Immunologic predictors of vaccine responsiveness in patients with lymphoma and CLL.

Patients with B-cell lymphomas have altered cellular components of vaccine responses due to malignancy and therapy, and the optimal timing of vaccination relative to therapy remains unknown. SARS-CoV-2 vaccines created an opportunity for new insights in vaccine timing because patients were challenged with a novel antigen across multiple phases of treatment. We studied serologic mRNA vaccine response in retrospective and prospective cohorts with lymphoma and CLL, paired with clinical and research immune parameters. Reduced serologic response was observed more frequently during active therapies, but non-response was also common within observation and post-treatment groups. Total IgA and IgM correlated with successful vaccine response. In individuals treated with CART-19, non-response was associated with reduced B and T follicular helper cells. Predictors of vaccine response varied by disease and therapeutic group, and therefore further studies of immune health during and after cancer therapies are needed to allow individualized vaccine timing.

Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel.

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines.

ABSTRACT: Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites.

Tisagenlecleucel Therapy: Nursing Considerations for the Outpatient Setting.

OBJECTIVE: Tisagenlecleucel is a CD19-directed, genetically modified, autologous T-cell immunotherapy indicated for pediatric and young adult patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia and for adult patients with relapsed/refractory diffuse large B-cell lymphoma. Treatment with any chimeric antigen receptor (CAR)-T cell therapy is a multistep process in which nurses and nurse practitioners are key to managing patient safety. Managing patients receiving CAR-T cell therapy in the outpatient setting (as Penn does with tisagenlecleucel and lisocabtagene maraleucel) requires an even more complex process. The objective of this manuscript is to provide guidance on the role of nurses in the outpatient administration of tisagenlecleucel therapy and postinfusion care in adult patients with diffuse large B-cell lymphoma. Oncology and apheresis nurses discuss institutional processes and perspectives related to the patient experience with tisagenlecleucel therapy at the Hospital of the University of Pennsylvania. DATA SOURCES: Author experience. CONCLUSION: Nurses are vital for the success of the patient management processes involved with tisagenlecleucel therapy. Nurses must be thoroughly educated in tisagenlecleucel therapy and adverse event management and be able to effectively communicate all aspects of therapy among the multidisciplinary team of the hospital, the product manufacturer, and patients and families. Establishment of the nurse cellular therapy coordinator at the Hospital of the University of Pennsylvania was advantageous in facilitating effective communication in all these situations. IMPLICATIONS FOR NURSING: This encompassing approach to patient management is particularly necessary during administration of tisagenlecleucel therapy and other CAR-T cell therapies that are managed in the outpatient setting.

Ceftazidime for neutropenic fevers: is it still an appropriate choice?

Infection continues to rank as a primary cause of treatment-related mortality in patients with cancer. For patients with neutropenic fevers, immediate empiric treatment with antibiotics is standard care. However, which specific antibiotic is best for initial treatment of high-risk patients has been much debated without consensus. Many major health centers use intravenous ceftazidime as first-line therapy for these patients. Yet updates to guidelines published by the Infectious Diseases Society of America and the National Comprehensive Cancer Network suggest that ceftazidime may no longer be an optimal choice. This article reviews the literature regarding ceftazidime therapy for the treatment of high-risk neutropenic patients with fevers. This critical analysis of existing research reveals significant pharmacologic, physiologic, social, and financial implications, and recommendations for further studies are made.

A feasibility study of dignity psychotherapy delivered via telemedicine.

OBJECTIVE: Dignity Psychotherapy has shown great promise as a value-affirming intervention for patients with advanced disease. We delivered the Dignity Psychotherapy intervention in a feasibility study of a series of eight cancer patients via videophone technology to deliver the therapy into their homes. METHODS: Once eligible patients were consented on this IRB-approved study, they completed baseline assessments and were scheduled to have the videophone placed in their homes. The Dignity Therapy sessions then encompassed a first session, which was transcribed and edited, followed by a second session to go over the edited transcript and allow the patient to make changes. Patients then filled out follow-up questionnaires and had the telemedicine equipment removed from their homes, and their legacy document delivered. RESULTS: Participants had a mean age of 56.32 years (range = 41-66, SD = 7.65) and were diagnosed with lung (n = 5, 62.5%), breast (n = 2, 25%), or colon cancer (n = 1, 12.5%). They reported overall benefit from the intervention along with a high level of satisfaction. We were able to deliver the intervention in a timely fashion, with minimal length between sessions and transcript delivery and few technical difficulties. SIGNIFICANCE OF RESULTS: Telemedicine can greatly extend the benefits of Dignity Psychotherapy by bringing it to patients who are dying at home. Our very preliminary work suggests that delivering the intervention to patients who are too ill to leave their homes or who are in rural locations may be a feasible way to help them.