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Body Composition as a Key predictor in Relapsed/Refractory DLBCL Treatment Response

New research highlights the meaningful role of body composition, specifically the ratio of skeletal muscle to visceral fat, in predicting treatment outcomes for patients wiht relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) receiving ADCs (Antibody-Drug Conjugates). The findings suggest that pre-treatment body composition analysis could serve as a valuable biomarker for evaluating treatment effectiveness.

Investigators utilized CT scans from the LOTIS-2 clinical trial to perform detailed body composition analyses. This involved both manual and advanced deep learning-based segmentation of three primary tissue areas: skeletal muscle, subcutaneous fat, and visceral fat. These measurements were taken at the third lumbar vertebra (L3), a standard method recognized for its accuracy in reflecting overall body muscle and fat distribution.

from these segmented regions, researchers developed several body composition ratio indices. These included the ratio of skeletal muscle to visceral fat, the ratio of subcutaneous fat to visceral fat, and the relationship of skeletal muscle to a combined measure of visceral and subcutaneous fat. The study aimed to establish agreement levels between manual and automated measurement methods and, crucially, to analyse how these body composition indices correlated with treatment response and time-to-event outcomes.

Kaplan-Meier curves were employed to estimate progression-free survival (PFS) and overall survival (OS). the results indicated that both manual and automated skeletal muscle/visceral fat indices,when categorized,were significant predictors in statistical models for those who did not achieve a complete metabolic response.

Specifically, the manual skeletal muscle/visceral fat index demonstrated a significant association with PFS, even though not with OS, in both univariable and multivariable analyses.

This observed association between body composition and treatment outcomes can be partly explained by emerging research. A separate 2023 study published in Ageing Research Reviews suggested that sarcopenia, a condition characterized by reduced muscle strength and quality, can negatively impact the efficacy of ADCs.Moreover, obesity can lead to dose reductions during treatment, which may also diminish the drug’s effectiveness. It’s important to note that these effects might become more apparent in real-world clinical settings after drug approval, as clinical trials often involve healthier patient populations.

The authors of the University of Miami study concluded that a patient’s skeletal muscle to visceral fat ratio before initiating treatment could be a valuable biomarker for assessing individuals with R/R DLBCL undergoing treatment with loncastuximab tesirine. They also noted that their proposed deep learning-based approach for body composition analysis performed comparably to manual methods, offering a more cost-effective choice.

references:

1. Kuker RA, Alderuccio JP, Han S, Polar MK, Crane TE, Moskowitz CH, Yang F. Deep learning-based body composition analysis for outcome prediction in relapsed/refractory diffuse large B-cell lymphoma: insights from the LOTIS-2 trial. JCO Clin Cancer Inform 2025; 9: DOI: 10.1200/CCI-25-00051
2. zhang FM, Wu HF, Shi HP, Yu Z, Zhuang CL. Sarcopenia and malignancies: epidemiology, clinical classification and implications. Age Res Rev. 2023;91:102057: doi:10.1016/j.arr.2023.102057.

How might visceral fat levels influence the pharmacokinetics and ultimately, the efficacy of ADC therapy in DLBCL patients?

Body Fat Signals Disease Progression in Diffuse Large B-Cell Lymphoma Patients Treated with ADC

Understanding the Link Between Adiposity and DLBCL Outcomes

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. While advancements in treatment, particularly with Antibody-Drug Conjugates (ADCs), have improved outcomes, important heterogeneity remains in patient responses. Emerging research highlights a crucial, often overlooked factor influencing disease progression and treatment efficacy: body fat composition. This isn’t simply about weight; itS about the type of fat and its metabolic activity. Understanding this connection is vital for personalized DLBCL management and optimizing ADC therapy.

How Body Fat Impacts DLBCL – The Biological Mechanisms

The relationship between obesity, body composition, and DLBCL isn’t coincidental. Several biological mechanisms are at play:

Chronic Inflammation: Visceral fat (fat stored around abdominal organs) is metabolically active, releasing pro-inflammatory cytokines like TNF-α and IL-6.Chronic inflammation creates a microenvironment that supports lymphoma cell survival and proliferation.This inflammatory state can also reduce the effectiveness of ADCs.

Immune Dysfunction: Obesity is associated with impaired immune function, including reduced natural killer (NK) cell activity and T-cell responsiveness. ADCs rely on a robust immune response to deliver thier cytotoxic payload; a compromised immune system diminishes their efficacy.

Altered ADC Pharmacokinetics: body fat can act as a reservoir for lipophilic drugs, possibly altering the distribution and bioavailability of ADCs. Higher fat mass may lead to lower circulating drug concentrations,reducing the therapeutic impact.This is a key consideration in ADC drug delivery and pharmacokinetic modeling.

Metabolic Syndrome & DLBCL risk: Conditions often associated with excess body fat – insulin resistance, hyperglycemia, dyslipidemia – are linked to an increased risk of developing DLBCL and poorer prognosis. metabolic syndrome creates a fertile ground for lymphoma development.

Specific Fat Depots and Their Role in DLBCL Progression

Not all fat is created equal. Research indicates that specific fat depots have a more pronounced impact on DLBCL outcomes:

Visceral Fat: As mentioned, visceral fat is strongly correlated with inflammation and immune dysfunction, directly impacting DLBCL progression and ADC response. Measuring visceral fat using imaging techniques like CT scans or MRI is becoming increasingly important.

Subcutaneous fat: While generally considered less harmful than visceral fat, subcutaneous fat (fat under the skin) can still contribute to systemic inflammation and metabolic disturbances.

Bone Marrow Adipose Tissue (BMAT): Increasing evidence suggests that BMAT plays a role in the DLBCL microenvironment, potentially providing a niche for lymphoma cells and influencing treatment resistance. bone marrow microenvironment studies are crucial.

Personalized Dosing: Adjusting ADC doses based on body composition, particularly visceral fat levels, may optimize drug exposure and improve treatment outcomes.Weight-based dosing may not be sufficient.

* Combination Therapies: Combining ADCs with therapies that target inflammation or modulate