A Prospective Study Evaluating the Safety and Efficacy of Combination Therapy with Fludarabine Plus Mitoxantrone Followed by Yttrium-90 (⁹⁰Y) Ibritumomab Tiuxetan (Zevalin®) and Maintenance Rituximab as Front Line Therapy for Patients with Intermediate or High Risk Follicular Non-Hodgkin’s Lymphoma.

Background: The combination of fludarabine and mitoxantrone (FM) as a front line therapy for advanced follicular lymphoma (FL) has been shown to result in higher complete response rates when compared with standard-dose CHOP. We assessed the safety and efficacy of FM followed by ⁹⁰Y ibritumomab tiuxetan (IT) and maintenance rituximab (MR) in previously untreated patients (pts) with FL.

Methods: Pts with newly diagnosed stage III-IV FL and an intermediate or high FLIPI scores were eligible. Pts were required to have an expected survival of at least 3 months, a performance status ≤2, and adequate bone marrow (BM) function (ANC 1500/mm³, platelets 100,000/mm³), liver, and renal function. Initial treatment consisted of 4 cycles of FM (fludarabine 25 mg/m² on days 1–3, mitoxantrone 12 mg/m² on day 1 of each 28-day cycle). After restaging, complete and partial responders with ≤25% BM involvement proceeded to the IT therapeutic regimen. Partial responders with >25% BM involvement received 2 additional cycles of FM before IT. The ⁹⁰Y IT dose (0.3 or 0.4 mCi/kg) was adjusted according to the patient’s platelet count. MR (375 mg/m² weekly× 4) was scheduled for every 6 months over 2 years.

Results: Twenty patients have been enrolled. The median age was 53 years (range: 32–79), and 12 pts were male. 14 pts had stage IV with BM involvement and 6 had stage III. The median FLIPI score was 2 (range, 1–4). Only 1 pt had 6 cycles of FM. At the time of this analysis: 13 pts underwent therapy with IT, 3 of them finished MR cycles, 1 had 3 cycles, 5 had 2 cycles, 1 had 1 cycle, and 3 are still awaiting their first cycle of MR. 7 pts finished FM therapy but still awaiting treatment with IT. Overall response was achieved in 100% of pts; CR in 14/20 pts (70%) and PR in 6/20 pts (30%). The responses to FM were converted from PR to CR in 5 pts: 1 after IT, 1 after 2 cycles of MR, and 3 after completing MR. Grades 3 or 4 hematologic toxicities were encountered in 6/20 pts (30%); with grades 3 or 4 neutropenia in 5 pts (25%) and grades 3 or 4 thrombocytopenia in 5 pts (25%). Platelets, ANC, and hemoglobin nadirs occurred at 3–7 weeks following ⁹⁰Y IT, and were reversible with median duration of nadirs of 4 weeks (range: 1–5). After median follow up of 16 months (range 3.5 – 39), only one pt developed progressive disease 14 months from registration, and after receiving IT therapy. Repeat BM biopsy at progression showed FL with focal areas of blastoid transformation. No death event has been reported to date.

Conclusions: The initial results from this prospective study suggest: 1- FM followed by ⁹⁰Y ibritumomab tiuxetan and maintenance rituximab regimen is safe and highly effective front line therapy for pts with intermediate or high risk FL (advanced stage with intermediate or high FLIPI scores at diagnosis). 2- The addition of IT and MR to the overall treatment strategy improves the quality of responses; and 3- Though the response rates are encouraging, longer follow-up will be required to evaluate the impact on progression-free survival and overall survival.