Bexxar for Lymphoma: Gone but Not Forgotten

Pam Harrison

November 13, 2014

The radiolabeled monoclonal antibody 131I-tositumomab (Bexxar, GlaxoSmithKline) is back in the news.

It was once indicated for the treatment of relapsed refractory low-grade follicular or transformed CD20-positive non-Hodgkin's lymphoma, but was withdrawn from the market in October 2013.

In February 2014, GlaxoSmithKline discontinued the manufacture of the product, primarily because of a decline in use of 30% a year from 2006, its peak sales year.

"In 2012, only 75 patients received the drug," writes Vinay Prasad, MD, from the Bloomberg School of Public Health, Johns Hopkins University, in Baltimore, in his essay published online November 10 in JAMA Internal Medicine.

A conservative estimate suggests that during the decade 131I-tositumomab was available, only 2000 to 3000 patients received it each year.

Dr Prasad details the difficult history of the drug, including negative results from a 2013 Southwest Oncology Group (SWOG) study in which investigators reported no benefit from 131I-tositumomab relative to CHOP-R alone (J Clin Oncol. 2013:31:314-320).

Dr Prasad writes as much about the drug's potential harms as he does its "unknown" benefits, citing severe allergic reactions at the time of infusion and prolonged and severe cytopenias.

"The narrative that circulated was that this was a drug with great efficacy, that it was a commercial failure, and that it was withdrawn for only commercial reasons," Dr Prasad told Medscape Medical News.

"But I feel the truth about Bexxar was different, upon closer look. The drug had great surrogate efficacy but no efficacy regarding real outcomes in any controlled clinical trial, and it had real toxicity. The 'right' story of Bexxar might not be that it was a good drug that didn't sell," he explained.

I feel the truth about Bexxar was different, upon closer look.

This story is news to Mark Kaminski, MD, professor of hematology at the University of Michigan in Ann Arbor, who helped develop the product.

"I'm puzzled as to why this editorial is coming out now," he told Medscape Medical News. "It's mostly a negative diatribe against Bexxar and, basically, much of what the editorialist is saying is not relevant or true. I was very surprised and disheartened that the biggest point of all was missed, which was that the drug wasn't financially viable."

In fact, Dr Kaminski is so disappointed at losing a valuable drug like Bexxar for patients with relapsed refractory lymphoma that he is making great efforts to bring a generic molecule to fruition that will serve as a bioequivalent to the original drug.

"I've treated at least 500 patients with Bexxar, so I know what the experience with it really is. I also have an idea of when to use it," he told Medscape Medical News. As Dr Kaminski and colleagues were the first to report, patients with advanced-stage follicular lymphoma respond well to a single course of the therapy.

In one of the earliest studies evaluating the drug (N Engl J Med. 2005;352:441-449), Dr Kaminski's team reported that 95% of patients with previously untreated stage III and IV follicular lymphoma achieved a response after a single course of treatment, and 75% of them achieved a complete response.

After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59%, and median progression-free survival was 6.1 years.

These results indicate that 131I-tositumombab, as initial treatment in this group of patients, can induce prolonged clinical and molecular remissions in patients with advanced follicular lymphoma, as Dr Kaminski pointed out. The benefits of the drug, at least as they apply to this patient population, are therefore far from "unknown," he said.

Furthermore, one of the problems with the most recent trials is that radioimmunotherapy — including Bexxar and 90Y ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals) — has been used as consolidation, "meaning that after giving chemotherapy, you try to reduce the amount of bulky disease first with chemotherapy, and then stick in radioimmunotherapy as a 'clean-up'," Dr Kaminski explained.

There are, however, real reasons why this approach is doomed to fail, he argued. "When you give radioimmunotherapy, there's a 'cross-fire' effect that occurs when the radiolabeled antibodies hit their target," he said.

In other words, it's not just the cells that have been contacted by the radiolabeled antibody that are killed, the cells that are adjacent to them are killed as well. "And the more cells you have in the vicinity, the more cross-fire there is," he added.

