Biologic Pathways of Cancer-Cachexia Syndrome (Muscle and Fat Wasting) Impact Clinical Outcomes in Aggressive B-Cell Non-Hodgkin Lymphoma

Introduction:

The biologic mechanisms fundamental to the onset of cancer cachexia (a state of involuntary weight loss and altered body composition) include pathways of inflammation, energy intake and expenditure, muscle function and integrity, appetite, and glucose utilization/IGF (insulin-like growth factor). The interplay of these pathways and how this drives lymphomagenesis is unknown. We seek to correlate measures of cachexia derived radiologically with clinical outcomes and identify potential biologic pathways and drugable targets common to cachexia and lymphomagenesis.

Methods:

We obtained data on clinical/disease characteristics and radiologic measures of cachexia including sarcopenia by skeletal muscle index (SMI), and adipopenia by visceral adipose index (VAI), at initial diagnosis for a retrospective cohort of patients with aggressive B-NHL treated at our institution between 2000 and 2015. Differences in overall survival (OS) between cachectic (males and females with SMI below a threshold of 56.8 and 47.4 cm² /m² respectively; males and females with VAI below 24.8 and 41.9 cm² /m² respectively) and non-cachectic groups, (SMI and VAI ≥ defined thresholds), were determined using optimal discovery threshold with log-rank test.

In a prospective cohort of 14 newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL), peripheral blood samples were collected under IRB consent. Relevant clinical parameters were annotated for each patient. Circulating molecular targets, (43 targets), involved in pathways of inflammation, energy intake and expenditure, muscle function and integrity, appetite, and glucose utilization/IGF pathway were measured using Luminex-based assays. Correlations between SMI and VAI and circulating targets were analyzed using Spearman test.

Results:

In our retrospective cohort of aggressive B-NHL, (n=112), 54 were male. The median age was 64 years. Median follow-up was 33 months. Males with sarcopenia had decreased PFS (5.4 vs 72.3 months, p<.0005) and OS (30.2 months vs NR, p=.02); similar findings were shown for males with adipopenia (21.6 months vs NR, p=.04). In females, a trend for decreased OS was shown in sarcopenics (32.8 months vs NR, p=0.08). In univariate analysis by cox regression, SMI and VAI below sex specific thresholds were significantly associated with poor OS (HR 4.8, p= 0.003 and HR 2.3, p = 0.05 respectively). Elevated LDH, presence of B-symptoms, ECOG of ≥ 2, advanced stage, presence of diabetes mellitus (DM) as a co-morbid condition, and low albumin also correlated with OS (p= .008-.03). In multivariate analysis, SMI and VAI did not retain their correlation with survival (p=0.153 and 0.277 respectively), although advanced stage did (HR 2.04, p= 0.04). In our prospective cohort of 14 patients, significant positive correlations correcting for sex were identified between SMI and markers of the glucose utilization/IGF pathway (IGF-binding protein 6, p=.04; IGF-1, p=.02), inflammation (LIGHT, p=.005), and energy intake and expenditure (leptin, p=.004).

Conclusion: The presence of cachexia measured by skeletal muscle and visceral adipose indices has sex-specific prognostic utility. Biologic pathways underlying this process may be relevant to the pathogenesis of aggressive B-NHL. Investigation of these pathways in a larger cohort is warranted to better delineate the mechanistic link between cachexia and lymphomagenesis and/or chemo-resistance.