Original Study

Clinical Characteristics of 95 Patients With Ocular Adnexal and Uveal Lymphoma: Treatment Outcomes in Extranodal Marginal Zone Subtype Craig A. Portell,1 Mary E. Aronow,2 Lisa A. Rybicki,1 Roger Macklis,3 Arun D. Singh,2 John W. Sweetenham1 Abstract Involved-field radiotherapy (IFRT) is effective for unilateral ocular adnexal lymphoma (OAL) but treatment for higher stages is unclear. We retrospectively evaluated 95 patients with OAL and report the characteristics and outcomes. Progression was more likely with rituximab than IFRT, but systemic progression was more likely with IFRT. IFRT remains the standard for localized OAL, but rituximab might have a role in higher stage OAL. Background: Lymphoma rarely presents in the ocular adnexa but is usually extranodal marginal zone (ENMZ) lymphoma when it does. Involved-field radiotherapy (IFRT) is the standard of care for unilateral disease, but the optimal management of more extensive disease is unclear. Patients and Methods: We retrospectively evaluated the clinical characteristics and outcomes of 95 patients with ocular adnexal lymphoma (OAL) or uveal lymphoma treated or diagnosed at our institution. All patients identified were included in the risk factor analysis for progression-free survival (PFS). The initial treatment-related outcomes were assessed for ENMZ OAL only (n ¼ 62). Results: With a median follow-up of 32 months, significant risk factors for PFS after initial treatment were age (hazard ratio, 1.33; 95% confidence interval, 1.02-1.74), female gender (hazard ratio, 2.04; 95% confidence interval, 1.04-4.00), and a history of lymphoma (hazard ratio, 2.31; 95% confidence interval, 1.12-4.78). In ENMZ, IFRT was associated with improved PFS (median, 5.4 years; P < .001). Progression occurred in 7 of 39 (23%), with 6 of the 7 (86%) at systemic sites. Singleagent rituximab was typically used for bilateral ocular or systemic presentations of ENMZ OAL. Progression occurred in 7 of 11 (64%), with no progression at systemic sites. All progression events in those initially treated with rituximab occurred in the ocular adnexa. Conclusion: The results of the present study have confirmed IFRT as the standard for unilateral ENMZ OAL. Single-agent rituximab was an effective agent for bilateral ocular or systemic ENMZ OAL, particularly for systemic control, but ocular progression should be closely monitored. Combined modality therapy should be studied further in bilateral and systemic ENMZ OAL. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 3, 203-10 ª 2014 Elsevier Inc. All rights reserved. Keywords: Extranodal marginal zone lymphoma of mucosal associated lymphoid tissue, Ocular adnexal lymphoma, Radiation, Rituximab

Introduction Current affiliation of Craig A. Portell: Division of Hematology and Oncology, University of Virginia, Charlottesville, VA. Current affiliation of John W. Sweetenham: Huntsman Cancer Center, University of Utah, Salt Lake City, UT. 1

Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute Cole Eye Institute Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 2 3

Submitted: Aug 21, 2013; Revised: Oct 7, 2013; Accepted: Oct 21, 2013; Epub: Nov 15, 2013 Address for correspondence: Craig A. Portell, MD, Division of Hematology and Oncology, University of Virginia, PO Box 800716, Charlottesville, VA 22908 E-mail contact: [email protected]

2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.10.011

The ocular adnexa, defined as the eyelids, conjunctiva, lacrimal apparatus, muscles, and other connective tissue in the orbit, are a rare site of lymphoma, representing  8% of extranodal presentations of non-Hodgkin lymphoma.1 Ocular adnexal lymphoma (OAL) often presents as unilateral or bilateral ocular-only disease (60%-80%), although OAL can also have concurrent systemic involvement (15%20%).2,3 Bilateral disease will be seen in 10% to 15% of ocular-only presentations.4 The ocular adnexa can also be a site of relapse in otherwise systemic lymphomas.2,5,6 Indolent subtypes of nonHodgkin lymphoma represents 80% to 85% of primary OALs,2,4 with extranodal marginal zone (ENMZ) of the mucosa-associated

