Clinical Manifestations and Treatment Results in Accordance with Frontline Treatment Modalities for Ocular Adnexal Mucosa-Associated Lymphoid Tissue Lymphoma (OAML)

Background: localized ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) was effectively treated with frontline radiotherapy. however it is sometimes associated with radiation-related complications of ocular structures, as well as distant relapse or delayed relapse. Although there are no definitive optimal treatment approaches for these patients, we investigated the results in accordance with frontline treatment modalities for OAML.

Patients and methods: 159 patients with biopsy-confirmed primary OAML between 2007 and 2015 were analyzed retrospectively. All the patients were sorted by risk-stratification with Ann-Arbor staging and the tumor, node, metastasis (TNM) staging system, and treatment modalities according to anatomic location, prognosis factors, which were supported by ophthalmologist.

Results: first-line radiotherapy had overall survival(OS) of 100%, event-free survival(EFS) of 90%. However frontline-radiotherapy group has 100% of survival with 55% of moderate to severe dry eye syndrome, 37.4% of cataract incidence , 11% of cataract-related operations, and 1% (n=1) of radiation-related blindness. Although 5-year EFS is good in radiotherapy group ( 90% vs 64% in radiotherapy group vs chemotherapy, p<0.001), most of aggressive factors ( young age at diagnosis, conjunctival lesions, Ann Arbor stage I, early T1N0M0 stage, and no distant extranodal metastasis including of bone marrow involvement ) showed in radiotherapy group in comparison with chemotherapy group. In subgroup analysis of first-line chemotherapy, rituximab-containing group has more good response of event-free survival (p= 0.041) with tolerable hematologic toxicities compared to frontline radiotherapy group.

Conclusion: OAML with localized to conjunctiva alone was treated with frontline-radiotherapy and non-conjuctival lesions treated with chemotherapy. Radiotherapy as first-line is good local control-therapeutic option in patients with localized to conjunctiva alone, but management of radiation-associated complication is concerned troubles. In advanced OAML including of extra-conjunctival lesions, systemic chemotherapy is best options. rituximab-based regimen could be feasible to obtain good disease-free survival and response rate.

Table 1. Patient's characteristics between frontline-chemotherapy and radiation group ( n= 159)

Factors	Primary Chemotherapy group (n = 68)	Primary Radiation group (n = 91)	P- value
Gender (male)	37 (54%)	28 (30.8%)	0.003
Age at diagnosis (median,  year)	50	43	0.003
involvement of both eyes at diagnosis	22 (32.4%)	23 (25.3%)	0.75
Conjuctival lesion at diagnosis	22 (32.4%)	76 (83.5%)	<0.001
Ki-67 on pathologic stain (median, %)	5	4	0.545
Ann-Arbor stage I	23 (66.2%)	3 (96.7%)	<0.001
LDH at diagnosis ( mg/L)	355	344	0.216
Patients no. with T1N0M0	21 (30.9%)	78 (85.7%)	<0.001
Bone marrow involvement	7 (10.3%)	0 (0%)	<0.001
Patients no. with N1~N3 staging	10 (14.7%)	0 (0%)	<0.001
Patients no. with T0N0M1~2	7 (10.3%)	0 (0%)	<0.001

Patients treated with frontline chemotherapy were classified in more aggressive or advanced stage which compare to patients treated with primary radiotherapy statistically.

Figure 1. *event-free survival / overall survival between primary chemotherapy group and patients with

radiotherapy

* event: from partial response to progressive disease after completion of primary treatments, or death.

Table 2.  Patient's characteristics between Rituximab containing group and non-rituximab in frontline chemotherapy subgroup (n=68)

Factors	Ritixumab-containing (n = 26)	No Rituximab (n = 42)	P- value
Gender (male)			0.942
Age at diagnosis (median,  year)	52	49	0.411
involvement of both eyes at diagnosis			0.057
Conjuctival lesion at diagnosis			0.087
Ki-67 on pathologic stain (median, %)	4	3	0.540
Ann-Arbor stage I			0.532
LDH at diagnosis ( mg/L)	353	356	0.782
Patients no. with T1N0M0			0.585
Patients no. with N1~N3 staging			0.659
Patients no. with T0N0M1~2			0.695

There are statistically no differences between patients treated with Rituximab-containing regimen and non-rixuximab in frontline chemotherapy subgroup.

Figure 2. * event-free survival between patients with rituximab-containing regimen and without rituximab in subgroup analysis of frontline-chemotherapy group

* event: from partial response to progressive disease after completion of primary treatments, or death