The Absolute Lymphocyte to Monocyte Ratio at Diagnosis Further Stratifies Survival Based on Cell of Origin in Diffuse Large B-Cell Lymphoma

Background: Diffuse large B-cell Lymphoma (DLCBL) is a heterogeneous disease. Current prognostic models have limitations, but emerging research utilizing the cell of origin and host immune factors, such as the absolute monocyte count (AMC) and absolute lymphocyte count (ALC), may improve risk stratification in these patients. In the rituximab era, the majority of relapses are observed within the first 24 months following treatment. Therefore, event free survival at 24 months (EFS24) is a reliable surrogate for overall survival in DLBCL [Maurer et. al., J Clin Oncol, 2014 Apr 1; 32(10): 1066-73]. The primary objective of this study was to determine if the ALC/AMC ratio predicts EFS24 in DLBCL risk-stratified by the cell of origin (COO).

Methods: Patients with de novo DLBCL who were evaluated at the University of Michigan Comprehensive Cancer Center between 1997 and 2011 and had archived diagnostic tissue available were eligible for participation in this retrospective study. We identified 243 eligible patients. The ALC and AMC were obtained from a complete blood count with differential at the time of diagnosis. Immunohistochemical staining for CD10, Bcl-6 and IRF4/MUM1 was performed and cases independently scored in a blinded fashion by up to three hematopathologists. A consensus opinion was obtained in order to determine the cell of origin (COO) using the Hans algorithm.

Results: The median age at diagnosis was 61 years with a median follow-up of 3.1 years. Among the 218 patients for whom the revised IPI could be calculated, 46% were high risk (IPI 3-5). Most patients received rituximab based chemoimmunotherapy (88%), largely R-CHOP (81%). The median ALC/AMC ratio for the entire cohort was 2 (interquartile range: 1-3). The ALC/AMC ratio was analyzed as a continuous variable on univariate analysis and was associated with inferior EFS (hazard ratio (HR) =0.81, 95% confidence interval (CI) 0.68-0.93, p=0.003). A receiver operating characteristic curve (ROC) was generated utilizing EFS24 to establish the optimal cut-off point for the ALC/AMC ratio. An ALC/AMC ratio of 1.6 was best able to risk-stratify patients for EFS24. The 24-month EFS for patients with an ALC/AMC ≥1.6 was 73% and for ALC/AMC <1.6 was 47% (p<0.001), and the 5-year OS was 68% vs 51% (p=0.004), respectively. On multivariate analysis the ALC/AMC ratio and R-IPI were both independently significant for EFS (HR 1.5, 95% CI 1.0-2.4, p= 0.036 and HR 1.88, 95% CI 1.2-2.9, p=0.003, respectively).

Tissue exhaustion precluded determination of the COO for many patients. Among the remaining 112 patients, 63% were GCB and 37% non-GCB. Mean ALC/AMC ratios for the GCB and non-GCB subtypes were not significantly different at 2.2 and 2.4, respectively. Among GCB DLBCL the EFS24 and 5-year OS for ALC/AMC ≥1.6 vs ALC/AMC <1.6 was 77% vs 46% (p = <0.0001) and 71% vs 50% (p = 0.0007), respectively. Among non-GCB DLBCL, the EFS24 was 70% for ALC/AMC ≥1.6 and 49% for ALC/AMC <1.6 (p=0.025). No significant difference in 5-year OS was observed when non-GCB DLBCL were stratified by the ALC/AMC ratio.

Conclusions: The ALC/AMC ratio is an independent prognostic factor for EFS24 in both GCB and non-GCB DLBCL.