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Description and Treatment—Ocular Adnexal Lymphoma lymphoid tissue (MALT) type occurring in 45% to 55% of primary OALs.2,4 Follicular lymphoma (FL) is the next most common histologic type, representing 23% of primary OALs.4 The uvea is also a common site of concurrent OAL and is often of the ENMZ subtype.7 Uveal lymphomas will also behave similarly to ENMZ OALs.7 Involved-field radiotherapy (IFRT) has been evaluated in singleinstitution series.8-13 A complete response occurred in 90% to 100%, with relapse in < 20% during a 5-year average follow-up period.8-10 However, these series mostly evaluated unilateral stage IE ENMZ OAL, and other studies have demonstrated that bilateral or systemic presentations of OAL have a greater risk of progression and lymphoma-related death.3,14 This suggests that systemic therapy could be useful for bilateral or systemic OAL. Furthermore, the use of rituximab as a single agent in ENMZ lymphoma of the MALT type at other anatomic sites has shown a promising response rate of 73%, with a duration of response of 10.3 months15-17; however, few small case reports of single-agent rituximab in OAL have been published.8,18-22 We present a retrospective description and risk assessment of patients with any type and presentation of lymphoma occurring in the ocular adnexa or uvea evaluated at the Cleveland Clinic. Treatment-related outcomes were reviewed for ENMZ OAL only. After 2005, our institution adopted a treatment algorithm according to the disease presentation: those with unilateral ENMZ OAL were treated with IFRT and those with bilateral or systemic ENMZ OAL were treated with single-agent rituximab. We hypothesized that systemic therapy with single-agent rituximab would be useful in bilateral or systemic presentations of ENMZ OAL.

Patients and Methods Patient Selection

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After approval by our institutional review board, the study population was identified by screening the clinic lists of lymphoma oncologists and ophthalmic oncologists at the Cleveland Clinic from January 2004 to January 2013. Patients with lymphoma occurring in the ocular adnexa or uvea were selected if they had been evaluated in that period and had lymphoma diagnosed after 1995. Lymphoma involving the uvea was also included, because uveal lymphoma is frequently ENMZ lymphoma, often seen in concert with other masses in the ocular adnexa, and behaves similarly to ENMZ OAL.7,23-25 Diagnostic biopsy was typically performed on the ocular adnexal disease site; however, in the presence of concurrent systemic involvement, biopsy specimens from other involved sites were obtained. Cases in which the diagnostic biopsy had been performed at outside institutions were routinely reviewed by pathologists at the Cleveland Clinic. Lymphomas were classified according to the standard classification schema at diagnosis. A pathologic review according to the 2008 update of the World Health Organization classification26 was not possible owing to unavailable tissue, either because of outside biopsy or small biopsy specimens with insufficient tissue remaining after the primary diagnosis. For reference, 7 patients were classified before 2001, 31 were classified between 2001 and 2007, and 58 were classified from 2008 onward. The outcomes were updated in April 2013. The staging evaluations included history, physical examination, and computed tomography (CT) of the chest, abdomen, and pelvis (91.6% of evaluable patients). Ocular imaging with either magnetic

Clinical Lymphoma, Myeloma & Leukemia June 2014

resonance imaging of the orbits (48.8%) or CT of the brain or orbits (39.5%), or both (11.6%), was also routinely performed. A complete bilateral ophthalmologic examination was performed on all patients, including an assessment of the best-corrected visual acuity, intraocular pressure, pupillary responses, external examination, slit lamp examination, and dilated fundus examination. Bilateral B-scan ultrasonography and slit lamp and fundus photography were also routinely performed. Lumbar puncture was performed in only 8 patients (8.4%), and central nervous system involvement by lymphoma was detected in only 1 patient. Bone marrow aspiration and biopsy was performed in 33.7% of patients and was involved by lymphoma in 7 of the 32 patients evaluated. Systemic involvement was defined as any disease, nodal or extranodal, occurring outside the ocular adnexa in concert with disease in the ocular adnexa. Bilateral ocular-only involvement was defined as disease identified in bilateral ocular adnexa or uvea without other systemic involvement at diagnosis.

