ASH: Encouraging Findings Reported for Ibritumomab Tiuxetan in Follicular Lymphoma

SAN DIEGO—Encouraging findings were reported from multiple studies of ibritumomab tiuxetan (Zevalin), a CD20-directed radiotherapeutic antibody, in diverse patient groups with follicular lymphoma (FL). Improved outcomes were reported in patients with newly diagnosed FL, relapsed/refractory FL, marginal zone lymphoma, and in patients who received autologous or allogeneic transplantation.

Findings of a phase II study of R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone) followed by ibritumomab tiuxetan and rituximab maintenance therapy in patients with untreated high-risk FL were reported by Nathan H. Fowler, MD, from the department of lymphoma/myeloma, division of cancer medicine at the University of Texas MD Anderson Cancer Center.

“This is the first report of a chemoimmunotherapy approach followed by both radioimmunotherapy (RIT) consolidation and rituximab (Rituxan) maintenance,” he noted. Previous studies have shown that R-FND is effective and can induce molecular remissions, and that both extended dosing of rituximab following induction and consolidation of first remission with ibritumomab tiuxetan RIT can improve complete response rates and progression-free survival (PFS) rates for patients with advanced FL. “Extended dosing of rituximab following induction, and consolidation or improvement of response with ibritumomab tiuxetan can increase progression free survival rates for patients with advanced follicular lymphoma.” 

Untreated patients with FL (grade 1-3) with high-risk disease (Follicular Lymphoma International Prognostic Index [FLIPI] score ≥ 3) who had adequate hematologic function and extensive disease (stage III/IV) were eligible for study entry. Patients received rituximab (375 mg/m² days 1 and 8 of cycle 1, and day 1 of subsequent cycles), fludarabine (25 mg/m² days 1–3), mitoxantrone (10 mg/m² day 1), and dexamethasone (20 mg days 1–5) for four 28-day cycles. RIT was given 12–16 weeks following R-FND pending hematologic recovery. Six weeks following RIT, patients received rituximab 375 mg/m² every 2 months for 1 year.

The primary objective was to determine the PFS rates based on 1999 International Working Group criteria. Secondary objectives included assessing the safety and tolerance of RIT and maintenance rituximab after R-FND, assessing the complete response and overall response (OR) rates, and determining overall survival (OS) following treatment.

Between October 2004 and April 2009, 49 patients were enrolled and 47 received treatment. Of those, 46 were eligible for efficacy analysis. The median age was 61 (37–78), 80% had bone marrow involvement, and all had stage III/IV disease. There were 24 (51%) patients with bulky disease (> 5 cm) and 42 (91%) had elevated β2M. A total of 36 patients completed all planned courses of treatment, 8 patients did not receive RIT, 2 due to neutropenia after R-FND. One patient had progressive disease while on treatment.

Following R-FND, the complete and partial response rates were 87% and 13%, respectively. With RIT consolidation, the complete response rate increased to 91%. At a median follow-up of 50 months, the projected 5-year overall survival and PFS rates were 93% and 74%.

Toxicity was mainly hematologic. Grade ≥ 3 neutropenia and thrombocytopenia occurred in 57% and 35% of patients, respectively. Thirty-seven patients required growth factors and 17 patients required transfusions.

Median time to hematologic recovery following RIT was 10 weeks. The most common nonhematologic adverse events (≥ grade 3) were fatigue (17%), dyspnea (13%), and myalgia (11%). There were 3 cases of myelodysplastic syndromes (MDS), one in a patient who did not receive FIT.

“The combination of R-FND followed by RIT intensification and rituximab maintenance results in OS and PFS outcomes that are better than traditional combinations in this high-risk population,” said Dr. Fowler. “Given the potential for serious toxicity seen in this trial and in other intensive treatment strategies, this approach may be most appropriate in high-risk FLIPI patients whose outlook with standard therapy is poor,” he concluded.

“Based on the results presented today it is clear that ibritumomab tiuxetan used in the front-line setting has the potential to alter the current paradigm of follicular lymphoma treatment,” commented Stephanie A. Gregory, MD, director of the section of hematology at Rush University Medical Center, Chicago. “It is exciting to see that a single injection of this antilymphoma targeted therapy could potentially obviate the need for additional therapies, significantly improving quality of life. The high CR rates suggest that there could be a meaningful impact on overall survival. We look forward to future clinical development.”

A phase III study of ibritumomab tiuxetan in diffuse large B-cell lymphoma and a trial to evaluate the drug in previously untreated follicular non-Hodgkin lymphoma patients are expected to begin next year.