Zevalin Improves Progression-Free Survival by 2 Years in Follicular Lymphoma
December 11, 2007 — The first randomized trial of radioimmunotherapy used to consolidate remission in advanced-stage follicular lymphoma has produced \"dramatic results,\" showing an improvement in progression-free survival of more than 2 years, said lead investigator Anton Hagenbeek, MD, PhD, from the University Medical Center Utrecht, the Netherlands. A single treatment with Zevalin (90Y-ibritumomab tiuxetan; Cell Therapeutics Inc.) administered after a first remission with chemotherapy prolonged progression-free survival by more than 2 years, he told the American Society of Hematology 49th Annual Meeting in Atlanta, Georgia.
These results, from a company-sponsored phase 3 trial known as the First-line Indolent Trial (FIT), \"show that radioimmunotherapy is the most effective single agent in the treatment of follicular lymphoma,\" Dr. Hagenbeek commented.
Ironically, these dramatic results come just days after the announcement that new Medicare rules have significantly reduced the reimbursement for radioimmunotherapy in the United States. The new rules state that starting January 1, 2008, hospitals using radioimmunotherapy, including Zevalin and a similar agent, Bexxar (tositumomab and iodine I 131 tositumomab; GlaxoSmithKline), will be reimbursed about $16,000 per treatment, although each treatment costs around $30,000.
\"This is really cutting us off at the knees,\" says Jane Winter, MD, from Northwestern University, in Chicago, Illinois. Radioimmunotherapy has not been used much in the United States because it is complicated to administer, requires highly trained physicists, and requires a commitment to training staff, she explained. But this latest move takes away any incentive to use it. \"At my center, this latest move means that we will be taking a loss of around $10,000 per patient, which we just cannot afford.\"
This announcement was made just as these new results are coming out, Dr. Winter said, and it is ironic, because \"this is a very compelling treatment, especially when you consider that it is delivered as a one-off,\" she told journalists after a press conference that she moderated. \"This is a big and important study, and it shows that the product is highly effective.\" Radioimmunotherapy is 1 of the biggest advances in the field of lymphoma, she said, but now \"the Europeans are going to gallop ahead of us.\"
Zevalin consists of an anti-CD20 monoclonal antibody combined with yttrium-90 radiation, and behaves \"like a wolf in sheep's clothing,\" Dr. Hagenbeek told journalists. \"It enters the body and searches for and targets only lymphoma cells, so that the radiation is going straight to where it needs to go,\" he explained. \"This reduces toxicity to normal tissues, which has always been a problem with external-beam radiation,\" he explained. The product was originally developed by Biogen Idec, and is in the final stages of being acquired by Cell Therapeutics for marketing in the United States; it is marketed by Bayer Schering Pharma elsewhere in the world. Zevalin has been available for several years in both Europe and the United States for relapsed and refractory follicular lymphoma, but new applications have been filed, on the basis of the FIT results, to expand the indication to consolidation of first remissions following chemotherapy.
The trial compared a single Zevalin treatment with observation in 414 patients with advanced (stage 3 or 4) follicular lymphoma who had achieved partial or complete remission after first-line chemotherapy. The choice of which chemotherapy regimen to use for induction was left to the physicians' discretion, and various combinations were used, including CVP, CHP, fludarabine, chlorambucil, and rituximab.
The primary end point of median progression-free survival was 37 months in the group receiving Zevalin and 13.5 months in the control group (P < .0001).
\"There are no data as yet on overall survival,\" said Dr. Hagenbeek, because the median follow-up so far is only 3.5 years. To date, only 11 patients have died — 6 in the Zevalin group (1 from neutropenic sepsis, 1 pancreatic carcinoma, 1 acute myeloid leukemia, and 3 progressive disease) and 5 in the control group (1 sepsis, 4 progressive disease).
Subgroup analysis showed that patients in the Zevalin group who had gained a complete remission after their chemotherapy had a median progression-free survival of 54.6 months, and those in the control group had a median progression-free survival 29.9 months (P = .01). Of patients who had a partial remission, those in the Zevalin group had median progression-free survival of 29.7 months, and those in the control group had a median progression-free survival of 6.3 months (P = .0001).
After Zevalin consolidation, 78 of 101 patients (77%) with partial remission converted to complete remission, compared with only 17 of 97 patients (17.5%) in the control group (P < .001). In total, 87% of patients who received Zevalin responded, with 76% achieving complete remission and a further 11% in unconfirmed complete remission.
Dr. Hagenbeek noted that previous trials using autologous stem cell transplantation reported conversion rates of partial to complete remissions of 41%, 38%, and 69%, so the 77% conversion rate in this study shows that \"we are not doing a bad job,\" he said.
The researchers also measured remission at a molecular level, using real-time quantitative polymerase chain reaction (RQ-PCR), and found that 90% of patients receiving Zevalin had converted from RQ-PCR-positive to RQ-PCR-negative status, which was associated with a significant prolongation of progression-free survival. \"In 90% of patients, we could not find any trace of disease, even on a molecular basis,\" Dr. Hagenbeek commented to journalists.
The treatment was \"tolerated very well,\" Dr. Hagenbeek said, noting that health-related quality-of-life measures were similar in the 2 groups.
The main toxicity was hematologic, with falls in platelet and neutrophil counts seen at 5 and 6 weeks after Zevalin therapy, respectively; grade 3/4 neutropenia developed in 67% of patients on the drug. Despite this, there was a low incidence of infections, Dr. Hagenbeek commented, and grade 3 or 4 infections were seen in 16 patients (8%) in the Zevalin group and 5 patients (2%) in the control group.
Dr Hagenbeek concluded that Zevalin has now been \"proven to be highly efficacious.\" In the discussion that followed his presentation, Bruce Cheson, MD, from Georgetown University, in Washington, DC, mentioned the recent Medicare decision to restrict reimbursement for radioimmunotherapy in the United States and expressed the hope that \"studies such as this will bring them back to their senses.\" The sentiment struck a chord with the predominantly US audience, and the comment was greeted with spontaneous applause. |
发表于 2007-12-26 15:12:17