⁹⁰Y-Ibritumomab Tiuxetan (Zevalin®) Consolidation of First Remission in Advanced Stage Follicular Non-Hodgkin’s Lymphoma: First Results of the International Randomized Phase 3 First-Line Indolent Trial (FIT) in 414 Patients.

Radioimmunotherapy is effective in patients with relapsed/refractory and newly diagnosed follicular non-Hodgkin’s lymphoma (FL). This study investigated the efficacy and safety of Zevalin consolidation in patients with advanced stage FL responding to first-line chemotherapy. The concept tested was whether a single infusion of Zevalin would prolong progression free survival (PFS) in patients with (minimal) residual disease. Major inclusion criteria were: CD20-positive grade 1 or 2 FL; stage III or IV at diagnosis; normal peripheral blood cell counts; <25% bone marrow involvement; age ≥18 yrs, and CR/CRu or PR after first line chemotherapy determined by physical examination, CT scans and bone marrow biopsy. From 8/2001 to1/2005, 414 patients were enrolled at 77 study centers in 12 European countries and Canada. After completing induction therapy, patients were randomized to receive either Zevalin (250 mg/m² rituximab on day -7 and on day 0 followed on day 0 by Zevalin 0.4 mCi/kg; maximal dose: 32 mCi;[n=208]) or no further treatment [n=206]). The primary end point was prolongation of PFS, calculated from randomization, which was approximately 2 wks before Zevalin administration. Secondary end points were change of response status, ie, PR to CR/CRu and BCL2-JH PCR status from positive to negative; safety/tolerability and quality of life. Patient demographics were similar in both groups (Zevalin/control): males 48%/50%; median age 55/53 yrs; at diagnosis, stage III 35%/31%, stage IV 64%/66%; B-symptoms 22%/20%; response status after induction, PR 49%/47%; CR: 51%/53%. Induction therapies included: CVP n=106, CHOP (-like) n=188, fludarabine combinations n=22, chlorambucil n=39 and rituximab-chemotherapy combinations n=59. With a median follow-up of 2.9 yrs, the median PFS increased from 13.5 (controls) to 37 mo (Zevalin; p<0.0001; HR 0.463). For patient subgroups in PR or CR after induction, median PFS was 6.3 vs 29.7 mo (p<0.0001; HR 0.304) and 29.9 vs 54.6 mo (p=0.01; HR 0.609), respectively. After Zevalin consolidation, 77% of patients in PR after induction therapy converted to CR; in total, 87% of patients were in CR(u), 76% in CR and 11% in CRu. Subgroup analyses based on induction treatment and outcome according to FLIPI will be presented. Toxicity was primarily hematologic. Median platelet count nadir was 45x10⁹/L; range 8–404x10⁹/L) at wk 7 (∼5 wks post Zevalin); median neutrophil nadir was 1.0x10⁹/L (range 0.02–6.6x10⁹/L) at wk 8(∼ 6 wks post Zevalin). Grade 3/4 infections occurred in 16 (8%) patients after Zevalin vs 5 (2%) in the control arm. So far, 11 patients have died, 5 in control arm (1 sepsis, 4 progressive disease); 6 in Zevalin arm (1 neutropenic sepsis after subsequent chemotherapy, 1 pancreas carcinoma, 1 AML, 3 progressive disease).

Conclusion: Zevalin consolidation of first remission in advanced stage FL is highly effective, resulting in a total CR(u) rate of 87% and prolongation of PFS by 2 yrs, with a favorable toxicity profile.