Statistical Analysis The clinical characteristics and outcomes were collected and managed in the research electronic data capture (REDCap) database hosted at the Cleveland Clinic.27 Statistical analyses were performed using SAS software (SAS Institute, Cary, NC). All statistical tests were 2-sided, and P < .05 indicated statistical significance. Three outcomes were assessed: overall survival (OS), progression, and progression-free survival (PFS). Events corresponding to PFS and OS were progression or all-cause mortality and all-cause mortality, respectively. Outcomes were calculated from the date of diagnosis until the date of the first event or the date of the last follow-up examination. To determine the natural history of ocular involvement, the date of ocular adnexal involvement was considered the date of diagnosis for those with a history of lymphoma. Disease progression was recorded as the date when additional therapy was initiated. Thus, patients with a partial response (PR), or who were observed, were considered to have progressive disease if they required additional therapy. Cox proportional hazards analysis was used to identify univariate prognostic factors for OS and PFS. Stepwise Cox analysis with a variable entry criterion of P < .10 and a variable retention criterion of P < .05 was used to identify the multivariate prognostic factors for PFS. Multivariate analysis could not be done for OS, because only 9 patients had died. The Cox results are presented as the hazard ratio (HR) and 95% confidence interval (CI). Age at diagnosis (as a continuous variable, per 10-year increase), gender, previous autoimmune or inflammatory disease, a history of lymphoma, a history of other malignancy, pathologic diagnosis (ENMZ vs. all others), bilateral ocular disease, and ocular disease site were analyzed as potential prognostic factors. In the patients with ENMZ lymphoma, treatment-related outcomes were estimated using the Kaplan-Meier method. Outcomes were compared among treatments using the log-rank test; for treatment-related analyses, the outcomes were calculated relative to the treatment start date rather than the diagnosis date.

Results Patient Characteristics, Histologic Diagnosis, and History The patient characteristics are listed in Table 1. Ninety-five consecutive patients, newly diagnosed with lymphoma involving

Craig A. Portell et al Table 1 Patient Characteristics Characteristic

Number of Patients (%)

Median age (years) at diagnosis (range)

64 (24-91)

Male gender

55 (57.9)

History of inflammatory or autoimmune disease

15 (15.8)

Bilateral ocular involvement

27 (28.4)

Ocular only (bilateral or unilateral) (n ¼ 87 ) a

50 (57.5)

Systemic disease at diagnosis (n ¼ 87a)

37 (42.5)

History of lymphoma

22 (23.2)

History of other malignancy (n ¼ 81)

10 (10.6)

Prostate

3 (30)

Breast

2 (20)

difficulties with small biopsy specimens obtained after OAL relapse or by the histologic changes. These patients included 2 patients who had initially presented with SLL and had developed progression with ENMZ lymphoma as OAL; 1 who had initially presented with DLBCL, with progression to FL as OAL; 1 who had initially presented with an undefined lymphoma, with progression to ENMZ lymphoma as OAL; and 1 who had initially presented with Hodgkin lymphoma, with later progression to ENMZ lymphoma as OAL. Finally, 1 patient was diagnosed with ENMZ OAL, who had been diagnosed with both systemic ENMZ lymphoma (12.5 years before the OAL diagnosis) and DLBCL (5.5 years before the OAL diagnosis). Both lymphomas were successfully treated and in remission at the OAL diagnosis.

Skin

2 (20)

Staging

Lung and uterus

1 (10)

Ureter

1 (10)

Colon

1 (10)

