Treatment of mucosa associated lymphoid tissue lymphoma with a long‐term once‐weekly regimen of oral azithromycin: Results from the phase II MALT—A trial

Abstract

The macrolide clarithromycin has been reported as active for therapy of mucosa associated lymphoid tissue (MALT) lymphoma. Pharmacokinetic properties, however, require continuous daily intake over a prolonged period of time. As the macrolide azithromycin is characterized by a long half-life as well as potential antineoplastic activity in vitro, we have performed a phase II trial of long-term once-weekly oral azithromycin for treatment of MALT lymphoma. In a 2-stage-design, 16 patients (10 f/6 m) with histologically verified and measurable MALT lymphoma were included in the first phase of the trial, which could be expanded to a maximum of 46 patients depending on remissions in the first phase. Patients were given oral azithromycin 1500 mg once-weekly 4 times a month, and restaging was performed after 3 and 6 months. Two patients had gastric and 14 extragastric MALT lymphoma; 12/16 patients were treatment-naive and received azithromycin as first line treatment. Tolerance of this regimen was excellent, and 14/16 patients received 6 months of treatment as scheduled, while 1 patient each discontinued after 4 (progressive disease) and 1 cycle (personal reasons), respectively. The most commonly observed side effects were mild nausea (n = 8) and diarrhea (n = 4). Efficacy, however, was low as only 4/16 patients (25%) responded, with 2 complete and 2 partial remissions, 9 patients (56%) had stable disease, and 3 patients 19%) were rated as progressive disease. As the predefined activity of more than 7/16 patients responding was not reached, the study was stopped after 16 patients. Although long-term once-weekly oral azithromycin showed some antilymphoma activity, the response rate was below the predefined threshold of interest. However, based on our data, one cannot rule out suboptimal dosing in our study; attempts to study azithromycin at a different mode of application might be warranted in the future.

Immunomodulatory treatment for mucosa‐associated lymphoid tissue lymphoma (MALT lymphoma)

“…While response rates (47% overall) and PFS (3‐year PFS 52%, 95% CI 39‐65), were in line with the previously reported data with no relevant difference for PFS between the regimens, nausea was slightly more common in patients with the high dose schedule, suggesting that 2 × 500 mg daily might be the preferable regimen. Finally, also the macrolide azithromycin was evaluated in a planned two‐step phase II trial (MALT‐A trial, oral azithromycin 1500 mg weekly), which was, however, closed after the first stage of 16 patients due to an ORR of only 25% scoring below the preset efficacy threshold 12 …”

“…However, given the high dependency of MALT lymphoma cells on the tumor microenvironment, this lymphoma entity appears highly suitable for potential immunomodulatory treatment beyond H. pylori eradication and several strategies have been assessed in the last years including IMiDs thalidomide and lenalidomide, and macrolide antibiotics clarithromycin and azithromycin 9‐14 . The aim of the present review is to discuss rationales for immunomodulatory therapies in MALT lymphoma and to present the status quo on immunomodulatory, chemotherapy‐free treatment strategies for these patients.…”

Biological Functions and Molecular Mechanisms of Antibiotic Tigecycline in the Treatment of Cancers

“…Currently, many kinds of antibiotics including anthracyclines [7,8] (e.g., daunorubicin, doxorubicin, aclarubicin, epirubicin, idarubicin, valrubicin, and mitoxantrone), bleomycins (e.g., bleomycin A2) [9], mitomycins (e.g., mitomycin C) [10], dactinomycin [11], and macrolides antibiotics (e.g., azithromycin [12]) are being used as chemotherapeutical drugs to treat various malignant tumors. However, these antibiotics also exert toxicity for normal tissues.…”

Experience with clarithromycin as antineoplastic therapy for extranodal marginal zone B‐cell lymphoma of the mucosa associated lymphoid tissue (MALT‐lymphoma) outside of clinical trials: Real‐world data from the University of Vienna

“…2,3 Interestingly, the macrolide antibiotics clarithromycin and azithromycin have been tested as antineoplastic agent in patients with MALT-lymphoma independently from antibacterial properties. [4][5][6][7] Various modes of immunomodulatory and direct antiproliferative activity have been defined in vitro, 8 including increased activity of NK-cells, accumulation of cytotoxic CD8+ and interferon-gamma producing T-cells, interaction with the TNF-and the VEGF pathway and decrease of IL-6 and IL-8. Macrolides have also been shown to directly inhibit the mTOR pathway.…”