Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy

Abstract

There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and MethodsEligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m 2 /d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m 2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. ResultsAt a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination (P = .0009). Progression-free survival was also significantly better with the combination (P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. ConclusionRituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

A MALT lymphoma prognostic index

“…This new index is specific for MALT lymphoma patients and was generated from a large cohort of 401 patients recently diagnosed and prospectively enrolled in the IELSG-19 randomized trial. 24,25 The natural history of MALT lymphoma patients has not changed since the completion of this trial (performed between 2003 and 2005), with few changes to available therapeutic options and no other published randomized phase III trials.…”

“…24 Notably, 7 out of 10 patients with histological transformation were in the high-risk group, 3 were in the intermediate-risk group, and none were in the low-risk group (Fisher exact test, P # .001). Nevertheless, the ability of MALT-IPI to identify different prognostic groups for each survival endpoint remained independent of histological transformation (Cox regression, data not shown).…”

“…This study was conducted with data from the final analysis of the international IELSG-19 randomized phase III trial (NCT 00210353), 24 conducted at 77 centers in 6 countries with the cooperation of major collaborative trial groups (Fondazione Italiana Linfomi, Groupe d'Etude des Lymphomes de l'Adulte, UK National Cancer Research Institute, and Grup per l'Estudi dels Limfomes de Catalunya i Balears). The study was approved by the institutional review board or ethics committee of each institution.…”

“…This trial compared chlorambucil alone to rituximab alone and to the combination of rituximab and chlorambucil (R-chlorambucil) as front-line therapy in MALT lymphoma patients, with event-free survival (EFS) as the primary endpoint. 23,24 Patients were stratified according to tumor site (gastric vs nongastric), nodal involvement, prior local therapy, and IPI risk group.…”

“…We therefore sought to develop a MALT lymphoma IPI (MALT-IPI) for patients treated during the rituximab era by developing a model using the patient data set of the largest recent controlled clinical trial in MALT lymphoma, namely the International Extranodal Lymphoma Study Group 19 (IELSG-19) randomized study, conducted by the International Extranodal Lymphoma Study Group in 6 European countries, which showed the superiority of the combination of chlorambucil and rituximab in comparison with either rituximab or chlorambucil given as single agents. 23,24 Patients and methods…”