Rituximab and dose-dense cyclophosphamide-vincristine-prednisone plus interferon in patients with FL

The combination of antiproliferative chemotherapy with immunotherapy is frequently used in treatment regimens for follicular lymphoma (FL). However, there is no consensus on the best combination to use. The recommended options by ESMO and NCCN include rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or bendamustine.^1,2 However, another anti-CD20 based immunochemotherapy regimen is also being evaluated.

The LNH-PRO-05 (NCT00842114) multicenter phase II study was designed to evaluate a combination of rituximab with dose-dense cyclophosphamide-vincristine-prednisone plus interferon-alpha-2b (R-CVP+INF) in patients with FL. Initially, the patients were treated with CVP +/- INF, the CVP-INF arm had improved progression-free survival (PFS) and overall survival (OS) at 10 years.³ The FL International Prognostic Index (FLIPI) score was found to have a significant impact on the outcome, with a score above two being associated with the worst outcome.⁴

The final results of the LNH-PRO-05 study were published by Jimena Cannata-Ortiz from University Hospital La Princesa, Madrid, ES, and colleagues in the British Journal of Haematology. This article focused on the outcomes for patients with FLIPI ≥ 2 who received R-CVP+INF.⁵

Study design and key patient characteristics

• Total number of patients N= 50 with newly diagnosed FL
• Patients received 8 cycles of R-CVP chemotherapy and interferon for 12 weeks
  • Rituximab 375 mg/m², D1/cycle
  • Cyclophosphamide 400 mg/m², D 1-5/cycle
  • Prednisone 100 mg/m²,
  • D 1-5/cycle
  • Vincristine 1.4 mg/m², max 2 mg, D 1/cycle
  • Interferon - IFN 3 MU/m² x 3 times/week, x 12 weeks
• The median age was 54 years
• Lactate dehydrogenase or β 2-microglobulin was elevated in 16% of patients,
• 62% of patients had FLIPI score of 2 and 38% had a score ≥ 3
• 10% of patients received prior radiotherapy

Key findings

• Complete response (CR) rate after 4 cycles was 82% and after 8 cycles reached 100%
• Molecular CR was observed in all studied patients (n= 25)
• Four patients had a clinical relapse
• At a median follow-up of 6.2 years (2–8 years), PFS was 91% and OS 98%
• Addition of R to the CVP+IFN improved all of the outcomes, especially in the high-risk population
  • CR rate of 100% vs. 86%
  • PFS of 92% vs. 49%
  • OS of 98% vs. 69%
• Neutropenia was the most common grade 3/4 side effect, followed by infection (observed in 36% and 9% of cycles, respectively)
• 40% of patients developed lymphopenia (median duration 8 months) and 14% grade 2 hypogammaglobulinemia (median duration 18 months)
• A single case of acute promyelocytic leukemia (APL) was reported after six years without lymphoma recurrence.
• Serious side effects were reported in 8% of cycles, eight further cases of delayed-neutropenia were reported during the follow-up

Conclusions

R-CVP+INF therapy showed improvement in CR in FL patients with a FLIPI score > 2 compared to rates between 20% and 50% previously reported in other phase III trials using rituximab-chemotherapy combinations.^6,7 The regimen was also associated with longer PFS, and OS at eight years. Therefore, this regimen can be considered as an alternative option to other immunochemotherapeutic approaches for the treatment of intermediate/high-risk patients.