients with hepatic MALT lymphoma has not identified evidence of bacterial infection.51

To date, no prospective studies have been performed, and only small retrospective series or case reports applying different antibiotics have been published in various non-GI MALT lymphomas, including lung, bladder, thyroid and salivary glands, and breast. In view of this, one might suspect some publication bias, as negative results (especially if only single individuals or small numbers have been treated) are unlikely to have been reported. Furthermore, the majority of patients received HP eradication including a macrolide antibiotic, and one therefore might speculate that direct antineoplastic effects of clarithromycin might have played a profound role in the antilymphoma activity observed.

As a consequence, antibiotic therapy as a frontline therapy remains experimental for the time being with the exception of OAML (and, of course, gastric MALT lymphoma). In areas with a low rate of CP infection, however, this approach might be either limited to asymptomatic patients in view of the indolent nature of MALT lymphoma or based on CP testing in patients with lymphoma threatening to impair the visual apparatus, if doxycycline is chosen. In addition, future studies with longer follow-up are necessary to establish the long-term activity of antibiotic treatment. As opposed to gastric MALT lymphoma, where long-term CRs, which may probably translate into cure of such patients, have been firmly established, the data on antibiotics in nongastric MALT lmyphomas including OAML are not yet mature enough to draw definite long-term conclusions. Studies on antibiotics are further hampered by the fact that potential infectious targets have yet to be identified in the large majority of localizations. According to the current knowledge, only 2 pathogens (ie, HP in gastric MALT lymphoma and CP in OAML) have been tested sufficiently to allow a clear definition of the causative role of these 2 agents. Much weaker data exist for association between Borrelia and lymphomas, whereas other agents remain speculative at best for the time being. Prospective studies on the use of antibiotics based on preclinical findings are warranted in order to define a rational approach to the use of antibiotics in patients with MALT lymphomas of various localizations.

Authorship

Contribution: B.K. and M.R. designed and drafted the manuscript, performed the search and review of the literature, and wrote and approved the final manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Markus Raderer, Division of Onoclogy, Department of Internal Medicine I, Waehringer Guertel 18–20, A-1090 Vienna, Austria; e-mail: markus.raderer{at}meduniwien.ac.at.

  • Submitted February 25, 2013.
  • Accepted June 4, 2013.

References

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