Indolent Non-Hodgkin Lymphoma: Skeletal Muscle Density Predicts Overall Survival With Rituximab Based Chemotherapy

Sarcopenia is an adverse risk factor for solid organ malignancies. Recent evidence suggests sarcopenia confers a poor prognosis in diffuse large B-cell lymphoma, but further study is needed to evaluate its role in other Non-Hodgkin Lymphoma (NHL) subtypes. Low skeletal muscle density (SMD) has also been identified as a risk factor for poor prognosis; it is more prognostic than sarcopenia in renal cell carcinoma and melanoma. Low SMD is hypothesized to be a marker of inflammation that suggests more active disease. SMD can be approximated using computed tomography (CT) images and measuring muscle radiation attenuation in Hounsfield Units (HU). An average muscle SMD of <30 HU is considered to be poorly functioning muscle and has the appearance of ectopic fat production. This study examines sarcopenia and SMD in follicular lymphoma (FL).

FL patients from 2004-2009 who received rituximab-based chemotherapy at our institution were retrospectively reviewed. Aside from baseline information (stage, age, gender, height, weight, performance status, FL International Prognostic Index 1 score [FLIPI-1], chemotherapy regimen received), progression free survival (PFS) and overall survival (OS) was collected as primary endpoints. Sarcopenia and SMD were calculated using Slice-o-Matic (Tomovision, Montreal Canada) with patients’ pre-treatment CT images. Skeletal muscle was defined as between -29 to 150 HU, intramuscular adipose tissue -190 to -30 HU; and visceral adipose tissue -150 to -50 HU. Skeletal muscle surface area and average radiation attenuation at the L3 vertebral body level were measured. Sarcopenia was pre-defined using skeletal muscle surface area cut-offs outlined in prior solid organ malignancy studies and from the elderly DLBCL study.

145 FL patients were identified. Median age was 59 years (range 29-83 years), with a median FLIPI-1 score of 2, median stage III, 79 male, and 66 female. The majority of patients received R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) chemotherapy with a median 8 cycles received (range 1-8) and 87 patients given maintenance rituximab. Median PFS and OS were 44.7 and 56.8 months, respectively. Patients with sarcopenia failed to have significant differences in either PFS or OS. The PFS hazard ratio (HR) of 1.26 suggested a trend for poor outcomes in sarcopenic patients (p=0.17). A specific cut-off for sarcopenia was not identifiable. However, comparing patients with SMD below the median to those above yielded a PFS of 40.9 vs 49.7 months (HR 1.91; p=0.01), respectively. Significant differences in OS similarly occurred for below and above the median SMD with 52.8 vs 63.3 months (HR 2.61;p=0.01). A discernible cut-off parameter for SMD was identified at 36.61 HU. PFS for those with lower than this SMD was a more pronounced detriment at 39.3 vs 55.3 months (HR 2.76; p=0.0005), respectively. OS of 51.9 vs 64.7 months (HR 4.67; p=0.0001) was also more pronounced at levels below and above the SMD cut-off parameter, respectively. Multivariate analysis found OS (HR = 4.08; p=0.004) in favor of the higher SMD group and independent of FLIPI-1 or gender.

In FL, SMD is a strong prognostic marker independent of the FLIPI-1 scores while sarcopenia has less of a prognostic role. SMD can be used as an additional tool to stratify FL patients. Evaluation of SMD and its mechanistic link with inflammation requires further study.

No relevant conflicts of interest to declare.