Y-90-Ibritumomab Tiuxetan In Patients With Extra-Nodal Marginal Zone B-Cell Lymphoma Of Mucosa-Associated Lymphoid Tissue (Malt Lymphoma) - The Zeno Study

Marginal zone lymphomas (MZL) represent about 17% of all non-Hodgkin lymphomas (NHL) (Zinzani & Broccoli, 2016) and are composed of three different entities: splenic MZL, nodal MZL and marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). MALT lymphoma group accounts for almost 7–8% of B-cell lymphomas and 60-70% of MZL (Zinzani, 2012; Sriskandarajah & Dearden, 2017). MALT is an indolent disease, and patients usually have good performance status with a good prognosis (Zinzani, 2012). Currently, no standard treatments are available for MALT lymphoma. 90Y-ibritumomab tiuxetan (90YIT) is a radio-conjugated murine monoclonal antibody approved with rituximab in Europe for adult patients relapsed or refractory (R/R) CD20 + follicular B-cell NHL or as consolidation of remission after induction therapy in previously untreated patients with follicular lymphoma. Several studies have been performed with 90YIT both in untreated and in R/R indolent lymphomas. In the setting of R/R patients, results were encouraging with an overall response rate (ORR) ranging from 70% to 95% (Gordon et al., 2004; Emmanouilides et al., 2006) with the ability to induce long-lasting responses (≥3 years) (Vanazzi et al., 2014). Impressive results have been obtained also with previously untreated indolent lymphomas with an ORR ranging from 94% to 100% (Samaniego et al., 2014; Lossos et al., 2015). We conducted a single-arm, single-centre, phase 2 clinical trial, aimed at evaluating the efficacy and safety of YIT in patients with de novo and R/R MALT lymphoma (EudraCT number 2012-001768-31). The trial was conducted in accordance with the Declaration of Helsinki and the study protocol was approved by the Local Ethical Committee. All patients provided written informed consent. The treatment plan consisted of an initial intravenous infusion of rituximab 250 mg/m2 on day 1, repeated on day 8, immediately followed by a weight-based dose of 90YIT. For patients with ≥ 150·000 platelets/mm3, 15 MBq 90YIT/kg, up to a maximum of 1200 MBq, were administrated; for patients with platelets between 150·000 and 100·000/mm3, 11 MBq 90YIT/kg, up to a maximum of 1200 MBq. Primary objective was efficacy of treatment, measured by ORR. Secondary endpoints were disease-free survival (DFS), one-year progression-free survival (PFS), one-year overall survival (OS) and safety of YIT. Seventeen patients were enrolled between February 2013 and November 2018. Sixteen patients were evaluable for efficacy analysis, as one patient refused to undergo YIT due to a rituximab infusion reaction after the first administration. Complete patients’ characteristics are reported in Table 1. Patients received a median 90YIT dose of 1124·5 MBq (range 740–1184 MBq): intended doses corresponded with the effective doses administered. Three months after 90YIT, the observed results were 10 complete responses (CR, 62·5%), five partial responses (PR, 31·3%) and one stable disease, leading to an ORR of 94%. With a median follow-up of two years, only four patients relapsed (three from CR and one from PR). Only one death occurred due to disease progression in a patient who underwent subsequent therapies after 90YIT. Seven patients are in continuous CR with a median duration of response of 24 months. Progression-free survival at 71·9 months was 42·6%, with the median reached at 37·3 months. DFS at 64 months was 45·7%, the median was reached at 33·2 months. The three relapses occurred at 9·6, 24·1 and 33·2 months respectively. Median OS was not reached (OS at 5·9 years 66·7%). Four patients had a rituximab reaction grade 1 at first administration. These adverse events (AEs) rapidly resolved and did not prevent the second rituximab infusion. Late AEs after YIT were only haematological and transient. The severity of haematological toxicities (expressed as the lowest, i.e. nadir, concentration of granulocytes, platelets, and haemoglobin reached after radioimmunotherapy) are reported in Table 2. Grade 3 to 4 thrombocytopenia and neutropenia occurred in seven patients (43·8%). Seven patients received granulocyte-colony stimulating factor (G-CSF); only one patient received platelets and blood transfusions. Extra-haematological AEs affected seven patients (43·8%), were all grade ≤ 2 and easily manageable. Only one serious AE was recorded during the follow-up period: a congestive heart failure not related to the study drug which resolved after hospitalization. At the median follow-up of two years, no secondary malignancies occurred. Considering our data, 90YIT results to be a highly effective treatment for MALT lymphoma in first-line setting and in R/R disease. The results obtained in the Zeno study are in line with those observed in the first-line setting but also in R/R disease with an ORR in our study of 94%, including 62·5% of CR and 31·3% of PR (Samaniego et al., 2014; Vanazzi et al., 2014; Lossos et al., 2015). Half of the patients (two out of four) who received 90YIT as first-line therapy obtained a CR. The other two patients who received 90YIT as first-line therapy obtained a PR and they both had intraorbital localization. Nine patients are in continuous CR with a median duration of response of 24 months showing the possibility of long-term responses according to data present in the literature (Vanazzi et al., 2014). This single-arm study was initially designed to enrol a total of 25 patients. However, the study was closed prematurely due withdrawal of further support by the manufacturer. Nevertheless, here we reported an ORR of 94%, leading to robust results with 16 patients treated and achieving primary objective. As expected, the safety profile was manageable with a good tolerance, in agreement with data present in literature (Samaniego et al., 2014; Vanazzi et al., 2014; Lossos et al., 2015). Patients’ comfort during treatment is increased as 90YIT requires only two days of infusion in contrast to other therapeutic strategies that come in the shape of “single-shot” therapy. Another advantage of 90YIT is that, unlike for some other chemotherapy agents, mucosal disruption is absent which reduces the risk of bacterial translocations and subsequent infections. Finally, in comparison to local radiotherapy, 90YIT is consistent with systemic therapy, thus it is able to prevent systemic relapse whereas local therapy cannot. In conclusion, YIT represents a highly effective and tolerable treatment option for MALT lymphoma, in a setting where currently there are no standard treatments and the therapy options are limited, especially in R/R patients. PLZ, GL and LA conceived the study; PLZ, GL, VS and LA designed the study, collected data and wrote the manuscript; LA analysed data; AB, MM, CP, AM, BC, LN, MC and MC, provided advice and assisted with data collection and interpretation; all authors approved the final manuscript. The authors declare no competing financial interests.