Effect of Circulating CCL3, Which Is Produced by Malignant Cells of Waldenström's Macroglobulinemia, on Patients' Survival

Abstract ²⁸⁹⁴

C-C motif ligand 3 (CCL3) chemokine, previously known as macrophage inflammatory protein-1 alpha, is a member of the C-C chemokine family. CCL3 has chemotactic function against monocytes, macrophages, mast cells, T-lymphocytes, dendritic cells, eosinophils and natural killer cells. Circulating CCL3 is elevated in hematopoietic malignancies, including multiple myeloma and chronic lymphocytic leukemia (CLL). CLL cells produce CCL3 and a recent study has shown that circulating CCL3 is an independent prognostic factor for survival in CLL patients (Sivina et al, Blood 2011;117 :1662–9). Waldenström's macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration along with an IgM monoclonal gammopathy. Our group has previously shown that malignant cells of WM patients express CCL3 (Terpos et al, Clin Lymphoma Myeloma Leuk 2011;11 :115–7). However, there is no information for the prognostic significance of CCL3 in WM.

To address this issue, we studied 41 newly-diagnosed patients with symptomatic WM who required therapy. Fifty-eight per cent were males and their median age was 66 years (range: 39–82 years). According to ISSWM, 22% were low risk, 60% were interemediate risk and 18% were high risk patients. Circulating CCL3 was evaluated using an ELISA methodology (R&D Systems, Minneapolis, MN, USA) in all patients and in 40 healthy, age- and gender-matched, individuals who served as controls. Bone marrow biopsy sections of all patients at diagnosis were immunochemically tested for the expression of CCL3 (using an anti-CCL3 monoclonal antibody by Santa Cruz Biotechnology, Santa Cruz, CA, USA), CD20, CD79a, CD138, MUM-1, as well as for mu, gamma, alpha heavy and kappa and lambda light immunoglobulin chains. The immunoreactivity of CCL3 was examined on the basis of positive lymphoplasmacytic and/or plasma cells with a cut-off value of >20% positive cells to be defined as positive expression.

Median circulating CCL3 levels were higher in WM patients 66 pg/ml (range 10.6–1627 pg/ml) compared to healthy controls (median 15.4 pg/ml, range: 1.4–54 pg/ml; p=0.01). In all WM cases, the whole number of the neoplastic cells, including CD20(+)/CD138(-)/MUM-1(-)/CIgM(kappa)(+) B-lymphocytes (small lymphocytes, lymphoplasmacytoid lymphocytes and rare immunoblasts) as well as CD20(-)/ CD138(+)/MUM-1(+)/CIgM(kappa)(+) plasma cells revealed strong cytoplasmic positivity for CCL3. Elevated circulating CCL3 correlated with high serum beta2-microglobulin levels (r=0.385, p=0.019), but there were no strong correlations between CCL3 levels and ISSWM stage, serum LDH, serum albumin, serum IgM levels or age.

All patients received rituximab-based regimens as first line therapy and 67% of them achieved at least a minor response. The median survival of all patients has not been reached yet, while the 3-year probability of survival was 77%. The 3-year probability of survival for low-, intermediate- and high-risk patients per ISSWM was 100%, 77% and 38%, respectively (p=0.018). We then evaluated the effect of circulating CCL-3 on patients' survival using as a cut-off value the level of 54 pg/ml, which was the highest CCL3 value of our control group. The median survival for WM patients with CCL3 levels ≥54 pg/ml was 67 months, while it has not been reached for patients with CCL3 levels <54 pg/ml (Figure; p=0.093).

In conclusion our results suggest that CCL3 is produced by WM cells and its high circulating levers are associated with a clear trend for inferior survival. These observations support a role of CCL3 in WM biology through interactions of the malignant clone with the marrow microenvironment and reveals CCL3 as a potential target for developing novel drugs against WM.

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