IELSG-38: A Phase II Study of Chlorambucil in Combination with Rituximab Followed By Maintenance Therapy with Subcutaneous Rituximab in Patients with Extranodal Marginal Zone B-Cell Lymphoma of Mucosa Associated Lymphoid Tissue (MALT)

Background The combination of rituximab with chlorambucil resulted in better event and progression-free survival in comparison to either agent alone in a randomized phase III study (IELSG-19) of previously untreated patients with MALT lymphoma. The International Extranodal Lymphoma Study Group (IELSG) designed the IELSG-38 as the first study to assess the role of maintenance with subcutaneous rituximab following first line treatment with rituximab and chlorambucil in this lymphoma subtype.

Patients and Methods Patients with MALT lymphoma arisen at any extranodal site, de novo, or relapsed following local therapy (including surgery, radiotherapy) and/or antibiotics, were eligible. Treatment consists of an induction phase with the combination of chlorambucil (6 mg/m²/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) and rituximab (375 mg/m² intravenously on day 1 of weeks 1, 2, 3, 4 and subcutaneously 1400 mg on weeks 9, 13, 17, and 21). At the end of induction phase, patients in complete response (CR), partial response (PR) and stable disease (SD) are eligible for maintenance treatment with subcutaneous rituximab 1400 mg every two months for two years. Disease assessments are performed at the end of week 8, at the end of induction phase and every year during maintenance. The study is ongoing and time-to-event analysis will be performed later on; here we present results of the CR rate at the end of induction phase (primary analysis of the main endpoint of the study).

Results As of 1^st March, 2016 the study has completed its accrual with 112 patients enrolled. Demographics: median age 65 (range 32-86); Female: Male= 53:59; Primary lymphoma site gastric: non-gastric= 36:76; Stage I:II:III:IV= 37:10:3:62; MALT IPI score low: intermediate: high= 34:43:35. In comparison with the IELSG-19 trial, the IELSG-38 trial did include patients with more frequent adverse characteristics (non-gastric localization 68% vs 57% and high risk MALT IPI score, 31% vs 17%).

At the time of data cut-off for this abstract (June 23, 2017), 15 patients have completed trial treatment and 78 were ongoing (20 during the first and 58 during the second year of maintenance). The most common Adverse Events (AEs) of grade ≥3 were hematologic (neutropenia in 39 patients, lymphopenia in 13), while non-hematologic AEs were observed in 12 patients.

Study treatment has been discontinued in 20 patients: 12 during the induction phase (4 due to drug related AEs, 3 due to not-related AEs, 2 due to transformation in high grade lymphoma, 1 due to second tumor detection misdiagnosed at study entry, 1 due to treatment delay not drug-related and 1 due to PI decision); 5 during the first year of maintenance (2 due to drug-related AEs, 2 due to progressive disease, 1 withdrew consent); 3 during the second year of maintenance (1 due to AEs, 1 due to progressive disease, 1 withdrew consent). The CR rate at the end of induction (main endpoint) is 58% (76% gastric vs 49% in non-gastric) in the efficacy-evaluable (EE) population (n=102) and 53% (gastric 69% vs non-gastric 45%) in the intention-to-treat (ITT) population (=112). PR is 37% and 24% in the EE and ITT population respectively. Seventy-seven patients are evaluable after 1 year of maintenance: CR rate is 69%, PR 26%, SD 2.5% and progressive disease (PD) 2.5%. Among 30 of them who had PR at the end of induction, 9 (30%) improved their response to CR after 1 year of maintenance. At present 15 patients are evaluable after 2 years of maintenance, their CR rate is 80%, PR 13% and PD 7%.

Conclusion The combination of rituximab and chlorambucil followed by 2-years maintenance with subcutaneous rituximab is feasible and active in untreated MALT lymphoma patients. Updated results will be presented at the meeting.