Obesity Is Associated with Increased Relapse Risk in Diffuse Large B-Cell Lymphoma
Authors: Tang Kevin , Mazzini Jorge , Mims Martha P. , Rivero Gustavo , Teegavarapu Purnima Sravanti 
Published: November 2021

Abstract
Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive Non-Hodgkin's lymphoma (NHL) characterized by clinical, biological and genetic heterogeneity. Despite the tremendous advancement in anticancer therapy against DLBCL, up to 40% of patients are refractory and/or relapse after first-line chemo-immunotherapy. Mechanisms responsible for chemo-immunotherapy failure are largely uncharacterized; however, it is believed the microenvironment contributes to tumor adaptation and survival. Several studies have shown that high body mass index (BMI) is associated with increased risk of developing DLBCL and obesity is an independent prognostic indicator of worse outcome when compared to non-obese patients. Weight gain alters the metabolic landscape of tumor microenvironment to inhibit T cell function and promote cellular growth. Obesity induced proinflammatory mediators can activate numerous signaling pathways including nuclear factor (NF)-KB that result in anti-apoptotic and increased proliferative efficiency in B-cells Here, we report the results of our retrospective study from two hospital systems in Houston, Texas evaluating the impact of BMI on progression-free-survival (PFS) in DLBCL patients receiving standard induction chemotherapy.
Methods: After Institutional Review Boards (IRB) approval, patients (pts) were identified by electronic medical record database query. Inclusion criteria included: (a) age&gt;18 years old, (b) DLBCL diagnosis confirmed by pathology review at Ben Taub Medical Center and Baylor St. Luke's Medical Center. BMI was calculated using patient's height and weight at diagnosis. For all comparison, we selected DLBCL pts with World Health Organization (WHO) predefined overweight, class I, II, III obesity to better capture effect of extreme BMI on DLBCL PFS. Cell-of-origin (COO) was determined by Hans classification. R-CHOP/R-EPOCH were classified as intense therapy whereas R-CVP/R-CEOP as non-intense therapy. Descriptive statistics was used to evaluate differential expression of clinical and laboratory variables. PFS among pts with BMI &lt;35 and BMI &gt;35 was estimated with Kaplan Meier Method. Cox regression model evaluated effect of independent variables on PFS for pts with DLBCL exhibiting obesity. SAS was used for all analysis.
Results: 123 pts were identified. Demographic, clinical and laboratory data was balanced among DLBCL pts with and without BMI &gt;35 (Table 1). Median BMI was 25.9 for pts with BMI&lt;35 v 37.3 in pts with BMI &gt;35. In the pts with BMI &lt;35, 36.9% were classified as germinal center b-cell (GCB) subtype and 63.1% were classified as non-GCB subtype (p= NS). Within the BMI &gt;35, 46.2% were GCB subtype and 53.9% were non-GCB subtype. 45.9% of pts had low International Prognostic Index (IPI) score in BMI&lt;35 compared to 56.52% in BMI&gt;35, whereas 54% had high IPI in BMI&lt;35 compared to 43.48% in BMI&gt;35. PFS was 2,864 days vs 763 days in patients with BMI &lt;35 and &gt;35, respectively (p=0.02). (Fig 1). To address effect of "type of therapy administered" (low v high intensity), COO, and age as confounders for our observation that PFS is inferior in DLBCL pts with BMI &gt;35, Cox regression model was performed confirming the independent predictive role for BMI &gt;35 only on DLBCL PFS.
Conclusions: Our study demonstrates that obesity (BMI &gt;35) results in increased relapse risk in DLBCL patients. In our population, risk of relapse was enhanced by higher BMI independent of age, therapy administered and COO. Obesity, by itself, especially BMI&gt;35 (Class II and Class III) may represent a unique factor for adverse outcome in DLBCL. The mechanism for which extreme obesity leads to inferior PFS in DLBCL is unclear. It is possible that obesity induces "high risk" mutations acquisition and/or adversely modifies tumor microenvironment resulting in chemotherapy cytotoxic attenuation. Larger studies are needed to externally validate our observation.
Figure 1 Figure 1.

Disclosures
Mims: Biogen: Current holder of individual stocks in a privately-held company; Incyte: Research Funding; IDEC: Current holder of individual stocks in a privately-held company; Celgene: Research Funding; Pfizer: Research Funding; AVEO: Research Funding.