December 6, 2010

Radioimmunotherapy Advancing — Zevalin and Bexxar Treat Follicular B-Cell Non-Hodgkin’s Lymphoma
By Arkadiy Kheyfits
For The Record
Vol. 22 No. 22 P. 24

There are two radioimmunotherapy (RIT) treatments currently approved for the treatment of follicular B-cell non-Hodgkin’s lymphoma under the brand names of Zevalin (ibritumomab tiuxetan) and Bexxar (tositumomab and iodine I–131). Both drugs operate under the same principles: Tumor cells are first targeted with a monoclonal antibody and then are ablated by the radioactive material covalently linked to the antibody.

According to the National Cancer Institute, 65,540 new cases of non-Hodgkin’s lymphoma were diagnosed last year in the United States. Eighty-five percent of non-Hodgkin’s lymphoma cases are of the B-cell subtype and are indolent, but only about one half of those diagnosed will be in remission for more than five years. As reported by the American Cancer Society, the remaining 50% will require further treatment to address recurrent or transformed non-Hodgkin’s lymphoma. Choices for treatment include external beam radiation, traditional chemotherapy, and immunotherapy, but there are limits to each.

With external beam radiation, large radiation doses often cannot be directed to the tumor site due to the diffuse nature of non-Hodgkin’s lymphoma. Chemotherapy is heavily cytotoxic, and lymphoma can develop resistance to chemotherapy after only a few courses. Immunotherapy, which utilizes man-made antigens to target cancer cells to either kill them or activate the body’s immune system, is a relatively new technology. Over the past decade, RIT, which links radioactive isotopes to antigens created to bind to a receptor on the cell surface of B cells, has been developed as a targeted option for treating diffuse disease.

Both Bexxar and Zevalin target the CD20 antigen found on all mature B cells, but a key difference is the radioactive material found in each drug. Bexxar contains iodine-131, a beta and gamma particle emitting substance. B particles are capable of short-range tissue destruction because they are of low path length but relatively high mass, while gamma particles do not cause local damage because of their long path length and high energy which directs them out of the body. Indeed, gamma-radiation accounts for the majority of radiographic imaging.

In contrast, Zevalin contains yttrium-90 (Y-90), a pure B emitter. A key practical difference between the two radionuclides relates to radiation safety. George Tidmarsh, MD, PhD, a pediatric oncologist and chief scientific officer at Spectrum Pharmaceuticals, producer of Zevalin, notes that the gamma emission of its Y-90 is advantageous.

“With Bexxar, much of the energy is deposited outside the body,” Tidmarsh says. “There are significant posttreatment precautions for patients, such as oftentimes not being able to sleep in the same room as their spouse or loved ones or having to carefully dispose of any clothing contaminated with radioactivity. The need for precaution does not exist with yttrium since much of the radiation is deposited directly in the tumor and not outside the body.”

Patient Selection
Before RIT can be administered, there is a careful patient selection process, according to Jorge Carrasquillo, MD, a nuclear medicine physician and director of targeted radiotherapy at Memorial Sloan-Kettering Cancer Center in New York City.

“The current guidelines include patients that have failed other therapies,” Carrasquillo says. “Patients also have to be sufficiently healthy to tolerate the treatment. Patients need to have low bone marrow involvement and a platelet count high enough to tolerate the cytopenic effect of the treatment.”

The reduced blood count that follows RIT treatment is delayed in comparison with common chemotherapy. Tidmarsh adds that “with standard chemotherapy, the time at which the lowest blood counts occur tend to be anywhere from seven to 14 days after the administration of the chemotherapy, with recovery typically by about three weeks. With RIT, the time to the lowest blood count takes several weeks, and recovery may take eight to 10 weeks.”

Patients eligible for RIT are then referred to either a nuclear medicine specialist or a radiation oncologist familiar with RIT. Treatment planning requires imaging to ensure correct dosimetry and confirm normal biodistribution of the pharmaceutical.

