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Arch Ophthalmol. 2002;120:1225-1227.

Lymphoid tumors are the most common primary orbital malignancy.^1-2 However, they constitute only about 2% of all nodal and extranodal lymphomas.³ Most published reports advocate the use of external beam radiotherapy or systemic chemotherapy for the treatment of orbital lymphoma.^4-7 Recent reports have suggested that immunotherapy may also be effective in the treatment of low-grade non-Hodgkin lymphoma (NHL).^8-10 We describe 4 patients in whom orbital NHL was treated effectively with immunotherapy using anti-CD20 monoclonal antibodies. To our knowledge, there are no previously published reports of monoclonal antibody therapy for NHL of the orbit.

Report of Cases
Between October 1999 and May 2001, 4 patients with the diagnosis of NHL of the orbit were treated at our institution with immunotherapy using monoclonal antibodies to CD20. When initially examined by us, all 4 patients had orbital lymphoma as a secondary extranodal site of involvement of previously diagnosed NHL. For each patient, clinical records and imaging studies were reviewed to establish the diagnosis and document response. Table 1 summarizes the clinical features, histologic classification, immunophenotype, and disease stage at the time of diagnosis of orbital lymphoma for each patient. Table 2 summarizes the staging system used in our series. All 4 patients underwent an orbital biopsy to confirm the diagnosis and the histologic classification of the orbital lymphoma. Patients 1, 2, and 3 received intravenous rituximab (Rituxan; Genentech, Inc, South San Francisco, Calif), 375 mg/m² weekly for 4 weeks. Patient 4 received intravenous rituximab, 250 mg/m², followed approximately 1 week later by a second infusion of rituximab, 250 mg/m², and yttrium 90–labeled (⁹⁰Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceuticals Corporation, San Diego, Calif), 0.4 mCi/kg (14.8 MBq/kg).

View this table: [in this window] [in a new window] Table 1. Clinical Features of Patients With Orbital Lymphoma Treated With Immunotherapy*

View this table: [in this window] [in a new window] Table 2. Ann Arbor Staging System for Lymphoma

In all 4 patients, the histologic features of the orbital lesion were similar to the previously established histologic classification of lymphoma. The histologic type in each patient, as confirmed by examination of an orbital biopsy specimen, was considered low grade. All patients had nearly complete resolution of their orbital lymphoma and remained without evidence of orbital disease at most recent follow-up (October 2001). Two patients had progression of lymphoma in other sites and received alternative therapy. The follow-up time after completion of immunotherapy ranged from 6 to 22 months (mean, 14.5 months). Figure 1 shows the orbital mass in patient 3, before and 3 months after completion of treatment with rituximab. Figure 2 shows the orbital lesion in patient 4, before and 2 months after completion of treatment with rituximab and ⁹⁰Y ibritumomab tiuxetan. The only adverse effects reported by the 4 patients were mild neutropenia and thrombocytopenia.

View larger version (59K): [in this window] [in a new window] Figure 1. Postcontrast magnetic resonance imaging scans of the orbit in patient 3. A, Before monoclonal antibody treatment, an infiltrative mass involving the left orbit is seen (arrows). B, Three months after treatment with rituximab, the orbital mass is much smaller.

View larger version (61K): [in this window] [in a new window] Figure 2. Computed tomographic scans of the orbit in patient 4. A, Before monoclonal antibody treatment, a mass in the inferior left orbit is seen (arrows). B, Two months after administration of rituximab and yttrium 90–labeled ibritumomab tiuxetan, the orbital mass has shrunken considerably.

Comment
Monoclonal antibodies can be used to recruit a patient's immune system to target antigens that are expressed on cancer cells. Rituximab is the first monoclonal antibody licensed by the US Food and Drug Administration to treat NHL.⁸ Rituximab is a genetically engineered chimeric (murine-human) monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B cells. Multicenter studies have demonstrated its efficacy against relapsed or refractory low-grade, CD20-positive, B-cell follicular NHL.^9-11 In these trials, up to 60% of patients with follicular lymphomas and a third of patients with diffuse large cell and mantle cell lymphomas achieved objective remissions.^12-14

In vitro, rituximab is capable of mediating antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity of CD20-expressing tumor cells.¹⁵ Direct effects have also been observed, including the induction of apoptosis in some B-cell NHL cell lines.¹⁶ In addition, rituximab can sensitize tumor cells to the cytotoxic effects of conventional chemotherapy. Thus, this agent may be a good addition to conventional chemotherapy in cases of refractory NHL. Another advantage of immunotherapy with rituximab is that patients can be treated repetitively, since immune responses occur in fewer than 1% of patients.

