Durable Responses Reported with Bexxar Alone or In Sequential Therapy for Low-Grade Non-Hodgkin's Lymphoma
Research Presented at ASH
ORLANDO, Fla., Dec. 11 /PRNewswire/ -- According to studies presented at the 43rd annual meeting of the American Society of Hematology (ASH), Bexxar® (tositumomab and iodine I 131 tositumomab), an investigational radioimmunotherapy being studied for the treatment of low-grade or transformed low-grade non-Hodgkin's lymphoma (NHL), provides durable, long-term responses when used either alone or following chemotherapy. Multiple presentations suggest that Bexxar, currently under review at the U.S. Food and Drug Administration (FDA), may offer an important new treatment option for relapsed or refractory NHL patients, and in particular for patients whose prognosis is usually very poor.
Reports of Durable, Objective Responses
Analysis of data on 582 patients with relapsed, refractory low-grade or transformed low-grade NHL who received Bexxar in clinical trials from 1990- 2000, by John Leonard, M.D., clinical director, Center for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York, and his colleagues, showed that Bexxar produced an overall response (defined as a reduction of at least 50 percent in overall tumor burden) in 57 percent of patients, half of whom remained in remission for 14.3 months or more [ASH Abstract #2527]. Furthermore, 28 percent of all patients showed a complete response (total elimination of disease confirmed by clinical or radiological evaluation) to Bexxar therapy, half of whom remained in remission for 4.8 years or longer. The average follow-up was 1.3 years with a maximum of 8.5 years.
``These results provide further evidence that Bexxar produces durable responses in patients with either low-grade or transformed low-grade NHL,'' said Dr. Leonard.
Novel First-Line Triple Modality Therapy
To evaluate a new approach to previously untreated NHL, investigators treated 35 patients in a clinical trial of ``triple modality'' therapy, the combination of chemotherapy (fludarabine), radiation (Iodine-131) and a monoclonal antibody (tositumomab) [ASH Abstract #3505]. All patients (100 percent) in the trial exhibited an investigator-assessed response to the treatment, with 77 percent achieving a complete response. After a median of 23 months of follow-up, more than half of the patients were showing no signs of disease progression.
``We are encouraged by the results of this study and the apparent utility of this triple modality approach using fludarabine and Bexxar radioimmunotherapy,'' said Dr. Leonard. ``Combination regimens have been successful in many cancers and offer new strategies for patients with lymphoma.''
The triple modality regimen consisted of three cycles of fludarabine followed by Bexxar, administered six to eight weeks later, for patients with previously untreated low-grade NHL. Ninety-seven percent of the participants were classified as stage III (widespread disease to both sides of the diaphragm), or stage IV (spread outside of the lymph system to one or more organs and the bone marrow). The patient population ranged in age from 25 to 82.
The hematologic side effects of the triple modality therapy were principally decreases in white blood cell counts that responded to supportive care. Three patients were hospitalized for neutropenic fever (one after fludarabine and two after fludarabine and Bexxar).
``This novel approach produces a high response rate in initial therapy for low-grade non-Hodgkin's lymphoma,'' concluded Dr. Leonard. ``We have also found that by using fludarabine to debulk or reduce a patient's tumor burden, including tumor in the bone marrow, we can expand the number of patients who can benefit from Bexxar therapy.''
Triple modality therapy, combining various chemotherapies with Bexxar, is being investigated for the treatment of other types of non-Hodgkin's lymphoma. Results from one such study, a Phase II clinical trial of CHOP, a standard combination chemotherapy regimen, followed by Bexxar, for treatment of newly diagnosed follicular NHL, were also reported at ASH by researchers affiliated with the Southwestern Oncology Group (SWOG) [ASH Abstract #3504]. In this study, 80 percent of the 71 patients evaluated following the sequential therapy had achieved an objective remission, either having a complete response (52 percent) or a partial response (28 percent). Grade 4 toxicities were reported in 38 percent of the 88 evaluable patients who had received CHOP. Thirteen percent of 60 presently evaluable patients who went on to receive Bexxar experienced additional Grade 4 toxicity. In 17 patients (24 percent), the addition of Bexxar to CHOP improved the overall best response, either from a partial to a complete response (15 patients or 21 percent) or from an unconfirmed to a confirmed complete response (2 patients or 3 percent). The investigators reported that ``the addition of I-131-tositumomab [Bexxar] radioimmunotherapy to 6 cycles of CHOP chemotherapy is feasible, well- tolerated and efficacious.''
Importance of Radiation Component of Bexxar Therapy Demonstrated
Investigators also presented data that clearly demonstrated the clinical utility of the radioactive component in Bexxar [ASH Abstract #3503]. This study, a randomized, open label, multicenter clinical trial of 78 patients treated at nine sites investigated the safety and efficacy of treatment with either Bexxar or its unlabeled antibody component, tositumomab. Seventeen percent of patients enrolled in this trial presented with transformed disease, a particularly difficult prognostic factor with respect to survival and response. Independently assessed confirmed overall responses were observed in 55 percent of the patients treated with Bexxar and 17 percent of patients treated with two doses of tositumomab. Confirmed complete responses were achieved in 33 percent of patients treated with Bexxar compared to 8 percent of patients treated with tositumomab.
The median duration of confirmed responses for patients treated with Bexxar has not been reached, whereas half of the patients treated with unlabeled tositumomab had relapsed after 18 months. The study allowed patients who did not respond or who relapsed after unlabeled tositumomab to crossover to receive Bexxar. Of the 19 patients who did so, 68 percent had a confirmed response and 42 percent had a confirmed completed response.
``We have demonstrated that radiolabeling with I-131 provides significant therapeutic benefits over an unlabeled anti CD-20 antibody,'' said Mark S. Kaminski, M.D., professor of internal medicine and co-director of the leukemia/lymphoma bone marrow transplant program at the University of Michigan Cancer Center.
Hematologic toxicity was observed in a greater number of Bexxar patients than tositumomab patients. ``In our assessment, the greater therapeutic activity of Bexxar outweighed the lower toxicity observed for the unlabeled antibody,'' said Dr. Kaminski.
Overall Bexxar Hematological Toxicity Reported
Dr. Kaminski also presented an analysis of hematologic toxicity following treatment with Bexxar based on data from 677 previously treated patients with relapsed or refractory low-grade NHL and 76 previously untreated patients [ASH Abstract #1433]. He and his colleagues found that Grade 4 neutropenia, anemia, and thrombocytopenia occurred in 16 percent, 2 percent, and 3 percent of patients respectively, with serious infections reported in 5 percent and Grade 3 or 4 bleeding events in only 1 percent. Twenty-three percent of these previously treated patients required some form of supportive care (such as growth factors or transfusions) for hematologic side effects. Hematologic toxicity was less frequent in previously untreated patients. No patients in this cohort exhibited hematologic toxicity that required treatment with either growth factors or transfusions. The researchers concluded that the hematologic side effects in patients who received Bexxar were manageable and reversible, and the use of supportive care was uncommon.
``Furthermore, because Bexxar therapy is administered as a single course of treatment, it avoids the repeated and cumulative treatment related toxicity that may result from successive cycles of standard chemotherapy,'' said Dr. Kaminski... |