The initial sites of ocular adnexal involvement are presented in Table 1. The orbital imaging findings using magnetic resonance imaging or CT were compared with the ophthalmologic examination findings. Generally, when a mass was seen on imaging, good concordance was found with the examination findings, except for cases of bilateral disease (Table 2). The examination and ancillary studies, in particular, B-scan ultrasonography, were able to detect small masses and uveal involvement not observed on radiographic imaging.28 Of those with imaging studies available, bilateral involvement was seen in 25 patients using the ophthalmologic studies and examination findings. Sixteen patients (64%) had bilateral involvement identified by ophthalmologic examination and B-scan ultrasonography that would have been missed using routine radiographic imaging (Table 2). Twelve patients (48%) with bilateral ocular involvement found by ophthalmologic examination presented with concurrent systemic involvement; 13 (52%) had no evidence of systemic involvement. Systemic disease evaluation was available for 87 of the 95 patients identified. Of these, 37 (42.5%) presented with systemic disease. The sites included the lymph nodes (n ¼ 20), lung (n ¼ 6), peripheral blood and/or bone marrow (n ¼ 6), spleen (n ¼ 4), parotid gland (n ¼ 4), bone (n ¼ 4), sinus (n ¼ 3), skin (n ¼ 3), breast (n ¼ 3), cerebrospinal fluid or dura (n ¼ 2), and soft tissue (n ¼ 4), with > 1 site possible for each patient.

Pathologic diagnosis (n ¼ 94) ENMZ

66 (70.2)

Follicular

14 (14.9)

DLBCL

3 (3.2)

Mantle cell

5 (5.3)

Other lymphoma

6 (6.4)

Site of involvement (>1 site per patient possible) Eyelid

6 (6.3)

Conjunctiva

39 (41.1)

Orbit

56 (58.9)

Uvea

18 (18.9)

Abbreviations: DLBCL ¼ diffuse large B-cell lymphoma; ENMZL ¼ extranodal marginal zone lymphoma. a Those evaluable for systemic involvement.

the ocular adnexa or uvea at the Cleveland Clinic from August 1996 to January 2013, were identified. The median follow-up was 31.7 months (range, 0.3-182.3 months). The most common histologic subtype was ENMZ lymphoma (70%). Autoimmune or chronic inflammatory disease was seen in 15 of the 95 patients (15.8%) and included hepatitis in 3, inflammatory bowel disease in 3, psoriasis in 2, sarcoidosis in 2, lupus in 1, multiple sclerosis in 1, autoimmune cerebellar degeneration in 1, uveitis/iritis in 1, and rheumatoid arthritis in 1. Twenty-two patients had a history of lymphoma that later progressed to involve the ocular adnexa. Systemic involvement was evaluable in 19 of the 22 patients; 13 (68%) had coexisting systemic involvement with the ocular adnexal involvement. FL was the most common histologic subtype to present in the ocular adnexa after a history of lymphoma (n ¼ 8), with a median interval from initial FL diagnosis to OAL progression of 124 months (range, 16-381 months). Other previous histologic subtypes included small lymphocytic lymphoma (SLL) in 3, ENMZ lymphoma in 3, mantle cell lymphoma in 3, diffuse large B-cell lymphoma (DLBCL) in 1, T-cell lymphoma in 1, and other undefined small cell lymphoma in 3. Six of the 22 patients had a different initial histologic subtype than OAL disease, which may be explained by the diagnostic

Prognostic Factors Of the entire 95-patient cohort, 9 deaths were recorded, with a 5-year OS of 74.2% (median not observed). The cause of death

Table 2 Ophthalmologic Examination Findings vs. Ocular Imaging Findings in Ocular Adnexaa Ophthalmologic Examination Findings Imaging Findings Mass, left only Mass, right only Bilateral mass No mass

Mass, Left Only

Mass, Right Only

Bilateral Mass

23b 0 1 5

0 23b 1 8

5 3 9b 8

Included only 86 patients with imaging and ophthalmologic findings available. Agreement between ocular imaging and examination findings.

a

b

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Description and Treatment—Ocular Adnexal Lymphoma was lymphoma related in 7, metastatic cancer of unknown origin (not lymphoma) in 1, and unknown in 1 (known lymphoma complete response [CR] for > 1 year before death). The significant adverse prognostic factors for OS on univariate analysis included advancing age at diagnosis (HR, 3.16; 95% CI, 1.48-6.76; P ¼ .003), and a history of nonelymphoma malignancy (HR, 6.07; 95% CI, 1.43-25.7; P ¼ .014). Too few deaths occurred for an informative multivariate analysis of OS. A summary of the clinical characteristics of the lymphoma-related deaths is provided in Table 3. The significant adverse prognostic factors for PFS on univariate analysis included advancing age at diagnosis, female gender, and a history of lymphoma. All factors remained significant on multivariate analysis for PFS: age at diagnosis (HR, 1.33; 95% CI, 1.02-1.74; P ¼ .039), female gender (HR, 2.04; 95% CI, 1.04-4.00; P ¼ .037), a history of lymphoma (HR, 2.31; 95% CI, 1.12-4.78; P ¼ .023).

