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.

The impact of B-cell-directed therapy on SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia.

Prior reports evaluating SARS-CoV-2 vaccine efficacy in chronic lymphocytic leukaemia (CLL) used semiquantitative measurements of anti-S to evaluate immunity; however, neutralization assays were used to assess functional immunity in the trials leading to vaccine approval. Here, we identified decreased rates of seroconversion in vaccinated CLL patients and lower anti-S levels compared to healthy controls. Notably, we demonstrated similar results with the Roche anti-S assay and neutralization activity. Durable responses were seen at six months; augmentation with boosters was possible in responding patients. Absence of normal B cells, frequently seen in patients receiving Bruton tyrosine kinase and B-cell lymphoma 2 inhibitors, was a strong predictor of lack of seroconversion.

Considerations for Managing Patients With Hematologic Malignancy During the COVID-19 Pandemic: The Seattle Strategy.

In January 2020, the first documented patient in the United States infected with severe acute respiratory syndrome coronavirus 2 was diagnosed in Washington State. Since that time, community spread of coronavirus disease 2019 (COVID-19) in the state has changed the practice of oncologic care at our comprehensive cancer center in Seattle. At the Seattle Cancer Care Alliance, the primary oncology clinic for the University of Washington/Fred Hutchinson Cancer Consortium, our specialists who manage adult patients with hematologic malignancies have rapidly adjusted clinical practices to mitigate the potential risks of COVID-19 to our patients. We suggest that our general management decisions and modifications in Seattle are broadly applicable to patients with hematologic malignancies. Despite a rapidly changing environment that necessitates opinion-based care, we provide recommendations that are based on best available data from clinical trials and collective knowledge of disease states.