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Physiological Fitness and the Pathophysiology of Chronic Lymphocytic Leukemia (CLL).

ABSTRACT: Chronic lymphocytic leukemia (CLL) is associated with physical dysfunction and low overall fitness that predicts poor survival following the commencement of treatment. However, it remains unknown whether higher fitness provides antioncogenic effects. We identified ten fit (CLL-FIT) and ten less fit (CLL-UNFIT) treatment-naïve CLL patients from 144 patients who completed a set of physical fitness and performance tests. Patient plasma was used to determine its effects on an in vitro 5-day growth/viability of three B-cell cell lines (OSU-CLL, Daudi, and Farage). Plasma exosomal miRNA profiles, circulating lipids, lipoproteins, inflammation levels, and immune cell phenotypes were also assessed. CLL-FIT was associated with fewer viable OSU-CLL cells at Day 1 (p = 0.003), Day 4 (p = 0.001), and Day 5 (p = 0.009). No differences between the groups were observed for Daudi and Farage cells. Of 455 distinct exosomal miRNAs identified, 32 miRNAs were significantly different between the groups. Of these, 14 miRNAs had ≤-1 or ≥1 log2 fold differences. CLL-FIT patients had five exosomal miRNAs with lower expression and nine miRNAs with higher expression. CLL-FIT patients had higher HDL cholesterol, lower inflammation, and lower levels of triglyceride components (all p < 0.05). CLL-FIT patients had lower frequencies of low-differentiated NKG2+/CD158a/b^neg (p = 0.015 and p = 0.014) and higher frequencies of NKG2A^neg/CD158b+ mature NK cells (p = 0.047). The absolute number of lymphocytes, including CD19+/CD5+ CLL-cells, was similar between the groups (p = 0.359). Higher physical fitness in CLL patients is associated with altered CLL-like cell line growth in vitro and with altered circulating and cellular factors indicative of better immune functions and tumor control.

SUBMITTER: Sitlinger A

PROVIDER: S-EPMC8151485 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose of reviewThere have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting.Recent findingsPlease check if the affiliations are presented correctly.Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.

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Physiological Fitness and the Pathophysiology of Chronic Lymphocytic Leukemia (CLL).

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