Treatment Outcomes for All Histologic Types The initial treatment by histologic subtype (89 patients with known treatment) and anatomic site of origin (62 patients with ENMZ) are listed in Table 4. IFRT only was used in 50 patients, with a median total radiation dose of 30 Gy (range, 4-45 Gy). The side effects of IFRT included cataracts (34%), retinopathy (8%), and optic neuropathy (6%). All 16 patients treated with rituximab received a standard induction schedule of 375 mg/m2 weekly for 4 doses. Additional doses of rituximab were allowed on a maintenance schedule.29 No significant complications were attributed to rituximab. The chemotherapy regimens included intravenous cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (RCHOP) in 6, bortezomib in 2, bendamustine, rituximab, and bortezomib in 1, oral chlorambucil in 2, and other lowdose therapy in 3. Doxycycline was used in 2 patients diagnosed at, but treated outside of, our institution and resulted in stable disease in 1 patient and a PR in the other. The chemotherapy regimens, combination therapies, and doxycycline were grouped for analysis. Patients with SLL, Waldenström macroglobulinemia (also know as lymphoplasmacytic lymphoma), or unspecified indolent lymphomas were grouped together for additional analysis. The median PFS was 41.2 months (n ¼ 66) for ENMZ lymphoma, 19.5 months (n ¼ 14) for FL, 55.1 months (n ¼ 6) for other indolent

lymphomas, and 33.6 months (n ¼ 5) for mantle cell lymphoma. The median PFS was not reached for DLBCL (n ¼ 3).

ENMZ-Specific Findings The ENMZ lymphoma outcomes were evaluated separately. Since 2005, our treatment protocol for ENMZ lymphomas in the ocular adnexa has been to treat unilateral ocular-only disease with IFRT and bilateral ocular-only or systemic disease with single-agent rituximab. The OS and PFS for ENMZ lymphoma are shown in Figure 1. The initial treatment-related outcomes are shown in Figures 2A and 3. A significant difference was found in PFS between the treatments (P < .001), with improved PFS with IFRT compared with rituximab (median PFS, 5.4 and 0.7 year, respectively; Fig. 2A). In evaluating the type of relapse (local vs. systemic), IFRT was associated with a lower rate of local progression than was rituximab (median not observed and 0.7 year for IFRT and rituximab, respectively; Fig. 2B). Alternatively, rituximab was associated with a lower rate of systemic progression (median, 5.8 years and not observed for IFRT and rituximab, respectively; Fig. 2C). Figure 3 outlines the treatment outcomes and second treatments after progression (n ¼ 22) for those with ENMZ lymphoma. Of the 39 patients treated with IFRT, 7 (18%) developed progression, 6 at distant sites, including other MALT sites (breast, skin), lymph nodes, and bone marrow. One patient developed progression in the liver as DLBCL. Only 2 of the 7 patients achieved a CR after second-line therapy. Two lymphoma-related deaths occurred in those treated with IFRT as the only initial treatment (Table 3). Of the 11 patients initially treated with rituximab, 7 (63.6%) developed progression, all at ocular sites without other systemic involvement. Second-line therapy achieved a CR in 4 of the 7 patients. No deaths occurred in those initially treated with single-agent rituximab. Two patients treated with chemotherapy (both with chlorambucil) developed systemic progression (1 breast only, 1 lung and lymph nodes) and ultimately died of lymphoma. Two patients treated with combination therapy developed progression (IFRT plus rituximab for 1 and chemotherapy plus rituximab for 1). Of these 2 patients, 1 developed progression in the skin and distant lymph nodes and ultimately died of lymphoma; the other developed progression in the contralateral ocular adnexa and survived. All