If the amount of bulky disease has been reduced to a bare minimum by previous exposure to chemotherapy, the opportunity to extend the damage is lost.

Patients also receive "cold" antibody prior to receiving the radiolabeled antibody. When that cold antibody is given, "it is going to sit on top of the target and block the access of the radiolabeled antibody," Dr Kaminski said.

"The trials that were done in consolidation didn't show an advantage for radioimmunotherapy, but there is a potential explanation for that," he said.

Purported Harm

Then there is the issue of purported harm. During long-term follow-up, there are reports of secondary malignancies in up to 15% of patients who receive radioimmunotherapy. This includes patients with cancers that are not life-threatening, such as certain skin cancers.

"What we are most concerned about is the development of acute leukemia or myelodysplastic syndrome," Dr Kaminski said. "But these are generally occurring in patients who have been exposed to chemotherapy prior to getting radioimmunotherapy, so the culprit is probably either one or the other, or both — you can't really point a finger at one alone."

Dr Kaminski also took issue with allegations that 131I-tositumomab can cause either severe allergic reactions at the time infusion — so, too, can rituximab, he noted — or severe and prolonged cytopenias.

"I can tell you that Bexxar has been used in patients who've had an allergic reaction to rituximab and they don't have a reaction to Bexxar," he said.

Furthermore, Dr Kaminski observed that cytopenias are hardly a "no-no" in the treatment of cancer.

"It happens all the time with chemotherapy," he said. If cytopenia does occur following administration of the drug, patients rarely require hospitalization for neutropenic fever or severe infection, he added.

"There is actually no other drug out there with a track record like this," Dr Kaminski said. "Approximately 30% of patients can achieve long-term remission with Bexxar lasting over a decade. That's the biggest disappointment with this drug, now that it's gone, for patients with this disease — it's was an easy treatment, it took only one week to finish, and if there were any side effects, they were all reversible. I've been giving Zevalin lately because I don't have Bexxar to work with, but I don't have as much confidence that it will be a solution for patients as much as Bexxar would have been."

Won't Be Missed

In contrast, Bruce Cheson, MD, professor of medicine at Georgetown University in Washington, DC, who writes the Cheson on Oncology videoblog on Medscape, believes that the product will not be missed. There were many reasons 131I-tositumombab failed, one of which was that it was too complicated to use, he told Medscape Medical News.

"It involved the synchronization of nurses and medical oncologists or hematologists and radiation and nuclear medicine people, and it really took a coordinated effort to treat a patient with this agent," he elaborated.

The other reason is more basic. Because only radiation and nuclear medicine experts are licensed to handle radioactive molecules such as 131I-tositumomab, "patients had to be referred from one doctor to somebody somewhere else, which meant not only losing control of the patient, but also losing income from the patient," Dr Cheson said.

There were also strict exclusion criteria when considering the use of 131I-tositumomab related to the amount of bone marrow involvement in lymphoma and peripheral blood counts.

Most important, at least in Dr Cheson's mind, "we now have a whole menu of novel targeted drugs for follicular lymphoma patients who relapse."

There are the kinase inhibitors, other monoclonal antibodies, drug antibody conjugates, and many more — all of them far less cumbersome to administer than 131I-tositumomab.

There are similar issues with the administration of 90Y ibritumomab tiuxetan, which has also shown promise in the treatment of lymphoma. In a January 2012 videoblog, Dr Cheson described radioimmunogics as very effective but very underutilized. Now, as happened with 131I-tositumomab, the use of this drug is also falling, he told Medscape Medical News.

"When I give talks about new therapies for lymphoma to my fellows, I ask them who knows what radioimmunotherapy is, and not one of them raises their hand," Dr Cheson said.

"Bexxar has been supplanted by more interesting, albeit more expensive, treatment approaches. When I give talks on treatment for follicular lymphoma now, I don't even mention it anymore."

Dr Prasad, Dr Kaminski, and Dr Cheson have disclosed no relevant financial relationships.

JAMA Internal Medicine. Published online November 10, 2014. Extract


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