A mechanism for improving the potency of rituximab and the survival benefit it confers is to conjugate this monoclonal antibody to a radionuclide ligand.¹⁷ Several potential advantages have been identified that favor the use of radiolabeled antibodies. First, radioimmunoconjugates kill tumor cells primarily by the emission of radioactive particles and therefore may be therapeutically effective, even in hosts with defective immune effector function. Furthermore, the beta particles emitted by the radioligand are tumoricidal over a larger area than just the cell to which the ligand attaches, allowing for elimination of antigen-negative tumor cells by radioactive "cross fire" from neighboring antigen-positive, antibody-coated cells. Yttrium 90–labeled ibritumomab tiuxetan is one such radiolabeled monoclonal antibody. Yttrium 90–labeled ibritumomab tiuxetan is a unique compound composed of a murine monoclonal antibody (ibritumomab), the linker-chelator tiuxetan, and the radioisotope ⁹⁰Y, which is securely chelated via the linker. Like its unlabeled chimeric counterpart, rituximab, ⁹⁰Y ibritumomab tiuxetan targets the CD20 antigen, which is present on 95% of B-cell lymphomas.¹¹ Yttrium 90–labeled anti-CD20 antibodies have been associated with response rates of 70% to 80% in the treatment of NHL.¹⁸

Since most primary and secondary orbital lymphomas are thought to be low-grade B-cell NHL,¹⁹ the use of rituximab or its radiolabeled counterpart, ⁹⁰Y ibritumomab tiuxetan, as an alternative treatment modality for orbital lymphomas is intriguing. Targeted immunotherapy may offer several advantages over conventional chemotherapy or external beam radiotherapy in the treatment of orbital lymphomas, including fewer adverse effects and the potential for repeated treatments.

The toxicity of rituximab in patients with NHL has been considerably less than that of traditional chemotherapy; in most patients, rituximab causes no significant alopecia, nausea, or myelosuppression. Common symptoms observed with the initial monoclonal antibody infusion include fever, chills, mild throat irritation, rash, and, rarely, rigors.^{9, 11-14} In general, treatment with rituximab is well tolerated. Fewer than 10% of patients develop more serious symptoms such as bronchospasm or hypotension. The more serious adverse effects of rituximab are observed in patients with high levels of malignant B cells circulating in the peripheral blood. For most patients, controlled administration of the initial infusion by starting at a low dose, with premedication using acetaminophen and diphenhydramine hydrochloride and a slow rate escalation, results in minimal adverse effects. After completion of rituximab therapy, which typically lasts 1 month, long-term complications are unusual. The most common long-term adverse effect is B-cell depletion, which can last 6 to 9 months.

Rituximab should also produce fewer adverse effects than external beam radiotherapy, which has been associated with ocular adverse effects such as superficial keratopathy, dry eye syndrome, cataract formation, radiation retinopathy, and neovascular glaucoma.^19-21 Whether treatment of orbital lymphoma with a radiolabeled monoclonal antibody such as ⁹⁰Y ibritumomab tiuxetan is associated with fewer radiation-induced ocular adverse effects compared with external beam radiotherapy remains to be determined. According to the results of most dosimetry studies, the median estimated radiation dose absorbed by various organs after administration of the radiolabeled antibody ⁹⁰Y ibritumomab tiuxetan ranges from 38 to 340 rad (0.38-3.40 Gy). The median estimated radiation dose absorbed by the tumor is 1700 rad.²² In contrast, the median total dose of radiation from external beam radiotherapy for NHL of the orbit is 4000 rad (40 Gy) (range, 2000-5000 rad [20-50 Gy]).⁷ Our limited experience, with patient 4 in this study, suggested no immediate ocular adverse effects from treatment with ⁹⁰Y ibritumomab tiuxetan.

Our small case series provides limited evidence that rituximab or ⁹⁰Y ibritumomab tiuxetan can be used effectively and safely for low-grade B-cell NHL affecting the orbit. Larger studies are required to study the efficacy of monoclonal antibody treatment for orbital lymphomas and to compare the toxicity profile of immunotherapy with that of other, more conventional forms of therapy, such as external beam radiotherapy and chemotherapy.

AUTHOR INFORMATION

Bita Esmaeli, MD; James L. Murray, MD; M. Amir Ahmadi, MD; Aresu Naderi, MD; Sanjay Singh, MD; Jorge Romaguera, MD
Houston, Tex

Christine A. White, MD
San Diego, Calif

Peter McLaughlin, MD
Houston

Corresponding author: Bita Esmaeli, MD, Ophthalmology Section, Department of Plastic Surgery, Box 443, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: besmaeli{at}mdanderson.org).

REFERENCES
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SECTION EDITOR: W. RICHARD GREEN, MD

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