Table 3 Lymphoma-Related Deaths

Pt. No. Initial Disease Sites 1 2 3 4 5 6 7

Left OA, chest, abdominal LN, spleen Right OA, abdominal LN, spleen Right OA Bilateral OA, breast Left OA Right OA, abdominal LN Bilateral OA, lung

Histologic Diagnosis

Initial Treatment

ENMZL

Chlorambucil

ENMZL

IFRT and rituximab

ENMZL ENMZL FLa ENMZL ENMZL

IFRT Chlorambucil Rituximab Observation, chlorambucil IFRT

Interval to First Progression (mo)

Other Treatment

Interval to Lymphoma-Related Death (mo)

Rituximab  2 courses

44

15

Rituximab

25

56b 33 9 15 16

Rituximab and chemotherapy Rituximab Chemotherapy Rituximab Rituximab and IFRT

57 93 12 55 46

4

Abbreviations: ENMZL ¼ extranodal marginal zone lymphoma; FL ¼ follicular lymphoma; IFRT ¼ involved field radiotherapy; LN ¼ lymph nodes; OA ¼ ocular adnexa; Pt. No. ¼ patient number. a Patient had a history of FL diagnosed 85 months before OAL diagnosis. b Progression was a transformation to DLBCL involving the liver.

206

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Craig A. Portell et al Table 4 Treatment Characteristics for Those Evaluable for Treatment Outcomes Number of Patients (%) Variable

IFRT

Rituximab

Chemotherapy

Combination Therapy

Observation 4 (6.5)

Histologic type ENMZ (n ¼ 62)

39 (62.9)

11 (17.7)

5 (8.1)

3 (4.8)

Follicular (n ¼ 13)

6 (46.2)

5 (38.5)

2 (15.4)

0

0

Indolent (n ¼ 6)

4 (66.7)

0

1 (16.7)

0

1 (16.7)

0

0

2 (66.7)

1 (33.3)

0

1 (20.0)

0

1 (20.0)

3 (60.0)

0 1 (3.8)

DLBCL (n ¼ 3) Mantle cell (n ¼ 5) ENMZ disease site Unilateral ocular only (n ¼ 26)

22 (84.6)

0

2 (7.7)

1 (3.8)

Bilateral ocular only (n ¼ 11)

7 (63.6)

4 (36.4)

0

0

0

Systemic (n ¼ 20)

6 (30.0)

7 (35.0)

3 (15.0)

2 (10.0)

2 (10.0)

Systemic unknown (n ¼ 5)

4 (80.0)

0

0

0

1 (20.0)

Abbreviations: DLBCL ¼ diffuse large B-cell lymphoma; ENMZ ¼ extranodal marginal zone; IFRT ¼ involved-field radiotherapy.

4 patients under observation developed progression; 1 in the same eye initially involved and 3 at distant sites (bone marrow, breast, kidney, and distant lymph nodes). One patient initially under observation died of an unknown cause.

Discussion Multiple retrospective studies have focused on unilateral stage IE ENMZ OAL treated with radiotherapy.8-13 In the present study, we evaluated the clinical and pathologic characteristics and treatment outcomes of a large cohort with all subtypes, presentations, and treatments of OAL. In our cohort, advancing age, female gender, and a history of lymphoma correlated with adverse PFS. Few deaths were observed with this mostly indolent disease. Other studies3,30-32 have suggested that stage is an important prognostic variable. We could not confirm this; however, the pivotal study on this matter was by Jenkins et al,3 which had the greatest level of evidence.

