A Six-Month Regimen of Oral Clarithromycin Is a Feasible and Active Therapy for Patients with Relapsed/Refractory Marginal Zone B-Cell Lymphoma of MALT-Type

Background: The antibiotic clarithromycin displays immunomodulatory properties, partially mediated by the suppression of IL-6 and other inflammatory cytokines. This macrolide can directly induce TNF-mediated apoptosis in mouse lymphoma cells, with a DNA fragmentation degree similar to that seen in cells treated with chemotherapeutic agents. In recent trials on multiple myeloma and Waldenstrom’s macroglobulinemia, the combination of clarithromycin with other immunomodulatory agents exhibited high tumour regression rates, and some case reports suggested an antineoplastic effect of clarithromycin in marginal zone B-cell lymphoma of MALT-type (EMZL) of the colon and the lung.

Method: This is a phase II trial aimed to assess tolerability and activity of a 6-month regimen of oral clarithromycin in patients (pts) with relapsed/refractory EMZL. Clarithromycin (500 mg) was given orally twice daily for 6 months to 14 HIV-negative pts (age ³18 ys; ECOG-PS ≤3) with relapsed/refractory EMZL and at least one measurable/parametrable lesion. Pre-registration assessments included physical examination, hemogram and biochemical profile, HIV, HBV and HCV serology, gastroscopy, gastric Helicobacter pylori (Hp) infection assessment (3 methods: histology, breath test, serology, and/or cagA in faeces), Chlamydia psittaci (Cp) infection assessment (PCR on tissue and PBMC, only in pts with ocular adnexal MALT lymphoma), total body CT scan, and bone marrow biopsy. Tolerability (physical examination and blood exams) was assessed every 8 weeks and objective response was assessed every 3 months.

Results: Median age of eligible pts was 59 ys. (range 36–81; 7 females). Clarithromycin was the salvage therapy at first relapse in 8 pts, and the 3^rd–6^th line of treatment in the others. All pts had local disease at the time of treatment, two pts had also systemic dissemination. Extranodal sites were stomach (n=2), conjunctiva (n=4), orbit (n=7), and breast (n=1). No pt had increased LDH serum levels; only one pt had B symptoms. Chronic infections were caused by HCV in 2 pts, Hp in 2 and Cp in 5. Hp and Cp infections were successfully eradicated with specific antibiotics as part of upfront treatment, that is with a median time from bacterial eradication to clarithomycin treatment of 14 (7–40) months. This excludes that a potential clarithomycin antitumor activity could be due to antimicrobial effect.

The treatment was completed in 13 pts and is ongoing in the remaining one. Two pts achieved a complete remission (22+, 24+) and 2 pts achieved a partial response (11+, 14), with an ORR of 31%; 1 pt had a minimal response (11+), 5 pts had stable disease (15+, 15+, 16+, 22, 24), 3 pts experienced disease progression (10, 10, 16). The median time to the best response was 10 months. Three of the major responses were observed among the 4 pts with conjunctival lymphoma, treatment is ongoing in the remaining one. The number of previous lines of treatment did not influence response. Tolerability was excellent-good in all pts but two (episodic nausea). No biochemical abnormalities were detected after 6 months of treatment. After a median follow-up of 15 months, 6 pts experienced disease progression, with a median time to progression of 11+ months. The pt with B symptoms experienced a high-grade transformation and was not responsive to clarithromycin. All pts but one (HCV-related cirrhosis) are alive with a median OS of 42 months.

Conclusions: This 6-month regimen of oral clarithromycin seems to be safe and active in EMZL, mostly in pts with conjunctival MALT lymphoma. Response to clarithromycin does not seem to be mediated by eradication of common MALT-related bacterial infections. Clarithromycin deserves to be further investigated in EMZL.