Copyright 2002 American Medical Association. All Rights Reserved.
Applicable FARS/DFARS Restrictions Apply to Government Use.2002
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.
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).
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.
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.
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.
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
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.
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: firstname.lastname@example.org).
Esmaeli B, Murray JL, Ahmadi MA, Naderi A, Singh S, Romaguera J, White CA, McLaughlin P. Immunotherapy for Low-Grade Non-Hodgkin Secondary Lymphoma of the Orbit. Arch Ophthalmol. 2002;120(9):1225-1227. doi: