Update on a Prospective Study Evaluating the Safety and Efficacy of Combination Therapy with Fludarabine, Mitoxantrone and Rituximab Followed by Yttrium-90 Ibritumomab Tiuxetan and Maintenance Rituximab as Front Line Therapy for Patients with Indolent Lymphomas

The First Line Indolent Trial (FIT) recently reported the superiority of consolidation therapy with 90Y-ibritumomab tiuxetan (Zevalin) versus observation in patients with advanced stage follicular lymphoma (FL) after induction with chemotherapy. The benefit of rituximab maintenance has also been shown in indolent lymphomas. We report the updated results of a single institution phase II clinical trial using a combination of the above in indolent lymphomas, namely chemo-immunotherapy followed by radioimmunotherapy and rituximab maintenance.

Patients with previously untreated indolent lymphomas including FL and marginal zone lymphomas (MZL), age ≥ 18, PS 0–2, measurable disease, with adequate bone marrow, liver and kidney function were eligible. Previous treatment with rituximab alone was allowed. Initial treatment consisted of 4–6 cycles of FM (fludarabine 25 mg/m2 on days 1–3, mitoxantrone 12 mg/m2 on day 1 of each 28-day cycle). The protocol was amended after enrolling the first four patients to include rituximab 375 mg/m2 on day 1 of each cycle. After 6 to 8 weeks, responding patients received Zevalin followed by maintenance rituximab (375 mg/m2 weekly × 4, repeated every 6 months for 2 years).

22 patients were enrolled between July 2003 and May 2007. The median age was 55 years (range 32–79 years). 11 patients were men. One patient had stage II, 7 had stage III, and 14 had stage IV disease. 20 patients had FL and 2 had MZL. In the FL group, 18 (90%) patients were intermediate or high risk. All but one patient had 4 or more cycles of chemotherapy with an ORR of 100%, a CR of 45% (n=10), a PR of 50% (n=11) and stable disease in one patient. 19 patients underwent therapy with Zevalin. With Zevalin, 6 patients with PR post chemotherapy converted to CR, resulting in an improved CR of 79% (n=15) and a PR of 21% (n=4). Of the 19 patients that underwent Zevalin, 16 proceeded to rituximab maintenance. Of those excluded from rituximab maintenance, one patient refused maintenance, one had prolonged cytopenias after Zevalin and one transformed to DLBCL just prior to rituximab maintenance, requiring alternative treatment. The decision was made to give rituximab maintenance on a different schedule at 375 mg/m2, 1 dose every 3 months, to 2 patients for mild cytopenias. With rituximab maintenance, 2 patients in PR converted to CR. All patients who received chemotherapy and Zevalin were included in the survival analysis (n=19). At a median follow up of 47.7 months, median PFS was 47.2 months and median OS was not reached. 7 patients relapsed and 1 patient transformed to DLBCL, with 6 patients requiring alternative treatment. 3 of these relapses occurred while on rituximab maintenance and one occurred 2 months after receiving Zevalin prior to the initiation of immunotherapy maintenance. Of all relapses/transformations, 2 patients are deceased. In the remainder of patients, 4 (24%) are in stable relapse and 13 (76%) in CR. The most common adverse effects of this regimen were hematological. With chemotherapy, 7 patients had grade 3/4 neutropenia and 4 patients had grade 3/4 thrombocytopenia. Post Zevalin, 11 patients experienced one or more grade 3/4 cytopenias: 8 patients had neutropenia, 8 had thrombocytopenia, and 4 had anemia with time to recovery of counts ranging between 2–4 weeks. 8 of these patients had bone marrow involvement at the start of treatment. One patient developed treatment related MDS that evolved to AML 4 years after the start of therapy. This patient died. Other grade 3/4 adverse effects included: grade 3 hypoxia and pneumonia post chemotherapy in a patient with grade 1 neutropenia and grade 2 cellulitis after Zevalin in a patient with grade 3/4 neutropenia.

Chemoimmunotherapy followed by consolidation with radioimmunotherapy and rituximab maintenance is well tolerated and able to improve complete remission rates and maintain durable responses in patients with untreated indolent lymphomas. The use of this approach in indolent NHL patients may become a new standard of care.

Off Label Use: Both radioimmunotherapy consolidation with zevalin and rituximab (immunotherapy) maintenance have been used in indolent lymphomas first line post chemo-immunotherapy. However, in this study, we looked at the combination of chemo-immunotherapy followed by zevalin consolidation and rituximab maintenance. This combination is off-label. Kassar:Alexion: Honoraria. Gregory:Amgen: Consultancy; Astellas: Research Funding; Celgene: Research Funding; Cephalon: Research Funding, Speakers Bureau; Genentech (Roche): Consultancy, Research Funding, Speakers Bureau; Glaxo-Smith-Kline: Research Funding; Immunomedics: Research Funding; NCIC CTG: Research Funding; Novartis: Consultancy, Research Funding; Onyx (Proteolix): Research Funding; Spectrum Pharmaceuticals: Consultancy.