Chlamydia Psittaci–Eradicating Antibiotic Therapy Andrés J.M
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VOLUME 23 ⅐ NUMBER 22 ⅐ AUGUST 1 2005 JOURNAL OF CLINICAL ONCOLOGY ORIGINAL REPORT Regression of Ocular Adnexal Lymphoma After Chlamydia Psittaci–Eradicating Antibiotic Therapy Andrés J.M. Ferreri, Maurilio Ponzoni, Massimo Guidoboni, Carlo De Conciliis, Antonio Giordano Resti, Benedetta Mazzi, Antonia Anna Lettini, Judit Demeter, Stefania Dell’Oro, Claudio Doglioni, Eugenio Villa, Mauro Boiocchi, and Riccardo Dolcetti From the Departments of Radiochemo- therapy, Pathology, Ophthalmology, and ABSTRACT Hematology, San Raffaele H Scientific Institute, Milan; Immunovirology and Purpose Biotherapy Unit, and Division of Experi- Some infectious agents contributing to lymphomagenesis have been considered targets mental Oncology 1, Department of for new therapeutic strategies. Chlamydia psittaci DNA has been detected in 80% of Pre-Clinical and Epidemiological ocular adnexal lymphomas. The present pilot study was carried out to assess whether C Research, Centro di Riferimento Onco- psittaci–eradicating antibiotic therapy is associated with tumor regression in ocular logico, Istituto di Ricovero e Cura a Carattere Scientifico National Cancer adnexal lymphomas. Institute, Aviano, Italy; and First Patients and Methods Department of Medicine, Semmelweis Nine patients with C psittaci–positive marginal-zone B-cell lymphoma of the ocular adnexa at University, Budapest, Hungary. diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence Submitted July 14, 2004; accepted of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and November 12, 2004. after treatment in seven patients. Objective lymphoma regression was assessed 1, 3, and 6 Supported in part by a grant from months after therapy conclusion and every 6 months during follow-up. the Italian Association for Cancer Research (R.D.). Results All patients completed antibiotic therapy with excellent tolerability. At 1 month from Presented in part as an oral presenta- tion at the Presidential Symposium of doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all four the 9th Annual Meeting of the Euro- positive patients. Objective response was complete in two patients, partial response pean Hematology Association, Geneva, (Ͼ 50%) was observed in two patients, and minimal response (Ͻ 50%) was observed in Switzerland, June 12, 2004; and three patients. Duration of response in the seven responders was 12ϩ,29ϩ,31ϩ,8ϩ,7ϩ, published in abstract form as: Ferreri 2ϩ, and 1ϩ months, respectively. AJM, Guidoboni M, Ponzoni M, et al: The high prevalence of Chlamydia Conclusion psittaci infection in ocular adnexal C psittaci–eradicating antibiotic therapy with doxycycline is followed by objective response lymphomas (OAL) provides the ratio- in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A nale for the use of antibiotics as a confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and potential therapeutic strategy in these well-tolerated therapy could replace other more aggressive strategies as first-line treatment patients. Hematol J 5:S111, 2004 (suppl 2, abstr 321). against ocular adnexal lymphomas. A.J.M.F., M.P., and M.G. contributed equally to this work. J Clin Oncol 23:5067-5073. © 2005 by American Society of Clinical Oncology Authors’ disclosures of potential con- flicts of interest are found at the end of mune responses able to promote and sustain this article. INTRODUCTION clonal B-cell expansion.4 These findings Address reprint requests to Andrés J.M. Ferreri, MD, Department of Radiochemo- A pathogenic link between some infectious provided the rationale for new therapeutic therapy, San Raffaele H Scientific Insti- agents, mainly bacteria and viruses, and modalities aimed at eliminating the source tute, Via Olgettina 60, 20132 Milan, Italy; e-mail: [email protected]. non-Hodgkin’s lymphomas has been clearly of chronic antigenic stimulation using spe- 1-3 5 © 2005 by American Society of Clinical established. In particular, in marginal cific antimicrobial drugs. This approach Oncology zone lymphomas of mucosa-associated was successfully associated with objective 0732-183X/05/2322-5067/$20.00 lymphoid tissue (MALT) type, the chronic tumor regression in a variable proportion of 5 DOI: 10.1200/JCO.2005.07.083 antigenic stimulation provided by these different lymphoma entities. The largest agents has been suggested to elicit host im- experience in this context is represented by 5067 Downloaded from ascopubs.org by University of Queensland on February 9, 2017 from 130.102.082.116 Copyright © 2017 American Society of Clinical Oncology. All rights reserved. Ferreri et al Helicobacter pylori eradication in patients with stage I biopsy. Stage of disease