Chlorambucil Plus Rituximab Produces Better Event-Free Survival in Comparison with Chlorambucil Alone in the Treatment of MALT Lymphoma: 5-Year Analysis of the 2-Arms Part of the IELSG-19 Randomized Study
Authors: Zucca Emanuele , Conconi Annarita , Martinelli Giovanni , Martelli Maurizio , Thieblemont Catherine , Johnson Peter W , Lopez-Guillermo Armando , Bouabdallah Reda , Tucci Alessandra , Vitolo Umberto , Coiffier Bertrand , Devizzi Liliana , Jardin Fabrice , Sebban Catherine , Pinotti Graziella , Morschhauser Franck , Pettengell Ruth , Bosly Andre , Montserrat Emili , Bellei Monica , Pileri Stefano A. , Copie-Bergman Christiane , Campo Elias , Jack Andrew , Mazzucchelli Luca , Cavalli Franco 
Published: October 2019

Abstract
Abstract 432
The IELSG-19 study was launched in 2003 by the International Extranodal Lymphoma Study Group to compare Chlorambucil alone versus the combination of Chlorambucil and Rituximab in the treatment of MALT lymphomas. Main contributors were the Italian Lymphoma Intergroup, the French GELA Group, the UK NCRI Group, the Catalan Hematology Group and the Oncology Institute of Southern Switzerland. MALT lymphoma pts with localized disease at any extranodal site who did not respond or were not suitable for local therapy (including H.pylori-negative gastric lymphomas or those who failed antibiotic therapy) were eligible, as well as those with disseminated or multifocal MALT lymphoma. Central histology review was performed. In arm A, Chlorambucil was given 6 mg/m2 daily p.o for 42 consecutive days (d 1–42). After restaging, responding patients and those with stable disease were kept on Chlorambucil 6 mg/m2 daily p.o for 14 consecutive days every 28 days for 4 cycles (d 56–70, 84–98, 112–126, 140–154). In arm B, Chlorambucil was given as in arm A, together with Rituximab, 375 mg/m2 iv on day 1, 8, 15, 22, 56, 84, 112 and 140. Because of the excellent initial recruitment a third arm with Rituximab alone (with a randomisation rate of 1:1:6) was introduced in 2006. The study planned accrual of 450 patients was reached in June 2010. A planned final analysis was performed according to protocol on the 227 pts enrolled in the first two arms before introduction of the third treatment arm: 119 men (52%) and 108 women (48%); 204 (90%) with no previous treatment. The sample size allowed the detection of a 20% improvement in event-free survival (EFS, main endpoint) with 5% significance and 80% power. The treatment was completed as per protocol in 86% of the 227 pts analysed (89% in Arm A and 80% in arm B, respectively), in 60% without any dose adjustment or delay. The primary MALT lymphoma site was the stomach in 94 pts (41%);133 pts (59%) had a non-gastric presentation. In 79 pts (35%) the lymphoma involved more than 1 extranodal site. Lymph node involvement was present in 85 pts (37%); 133 pts (59%) had localized disease (Ann Arbor stage I-II). The ECOG performance status was 0 in 168 pts (74%). According to the international prognostic index (IPI) 133 pts (59%) had a low risk, 48 (21%) a low-intermediate risk, 39 (17%) an intermediate-high risk, and only 7 (3%) a high risk score. B-symptoms were present in 21 pts (9%) and LDH levels were higher than normal in 17 (7%). The main risk factors were equally distributed between the two arms. Outcome analysis was performed on all randomised patients on an intent-to-treat basis, median follow-up time is 60 months. The 5-year EFS was significantly better for the patients treated with Chlorambucil plus Rituximab (68%; 95% CI, 58%-76%) in comparison with those receiving Chlorambucil alone (50%; 95% CI, 40%-59%). Overall survival (OS) at 5 years was identical in the two arms (88%). There was no outcome difference between pts with gastric and non-gastric localization (note that H. pylori-positive gastric MALT lymphoma pts still responding to antibiotics were not eligible). Among the main clinical characteristics, more than one extranodal site, advanced stage, the presence of lymph nodal involvement and an unfavourable IPI were significantly associated with shorter EFS and OS. With respect to toxicity, both treatments were well tolerated and no unexpected side effects were recorded. Severe hematologic toxicity was uncommon in both arms but grade 3–4 neutropenia was significantly more frequent in the Chlorambucil plus Rituximab arm (19 vs. 2 episodes, p<0.001). In conclusion, this is the largest randomised trial ever conducted in MALT lymphoma. While awaiting the analysis of the whole study (to include the third arm with Rituximab alone, added later on), the current results confirm the activity of Rituximab in combination with chemotherapy but also indicate that differences in EFS and response rate may not automatically translate into improved survival overall.
Table 1. All Arm A Chlorambucil Arm B R-Chlorambucil p-value n 227 113 114 sex (M/F) 119/108 63/50 56/58 n.s. median age (years) 60 60 59 n.s. previously untreated 204 100 104 n.s. primary gastric site 94 48 46 n.s. primary non-gastric site 133 65 68 n.s. lymph node involvement 85 42 43 n.s. low to low-intermediate IPI 181 90 91 n.s. median follow up (months) 60 60 62 n.s. 5-year EFS 59% 50% 68% 0.0024 best response -CR 71% 65% 78% 0.017 -PR 19% 22% 16% 5-yr OS 88% 88% 88% n.s.
Figure 1. Figure 1.

Disclosure:
Zucca: Roche: Research Funding; Mundipharma: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Among indolent lymphomas, Rituximab is not specifically approved for MALT lymphoma but only for follicular lymphoma. Johnson:Roche: Membership on an entity's Board of Directors or advisory committees. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees. Coiffier:Roche: Research Funding. Morschhauser:Roche: Honoraria. Pettengell:Roche: Honoraria.