Baseline Serum Cytokines Profiles in Mantle Cell Lymphoma Correlates with Outcome

There is a growing awareness of the biological heterogeneity of MCL, which likely translates into differences in outcomes. Cytokines play an important role in the pathogenesis of lymphoma. Recent reports suggest that cytokine profiles can identify DLBCL (ASH 2010: Abstract 991) and HL pt (ASH 2011: Abstract 429) subsets with inferior outcomes. A distinct cytokine profile for MCL has not yet been defined. We therefore examined serum cytokines levels in MCL pts to gain insight into which may have biological relevance and their association with clinical outcomes.

Serum samples from MCL pts (57% newly diagnosed, 43% relapsed) were prospectively collected and linked to relevant clinical data from our MCL outcomes database. Cytokine levels were determined quantitatively utilizing a commercially available protein array system. We first used Wilcoxan tests to identify relevant cytokines by comparing the distribution of 507 serum cytokines levels in MCL cases (n=97) to serum cytokines levels from normal controls (n=20). For cytokines that showed significant differences, we report the ratio of median values (cases vs. controls). To maintain a type I error rate of.05 we adjusted for multiple comparisons (Hochberg's method). Using Cox regression model and adjusting for multiplicity, we next examined the association between serum cytokines levels and outcome (PFS) in a MCL cohort uniformly treated with R-HyperCVAD (R-HCVAD).

214 pts with MCL were identified of which 97 pts had available serum samples. Clinical characteristics were as follows: med age 62 yr, med MIPI score of 4, med Ki67 25% (range 5–95%) and median follow up of 35 months. Our analysis identified 22 cytokines with statistically significantly distinct levels in MCL pts (vs. normal serum controls) including (p<.05): angiopoietin-1, angiostatin, endothelin, FGFR3, FGF18, GDF3, APJ, 6Ckine, CXCR4, BDNF, Glut1, Inf γ, IL2, IL3Rα, IL4R, IL10, IL15, IL17C, Gro.a, LeptinR, MCP1 and NrCAM. In univariate analysis, we were able to identify 6 cytokines (analyzed as continuous variables) that at baseline correlated with outcome (PFS) in a cohort (n=42) of uniformly treated MCL pts with R-HCVAD in the front-line setting (p<.05). These cytokines were as follows: Activin receptor type 1, Macrophage inflammatory protein 1 β (CCL4), Neutrophil collagenase (MMP8), Neurturin, Serum amyloid A protein and Ubiquitin (Table).

Our results are the first to demonstrate a serum cytokines signature associated with MCL and additionally suggest an association between serum cytokines levels and outcome in MCL patients treated with R-HCVAD. These results may provide new insight into the biology of MCL and add to the known heterogeneity of MCL biology. An elevated pretreatment baseline serum cytokines subset, (mostly related to tumor and inflammatory processes) was found to be associated with an increased likelihood of disease relapse and an inferior outcome in patients with MCL treated with R-HCVAD and may predict pts at higher risk of relapse in that setting.

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