Serum Levels Of CD178 (Soluble FasL) Predict Treatment Response and Survival In Chronic Lymphocytic Leukaemia (CLL)

CLL cells have prolonged survival in vivo, but rapidly undergo apoptosis when cultured ex vivo indicating the importance of the tumour microenvironment in resistance to apoptosis. Chemokines and their receptors have been identified as playing a critical role in the CLL microenvironment and we have previously identified CCL2, CXCL2, IL-6 and IL-8 as pro-survival factors in our in vitro long-term CLL culture model. We examined the in vivo significance of these and other chemokines by examining serum levels in a cohort of uniformly treated patients with CLL.

Serum samples were collected from 32 Australian patients participating in the German CLL Study Group CLL8 trial prior to treatment and were assessed for circulation levels of several cytokines and chemokines. Serum samples from 7 age matched healthy donors were used as controls. Serum concentration of CCL21, CXCL12, CXCL13, CCL19 and CXCL2 were examined using enzyme-linked immunosorbent assays (ELISA) and levels of CCL2, CCL3, CCL4, sCD54, sCD178, IL6 and IL-8 were examined using flex sets of BD Cytometric Bead Arrays System. Levels of these cytokines and chemokines were compared both to the healthy donor control samples and correlated with known prognostic and clinical factors. The levels were also evaluated in respect to response to therapy, progression-free survival (PFS) and overall survival (OS).

32 patients were studied: median age 62yrs, 84% male, Binet stage B 63%, stage C 37%. 15 received FCR and 17 FC with a median PFS of 45 months and median OS not reached. Compared to controls, patients with CLL had significantly higher serum levels of CXCL13 (117pg/ml vs 15pg/ml, p=0.0001), CCL3 (273pg/ml vs 103pg/ml, p=0.0007), CCL4 (13pg/ml vs 0pg/ml, p=0.0057), CD178 (45pg/ml vs 26pg/ml, p=0.01) and IL-6 (5pg/ml vs 0, p=0.02) and significantly lower levels of CXCL12 (803pg/ml vs 1177pg/ml, p=0.003) and sCD154 (345pg/ml vs 2121pg/ml p=0.0004).

CCL2 levels did not correlate with any baseline clinical feature, response to therapy, PFS or OS. CXCL2 levels reduced with more advanced Rai stage disease (p=0.0083) but did not predict PFS or OS. CD178 levels did not correlate with any baseline clinical feature but predicted response to therapy with lower levels predicting improved response (p=0.04). Higher CD178 also strongly predicted worse PFS (HR 1.026, p<0.001) and OS (HR 1.02, p=0.018), a consistent effect whether treated with FC (HR 1.023, p=0.024) or FCR (HR 1.026, p=0.026). No other chemokine levels predicted PFS.

Baseline serum levels of CD178 (soluble FasL) may be a useful predictor of response to therapy and outcome in CLL. Further studies to confirm these findings and to define the biological mechanism of FasL overexpression and function are required.

We thank the German CLL Study Group and Roche for access to patient samples and data from the CLL8 study, and the Leukaemia Foundation of Australia for grant support.

Mollee:Roche Australia: Sponsorship for attending ICML Lugano 2013 Other.