Phase II Study with R-FND Followed by 90-Y Ibritumomab Tiuxetan Radioimmunotherapy and Rituximab Maintenance for Untreated High-Risk Follicular Lymphoma

Follicular lymphoma (FL) patients (pts) with high-risk features using the FL International Prognostic Index (FLIPI) have an expected 5-year survival of approximately 50% with conventional chemotherapy. The incorporation of anti-CD20 monoclonal antibody therapy has improved results in this poor risk subgroup. (Buske, Blood 2006;108:1504) We have previously demonstrated that R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) is an effective regimen for indolent lymphoma, capable of inducing molecular remissions. (McLaughlin, ASCO 2003;102:564). Both extended dosing of rituximab following induction, and consolidation of first remission with 90-Y ibritumomab tiuxetan radioimmnotherapy (RIT) can improve complete response rates and progression free survival (PFS) rates for patients with advanced FL. (Morschhauser, JCO 2008;32:5156; Salles, Lancet 2011;377:42) This is the first report of a chemoimmunotherapy approach followed by both RIT consolidation and rituximab maintenance.

Untreated patients with FL (grade 1–3), with high risk disease (FLIPI score ≥ 3) who had adequate hematologic function and extensive stage (III/IV) disease were eligible for study entry. Patients received rituximab (375mg/m² days 1 and 8 of cycle 1, and day 1 of subsequent cycles) fludarabine (25mg/m² days 1–3), mitoxantrone (10mg/m² day 1), and dexamethasone (20mg 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 375mg/m² every two months for one year. The primary objective of the study was to determine the PFS rates based on 1999 International Working Group criteria. The secondary objectives included assessing the safety and tolerance of RIT and maintenance rituximab after R-FND, assessing the CR and overall response rates, and determining the overall survival following treatment.

Forty nine patients were enrolled and 47 received treatment between October 2004 and April 2009. Forty-six patients were eligible for efficacy analysis. The median age was 61 (37–78), 80% had bone marrow involvement, and all had stage III/IV disease. Twenty four (51%) patients had bulky disease (>5cm) and 42 (91%) had elevated β2M. Thirty six patients completed all planned courses of treatment. Eight patients did not receive RIT, two due to neutropenia after R-FND. One patient had progressive disease while on treatment. Following R-FND, the complete (CR + CRu) and partial response rates were 87% and 13%. With RIT consolidation, the CR rate increased to 91%. At a median follow up of 50 months, the projected five 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. The median time to hematologic recovery following RIT was 10 weeks. The most common non-hematologic adverse events (≥Gr 3) were fatigue (17%), dypsnea (13%), and myalgia (11%). There were 3 cases of myelodysplasia (MDS), one in a patient who did not receive RIT.

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. Given the potential for serious toxicity (eg. MDS) seen in this trial and other intensive treatment strategies, this approach may be most appropriate in high-risk FLIPI patients whose outlook with standard therapy is poor.

This study was sponsored by Genentech and Spectrum.

Fowler:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Younes:Genentech, SBIO, Seattle Genetics, Syndax, Sanofi-Aventis: Honoraria, Research Funding.