Rituximab Maintenance Treatment For a Maximum Of 5 Years In Follicular Lymphoma: Results Of The Randomized Phase III Trial SAKK 35/03
Authors: Taverna Christian J. , Martinelli Giovanni , Hitz Felicitas , Mingrone Walter , Pabst Thomas , Cevreska Lidija , del Giglio Auro , Vanazzi Anna , Laszlo Daniele , Raats Johann , Rauch Daniel , Vorobiof Daniel A. , Lohri Andreas , Zucca Emanuele , Biaggi Rudolf Christine , Rondeau Stephanie , Rusterholz Corinne , Ghielmini Michele 
Published: October 2019

Abstract

Background
Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance treatment remains unknown.

Methods
270 patients (median age 57 years: range 25-82) with either untreated, relapsed, stable or chemotherapy resistant follicular lymphoma of all grades were treated with 4 weekly doses of rituximab monotherapy (375 mg/m²). Patients responding to the induction treatment (partial or complete response) received rituximab (375 mg/ m²) maintenance and were randomized either to a short maintenance consisting of four administrations every two months (arm A), or a prolonged maintenance for a maximum of five years or until disease progression or unacceptable toxicity (arm B). The primary endpoint was event-free survival (EFS) from randomization. Sample size calculation allowed detecting a median EFS increase with prolonged maintenance from 2.5 to 4.5 years with 80% power. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and objective response. Comparisons between the two treatment arms were performed using the log-rank test for survival endpoints.

Results
From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. 124 patients were chemotherapy-naïve. The median EFS is 3.4 years (95% CI 2.1-5.3) in arm A and 5.3 years (95% CI 3.5-NA) in arm B. Using the prespecified log-rank test this difference is statistically not significant (p=0.14). We observed an unexplained difference in disease progression and relapse during the first 8 months after randomization (3 in arm A vs. 10 in arm B) when treatment in both arms was the same which led to an early crossing of the EFS curves at 18 months. Considering only patients at risk after 8 months from randomization EFS in arm B is significantly prolonged compared to arm A (median EFS 7.1 (95% CI 4.4-NA) vs. 2.9 years (95% CI 1.8-4.8); log-rank test p=0.004). Median PFS is significantly longer in arm B (7.4 (95% CI 5.1-NA) vs. 3.5 years (95% CI 2.1-5.9); log-rank test p=0.04). There is no significant difference in OS and in the observed best response. Maintenance treatment was stopped due to unacceptable toxicity in no patient in arm A vs. 3 in arm B. Six subsequent cancers developed in arm A and 8 in arm B. One infection grade ≥3 was reported in arm A whereas seven infections grade ≥3 occurred in 5 patients in arm B.

Conclusions
EFS, the primary endpoint was not met which is mainly due to the early separation of the survival curves favouring arm A, at a time when the treatment in both arms was the same. However, a retrospectively defined analysis considering only EFS events from the time when treatment was different in the two arms, shows a statistically significant increase in EFS with long-term maintenance compared to the 8 months maintenance regimen. Long-term rituximab maintenance also doubles the median PFS without leading to increased undue toxicity.

Disclosures:
Off Label Use: Rituximab for 5 years. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.