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Earlier use of Bexxar may improve outcomes in non-Hodgkin's lymphoma


Treatment outcomes associated with the Bexxar therapeutic regimen ( Tositumomab and Iodine I 131 - Tositumomab ) in non-Hodgkin's lymphoma patients were significantly improved when Bexxar was administered earlier in the treatment sequence.

The review compared the treatment responses of 1,177 patients from 10 clinical trials in which Bexxar was used as either first-line, second-line, third-line, or fourth-line ( or greater ) treatment.

" Response rates, complete response rates and associated durations of response to the Bexxar therapeutic regimen all increased significantly as the number of prior therapies decreased, " said Stephanie A. Gregory, of the Rush University Medical Center, and the lead author of the study. " Durable complete responses were observed in every treatment sequence studied. In addition, the frequency of complete responses was much greater when Bexxar was used earlier. These data suggest that Bexxar should be administered early in the course of relapsed lymphoma for optimal outcome, and not reserved as a salvage treatment. "

The median patient age across all 10 studies included in the analysis was 57 years ( range 21-90 ), with slightly more males than females ( 54 percent versus 46 percent ).
The median time from non-Hodgkin's lymphoma diagnosis to initiation of treatment with Bexxar was 40 months.
Ninety percent of the patients had stage III/IV disease, 47 percent had a tumor diameter of 5 cm or greater, and 44 percent had detectable tumor in the bone marrow.

Comparisons of response rates were made between the 540 patients who received Bexxar after at least three prior therapies ( fourth-line or greater ), 228 who received it after two prior therapies ( third-line ), 226 who received after one prior therapy ( second line ), and 141 who were previously untreated ( first-line ).

The differences in response rate, median duration of response, complete response rate, median duration of complete response, and progression free survival greater than one year were highly statistically significant ( p < 0.001 ) between each treatment sequence.
The complete response rate with Bexxar as fourth-line or greater therapy was 23 percent, compared to 46 percent as a second-line treatment.
Similarly, progression free survival greater than 1 year was 59 percent for second-line patients compared to 27 percent for those patients who received Bexxar as fourth-line or greater therapy.

The Bexxar therapeutic regimen is indicated for the treatment of patients with CD20 antigen expressing relapsed or refractory, low-grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin's lymphoma.
Determination of the effectiveness of the Bexxar therapeutic regimen was based on overall response rates in patients whose disease is refractory to chemotherapy alone or to chemotherapy and Rituximab.
The effects of the Bexxar therapeutic regimen on survival are not known.
The Bexxar therapeutic regimen is not indicated for the initial treatment of patients with CD20 positive non-Hodgkin's lymphoma.
The Bexxar therapeutic regimen is intended as a single course of treatment.
The safety of multiple courses of the Bexxar therapeutic regimen, or combination of this regimen with other forms of irradiation or chemotherapy, has not been evaluated.

Bexxar pairs the targeting ability of a monoclonal antibody ( Tositumomab ) and the therapeutic action of radiation ( Iodine-131 ). Combined, these agents form a radioimmunotherapeutic regimen that is able to bind to the target antigen CD20 found on B cells, including normal cells and those that are cancerous in non-Hodgkin's lymphoma, thereby delivering the dose of radiation.
Bexxar, which is given in four visits over one to two weeks, is specifically dosed based on an individual's drug clearance rate, allowing the delivery of a predetermined amount of radiation to each patient.

The Bexxar therapeutic regimen has been studied for more than 14 years.
It was originally approved by the U.S. Food and Drug Administration ( FDA ) in 2003 for use in patients who had relapsed following chemotherapy and were refractory to Rituximab. The approval was based on a multicenter, single-arm, clinical trial in 40 patients who had received a median of four prior chemotherapies and whose disease had not responded to or had progressed after at least 4 doses of Rituximab.
In this study, 68 percent responded to Bexxar. The median duration of response was 16 months.

The FDA recently expanded the indication for Bexxar based on a multicenter, single-arm, open-label study of 60 chemotherapy-refractory patients. The median age of study participants was 60 years ( range 38-82 ), the median time from diagnosis to protocol entry was 53 months ( range 9-334 ), and the median number of prior chemotherapy regimens was 4 ( range 2-13 ).
Fifty-three patients had not responded to prior therapy and 7 patients had responded with a duration of response of less than 6 months.
As determined by an independent panel of oncologists and radiologists that reviewed patient records and radiologic studies, the overall response rate for Bexxar in this study was 47 percent with a median duration of response of 12 months and the complete response rate was 20 percent with the median duration of response of 47 months after a median follow-up of 30 months.

Patients who are pregnant or allergic to any components of the regimen should not receive Bexxar.
Serious hypersensitivity reactions, including some with fatal outcome, have been observed with the Bexxar therapeutic regimen.
Treatment with Bexxar resulted in very severe decreases in blood counts ( platelets, white blood cells, and red blood cells ) in the majority of patients, which could be life-threatening, for an extended period of time ( about a month ), and in some patients, these decreases persisted for more than 90 days.
Infections occurred in almost half the patients, bleeding in one of eight patients, and treatment with supportive care was required in about one of four patients.
Other less severe reactions during or following the infusion have included fever, chills, sweating, nausea, low blood pressure, shortness of breath and difficulty breathing.
Patients may also experience weakness, fever, nausea, increased cough, infection, pain, chills, rash or headache.
There is a risk of hypothyroidism following the administration of Bexxar.
Because the Bexxar therapeutic regimen contains a murine component, administration of Bexxar resulted in the development of antibodies, called HAMA, in some patients.
The development of a second type of blood cancer and solid tumors has been observed following certain cancer therapies, including Bexxar.
At a median follow-up of 29 months, forty-four cases of myelodysplastic syndrome and/or leukemia and 65 cases of secondary tumors in 54 patients were reported among the 995 patients enrolled in Bexxar studies.
The risk of developing secondary cancers in patients receiving Bexxar compared to the background rates in this population cannot be determined due to the lack of appropriate comparative studies.
After being treated with Bexxar, less than five percent of patients suffered hair loss or developed severe nausea, vomiting or mucositis ( sores in the mouth or gastrointestinal tract ). Healthcare providers must be specifically trained to administer Bexxar.

Source: 41st Annual Meeting of the American Society of Clinical Oncology ( ASCO ), 2005

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