In this study, based on the long-term follow-up, we investigated the feasibility of doxycycline therapy as a first-line treatment for patients with MALT lymphoma confined to the conjunctiva. Among 67 patients who received oral doxycycline as an initial treatment, no mortality was observed during the mean follow-up duration of 109.7 months. CR and PR were 49.2% after the initial one or two cycles of doxycycline treatment. Approximately two-thirds (64.2%) of patients received doxycycline treatment alone, and most of the remaining patients were successfully salvaged by other treatments. The median PFS was 168 months (range, 1-179 months), and the 3-, 5- and 10-year PFS rates were 70%, 65% and 62%, respectively. T1c stage was significantly associated with an increased risk of progression. There were no serious complications associated with the oral administration of doxycycline.
According to the results of a previous study [7], we only enrolled patients with stage T1N0M0 OAML (conjunctival MALT lymphoma) in this study. The mean age at diagnosis was 43.0 years, 47 of 67 (70.1%) patients were female, and 32 of 67 (47.8%) patients had bilateral disease. These findings correspond well to the characteristics (young age onset, female predilection, and higher rate of bilateral cases) of conjunctival MALT lymphoma compared with other OAMLs in Korean patients described elsewhere [14–17].
Although the local control rate and 10-year overall survival rates of OAML with EBRT exceed 95% and 84%, respectively, chronic complications, including cataracts and dry eye, are common and even serious vision-threatening complications, such as retinopathy or corneal perforation, can occur [18]. In line with this, oral doxycycline targeting Cp, similar to the association of gastrointestinal MALT lymphoma with H. pylori infection [19, 20], would be a safer and better tolerated alternative therapeutic option for indolent conjunctival lymphoma [6–8, 21]. Chronic antigenic stimulation has been speculated to be a pivotal process associated with the pathogenesis of conjunctival MALT lymphoma, and microorganisms, including Cp, have been identified as causative factors [4, 5, 18]. Cp infection is known to be involved in the pathogenesis of OAML by inducing lymphoid proliferation and causing chromosomal aberration [22–24]. Primary treatment with oral doxycycline in patients with ocular adnexal MALT lymphoma has shown an acceptable 5-year PFS rate of 58% on average without compromising salvage treatment in two of the largest previous studies [7, 8]. Moreover, PFS in patients with T1N0M0 stage disease was significantly better than in patients with more advanced stages [7], and Cp eradication was associated with an improved response rate and 5-year PFS [8]. Meanwhile, the prevalence of Cp infection in patients with OAML varies greatly by geographic area, with high rates in Italy (87%), Korea (79%), and Austria (54%) but virtually absent in Japan, China, and some regions of the United States [24–27]. Therefore, it is rational that resolving Cp infection using doxycycline is actively considered a first-line therapy for MALT lymphoma confined to the conjunctiva in countries with a high prevalence of Cp infection, such as Korea and Italy, or that Cp DNA was confirmed in the lymphomatous tissue or conjunctival swab.
In this study, the clinical outcome of doxycycline as a first-line treatment showed complete tumor regression in 25 patients and partial tumor regression in 8 patients, with an overall initial response rate of 49.2%, which was very similar to that of a previous report from the same institution [7]. The median PFS in all the patients was 168 months, and the 5- and 10-year PFS rates were 65% and 62%, respectively. The 5-year PFS was slightly higher than that of previous studies [7, 8], which is thought to be because we included only patients with T1N0M0 stage disease. There were no serious adverse events associated with doxycycline therapy, and most patients were successfully salvaged by the current best treatment modalities, including EBRT and chemotherapy, after recurrence or progression from CR and PR or doxycycline failure. Interestingly, some patients progressed after 5 years, but no further progression was observed after 6 years regardless of treatment. Our results solidify the suggestion of doxycycline as a first-line therapy for patients with conjunctival MALT lymphoma without compromising salvage treatment after progression or doxycycline failure.
Regarding clinical risk factors for PFS, the multivariate Cox proportional hazards regression analysis revealed that T1c stage was an independent predictor for poorer PFS compared with T1a/b stage. This is a notable finding from this study, which implies that a first-line treatment modality would be considered separately according to T1a/b or T1c stage despite the same T1N0M0 tumors. As in a previous report, sex, laterality, serum LDH level, lymphocytosis and neutrophilia were not significantly associated with PFS [7]. Our results provided another new insight that 3 or more administrations of doxycycline had no additional gain for patients who required more than 2 cycles of doxycycline treatment. Therefore, it is recommended to use doxycycline for a maximum of two times only as an initial treatment and to consider other treatment for cases of recurrence after CR, a regrowing mass after PR, or doxycycline-resistant SD or PD cases.
Based on current evidence and the results of the present study, we cautiously suggest treatment for conjunctival MALT lymphoma, as shown in Fig. 3B. Briefly, first-line doxycycline therapy can be actively considered for T1aN0M0 or T1bN0M0 stage disease, especially when the patients are from countries with a high prevalence of Cp infection or Cp DNA is positive in the excised specimen or conjunctival swab. The patients should be closely followed up according to the program schedule unless recurrence after CR or progression after PR is evident.
This study has some limitations. First, Cp DNA was not evaluated from all the excised tissues or conjunctival swabs. Although it has been documented that the Cp infection rate in Korea is as high as 60–79% and Cp positivity was not associated with doxycycline response in a previous report [6, 25], Ferrari et al. reported that successful Cp eradication was associated with outcomes and that there was no clinical benefit of doxycycline in patients with Cp-negative OAML [8]. As Ferrari et al. also reported that Cp DNA detection can be easily performed with a noninvasive method such as a conjunctival swab [8], Cp DNA detection should be considered in conjunctival MALT lymphoma in future research. Second, various second and salvage treatments were implemented according to the preferences of individual patients and physicians. In future clinical protocols, there should be standardized second and salvage treatment after initial doxycycline treatment.
In conclusion, when used together with appropriate salvage treatment, up to 2 cycles of oral doxycycline treatment can be used as a first-line treatment for T1a and T1b stage conjunctival MALT lymphoma, especially in patients from countries with high Cp prevalence or with confirmed Cp DNA. Although conjunctival MALT lymphoma has a benign nature, it may continue to progress in some patients, so at least 6 years of follow-up is needed.