was defined according to the Ann Arbor 19 marginal-zone lymphomas of MALT type of the stomach, staging system. which is followed by objective tumor response in 70% to Trial Design 5-7 80% of patients. Moreover, some cases of tumor regres- Enrolled patients were treated with doxycycline 100 mg, bid sion after antimicrobial therapy have been reported in orally, for 3 weeks; they did not receive any concomitant antiblas- Borrelia burgdorferi–associated cutaneous MALT lympho- tic, antibiotic, or corticosteroid therapy in the period from the mas,8,9 hepatitis C virus–associated splenic lymphomas start of antibiotic therapy to the maximum response assessment. with villous lymphocytes,10 and, more recently, Campy- Doxycycline (100-mg tablets, Bassado; Pharmacia, Rome, Italy) is a tetracycline derivative with uses similar to those of tetracycline. It lobacter jejuni–associated immunoproliferative small intes- 11 was preferred to other tetracyclines because of its fairly reliable tinal disease. absorption from the gastrointestinal tract, its long half-life (12 to Chlamydia psittaci DNA has been recently detected in 24 hours), its wide distribution in body tissues and fluids, and the tumor biopsies from 80% of patients with ocular adnexal fact that it can be administered to patients with renal insufficiency. lymphomas (ie, conjunctiva, lachrymal gland, and orbital The primary end points of this study were eradicating activity soft tissues) and in the peripheral-blood mononuclear cells and objective lymphoma response after a 3-week doxycycline reg- (PBMCs) of 40% of these patients.12 C psittaci is the etio- imen. The presence of C psittaci DNA in patients’ PBMC was the parameter for eradicating activity assessment. PBMC analysis was logic agent of psittacosis, a human infection caused by 13-15 performed before the start of antibiotic therapy in seven patients exposure to infected birds, cats, and other pets. This (in three patients treated at diagnosis and in four patients treated at microorganism is an obligate intracellular bacterium grow- relapse); in relapsed patients, the period between the diagnosis of ing in eukariotic cells and has a tendency to cause persistent lymphoma and PBMC sampling was longer than 5 years. C psittaci infections.16 In particular, C psittaci–related follicular con- eradication was monitored by assessing patients’ PBMC obtained at 1 junctivitis16,17 may favor the development of ocular adnexal month after completion of antibiotic therapy and at 1 year of follow- lymphomas through a chronic antigenic stimulation.12 up; all molecular analyses were performed by blinded investigators. All nine patients were assessable for antilymphoma activity. Similar to what was adopted for gastric lymphomas, for Objective response was assessed 1, 3, and 6 months after conclu- which H pylori eradication is a well-established therapeutic sion of antibiotic therapy and every 6 months during follow-up 7 strategy, eradication of C psittaci infection with a specific using contrasted computed tomography scan or magnetic reso- antibiotic therapy may constitute an attractive, novel ther- nance imaging of the orbits and any other radiologic procedure apeutic approach for ocular adnexal lymphomas. In this that was positive before antibiotic therapy. Objective response was 20 article, we report the results, in terms of C psittaci eradica- defined according to the WHO criteria, and duration of re- tion rate and objective lymphoma response, of a pilot study sponse was calculated from therapy conclusion to date of lym- phoma progression. This pilot study conformed to the tenets of carried out in nine patients with C psittaci–positive, the Declaration of Helsinki and was approved by the institutional marginal-zone, B-cell lymphoma of MALT type of the oc- review boards of the participating institutions; the nine enrolled ular adnexa treated with the antibiotic doxycycline. patients provided signed informed consent. PATIENTS AND METHODS RESULTS Study Group Study Group Nine immunocompetent adults with C psittaci–associated, marginal-zone, B-cell lymphoma of MALT type of the ocular The clinical characteristics of the nine patients entered adnexa (lachrymal gland, conjunctiva, and orbital soft tissue) and onto this study are listed in Table 1. Sites of disease at measurable disease at diagnosis (n ϭ 4) or relapse (n ϭ 5) were diagnosis and relapse and previous therapeutic manage- included in this pilot experience. Preliminary therapeutic data of ment of the nine patients are listed in Table 2. Experimental patients 1 through 4 have been previously included in our article treatment with doxycycline was indicated at lymphoma describing the association between C psittaci and ocular adnexal diagnosis in four patients (patients