Immunotherapy and Radioimmunotherapy for Low Grade Indolent NHL of the Orbit

Although external beam radiotherapy is effective at controlling orbital lymphomas, it is associated with the risk of distant relapse and ocular toxicity. Systemic chemotherapy is an effective treatment for

TABLE 13.2. Ann Arbor Staging System for Lymphoma.

Stage Description

I* Involvement of a single lymph node region or lymphoid structure (e.g. spleen or Waldeyer ring) II* Involvement of two or more lymph node regions on same side of the diaphragm or localized involvement of an extranodal lymphoid structure and of one or more lymph node region on same side of diaphragm

III Involvement of lymph nodes on both sides of diaphragm ± extranodal sites

IV Involvement of two or more extranodal sites or liver or bone marrow

^Involvement of an extranodal organ or site is designated with the suffix E (stage IE or stage IIE).

higher grade or more advanced stages of lymphoma, but in the elderly patient the presence of comorbid disease may mitigate against intensive chemotherapy approaches. Thus, new and alternative treatment options for orbital lymphoma may be desirable.

Recent reports have suggested that monoclonal antibody therapy may be effective in the treatment of low-grade NHLs.33-35 Investigators have characterized the patterns of expression of surface antigens on B cells and have developed targeted therapy with monoclonal antibodies directed against several of these antigens. One of these surface antigens is CD20, which is a hy-drophobic phosphoprotein that is expressed on mature B cells and most B-cell malignancies but not on stem cells, pre-B cells, or plasma cells. Rituximab (Rituxan) is a genetically engineered chimeric mouse/human antibody discovered in 1990 by IDEC Pharmaceuticals; it binds with high affinity to cells expressing the CD20 antigen and causes tumor lysis via both complement-dependent and antibody-dependent cellular cytotoxic-ity.36 It also can sensitize chemoresistant human lymphoma cell lines and induce apoptosis in vitro. Rituximab was approved by the U.S. Food and Drug Administration in 1997 for the indication of relapsed or refractory CD20-positive B-cell low-grade or follic-ular NHL. It is the first monoclonal antibody approved for the treatment of cancer and the first single agent approved specifically for therapy of lymphoma. It is administered as an intravenous infusion at a dose of 375 mg/m2 once weekly for 4 consecutive weeks. Outpatient therapy is feasible and is completed within 22 days (treatment on days 1, 8, 15, and 22). The overall response rate to rituximab is 48% for relapsed low-grade lymphomas. The response rate is somewhat higher for follicular lymphomas (58%).33-36

FIGURE 13.5. Computed tomography scans of the orbit in a patient with low-grade follicular lymphoma of the left lacrimal gland. (A) Before monoclonal antibody treatment, a mass was visible in

Rituximab is well-tolerated and does not deplete marrow reserves. Most side effects are mild and infusion related, usually occurring with the first infusion. The common reported side effects include transient chills, fever, nausea, fatigue, headache, and pruritis; less frequently there can be bronchospasm, hypotension, rash, or anaphylaxis.

Radioimmunotherapy refers to administration of a monoclonal antibody in combination with a radioactive ligand. Beta particles emitted by commonly used radioisotopes are tumoricidal over a distance of many cell diameters, allowing eradication of antigen-negative tumor cells by radioactive cross fire from neighboring antigen-positive antibody-coated cells. This additional mechanism for tumor lysis leads to a more dramatic treatment effect than the nonradioactive antibody.

IDEC-Y2B8 (Zevalin) is a murine IgG1 k monoclonal antibody directed against the CD20 antigen that is conjugated to MX-DTPA and bound to the beta-emitting radioisotope yttrium-90.37 Zevalin is usually given as a single dose following an infusion of ritux-imab. Radioimmunothearpy with Zevalin in combination with rituximab has shown greater efficacy for treatment of low-grade lymphoma than rituximab alone. Dosimetry has shown that at doses of up to 0.4 mCi/kg, no normal organ, including red marrow, received a radiation dose greater than 14 Gy.38

The experience at M. D. Anderson for treating low-grade lymphomas of the orbit with rituximab therapy alone or in combination with Zevalin, its radioactive-liganded counterpart, has been positive.12 Three patients with low-grade lymphoma of the orbit were treated with four weekly doses of rituximab; two additional patients were treated with one dose of ritux-

the inferior left orbit (arrows). (B) Two months after administration of rituximab and yttrium-90-labeled ibritumomab tiuxetan, the orbital mass had shrunk considerably.

imab followed by Zevalin. All five patients achieved complete resolution of their orbital lymphoma in response to monocloncal antibody therapy (Figure 13.5). The potential benefits of radioimmunotherapy include fewer side effects than accompany external beam radiation therapy and systemic chemotherapy, repeatability in case of recurrence, and a shorter duration of therapy than is possible with both the other two modalities. If in larger studies monoclonal antibody treatment proves to be as effective as external beam radiotherapy or chemotherapy for the treatment of indolent lymphomas of the orbit, it may indeed be an exciting alternative therapy for orbital lymphomas.

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