Figure 1 Overall Survival and Progression-Free Survival in All Patients With Extranodal Marginal Zone Ocular Adnexal Lymphoma. Median Overall Survival not Observed, and Median Progression-Free Survival at 3.4 Years

Non-ENMZ OAL was generally indolent, with most being FL or other undefined small indolent lymphomas. Of the 14 patients with FL, 9 had a history of lymphoma. The interval from the initial lymphoma diagnosis to the OAL diagnosis was prolonged (median, 124 months; range, 16-381 months), which has been reported in other studies.2-4 These findings suggest that FL presentation in the ocular adnexa rarely occurs at the initial diagnosis of FL but, instead, occurs at relapse, often with concurrent systemic disease. We also found adverse PFS for those with a history of lymphoma; this might predominantly represent the natural history of those with FL vs. those with ENMZ lymphoma. This finding is in contrast to another larger study by Jenkins et al,2 which found little difference in lymphoma-related death for the different histologic subtypes of indolent lymphomas. The discrepancy might have been related to the small numbers of patients in our study and the evaluation of different outcomes. Chlamydophila psittaci has been implicated as an etiologic agent in ENMZ OAL in some reports,33,34 although others have not been able to identify an association between OAL and C psittaci infection.35-39 C psittaci might have a greater influence in certain geographic locations.40 A phase II study by Ferreri et al41 suggested a clinical benefit of eradication of C psittaci with oral doxycycline (CR, 15%; PR, 41%) for those with unilateral ENMZ OAL. However, the causative association between ENMZ OAL and C psittaci has not been established in the United States. Thus, we considered doxycycline use in our geographic region experimental during the study and did not include it in our treatment algorithm. Two patients included in our cohort who were diagnosed at our institution but treated outside our institution were empirically treated with doxycycline. The small numbers have made conclusions on the effectiveness of doxycycline difficult to interpret. All patients with ENMZ OAL, including those with higher stage disease, were included in our study. Compared with previous reports,4,8,10 we observed a greater proportion of patients with bilateral ENMZ OAL (28.4% vs. 10%-17%). This might be a reflection of our routine practice of bilateral ophthalmologic examination and bilateral B-scan ultrasonography for all patients with OAL. This practice might have identified an increased number of

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Description and Treatment—Ocular Adnexal Lymphoma Figure 2 Treatment Outcomes for Progression-Free Survival in Patients With Extranodal Marginal Zone Ocular Adnexal Lymphoma Evaluable (n [ 62). Treatment Outcomes Stratified by (A) all Progression, (B) Progression Limited to the Ocular Structures, and (C) Progression Limited to Systemic Sites. Those Treated With Chemotherapy, Doxycycline, or Combined Modality Therapy Were Combined Into an “Other” Category

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uveal lymphomas, which are rarely identified in the contralateral orbit without such techniques.7,24,42 Most uveal lymphomas are of the ENMZ lymphoma type and behave similarly to ENMZ OAL,23-25 justifying their inclusion in our study. Uveal lymphoma occurred in 18 patients, and the inclusion of uveal involvement was upstaged 10 patients (52.6%). The inclusion of uveal lymphoma, stringent ocular staging, and comprehensive systemic staging also likely increased the proportion of systemic disease in our cohort (35% of ENMZ OAL) compared with that in other studies (18% of ENMZ OAL2). Other studies included only unilateral ocular-only presentations9,11,12 or included few patients with bilateral ocular-only or systemic presentations.8,10 Staging with the bilateral ocular examination and whole body imaging is important to exclude distant and bilateral disease. Furthermore, bilateral ocular-only presentations have been associated with a greater risk of systemic relapse,14 suggesting a role for systemic therapy in this setting. Our general treatment algorithm for ENMZ OAL has been to treat those with unilateral ocular-only disease with IFRT and those with bilateral ocular-only and systemic disease with single-agent rituximab. Thus, the treatment outcomes in our study were biased

Clinical Lymphoma, Myeloma & Leukemia June 2014

toward a lower risk population treated with IFRT. IFRT was effective at treating the ocular disease sites (Figs. 2B and 3), because a CR occurred in 64%, and few progression events occurred in the ocular adnexa. When progression occurred in those treated with IFRT, it was at systemic sites, as previously reported.8,11 It is possible that the greater rate of systemic progression after IFRT resulted from the low level of bone marrow involvement at diagnosis. However, previous studies have not demonstrated a benefit of bone marrow biopsy in the initial staging of unilateral ENMZ OAL.8 In contrast, single-agent rituximab was not as effective for local control, with a PR the most likely response (CR, 9%; PR, 64%) and all progression events occurring exclusively in the ocular adnexa (Figs. 2B and 3). Increased local failure with rituximab could be explained by the advanced local disease extent at the initial presentation or a more aggressive biology of the primary tumor at this higher stage and, thus, higher risk population. Drug penetration should not have been an issue in the ocular adnexa and uvea, because no bloodebrain barrier is present at either site. Rituximab is also not as direct and potent as IFRT, particularly in the ocular adnexa. Although local failures were common, systemic progression was not observed in the rituximab-treated group (Fig. 2C). The

Craig A. Portell et al Figure 3 Treatment Outcomes After Initial and Subsequent Treatment for Patients With Extranodal Marginal Zone Ocular Adnexal Lymphoma Evaluable for Treatment (n [ 62). CR, complete remission; PD, progressive disease; PR, partial remission; SD, stable disease. Those Treated With Chemotherapy, Doxycycline, or Combined Modality Therapy Were Combined Into an “Other” Category

absence of systemic progression in this higher risk group suggests that rituximab is effective at treating and preventing disease outside the ocular adnexa (Fig. 2C). The patients were effectively salvaged with either additional courses of rituximab or IFRT, with no deaths in this group (Fig. 3 and Table 3).

Conclusion The presented results lend credence to our treatment strategy of using IFRT for unilateral ENMZ OAL and single-agent rituximab for bilateral ocular-only or systemic ENMZ OAL. IFRT has the best overall PFS compared with other treatments but was restricted to lower risk patients. Thus, IFRT should be the treatment of choice for unilateral presentations, particularly for ENMZ OAL. Rituximab was effective at treating ocular disease, but not to the degree with IFRT. However, rituximab was highly effective in treating systemic disease and seemed to provide protection against systemic progression. Thus, single-agent rituximab is a reasonable treatment option for bilateral ocular-only or systemic presentations, although such cases should be followed up closely with periodic ophthalmologic examination and systemic staging. Consideration of IFRT for persistent sites of OAL after treatment with rituximab would be reasonable but requires additional study. Overall, this strategy could potentially spare some patients from the increased, albeit low risk, of cataracts and retinopathy associated with radiotherapy, particularly when bilateral sites are involved.

Clinical Practice Points  OAL is not always ENMZ lymphoma and can be a site of relapse

in patients with a history of lymphoma.  Careful staging, including bilateral ophthalmologic examination

and radiographic imaging, is important to rule out bilateral and systemic disease.

 Adverse risk factors for PFS after initial therapy included

advancing age, female gender, and a history of lymphoma.  IFRT remains the standard of care for patients with unilateral

ENMZ OAL. Progression is rare after radiotherapy but will typically develop at nonocular sites.  Rituximab is a reasonable option for bilateral or systemic ENMZ OAL, although progression is common, particularly at ocular sites. Close ophthalmologic follow-up is recommended after single-agent rituximab.

Acknowledgments This work was presented in abstract form at the 2012 American Society of Oncology Meeting, Chicago, IL (abstract number 8071).

Disclosure Dr Sweetenham reports grants from Novartis, grants and personal fees from Seattle Genetics, grants from Millennium, grants from Genentech, and grants from Aegera, all of which were outside the submitted work. All other authors state that they have no conflicts of interest.

References 1. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972; 29:252-60. 2. Jenkins C, Rose GE, Bunce C, et al. Histological features of ocular adnexal lymphoma (REAL classification) and their association with patient morbidity and survival. Br J Ophthalmol 2000; 84:907-13. 3. Jenkins C, Rose GE, Bunce C, et al. Clinical features associated with survival of patients with lymphoma of the ocular adnexa. Eye (Lond) 2003; 17:809-20. 4. Ferry JA, Fung CY, Zukerberg L, et al. Lymphoma of the ocular adnexa: a study of 353 cases. Am J Surg Pathol 2007; 31:170-84. 5. Rasmussen PK, Ralfkiaer E, Prause JU, et al. Diffuse large B-cell lymphoma of the ocular adnexal region: a nation-based study. Acta Ophthalmol 2013; 91: 163-9.

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