Novel approaches in marginal zone lymphoma: Systematic review.

e20089 Background: Marginal zone lymphoma represents no more than 17% of NHLs and there is no standard of care. We reviewed the efficacy of novel drugs with main focus on ORR and PFS/OS (when available). Methods: Literature search was performed based on PRISMA guidelines in PubMed, Cochrane, EMBASE, Clinicaltrials.gov. Studies which did not give separate results for MZL were excluded. Results: 23 trials (n = 1491 patients) were included. 57% were refractory to previous line of therapy. 9 studies were conducted specifically in MZL (n = 440). The most common intervention was Rituximab and its combinations. PFS and OS were inconsistently reported. 1. Monotherapy in untreated MZL: In a phase III study, ORR was reported at 82.8% vs 81.3% with PFS of 75% vs 78% at 3 years in Obinutuzumab vs Rituximab. In Phase II Ibritumumumab tiuxetan showed 100% ORR in 11 patients with 5-year PFS of 82%. Most common grade 3-4 AE were hematological. Lenalidomide was studied in 18 EMZL patients, with 60% being untreated. In this study, ORR was reported at 61% with CR 33%. 2. Combination therapy in untreated MZL: Lenalidomide+Rituximab showed 93% ORR and median PFS 59.8 months with manageable toxicities. Ibrutinib in combination with Rituximab and Lenalidomide produced ORR of 90% with CR 60%. The addition of Bendamustine to Rituximab showed ORR and CR of 91% and 73% with 3-year PFS of 93% in a study of only SMZL (n = 56). 3. Monotherapy in R/R MZL: Ibrutinib demonstrated ORR of 50%, 54% and 41% in EMZL, SMZL and NMZL, respectively with median PFS of 14.2 months. Less hematologic toxicity was seen in MZL patients receiving Ibrutinib monotherapy compared to other regimens. In 30 patients receiving Everolimus, ORR was reported at 25%. Bortezomib has significant activity in EMZL with ORR of 48%. PI3Kδ inhibitors Idelalisib, Copanlisib and Duvelisib showed clinical activity. Umbrelisib and Ofatumumab demonstrated ORR > 50%. Vorinostat demonstrated an ORR of 22%. 4. Combination therapy in R/R MZL: Rituximab+Lenalidomide had a higher ORR (39.4 vs. 14.1%) and higher PFS (58 vs. 36% at 2-year) compared to Rituximab monotherapy. Combination of Tirabrutinib and Entospletinib showed 20% ORR in a small group of MZL patients. Addition of Idelalisib to Tirabrutinib demonstrated ORR 40%. Ibrutinib and Venetoclax combination demonstrated ORR > 50%. Ublituximab and Umbralisib showed clinical activity. Conclusions: With expanding armamentarium of targeted agents, our review has demonstrated positive results especially in terms of ORR in patients with MZL. Further studies are required to explore the role of these drugs and their impact on survival.