THE IELSG39 TRIAL: EFFICACY OF FIRST‐LINE CHLAMYDIA PSITTACI ERADICATION WITH A SIX‐MONTH REGIMEN OF DOXYCYCLINE IN PATIENTS WITH STAGE‐I MALT LYMPHOMA OF THE OCULAR ADNEXAE (2023)

Introduction: In geographical areas where ocular adnexal MALT lymphoma (OAML) is frequently associated with Chlamydia psittaci (Cp) infection, monotherapy with a 3-week regimen of doxycycline has been associated with an overall response rate (ORR) of 65% and a 2-year progression-free survival (PFS) of 60% (IELSG27 trial; Ferreri, et al. JCO 2012). However, successful Cp eradication has been achieved only in half of patients (pts), which strongly conditioned therapeutic results. This could be explained by the well-known prolonged persistence of Cp within macrophages under the form of elementary bodies, a metabolically inert condition, refractory to antibiotics. Accordingly, a prolonged exposure to effective antibiotics could result in a higher bacterial eradication rate and better lymphoma control. This hypothesis was tested in a multicentre phase II trial (IELSG39), where OAML pts were treated with a six-month regimen of doxycycline. Herein, we report primary endpoint results. Methods: HIV-negative adults with untreated stage-IEA OAML were enrolled and treated with doxycycline 100 mg twice daily for 4 weeks followed by 4 weeks rest, repeated for 3 times. Cp DNA was assessed by real-time PCR on tumor tissue at diagnosis and monitored on conjunctival swabs and PBMC every 6 months. Tumor response (orbit MRI & ophthalmologist exam) was assessed every 6 months. The primary endpoint was the 2-year PFS; the primary objective was to improve the 2-yr PFS achieved in the IELSG27 trial (60%; P0) to 75% (P1). To detect such a difference, 30 pts with Cp-positive OAML were required (one-sided test; α 5%; β 80%); whenever ≥17 pts with Cp-pos OAMZL were progression-free at 2 years, the experimental therapy would be considered effective. Results: 44 pts (median age 58 yo, range 31–85; male:female ratio 0.63) were enrolled between March 2013 and May 2016. Cp DNA was detected in 21 (64%) of 33 assessed pts; PCR analysis is ongoing in 11. Doxycycline was well tolerated; all pts completed the treatment in the planned time. The best objective response was complete in 14 pts and partial in 14, with an ORR of 64% (95% CI = 50–78). The median time to the best response was 9 months (range 3–34). The primary endpoint was met: 32 pts remain relapse-free at 2 years: 18 had a Cp-pos OAML, 7 were Cp-neg, and PCR results are pending in 7. At a median follow-up of 83 months (range 10–115), 23 pts remain relapse-free, with a 2- and 5-yr PFS of 75% (95% CI 74–77) and 55% (95% CI 49–59), respectively. Pts with Cp-pos OAML had a 2- and 5-yr PFS of 90% (95% CI 90–91) and 65% (95% CI 61–69). All pts are alive. Full data on bacterial eradication rate and monitoring will be presented at the congress. Conclusions: This six-month regimen of doxycycline was safe and effective in pts with stage-I OAML. This treatment achieved the predetermined efficacy threshold and compares favourably with the 3-week regimen used in the IELSG27 trial, suggesting that a prolonged exposure to antibiotics improves lymphoma control. Keywords: extranodal non-Hodgkin lymphoma, indolent non-Hodgkin lymphoma, Therapeutics and Clinical Trials in Lymphoma - Other No conflicts of interests pertinent to the abstract.