Durable Responses Reported With Radioimmunotherapy in Low-Grade Non-Hodgkin’s Lymphoma

According to studies presented at the 43rd annualmeeting of the American Society of Hematology (ASH), tositumomab/iodine-131tositumomab (Bexxar), an investigational radioimmunotherapy being evaluated forthe treatment of low-grade or transformed low-grade non-Hodgkin’s lymphoma(NHL), produced durable, long-term responses when used alone or followingchemotherapy. Multiple presentations suggested that tositumomab/iodine-131tositumomab may be an important new treatment option for patients with relapsedor refractory NHL and, in particular, for patients whose prognosis is poor.

John Leonard, md, clinical director of the Center for Lymphoma and Myeloma,Weill Medical College of Cornell University, New York, and his colleaguesanalyzed data on 582 patients with relapsed, refractory low-grade or transformedlow-grade NHL who received tositumomab/iodine-131 tositumomab in clinical trialsconducted between 1990 and 2000. The analysis showed that the radioimmunotherapycombination produced an overall response in 57% of patients, with 50% remainingin remission for at least 14.3 months. Moreover, 28% of all patientsachieved a complete response, and 50% of those who did so remained in remissionfor 4.8 years or longer. The median follow-up was 1.3 years, with amaximum follow-up of 8.5 years.

First-Line Triple-Modality Therapy

In another trial reported by Dr. Leonard, investigators treated 35 previouslyuntreated NHL patients with triple-modality therapy—the combination offludarabine (Fludara), tositumomab, and iodine-131-labeled tositumomab. Allpatients in the trial exhibited a response to treatment, with 77% achieving acomplete response. After a median follow-up of 23 months, more than half showedno signs of disease progression.

"This novel approach produces a high response rate in initial therapyfor low-grade non-Hodgkin’s lymphoma," said Dr. Leonard. "We havealso found that by using fludarabine to debulk or reduce a patient’s tumorburden, including tumor in the bone marrow, we can expand the number of patientswho can benefit from Bexxar therapy."

Triple-modality therapy (various chemotherapies combined with tositumomab/iodine-131tositumomab) is being investigated for the treatment of other types of NHL aswell. Results from one such study, a phase II clinical trial of CHOP(cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin],prednisone) followed by the radioimmunotherapy combination in newly diagnosedfollicular NHL, were reported at the ASH meeting by researchers affiliated withthe Southwest Oncology Group. In this study, 80% of the 71 patients evaluatedfollowing sequential therapy achieved an objective remission, ie, either acomplete (52%) or partial (28%) response. In 17 patients (24%), the addition oftositumomab/iodine-131 tositumomab to CHOP improved the overall best response,either from a partial to a complete response (15 patients, or 21%) or from anunconfirmed to a confirmed complete response (2 patients, or 3%).

Importance of Radiation Component

Investigators also presented data that clearly demonstrated the clinicalutility of the radioactive component in tositumomab/iodine-131 tositumomab.Their randomized open-label trial in 78 patients treated at nine sitesinvestigated the safety and efficacy of tositumomab/iodine-131 tositumomab andits unlabeled antibody component, tositumomab. Of patients enrolled in thistrial, 17% presented with transformed disease. Confirmed overall responses werereported in 33% of patients treated with the radioimmunotherapy combination,compared to 8% of patients treated with tositumomab alone.

The median duration of confirmed responses for patients treated with thecombination had not been reached, whereas half the patients treated withunlabeled tositumomab had relapsed after 18 months. The study allowed patientswho did not respond or who relapsed after unlabeled tositumomab therapy to crossover to tositumomab/iodine-131 tositumomab. Of the 19 patients who did so, 68%had a confirmed response and 42% had a confirmed complete response.

"We have demonstrated that radiolabeling with I-131 provides significanttherapeutic benefits over an unlabeled anti-CD20 antibody," said Mark S.Kaminski, md, professor of internal medicine and codirector of theleukemia/lymphoma bone marrow transplant program at the University of MichiganCancer Center.

Hematologic toxicity was observed in a greater number of patients receivingtositumomab/iodine-131 tositumomab than patients receiving tositumomab. "Inour assessment, the greater therapeutic activity of Bexxar outweighed the lowertoxicity observed for the unlabeled antibody," said Dr. Kaminski.

Hematologic Toxicity

Dr. Kaminski also presented an analysis of hematologic toxicity followingtreatment with tositumomab/iodine-131 tositumomab, based on data from 677previously treated patients with relapsed or refractory low-grade NHL and 76previously untreated patients. He and his colleagues found that grade 4neutropenia, anemia, and thrombocytopenia developed in 16%, 2%, and 3% ofpatients, respectively, with serious infections reported in 5% and grade 3/4bleeding events in 1%.

Among the previously treated patients, 25% required supportive care (such asgrowth factors or transfusions) for hematologic side effects. Hematologictoxicity occurred less frequently in previously untreated patients. No patientsin the latter cohort exhibited hematologic toxicity that required treatment witheither growth factors or transfusions. The researchers concluded that thehematologic side effects in patients who received tositumomab/iodine-131tositumomab were manageable and reversible, and the use of supportive care wasuncommon.

"Furthermore, because Bexxar therapy is administered as a single courseof treatment, it avoids the repeated and cumulative treatment-related toxicitythat may result from successive cycles of standard chemotherapy," said Dr.Kaminski.