Tidmarsh clarifies the differences between treatment with Bexxar vs. Zevalin: “[Patients treated with Zevalin] are given a standard dose of Y-90, whereas with Bexxar, the treatment is individualized depending upon how fast the patient eliminates the radioactivity from the body.” Treatment with Zevalin requires only a single whole-body scan, with Zevalin tagged with indium-111 instead of Y-90 to determine biodistribution. The dosimetry is then based upon platelet count and body weight.

Carrasquillo explains that Bexxar requires “three sets of scans taken over a week: one on the day of injection, another at three to four days, and a final one after six or seven days. Dosimetry calculations are performed by a medical physicist and then checked.” Multiple scans are required to determine the effective half-life of the drug once it is injected into the body.

After diagnostic scanning, patients are given “radiation safety instructions … to follow, any questions are answered, and then the cold antibody is infused followed by the hot infusion of the drug using an infusion pump over 20 minutes. We keep the patient for an hour for observation and then the patient is free to leave,” Carrasquillo says.
“Patients tolerate the treatment very well,” he adds. “I think the toxicity is less than seen with chemotherapy regimens.”

Both Carrasquillo and Tidmarsh agree that RIT has clinically proven efficacy. “The data has shown that those patients experience profound tumor shrinkage when treated with Zevalin,” Tidmarsh says. “In some cases, there is a complete remission of the tumor, and those responses—elimination of detectable evidence of disease—in some patients lasts for a very long time—years and years.” Tidmarsh adds that he is referring to patients who have failed previous chemotherapy treatments and are turning to Zevalin as a result.

New Indication
In the past few years, an important new indication has been FDA approved for Zevalin use. As of September 2009, Zevalin is approved for use as a consolidation therapy, immediately following a course of chemotherapy, as a first-line treatment for follicular B-cell non-Hodgkin’s lymphoma. The approval is the result of a large randomized study presented at last year’s American Society of Hematology annual meeting called the First-line Indolent Trial (FIT).

“Patients with follicular lymphoma were randomized to receive chemotherapy in a traditional format,” Tidmarsh says. “All patients were treated with six cycles of traditional chemotherapy to eliminate as much of the disease as possible, and those patients not showing progression during those six cycles but had shown some benefit were observed or treated with Zevalin. The study showed that those who were treated with Zevalin on top of their initial first-line chemotherapy experienced a much longer period of time until their lymphoma progressed to the point where treatment was again required.”

Carrasquillo believes the FIT trial will lead to a more widespread use of Zevalin but notes that there are obstacles that block the path. “An article by Schaefer and colleagues [reported on] surveys to physicians regarding RIT,” he says. “The results indicated that the majority of physicians had a favorable view of RIT, but when asked why these tests were rarely ordered, some responded that RIT wasn’t available in many nuclear medicine departments, presumably because of the high cost of the procedure resulted in fear of lack of adequate reimbursement. Other concerns included fear by the oncologists that patients would be lost to them if they were referred elsewhere. Related to that, oncologists have multiple drug regimens that can be used with this disease that are effective, though perhaps not as effective as RIT, and they tend to rely on what is tried and to them true rather than RIT.”

Carrasquillo believes the remedy for the concerns expressed in the article is making RIT more available in nuclear medicine departments and enhanced education of referring physicians regarding the benefits of using Zevalin as an adjunct therapy with traditional chemotherapy.

Tidmarsh is hopeful that with the new indication, Zevalin consolidation therapy can supersede the current standard of care.

“I could see a day in which we look at the comparison of what’s normally done for newly diagnosed lymphoma patients, which is typically chemotherapy followed by infusion every eight weeks for two years of rituxomab,” Tidmarsh says. “We currently lack a randomized study, but I predict that such a study would find the outcome with Zevalin is at least as good as with rituxomab maintenance therapy without the substantial side effects of the current regimen. And I think what we’ll find is that there will be a significant benefit to the patient as well as the overall healthcare system in terms of cost; giving a single dose of Zevalin right after up-front chemotherapy is cost-effective vs. the ongoing injections of rituxomab. If the data collection to prove cost-effectiveness is soon forthcoming, we may see a notable change in the way newly diagnosed lymphoma is managed.”

— Arkadiy Kheyfits is a freelance writer based in Brooklyn, N.Y.