Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study

The LyMa (ClinicalTrials.gov, NCT00921414) is a prospective randomised phase III trial conducted by the LYSA group (GOELAMS and GELA groups) and that assessed the potential benefit of Rituximab maintenance after autologous stem cell transplantation (ASCT) in young previously untreated Mantle Cell Lymphoma (MCL) patients (<66y).

Patients were enrolled at times of diagnosis. All patients received 4 courses of R-DHAP followed by ASCT (patients who did not reach at least a PR after these 4 courses could receive 4 additional courses of R-CHOP). The conditioning regimen of ASCT was Rituximab (500mg/m2) plus BEAM. Patients achieving a complete or partial response after ASCT were then randomly assigned to receive 3 years of Rituximab maintenance therapy (375mg/m², one injection every two months) or wait and watch (WW) (1:1).

The primary endpoint was EFS at 4 years after randomization, EFS being defined as death of any cause, disease progression, severe allergic reaction to Rituximab or severe infection. PFS and OS were secondary objectives. Herein, we present the first planned interim analysis. Analysis was performed by intention to treat.

From September 2008 to August 2012, 299 patients were included (one patient withdrawn his consent, data of one patient with incomplete data at time of the present analysis). Median age at registration was 57y (27-65) and 236 (78,9%) patients were male. MIPI score was low in 53,2% (n=159), intermediate in 27,4% (n=82) and high in 19,4% (n=58). In all, 257 (86%) patients proceeded to ASCT. The CR/CRu rates before and after ASCT were 81,4% and 92%, respectively. At the time of the present interim analysis, 58 patients died. With a median follow-up calculated from time of inclusion of 35.8 months, median PFS and OS are not reached. The estimates 3y-PFS and -OS are 73.7% (95%CI ; 67.8-78.7) and 82.6% (95%CI ; 77.3-86.8), respectively. Last randomization was done in February 2013. Two hundred and thirty eight patients were randomised: 119 patients were assigned to rituximab maintenance and 119 to WW. The mFU (n=238) calculated from date of randomization is 29.7 months. Median EFS and PFS are not reached : the 2y-EFS is 87.5% (95%CI ; 82.4-91.2) and 2y-PFS is 87.5% (95%CI ; 82.4-91.2). The EFS and PFS are statistically different between the treatment arms (p=0.015 for both) : the 2y-EFS is 93.2% (95%CI, 86.9-96.6) in the Rituximab arm versus 81.5% (95%CI, 72.7- 87.7) in the WW arm (HR=2.1). OS does not differ between the two groups. The 2y-OS is 93.4% (95%CI, 86.6-96.9) in the Rituximab arm versus 93.9% (95%CI, 86.7-97.3) in the WW arm.

This planned interim analysis of the LyMa trial shows that a 3 years of rituximab maintenance after R-DHAP plus ASCT as first-line treatment for young patients with MCL significantly improves both EFS and PFS. Thus, as reported in elderly MCL, the Lyma trial demonstrates that Rituximab should be used in maintenance therapy after ASCT and provides the rational for a new standard of care in MCL.