Efficacy, Safety, and Molecular Response Predictors of Oral Ixazomib and Short-Course Rituximab in Untreated iNHL.

Indolent B-cell non-Hodgkin lymphoma (iNHL) patients generally require treatment but experience normal survival, emphasizing the need for simpler, safer therapies. Proteasome inhibitors target aberrant signaling pathways within iNHL and have manageable toxicities. We evaluated the oral proteasome inhibitor ixazomib as initial monotherapy, and combined with rituximab, for first-line treatment of iNHL. Treatment-naïve iNHL patients needing therapy received oral ixazomib 4 mg weekly until progressive disease or unacceptable adverse events. A 4-week course of rituximab was added during month 7. The primary endpoint was overall response rate (ORR) during the ixazomib monotherapy window. Correlates included gene expression profiling and response to SARS-CoV-2 vaccination. Thirty-three patients with follicular lymphoma (FL) (n=20), marginal zone lymphoma (n=7), and other iNHL were treated with median follow-up of 30.3 months. During the 6-month ixazomib window the ORR was 24%, including 35% in FL. Best ORR over the entire study period was 52% overall and 65% in FL; CR was achieved in 33% and 45%, respectively. The median duration of response was 25.8 months (range, 0 - 49.7), and the 24-month progression-free and overall survival were 51% (95% CI 32-67%) and 91% (95% CI 74-97%). Ixazomib was well-tolerated. Baseline downregulation of proteasome genes PSMB9 (P = 0.03) and PSMB8 (P = 0.007) were associated with response. All evaluated patients generated anti-S antibodies to SARS-CoV-2 vaccination, median 254.9 BAU/mL. Ixazomib demonstrated efficacy alone and with short course rituximab in untreated iNHL while exhibiting favorable toxicity, convenience, and retention of B-cell immune response. This trial is registered at www.clinicaltrials.gov as NCT02339922.