Researchers from the University of Michigan have reported that “a single one-week treatment with Bexxar® (tositumomab and iodine I 131 tositumomab) induced complete remissions lasting more than five years in most patients who had previously untreated follicular lymphoma.” The details of this phase II study were published in the February 3, 2005 issue of the New England Journal of Medicine.[1]
Low-grade follicular non-Hodgkin’s lymphoma (NHL) is an incurable disease; however, patients treated with autologous or allogeneic stem cell transplantation are a possible exception to this generalization. One of the major problems with evaluating survival benefit of new treatments is the relatively long life expectancy of many patients with this disease. However, given the ultimately fatal outcome of virtually all patients with low-grade NHL, continued exploration of new treatments is warranted.
Bexxar® is an anti-CD20 monoclonal antibody linked to radioactive iodine. Bexxar® is usually administered in a single non-myeloablative dose that does not require stem cell support. Bexxar® was originally approved by the US Food and Drug Administration in July of 2003 for the treatment of patients with CD20 positive, follicular NHL, with and without transformation, whose disease is refractory to Rituxan® (rituximab) and chemotherapy. In January of 2005, the FDA expanded the indication to include patients who were not refractory to chemotherapy or Rituxan®. The advantage to Bexxar® and similar agents is that there are fewer side effects because radiation is localized in the lymphoma, thereby sparing more normal tissue.
Previous studies have shown good activity of Bexxar® for the treatment of refractory low-grade lymphomas. In a recent SWOG trial, 90 patients with newly diagnosed advanced follicular lymphoma received 6 cycles of CHOP followed by Bexxar®.[2] These authors reported that the complete response rate was 72% for the 87 patients with complete data. After CHOP therapy, Bexxar® was found to improve overall best response in 57% of the 47 evaluable patients. Progression-free survival at two years was 81%, with 14 relapses or deaths. The two-year estimate for overall survival was 97%. These authors are currently carrying out a randomized SWOG trial to determine if these results are superior to CHOP alone.
Bexxar® has also been evaluated in patients with stage III/IV follicular lymphoma, small lymphocytic lymphoma or monocytoid B-cell lymphoma treated with fludarabine induction.[3] Following Bexxar® treatment, 86% of patients achieved a complete response and 6% achieved a partial response. Median progression-free survival had not yet been reached at the time of this follow-up and the 5-year overall survival was 90.2%.
In this recent study, a total of 76 patients with stage III or IV follicular lymphoma were treated with a single dose of Bexxar® without any other therapies. Sixty-nine of these patients were 60 years of age or younger. The complete response rate was 75%. The researchers reported that 59% of patients were alive and progression-free at 5 years, with a median progression-free survival of 6.1 years. Overall survival was 89% at 5 years. Patients with a complete response had a better survival, as did those who were PCR-negative after treatment. Table 1 summarizes some of the major findings of this study.
Table 1: Results from a Single Dose of Bexxar® in Previously Untreated Follicular Lymphoma
| Complete Response Rate | 5-year Progression-free Survival |
Stage III | 87% | 82% |
Stage IV | 70% | 49% |
No Bone Marrow Involvement | 89% | 81% |
Bone Marrow Involvement | 67% | 47% |
No Bulky Disease | 88% | 63% |
Bulky Disease | 58% | 54% |
BCL2 Gene | 77% | 51% |
No BCL2 Gene | 76% | 70% |
Comments: This study suggests that Bexxar® can be moved to up-front treatment without adding significantly to toxicity. However, this study included predominantly younger patients with follicular lymphoma, which is not representative of the entire population of such patients. It will also be important to document accurately the benefits of this up-front strategy versus administering Bexxar® only when the disease progresses. Unless Bexxar® can result in some “cures” rather than palliation, there may be no net benefit from early administration rather than waiting until the disease progresses. It is also not yet clear if patients should receive induction therapy before Bexxar® for optimal results.
References:
[1] Kaminski MS, Tuck M, Estes J, et al. 131I-Tositumomab Therapy as Initial Treatment for Follicular Lymphoma. New England Journal of Medicine. 2005;352:441-449
[2] Press OW, Unger JM, Braziel RM, et al. A Phase II Trial of CHOP Chemotherapy Followed by iodine I 131 Tositumomab for Previously Untreated Follicular Non-Hodgkin’s Lymphoma: Southwest Oncology Group Protocol S9911. Blood. 2003;102:1606-1612.
[3] Leonard J, Coleman M, Kostakoglu L, et al. Durable remissions with fludarabine followed by Tositumomab and Iodine I 131 tositumomab (BEXXAR® therapeutic regimen) for patients with previously untreated follicular non-Hodgkin’s lymphoma. Proceedings from the 2004 annual meeting of the American Society of Clinical Oncology. 2004. Abstract #6518.
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