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The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

Background: JULIET, a pivotal phase II trial of Tisa-cel, an anti-CD19 CAR-T cell therapy in pts with r/r LBCL demonstrated durable activity with a manageable safety profile (Schuster et al., 2021). We sequentially characterized peripheral blood T cell functionality by immunophenotyping and correlated with efficacy endpoints. Methods: Immunophenotypic characterization of both non-CAR-T and CAR-T cells was performed by flow cytometry in 378 blood samples from 111 pts collected at enrollment and within the first month post Tisa-cel infusion. Proportions of T cell subsets were identified by maturation (CCR7/CD45RA/CD45RO) and exhaustion (PD1/LAG3/TIM3) markers and then correlated with durable clinical response (Complete Response (CR) ≥ 6 mo vs. Non-response (NR)/Relapse), PFS and OS. Results: At enrollment, low T cell levels (median) of these subsets also had significantly shorter PFS and OS, with LAG+PD1+CD8+ ranked on top (mPFS: 2 vs. 34 mo; mOS: 4.6 mo vs. not reached, both p Conclusions: Decreased circulating T cells at enrollment, and increased circulating exhausted T cells in non-CAR-T (at enrollment and D28) and CAR-T (at D28) compartments, were associated with poor response and survival, suggesting these flow measurements may serve as surrogate for overall T cell function, which is critical for optimal Tisa-cel efficacy and early prognostication in LBCL. Citation Format: Ulrich Jäger, Xia Han, Davide Germano, David Quinn, Dalia Gaddis, Aisha Masood, Tanya Mulvey, Jennifer Mataraza, Michael R. Bishop, Gilles Salles, Richard Maziarz, Stephen Schuster. Higher levels of circulating exhausted T-cells at pre- and post-infusion negatively associated with clinical efficacy in tisagenlecleucel (Tisa-cel) treated relapsed/refractory large B-cell lymphoma (r/r LBCL) patients (pts) in JULIET trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5186.

Under physiologic conditions, the circulating red blood cell mass is maintained at a size optimal for oxygen transport by appropriate adjustments in the rate of red blood cell production. Early clues to how adjustments in erythropoiesis are made were provided by observations in high altitude dwellers (6). The work of Jourdanet (15) and Viault (24) in the nineteenth century and, among many, Hurtado et al. (11) in this century, led to the conclusion that a low arterial oxygen tension stimulated erythropoiesis. Erythropoiesis, however, is also stimulated by anemia despite normal arterial oxygen tension. These apparent contradictory observations are reconciled by the hypothesis that it is the tissue oxygen tension, as determined by the supply and demand of oxygen, that regulates red blood cell production, rather than arterial oxygen pressure per se (9). The link between tissue oxygen tension and erythropoiesis is provided by the polypeptide growth factor erythropoietin. This hormone is primarily produced in the kidney and acts as the mediator in the feedback circuit that regulates red blood cell production (Fig. 6.1). This basic feedback system operates under physiological conditions to maintain the red blood cell mass at an optimal size and also provides the mechanisms to respond to anemia or hypoxia.