Rosenthal, Allison C

AbstractCutaneous T-cell lymphomas (CTCLs) are a spectrum of diseases with varied clinical courses caused by malignant clonal proliferation of skin-tropic T cells. Most patients have an indolent disease course managed with skin-directed therapies. In contrast, others, especially in advanced stages of disease or with specific forms, have aggressive progression and poor median survival. Sézary syndrome (SS), a leukemic variant of CTCL, lacks highly consistent phenotypic and genetic markers that may be leveraged to prevent the delay in diagnosis experienced by most patients with CTCL and could be useful for optimal treatment selection. Using single-cell mRNA and T-cell receptor sequencing of peripheral blood immune cells in SS, we extensively mapped the transcriptomic variations of nearly 50 000 T cells of both malignant and nonmalignant origins. We identified potential diverging SS cell populations, including quiescent and proliferative populations shared across multiple patients. In particular, the expression of AIRE was the most highly upregulated gene in our analysis, and AIRE protein expression could be observed over a variety of CTCLs. Furthermore, within a single patient, we were able to characterize differences in cell populations by comparing malignant T cells over the course of treatment with histone deacetylase inhibition and photopheresis. New cellular clusters after progression of the therapy notably exhibited increased expression of the transcriptional factor FOXP3, a master regulator of regulatory T-cell function, raising the potential implication of an evolving mechanism of immune evasion.

Abstract Polatuzumab vedotin (PV) is an antibody–drug conjugate targeting CD79b that is approved for patients with relapsed/refractory large B-cell lymphoma (LBCL). Patients who relapse after chimeric antigen receptor (CAR) T-cell therapy were not included in the registration study, and reports of PV use after CAR T cells are limited. This multicenter retrospective analysis included patients with LBCL who relapsed or progressed after CAR T-cell therapy and subsequently received PV with or without rituximab and bendamustine between July 2019 and May 2021. Response to treatment and progression were assessed based on the 2014 Lugano criteria. Fifty-seven patients were included in the study: 18 (32%) patients were primary refractory to CAR T-cell therapy, and 34 (60%) patients received PV-based therapy immediately after CAR T-cell therapy. PV was combined with rituximab in 54 (95%) patients and administered with bendamustine in 35 (61%) patients. A response was achieved in 25 (44%) patients, including complete remission in 8 (14%). No significant association between baseline characteristics and response was observed. After a median follow-up of 47 weeks (95% confidence interval [CI], 40-54), 46 (81%) patients had disease progression or died, and the median progression-free survival was 10 weeks (95% CI, 5-15). On a multivariate analysis, bone marrow involvement (hazard ratio, 5.2; 95% CI, 1.8-15; P = .003) and elevated lactate dehydrogenase levels (hazard ratio, 5.0; 95% CI, 1.4-16; P = .01) were associated with shorter progression-free survival. Studies aimed at better characterizing the intrinsic mechanism of resistance and identifying optimal consolidation strategies for these patients are warranted.

Objective/background: Despite the success of chimeric antigen receptor (CAR) T-cell therapy in patients with aggressive non-Hodgkin lymphoma (aNHL), some patients still fail treatment, and their prognosis is dismal. Methods: We performed a retrospective study of aNHL patients treated with axicabtagene ciloleucel (axi-cel) at two Mayo Clinic centers between 2018 and 2020. We evaluated predictive factors, toxicities, and responses to salvage regimens after CAR T-cell therapy. Results: Thirty-four patients received axi-cel with a median length of hospitalization of 14 days. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome of any grade occurred in 91% and 41% of patients, respectively. Furthermore, 71% of patients responded to therapy, with 53% achieving a complete response (CR). The CRS grade and absolute lymphocyte count at leukapheresis (ALC Leuk ) correlated with CR and overall survival (OS), respectively. After a median follow-up of 6.8 months (interquartile range [IQR] 4.6–14.9), 15 patients (44%) showed progressive disease (PD). Most patients (60%) progressed during the first 3 months and had persistent CD19 tumor expression. Elevated C-reactive protein at baseline increased the risk of PD, whereas elevated ferritin increased PD and mortality risk. Twelve patients received salvage therapy, but only three responded. Median OS of relapsed/refractory patients to axi-cel was 3 months (IQR 1.3–5.1). Conclusion: The grade of CRS and ALC Leuk correlated with better outcomes to axi-cel therapy. In addition, elevated inflammatory markers at baseline were associated with PD and shorter survival. Relapses after treatment frequently occur within months after axi-cel infusion; they confer a poor prognosis and create an urgent need for novel and effective treatment options in this patient population.

The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.

AbstractOur aim was to evaluate whether quality of life (QOL) scores at diagnosis predict survival among patients with aggressive lymphoma. Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE and systematically followed for event‐free and overall survival (OS). QOL was measured with the Functional Assessment of Cancer Treatment‐General (FACT‐G), which measures 4 domains: physical, social/family, emotional, and functional well‐being (WB); a single item Linear Analogue Self‐Assessment (LASA) measuring overall QOL; and a spiritual WB LASA. From 9/2002 to 12/2009, 701 patients with aggressive lymphoma who completed baseline QOL questionnaires were enrolled. At a median follow‐up of 71 months (range 6‐128), 316 patients (45%) had an event and 228 patients (33%) died. All baseline QOL measures but emotional WB were significantly associated with OS (all P < 0.04); of which all but LASA spiritual remained significant after adjusting for IPI and NHL subtype. The strongest associations were with total FACT‐G (adjusted HR = 0.86, 95% CI: 0.79‐0.94, P = 0.00062) and functional WB (adjusted HR = 0.88, 95% CI: 0.83‐0.93, P < .0001). QOL LASA was associated with OS (adjusted HR = 0.92, 95% CI: 0.87‐0.97, P = 0.0041). Patients with clinically deficient QOL (overall QOL ≤50) had a median OS of 92 months compared with 121 months for patients with QOL >50 (P = 0.0004). In this large sample of patients with aggressive lymphoma, we found that baseline QOL is independently predictive of OS. QOL should be assessed as a prognostic factor in patients with aggressive lymphoma.